Clinical pharmacy complete notes

Clinical pharmacy complete notes 4th proff Pharm D.

1. Reference
Dr. Hamid Lectures
Dr. Furqan Lectures
Roger Walker Clinical Pharmacy and Therapeutics
Dipiro - Pharmacotherapy Handbook
Pharmacotherapy- A Pathophysiologic Approach

GHULAM MURTAZA HAMAD
4th PROFF. EVENING
PUNJAB UNIVERSITY COLLEGE OF PHARMACY, LAHORE
CLINICAL PHARMACY
4
th
PROFESSIONAL

2. GM Hamad

TABLE OF CONTENTS

Contents
1. General Introduction to Clinical Pharmacy
2. Disease Management
3. Patient Profile and Patient Counseling
4. Clinical Trials of Drug Substances
5. Emergency Treatment
6. Drug Interactions
7. ADRs and Pharmacovigilance
8. Pharmacotherapy Plan
9. Drug Induced Diseases
10. Utilization of Clinical Drug Literature
11. Online Pharmaceutical Care Services and Globalizations
12. Pharmaceutical Care in Multiple Environment

3. GM Hamad

GENERAL INTRODUCTION TO CLINICAL
PHARMACY
HISTORICAL BACKGROUND
• In 1944 Clinical Pharmacy was initiated as an educational experiment by
Professor L. Wait Rising, University of Washington & later by Professor H.
W. Youngken Jr.
• The program suffered a setback after a vote by American Council on
Education.
• Dean Joseph Kowalewski, University of Cincinnati, Ohio & Dr Harry C.
Shirkey (pharmacist & physician)—1948.
• Pharmacy students were shown an anaesthetized patient before surgery.
They could then witness the stages of anesthesia and apply the techniques
as they had been taught.
• Clinical pharmacy has brought a wind of change, a new base of hope into
pharmacy profession.
• A new era of dynamism where pharmacists are reshaping their profession.
• Pharmacists in various specialties are working like pediatrics, geriatrics,
oncology, diabetic & asthma clinics.
THE ORIGIN OF CLINICAL PHARMACY
• Whitney (Michigan) 1930s & Clark (New York Hospital) 1940s are believed
to be pioneers in this field.
• In late 40s Flack (Jefferson Hospital Philadelphia), Purdum (John Hopkins's)
& Francke (Michigan) developed programs which combined internship &
advanced degrees in clinical pharmacy.
• The experiment (clinical pharmacy) worked & the U.S Government, by Act
of Congress, gave capitation grants to schools of pharmacy offering
undergraduate clinical orientation in their curricula.
• The changes were not confined to the U.S, they spread to Canada, then to
Europe such as Britain, France & African countries as Zimbabwe & Nigeria.
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• Even Pakistan is not behind this. Few years back the Pharmacy council of
Pakistan introduced a new scheme of study spanning over a period of 5-
year Doctor of Pharmacy (Pharm-D) degree program (more patient-
oriented).
INTRODUCTION
• The term “clinical “means “reclining in bed”
• Clinical implies observation or examination of living patient in order to
make a proper judgment or decision.
• With respect to pharmacy, clinical means that the pharmacy should be
practiced on hospital patients.
• Today the term has been used to describe a concept, a role, a philosophy, a
mode of practice, an emphasis, an orientation and a type of pharmacist, but
the centerpiece of all activities still is a patient.
DEFINITION
• Clinical pharmacy can be defined as:
“The area within the pharmacy practice dealing with patient care with
particular emphasis on drug therapy”
• It is patient-oriented and includes not only dispensing of the required
medication but also advising patients on proper use of all medications
(both prescribed & patient selected)
• It also utilizes pharmacist as the source of information for other health-care
professionals & all matters pertaining to drugs & their dosage forms.
“Clinical Pharmacy means the philosophy of safe & appropriate drug
usage in patients”
• Pharmacy practice is moving toward a model that integrates Patient-
focused Care & Drug Distribution Services.
• Clinical pharmacy is a health specialty → describes the activities & services
of Pharmacist to develop & promote the Rational and Appropriate use of
medicinal products & devices.
• Clinical pharmacy encourages pharmacist & support staff to shift their focus
from a solely product-oriented role towards more direct engagement with
patients & and the problems they encounter with medicines.
• Clinical Pharmacy—for its importance to patient care is now engaged in
more patient- oriented concept → “PHARMACEUTICAL CARE”
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OBJECTIVE
• The objective of clinical pharmacy practice is to optimize patient outcomes
by working to achieve quality use of medicine (QUM).
QUALITY USE OF MEDICINE (QUM)
• Judiciously, using medicines only after considering all other options.
• Appropriately, choosing a medicine after appraisal of factors including risk-
benefit analysis, treatment length and cost.
• Safely, minimizing misuse and abuse.
• Efficaciously, having a quantifiable benefit to the patient’s health and/or
quality of life.
• Clinical pharmacy practice is the practice of pharmacy as part of a
multidisciplinary healthcare team directed at achieving QUM. This may
include:
­ Participation in the management of individual patients.
­ Application of the best available evidence in daily clinical practice.
­ Contribution of clinical knowledge and skills to the healthcare team.
­ Identification and reduction in risks associated with medicines use.
­ Involvement in the education of patients, carers, and other health
professionals.
­ Involvement in research.
KEY POINTS—CLINICAL PHARMACY
• Comprises a set of functions that promote the safe, effective & economic
use medicines for individuals.
• Allowed pharmacists to shift from a product-oriented role towards direct
engagement with patients & the problems they encounter with medicines.
• The practice is generally an essential component of Pharmaceutical care.
• Pharmaceutical care is a co-operative patient centered system for achieving
specific & positive patient outcomes from responsible provision of
medicines.
• Three elements:
I. Patient assessment.
II. Determination of care plan.
III. Evaluating the outcome.
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• Ability to consult with patients is a key process in the delivery of
pharmaceutical care & requires regular reviews & development regardless
of experience.
DEVELOPMENT OF CLINICAL PRACTICE IN PHARMACY
• USA → Approach was to develop unit dose dispensing & pursue
decentralization of pharmacy services.
• UK → Unification of the prescription and the administration record &
pharmacist required to visit the ward to order medicines.
• Clinical pharmacy emerged from the presence of pharmacist in patient
areas and their interest in promoting safe use of medicines.
• In 1980s the clinical pharmacy practice grew because of its ability to
promote safe use of medicines in hospitals.
• This role of pharmacist was recognized in UK in 1988—endorsed the
implementation of clinical pharmacy services to secure value for money
from medicines.
DEFINITIONS (TO IDENTIFY PRACTICE AREAS)
CLINICAL PHARMACY
“It comprises a set of functions that promote the safe, effective & economic
use of medicines for individual patients. Clinical pharmacy process requires
the application of knowledge of pharmacology, ph-kinetics, pharmaceutics &
therapeutics to patient care”
PHARMACEUTICAL CARE
“It is a co-operative, patient centered system for achieving specific & positive
patient outcomes from the responsible provision of medicines”
MEDICINES MANAGEMENT
“It encompasses the way in which medicines are selected, procured, delivered,
prescribed, administered & reviewed to optimize the contribution that
medicines make to producing informed and desired outcomes of patient care”
PHARMACEUTICAL CARE
• Pharmaceutical care—a landmark in the landscape of pharmacy practice.
• It is defined as:
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“Responsible provision of drug therapy for the purpose of achieving
definite outcomes that improve the patient’s quality of life”
• The delivery of pharmaceutical care is dependent on the practice of clinical
pharmacy, but the key feature of care is that practitioner takes
responsibility for patients’ drug-related needs and is held accountable for
that commitment.
• Pharmaceutical care is predicted on a patient-centered approach to
identifying, preventing or resolving MRPs.
• Center to this is to establish a therapeutic relationship—a partnership in
which the pharmacist takes responsibility for resolving MRPs in line with
patient’s wishes, expectations and priorities.
BENEFITS OF PHARMACEUTICAL CARE
• The ability to demonstrate that clinical pharmacy improves pt. outcomes is
of great importance to pharmaceutical care model.
• Example:
­ “In USA pharmacist participating in ward rounds has been shown to
reduce adverse drug events by 66% to 78% in general medical and
intensive care settings”
­ In Pakistan if this system is in place it will definitely contribute to
reduce the mortalities as result of drug misadventures.
KEY ELEMENTS OF CARE PROCESS
Elements Purpose
Assessment To establish a full medication history &
highlight actual & potential drug
related problems.
Care plan To optimize care & the responsibilities
of both the pharmacist & patient in
attaining the stated goal.
Evaluation Reviews the progress against the
stated patient outcomes.
MEDICATION RELATED PROBLEMS (MRP)
• When the outcome is not optimal.
• Some MRPs are associated with significant morbidity & mortality.
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• Non-compliance & inappropriate prescribing and monitoring may be the
causes.
• Identification of underlying medication related problems is very important.
CATEGORIES OF MRP
• Untreated indication.
• Treatment without indication.
• Improper drug selection.
• Too little drug.
• Too much drug.
• Non-compliance.
• Adverse drug reactions.
• Drug interactions.
Pharmacists working in community pharmacy can contribute to great extent to
reduce MRPs.
PHARMACEUTICAL CONSULTATION
• Pharmaceutical care requires more than scientific expertise.
• A system that clearly describes the role & responsibilities of pharmacist &
provides the necessary infrastructure to support them.
• A clear process by which the pharmacist can deliver their contribution to
patient care.
CONSULTATION PROCESS
• The ability of pharmacist to consult effectively is fundamental to
pharmaceutical care.
• To establish a therapeutic relationship.
• Description of pharmaceutical care has been confined to the use of
mnemonics as WWHAM, ENCORE & AS METTHOD.
WWHAM
• Who is it for?
• What are the symptoms?
• How long has it been going on?
• Action taken?
• Medicines taken?
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ENCORE
• Evaluate the symptoms (onset, recurrence & duration)
• No medication is always an option.
• Care—when dealing with specific patient group (elderly, children, young,
pregnant women, nursing mothers etc.)
• Observe the patient for signs of systemic disturbance, ask about fever, loss
of weight.
• Refer when in doubt.
• Explain any course of action recommended.
AS METTHOD
• Age of the patient?
• Self or for someone else?
• Medication being taken.
• Exactly want do you mean (by the symptoms)
• Time & duration of the symptoms?
• Taken any action (medicine or seen a doctor)
• History of any disease?
• Other symptoms?
• Doing anything to alleviate the symptoms?
PHARMACEUTICAL CONSULTATION PROCESS
Element Goal Examples
Introduction Building a therapeutic
relationship.
Invites pt. to discuss
medication or health-
related issue, discuss
structure & purpose of
consultation.
Data collection &
problem identification
Identify the patient’s
medication related
needs.
Take full medication
history, establish pt.’s
understanding of illness
& prescribed treatment.
Actions & solutions Establishing an
acceptable management
plan with patient.
Involve pt. in designing
management plan.
Tailor info to address
pt.’s perception of illness
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& treatment, Check pt.’s
understanding, refer
appropriately.
Closure Negotiating safety
netting strategies with
patient.
Provide info to guide
patient when it
experiences problem.

CONSULTATION BEHAVIORS
• Active listening.
• Appropriate use of open & closed questions.
• Respect patient.
• Avoid jargon (slang, inappropriate language)
• Demonstrate empathy.
• Deals sensitively with potentially embarrassing or sensitive issues.
DRUG USE PROCESS (DUP)
• A system necessary to aggregate large amount of data in a reliable manner
DUP STAGES
• Need for a drug.
• Drug selection.
• Regimen selection.
• Drug provision.
• Drug administration.
• Monitoring drug therapy.
• Patient counseling.
• Evaluation of effectiveness.
DRUG USE PROCESS (DUP) INDICATORS
DUP Stage Action
Need for a drug Appropriate indication for each drug and all medication
conditions are addressed therapeutically.
Drug selection Selection and recommendation of most appropriate drug
based upon the ability to reach therapeutic goals with
consideration of patient variables, formulary and cost of
therapy.
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Regimen
selection
Select the most appropriate drug regimen for achieving the
desired therapeutic goals at the least cost without diminishing
effectiveness or causing toxicity.
Drug provision Facilitate the dispensing and supply process for accurate
preparation of drugs, ready to administer form and delivered
to patient on a timely basis.
Drug
administration
Ensure that appropriate devices and techniques are used for
drug administration.
Monitoring
drug therapy
Monitor drug therapy for effectiveness or adverse effects in
order to determine whether to maintain, modify or
discontinue.
Patient
counseling
Counsel and educate patients or caregivers about the
patient’s therapy to ensure proper use of medicines.
Evaluation of
effectiveness
By reviewing all the previous steps of DUP and taking
appropriate steps to ensure that the therapeutic goals are
achieved.
ROLE OF CLINICAL PHARMACIST
• Cares for patients in all healthcare settings.
• In-depth knowledge of medications, integrated with foundational
understanding of the biomedical, pharmaceutical, sociobehavioral and
clinical sciences.
• Applies evidence-based therapeutic guidelines, evolving sciences, emerging
technologies and relevant legal, ethical, social, cultural, economic and
professional principles.
• Assumes responsibility and accountability for managing medication therapy
in direct patient care settings, practicing independently or in consultation
or collaboration with other healthcare professionals.
• As researchers generate, disseminate and apply new knowledge that
contributes to improved health and quality of life.
• Expert in the therapeutic use of medication, evaluate and recommend to
patient and other healthcare professionals.
• Primary source of scientifically valid information and advice regarding safe,
appropriate and cost-effective use of drugs.
CLINICAL PHARMACY FUNCTIONS
1) Establishing the need for drug therapy.
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2) Selecting the medicine.
3) Administering the medicine.
4) Providing the medicine.
5) Monitoring therapy.
6) Patient advice & education.
7) Evaluating effectiveness.
1. ESTABLISHING THE NEED FOR DRUG THERAPY
• Establishment of diagnosis & then balancing the risks and benefits of
treatment against the risks posed by the disease.
• Pharmacist’s role:
­ Providing information to the prescriber on the expected risks of
drug therapy.
RELEVANT PATIENT DETAILS
• Background information on patient’s health & social circumstances → help
in prevention of existing and potential MRPs.
• Once diagnosis & previous medical history (PMH) are established → it is
possible to identify the medicines that are expected to be prescribed for
each indication.
MEDICATION HISTORY
• Identifies & documents allergies or serious adverse drug reactions.
2. SELECTING THE MEDICINE
• Clinical & cost-effective selection of a medicine in the context of
individual patient care.
• Scrutinize for appropriateness.
IDENTIFY DRUG-PATIENT INTERACTIONS
• Contraindications & cautions (related to age group)
• Allergy or previous evidence of ADRs.
• Hepatic and renal functions or CHF.
IDENTIFY DRUG-DISEASE INTERACTIONS
• When a medicine has potential to make pre-existing condition worse.
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DRUG-DRUG INTERACTIONS
• The change in the effect of one drug by prior or concurrent use of another
drug.
DRUG-FOOD INTERACTIONS
• Different nutritional ingredients (vitamins, amino acids, minerals etc.) in the
diet may affect drugs in many ways.
3. ADMINISTERING THE MEDICINE
• Several factors influencing the bioavailability should be considered i.e.
rate & extent of absorption, degree of plasma protein binding & volume
of distribution, hepatic metabolism.
• Calculating the appropriate dose.
• Selecting an appropriate regimen.
SPECIALIZED AREAS IN PHARMACY PRACTICE
• Pharmaceutical care / patient care.
• Medication use evaluation / medication utilization reviews.
• Home medication review (HMR).
• Medication therapy management (MTM).
• Drug use process (DUP).
• Chronic disease management (CDM) [Asthma, Warfarin, Diabetes, CVD,
Arthritis]
• Quality use of medicine (QUM), rational use of drugs (RUD).
• Community pharmacy.
• Public health pharmacy (disease prevention / communicable diseases /
vaccination).
• Minor illness treatment (flu, cough etc.)
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DISEASE MANAGEMENT
UNIT I: CARDIOVASCULAR UNIT (HYPERTENSION, ISCHEMIC HEART
DISEASES E.G. ANGINA PECTORIS, MI, HEART FAILURE)
HYPERTENSION
DEFINITION
“Hypertension is defined as persistently elevated arterial blood pressure (BP)”
• Blood pressure measurement includes systolic and diastolic components,
and both are important in determining an individual's cardiovascular risk.
Classification of Blood Pressure in Adults
Classification Systolic (mm Hg) Diastolic (mm Hg)
Normal <120 And <80
Prehypertension 120–139 Or 80–89
Stage 1 hypertension 140–159 Or 90–99
Stage 2 hypertension ≥160 Or ≥100

• Isolated systolic hypertension is diastolic blood pressure (DBP) values less
than 90 mm Hg and systolic blood pressure (SBP) values of 140 mm Hg or
more.
• Hypertensive crisis (BP >180/120 mm Hg) may be categorized as
hypertensive emergency (extreme BP elevation with acute or progressing
end-organ damage) or hypertensive urgency (high BP elevation without
acute or progressing end-organ injury).
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PATHOPHYSIOLOGY

PRIMARY HYPERTENSION
• Hypertension may result from an unknown etiology (primary or essential
hypertension).
Factors contributing to development of primary hypertension include:
• Humoral abnormalities involving the renin–angiotensin–aldosterone
system (RAAS) or natriuretic hormone.
• Disturbance in the CNS, autonomic nerve fibers, adrenergic receptors, or
baroreceptors.
• Abnormalities in renal or tissue autoregulatory processes for sodium
excretion, plasma volume, and arteriolar constriction.
• Deficiency in synthesis of vasodilating substances in vascular endothelium
(prostacyclin, bradykinin, and nitric oxide) or excess vasoconstricting
substances (angiotensin II, endothelin I)
• High sodium intake or lack of dietary calcium.
SECONDARY HYPERTENSION
• Secondary hypertension (<10% of cases) is usually caused by chronic kidney
disease (CKD) or renovascular disease. Other conditions are Cushing
syndrome, coarctation of the aorta, obstructive sleep apnea,
hyperparathyroidism, pheochromocytoma, primary aldosteronism, and
hyperthyroidism.
• Some drugs that may increase BP include corticosteroids, estrogens,
nonsteroidal anti-inflammatory drugs (NSAIDs), amphetamines,
sibutramine, cyclosporine, tacrolimus, erythropoietin, and venlafaxine.
HYPERTENSION
PRIMARY
HYPERTENSION
SECONDARY
HYPERTENSION
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TARGET ORGAN DAMAGE DUE TO HYPERTENSION
CARDIOVASCULAR
• Constriction of arterioles and insufficient blood flow to coronary
vasculature leads to angina, myocardial infarction; left ventricular
hypertrophy may occur due to increased cardiac output leading to heart
failure.
RENAL
• Arteriolar nephrosclerosis leads to polyuria, nocturia, protein and red blood
cells in urine, elevated serum creatinine, renal insufficiency.
CEREBRAL
• Decreased blood flow and decreased oxygen supply lead to transient
ischemic attacks, cerebral thrombosis, hemorrhage.
RETINAL
• Damage to arterioles of retina leads to hemorrhage, visual disturbances.
CLINICAL PRESENTATION
• Patients with uncomplicated primary hypertension are usually
asymptomatic initially.
• Patients with secondary hypertension may have symptoms of the
underlying disorder.
• Patients with pheochromocytoma may have headaches, sweating,
tachycardia, palpitations, and orthostatic hypotension. In primary
aldosteronism, hypokalemic symptoms of muscle cramps and weakness
may be present. Patients with Cushing syndrome may have weight gain,
polyuria, edema, menstrual irregularities, recurrent acne, or muscular
weakness in addition to classic features (moon face, buffalo hump, and
hirsutism).
DIAGNOSIS
• Elevated BP may be the only sign of primary hypertension on physical
examination.
• Signs of end-organ damage occur primarily in the eye, brain, heart,
kidneys, and peripheral blood vessels.
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• Funduscopic examination may reveal arteriolar narrowing, focal arteriolar
constrictions, arteriovenous nicking, retinal hemorrhages and exudates,
and disk edema. Presence of papilledema usually indicates a hypertensive
emergency requiring rapid treatment.
• Cardiopulmonary examination may reveal abnormal heart rate or rhythm,
left ventricular (LV) hypertrophy, coronary heart disease, or heart failure
(HF).
• Peripheral vascular examination may reveal aortic or abdominal bruits,
distended veins, diminished or absent peripheral pulses, or lower extremity
edema.
• Patients with renal artery stenosis may have an abdominal systolic-diastolic
bruit.
• Baseline hypokalemia may suggest mineralocorticoid-induced
hypertension. Protein, blood cells, and casts in the urine may indicate
renovascular disease.
• Laboratory tests: Blood urea nitrogen (BUN)/serum creatinine, fasting lipid
panel, fasting blood glucose, serum electrolytes (sodium and potassium),
hemoglobin and hematocrit, spot urine albumin-to-creatinine ratio, and
estimated glomerular filtration rate. A 12-lead electrocardiogram (ECG)
should also be obtained.
• Laboratory tests to diagnose secondary hypertension: Plasma
norepinephrine and urinary metanephrine levels for pheochromocytoma,
plasma and urinary aldosterone concentrations for primary aldosteronism,
plasma renin activity, captopril stimulation test, renal vein renin, and renal
artery angiography for renovascular disease.
TREATMENT
TREATMENT GOALS
• The overall goal is to reduce morbidity and mortality by the least intrusive
means possible. The goal BP for most patients, including those with
diabetes or CKD (no dialysis), is less than 140/90 mm Hg. Lower goals may
be an option in certain populations. The goal for patients 80 years of age or
older without diabetes or CKD is less than 150/90 mm Hg.
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NONPHARMACOLOGIC THERAPY
• LIFESTYLE MODIFICATIONS
1. Weight loss if overweight or obese.
2. Exercise.
3. Diet (low salt intake)
4. Smoking cessation
5. Alcohol restriction
• Lifestyle modification alone is sufficient for most patients with
prehypertension but inadequate for patients with hypertension and
additional CV risk factors or target-organ damage.
PHARMACOLOGIC THERAPY
• Initial drug selection depends on the degree of BP elevation and presence
of compelling indications for selected drugs.
• Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor
blockers (ARBs), calcium channel blockers (CCBs), and thiazide diuretics are
acceptable first-line options.
• β-Blockers are used to either treat a specific compelling indication or as
combination therapy with a first-line antihypertensive agent for patients
without a compelling indication.
• Most patients with stage 1 hypertension should be treated initially with a
first-line antihypertensive drug or a two-drug combination. Combination
therapy is recommended for patients with stage 2 hypertension, preferably
with two first-line agents.
DRUG THERAPY
• Diuretics: reduce blood volume.
• Sympatholytics: reduce ability of sympathetic system to raise blood
pressure.
• Calcium channel blockers: reduce peripheral resistance.
• ACE inhibitors, angiotensin II antagonists: reduce peripheral resistance.
1. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
• ACE inhibitors are a first-line option, and if they are not the first agent
used, they should be the second agent tried in most patients.
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• ACE inhibitors block conversion of angiotensin I to angiotensin II, a
potent vasoconstrictor and stimulator of aldosterone secretion. ACE
inhibitors also block degradation of bradykinin and stimulate synthesis
of other vasodilating substances, including prostaglandin E2 and
prostacyclin.
• Starting doses should be low with slow dose titration. Acute
hypotension may occur at the onset of therapy, especially in patients
who are sodium or volume depleted, in HF exacerbation, very elderly, or
on concurrent vasodilators or diuretics. Start administering doses in
such patients, using half the normal dose followed by slow dose
titration.
• E.g. Captopril, Enalapril, Ramipril, Fosinopril.
SIDE EFFECTS
• Hypotension (especially first dose)
• Hyperkalemia
• Cough
• Renal impairment
2. ANGIOTENSIN II RECEPTOR BLOCKERS
• ARBs are a first-line therapy option in most patients with hypertension
and reduce CV events similar to ACE inhibitors. The combination of an
ACE inhibitor and ARB has no additional CV event lowering but is
associated with a higher risk of side effects (renal dysfunction,
hypotension).
• Angiotensin II is generated by the renin–angiotensin pathway (which
involves ACE) and an alternative pathway that uses other enzymes such
as chymases. ACE inhibitors block only the renin–angiotensin pathway,
whereas ARBs antagonize angiotensin II generated by either pathway.
The ARBs directly block the angiotensin II type 1 receptor that mediates
the effects of angiotensin II.
• Unlike ACE inhibitors, ARBs do not block bradykinin breakdown.
Although this accounts for the lack of cough as a side effect, there may
be negative consequences because some of the antihypertensive effect
of ACE inhibitors may be due to increased levels of bradykinin.
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• All ARBs have similar antihypertensive efficacy and fairly flat dose-
response curves.
• Addition of a CCB or thiazide diuretic significantly increases
antihypertensive efficacy.
• E.g. Candesartan, Losartan, Valsartan, Telmisartan, Amlodipine.
SIDE EFFECTS
• Renal insufficiency
• Hyperkalemia
• Orthostatic hypotension.
3. CALCIUM CHANNEL BLOCKERS
• Calcium channel blockers (CCBs), including both dihydropyridine and
non-dihydropyridine types, are first-line therapy options. They are also
used in addition to or instead of other first-line antihypertensives for the
compelling indications of coronary artery disease and diabetes.
• CCBs cause relaxation of cardiac and smooth muscle by blocking voltage-
sensitive calcium channels, thereby reducing entry of extracellular
calcium into cells. This leads to vasodilation and a corresponding
reduction in BP.
• Verapamil decreases heart rate, slows atrioventricular (AV) nodal
conduction, and produces a negative inotropic effect that may
precipitate HF in patients with borderline cardiac reserve. Diltiazem
decreases AV conduction and heart rate to a lesser extent than
verapamil.
SIDE EFFECTS
• Cardiac conduction abnormalities such as bradycardia, AV block, and HF.
• Constipation.
• Dizziness, Flushing, Headache, Gingival hyperplasia, and Peripheral edema.
4. DIURETICS
• Diuretics lower BP by causing diuresis. The reduction in plasma volume
and stroke volume associated with diuresis decreases cardiac output
and BP. The initial drop in cardiac output causes a compensatory
increase in peripheral vascular resistance.
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• With chronic therapy, extracellular fluid volume and plasma volume
return to near pretreatment levels, and peripheral vascular resistance
falls below baseline. Reduced peripheral vascular resistance is
responsible for the long-term hypotensive effects.
• Thiazides (e.g. Bendroflumethiazide, indapamide)
• Loop diuretics (e.g. furosemide) are used mainly in pulmonary oedema
due to ventricular failure, chronic heart failure.
• Potassium-sparing diuretics (e.g. amiloride (+ hydrochlorothiazide),
spironolactone)
• Caution: Hypokalemia.
THIAZIDE DIURETICS
• Thiazides are the preferred type of diuretic and are considered a first-line
option for most patients with hypertension.
• Reduce sodium and water retention in the distal convoluted tubule in the
kidney resulting in a reduction of the peripheral resistance.
• Cause loss of potassium and magnesium salts.
• Potassium supplementation should be considered.
• Maximal hypotensive effect is reached at relatively low doses.
POTASSIUM-SPARING DIURETICS
• Retain potassium and therefore no need to consider potassium
supplementation.
• Act in the distal convoluted tubule.
• Are weak diuretics and in fact may be found in combination products with
thiazides.
SIDE EFFECTS
• Side effects of thiazides include hypokalemia, hypomagnesemia,
hypercalcemia, hyperuricemia, hyperglycemia, dyslipidemia, and sexual
dysfunction.
• Loop diuretics have less effect on serum lipids and glucose, but
hypokalemia is more pronounced, and hypocalcemia may occur.
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• Potassium-sparing diuretics may cause hyperkalemia, especially in patients
with CKD or diabetes and in patients receiving concurrent treatment with
an ACE inhibitor, ARB, direct renin inhibitor, or potassium supplement.
5. B-BLOCKERS
• β-Blockers are only considered appropriate first-line agents to treat
specific compelling indications (e.g., post-MI and coronary artery
disease). Their hypotensive mechanism may involve decreased cardiac
output through negative chronotropic and inotropic effects on the heart
and inhibition of renin release from the kidney.
• Atenolol, betaxolol, bisoprolol, metoprolol, and nebivolol are cardio
selective at low doses and bind more avidly to β1-receptors than to β2-
receptors.
• Acebutolol, carteolol, and pindolol possess intrinsic sympathomimetic
activity (ISA) or partial β-receptor agonist activity.
• Atenolol and nadolol have relatively long half-lives and are excreted
renally; the dosage may need to be reduced in patients with renal
insufficiency.
SIDE EFFECTS
• Bradycardia, Heart failure, Hypotension, Bronchospasm, Peripheral
vasoconstriction, Fatigue, Depression, Vivid dreams.
6. α1-RECEPTOR BLOCKERS
• Prazosin, terazosin, and doxazosin are selective α1-receptor blockers
that inhibit catecholamine uptake in smooth muscle cells of peripheral
vasculature, resulting in vasodilation and BP lowering.
• A first-dose phenomenon characterized by orthostatic hypotension
accompanied by transient dizziness or faintness, palpitations, and even
syncope may occur within 1 to 3 hours of the first dose or after later
dosage increases. The patient should take the first dose (and
subsequent first increased doses) at bedtime. Occasionally, orthostatic
hypotension and dizziness persist with chronic administration.
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LAST LINE DRUGS
CENTRAL α2-AGONISTS
• Clonidine, guanabenz, moxonidine, and methyldopa lower BP primarily by
stimulating α2-adrenergic receptors in the brain.
SIDE EFFECTS
• Depression
• Vasodilation
DIRECT ARTERIAL VASODILATORS
• Hydralazine and minoxidil cause direct arteriolar smooth muscle
relaxation. Compensatory activation of baroreceptor reflexes results in
increased sympathetic outflow from the vasomotor center, increasing heart
rate, cardiac output, and renin release.
SIDE EFFECTS
• Potent vasodilation
• Marked fluid retention
• Hirsutism
• Reflex tachycardia
RESERPINE
• Reserpine depletes norepinephrine from sympathetic nerve endings and
blocks transport of norepinephrine into storage granules. When the nerve
is stimulated, less than the usual amount of norepinephrine is released into
the synapse. This reduces sympathetic tone, decreasing peripheral vascular
resistance and BP.
SIDE EFFECTS
• Nasal stuffiness
• Increased gastric acid secretion
• Diarrhea
• Bradycardia
DIRECT RENIN INHIBITOR
• Aliskiren blocks the RAAS at its point of activation, resulting in reduced
plasma renin activity and BP.
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SIDE EFFECTS
• Many of the cautions and adverse effects seen with ACE inhibitors and
ARBs apply to aliskiren.
COMPELLING INDICATIONS
• Compelling indications for specific therapy involve high-risk conditions that
can be direct sequelae of hypertension (HF, IHD, chronic kidney disease,
recurrent stroke) or commonly associated with hypertension (diabetes,
high coronary disease risk).
1. HEART FAILURE WITH REDUCED EJECTION FRACTION (HFREF)
• Standard pharmacotherapy consists of three to four drugs: ACE inhibitor
or ARB plus diuretic therapy, followed by addition of an evidence-based
β-blocker (i.e., bisoprolol, carvedilol, and metoprolol succinate) and
possibly an aldosterone receptor antagonist.
• After implementation of a standard three-drug regimen, an aldosterone
antagonist (spironolactone and eplerenone) may be considered.
2. POSTMYOCARDIAL INFARCTION
• β-Blockers (without ISA) and ACE inhibitors (or ARBs) are recommended.
β-Blockers decrease cardiac adrenergic stimulation and reduce risk of
subsequent MI or sudden cardiac death. ACE inhibitors improve cardiac
function and reduce CV events after MI. These two drug classes, with β-
blockers first, are the drugs of first choice for post-MI patients.
3. CORONARY ARTERY DISEASE
• β-Blockers (without ISA) are first-line therapy in chronic stable angina;
they reduce BP and decrease myocardial oxygen consumption and
demand. Long-acting CCBs (the nondihydropyridine CCBs diltiazem and
verapamil) may be either alternatives or add-on therapy
(dihydropyridines) to β-blockers in chronic stable angina. Once ischemic
symptoms are controlled with β-blocker and/or CCB therapy, other
antihypertensives (e.g., ACE inhibitor or ARB) can be added to provide
additional CV risk reduction. Thiazide diuretics may be added thereafter
to provide additional BP lowering and further reduce CV risk.
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• For acute coronary syndromes, first-line therapy includes a β-blocker
and ACE inhibitor (or ARB); the combination lowers BP, controls acute
ischemia, and reduces CV risk.
4. DIABETES MELLITUS
• Treat all patients with diabetes and hypertension with an ACE inhibitor
or ARB. Both classes provide nephroprotection and reduced CV risk.
• CCBs are the most appropriate add-on agents for BP control in patients
with diabetes. The combination of an ACE inhibitor with a CCB is more
effective in reducing CV events than an ACE inhibitor plus a thiazide
diuretic.
• A thiazide diuretic is recommended add-on therapy to lower BP and
provide additional CV risk reduction.
• β-Blockers, similar to CCBs, are useful add-on agents for BP control in
patients with diabetes.
5. CHRONIC KIDNEY DISEASE
• In addition to lowering BP, ACE inhibitors and ARBs reduce
intraglomerular pressure, which may further slow CKD progression.
• Start with low doses and evaluate the serum creatinine soon after
starting therapy to minimize the risk of rapid and profound BP drops
that could precipitate acute kidney failure.
6. RECURRENT STROKE PREVENTION
• A thiazide diuretic, either as monotherapy or combined with an ACE
inhibitor, is recommended for patients with history of stroke or
transient ischemic attack.
• Implement antihypertensive drug therapy only after patients have
stabilized after an acute cerebrovascular event.
SPECIAL POPULATIONS
DRUG THERAPY IN ELDERLY
• Calcium channel blockers indicated as first-line agents.
• Diuretics less effective when there is compromised renal function.
• Beta-blockers less potent in the elderly.
• Effect of ACE inhibitors may be decreased due to lower renin levels.
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CHILDREN AND ADOLESCENTS
• Secondary hypertension is more common in children and adolescents than
in adults.
• Medical or surgical management of the underlying disorder usually
normalizes BP.
• Nonpharmacologic treatment (particularly weight loss in obese children) is
the cornerstone of therapy of primary hypertension.
• ACE inhibitors, ARBs, β-blockers, CCBs, and thiazide diuretics are all
acceptable drug therapy choices.
HYPERTENSION IN PREGNANCY
• Two conditions associated with hypertension in pregnancy are:
­ Pre-eclampsia – pregnancy-induced hypertension, 140/90 mmHg
developing during pregnancy in a woman whose blood pressure was
previously normal.
­ Eclampsia – occurrence of convulsions caused by hypertension.
• Methyldopa is the drug of choice.
• Calcium channel blockers (amlodipine and nifedipine): manufacturer
advises avoidance, but risk of uncontrolled maternal hypertension should
be balanced against risk of use of drug.
• Beta-blockers tend to cause birth of smaller babies.
• ACE-Is and ARBs cannot be used – they may damage the fetus and cause
problems in the neonate.
• Diuretics avoided because of decreased intravascular volume.
HYPERTENSIVE URGENCIES AND EMERGENCIES
HYPERTENSIVE URGENCIES
• Hypertensive urgencies are ideally managed by adjusting maintenance
therapy, adding a new antihypertensive, and/or increasing the dose of a
present medication.
• Acute administration of a short-acting oral drug (captopril, clonidine, or
labetalol) followed by careful observation for several hours to ensure a
gradual BP reduction is an option.
­ Oral captopril doses of 25 to 50 mg may be given at 1- to 2-hour
intervals. The onset of action is 15 to 30 minutes.
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­ Labetalol can be given in a dose of 200 to 400 mg, followed by
additional doses every 2 to 3 hours.
HYPERTENSIVE EMERGENCIES
• Hypertensive emergencies require immediate BP reduction to limit new or
progressing end-organ damage.
• This may be a medical emergency and requires prompt reduction of blood
pressure within minutes to 1 hour.
• Conditions that predispose to hypertensive emergency include
pheochromocytoma, renal vascular disease, head injury, severe burns,
eclampsia.
• Goal of treatment: diastolic pressure 100–119 mmHg.
• Nitroprusside is the agent of choice for minute-to-minute control in most
cases. It is usually given as a continuous IV infusion at a rate of 0.25 to 10
mcg/kg/min.
• Major complications that occur in a hypertensive emergency include:
­ Angina
­ Myocardial infarction
­ Congestive heart failure
­ Cerebral infarction
­ Intracranial hemorrhage
EVIDENCE BASED RECOMMENDATIONS IN TREATMENT OF
HYPERTENSION
QUALITY OF EVIDENCE
­ 1 = Evidence from more than one properly randomized, controlled trial.
­ 2 = Evidence from at least one well-designed clinical trial with
randomization; from cohort or case-controlled analytic studies; or dramatic
results from uncontrolled experiments or subgroup analyses.
­ 3 = Evidence from opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert communities.
STRENGTH OF RECOMMENDATIONS
­ A = good
­ B = moderate
­ C = poor evidence to support recommendation.
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ALGORITHM FOR TREATMENT OF HYPERTENSION


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ISCHEMIC HEART DISEASE (IHD)
INTRODUCTION
• Ischemic heart disease (IHD), sometimes described as Coronary artery
disease (CAD) or Coronary heart disease (CHD).
“Ischemic heart disease (IHD) is defined as a lack of oxygen and decreased or no
blood flow to the myocardium resulting from coronary artery narrowing or
obstruction”
• IHD may present as an Acute Coronary Syndrome (ACS) which includes:
­ Unstable angina
­ Non–ST-segment elevation
­ ST-segment elevation myocardial infarction (MI)
­ Chronic stable exertional angina
­ Ischemia without symptoms
­ Ischemia due to coronary artery vasospasm (variant or Prinzmetal
angina).
PATHOPHYSIOLOGY
• Angina pectoris usually results from increased myocardial oxygen demand
(MVo2) in the setting of a fixed decrease in myocardial oxygen supply
because of atherosclerotic plaque.
• Major determinants of MVo2 are heart rate (HR), contractility, and
intramyocardial wall tension during systole. A doubling in any of these
individual parameters requires a 50% increase in coronary flow to maintain
myocardial supply.
• A clinically useful indirect estimate of MVO2 is the double product (DP),
which is HR multiplied by systolic blood pressure (SBP) (DP = HR × SBP).
• The caliber of the resistance vessels delivering blood to the myocardium
and MVO2 are the prime determinants in the occurrence of ischemia.
• The normal coronary system consists of large epicardial or surface vessels
(R1) that offer little resistance to myocardial flow and intramyocardial
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arteries and arterioles (R2), which branch into a dense capillary network to
supply basal blood flow.
• Under normal circumstances, the resistance in R2 is much greater than that
in R1. Myocardial blood flow is inversely related to arteriolar resistance and
directly related to the coronary driving pressure.
• Atherosclerotic lesions occluding R1 increase arteriolar resistance, and R2
can vasodilate to maintain coronary blood flow.
• With greater degrees of obstruction, this response is inadequate, and the
coronary flow reserve afforded by R2 vasodilation is insufficient to meet
oxygen demand.
• Relatively severe stenosis (greater than 70%) may provoke ischemia and
symptoms at rest, whereas less severe stenosis may allow a reserve of
coronary blood flow for exertion.
• The diameter and length of obstructing lesions and the influence of
pressure drop across an area of stenosis also affect coronary blood flow
and function of the collateral circulation.
• Dynamic coronary obstruction can occur in normal vessels and vessels with
stenosis in which vasomotion or spasm may be superimposed on a fixed
stenosis.
• Persisting ischemia may promote growth of developed collateral blood
flow.
• Critical stenosis occurs when the obstructing lesion encroaches on the
luminal diameter and exceeds 70%.
• Lesions → 50% to 70% obstruction may reduce blood flow → to clinical
events such as MI.
• If the lesion 80% to 90% enlarged, resistance in vessels is tripled.
• Abnormalities of ventricular contraction → regional loss of contractility →
burden on the remaining myocardial tissue, resulting in heart failure,
increased MVO2, and rapid depletion of blood flow.
• Zones of tissue with marginal blood flow may develop that are at risk for
more severe damage if the ischemic episode persists or becomes more
severe.
• Nonischemic areas of myocardium may compensate → developing more
tension than usual in an attempt to maintain cardiac output.
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• The left or right ventricular dysfunction → associated with clinical findings
of an S3 gallop, dyspnea, orthopnea, tachycardia, fluctuating blood
pressure, transient murmurs, and mitral or tricuspid regurgitation.
CLINICAL PRESENTATION
• Many episodes of ischemia do not cause symptoms of angina (silent
ischemia).
• Patients often have a reproducible pattern of pain or other symptoms that
appear after a specific amount of exertion.
• Increased symptom frequency, severity, or duration, and symptoms at rest
suggest an unstable pattern that requires immediate medical evaluation.
• Symptoms → a sensation of pressure or burning over the sternum or near
it, which often radiates to the left jaw, shoulder, and arm.
• Chest tightness and shortness of breath may also occur → sensation usually
lasts from 30 seconds to 30 minutes.
• Precipitating factors → exercise, cold environment, walking after a meal,
emotional upset, fright, anger, and coitus.
• Relief occurs with rest and within 45 seconds to 5 minutes of taking
nitroglycerin.
• Variant or Prinzmetal angina → secondary to coronary spasm are more
likely to experience pain at rest and in the early morning hours
• Pain is not usually brought on by exertion or emotional stress nor is it
relieved by rest; the electrocardiogram (ECG) pattern is that of current
injury with ST-segment elevation rather than depression.
• Unstable angina is stratified into categories of low, intermediate, or high
risk for short-term death or nonfatal MI.
• Features of high-risk unstable angina include (but are not limited to):
­ Accelerating tempo of ischemic symptoms in the preceding 48 hours.
­ Pain at rest lasting more than 20 minutes.
­ Age greater than 75 years.
­ ST-segment changes.
­ Clinical findings of pulmonary edema, mitral regurgitation, S3, rales,
hypotension, bradycardia, or tachycardia.
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• Episodes of ischemia may also be painless, or “silent,” in at least 60% of
patients, perhaps due to a higher threshold and tolerance for pain than in
patients who have pain more frequently.
DIAGNOSIS
• Pain: gripping or tight in nature occurring in the retrosternal region of the
chest; pain may radiate to neck, back, left shoulder with possible
involvement of jaw, teeth or epigastrum.
• Sweating, pallor.
• Fever after myocardial infarction may occur within 12 hours.
• Differential diagnosis when symptoms are presented:
­ Symptoms of ischemic heart disease may be very similar to chest
pain that is related to other conditions such as:
▪ Gastrointestinal problems: dyspepsia, gastroesophageal reflux
disease, ulceration, carcinoma.
▪ Musculoskeletal pains.
▪ Panic attack.
▪ Pulmonary embolism.
• Diagnostic tests
­ ECG: ST-segment depression, T-wave inversion indicating angina and
ST-segment elevation indicating myocardial infarction.
­ Exercise tolerance test (ETT).
­ Blood tests: elevation of cardiac-specific troponin I and T, creatine
kinase.
TREATMENT
TREATMENT GOALS
• To prevent myocardial infarction and associated mortality.
• To increase length of pain-free survival with a good quality of life.
NON-PHARMACOLOGICAL THERAPY
RISK FACTOR MODIFICATION
• Primary prevention through the modification of risk factors should
significantly reduce the prevalence of IHD.
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• Secondary intervention is effective in reducing subsequent morbidity and
mortality.
• Risk factors for IHD are additive and can be classified as:
­ Unalterable risk factors include gender, age, family history or genetic
composition, environmental influences, and, to some extent,
diabetes mellitus.
­ Alterable risk factors include smoking, hypertension, hyperlipidemia,
obesity, sedentary lifestyle, hyperuricemia, psychosocial factors such
as stress and type A behavior patterns, and the use of drugs that may
be detrimental (e.g. progestins, corticosteroids and cyclosporine).
LIFESTYLE MODIFICATIONS
• Daily physical activity
• Weight management
• Dietary therapy
• Smoking cessation
• Psychological interventions
• Limitation of alcohol intake.
SURGICAL REVASCULARIZATION
• Surgical revascularization options for select patients include coronary artery
bypass grafting (CABG) or percutaneous coronary intervention (PCI) with or
without stent placement.
RATIONALE OF DRUG TREATMENT IN ANGINA
• Decrease workload of the heart.
• Improve coronary blood supply.
RATIONALE OF DRUG TREATMENT IN MYOCARDIAL INFARCTION
• Immediate care: remove pain, prevent deterioration, limit infarct size.
• Management of complications: heart failure, arrhythmias.
• Prevention of second infarction.
TREATMENT OF ANGINA
ANTIPLATELET THERAPY
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• Aspirin almost completely blocks cyclooxygenase-1 (COX-1) activity and
subsequent thromboxane A2 production, leading to reduced platelet
activation and aggregation for the life of the platelet. Aspirin 75 to 162 mg
daily should be continued indefinitely in the absence of contraindications.
• Clopidogrel 75 mg daily is an alternative for patients unable to take aspirin
due to allergy or intolerance.
NITRATES
• Acts on vascular smooth muscles.
• Reduce myocardial oxygen demand.
• Increase myocardial oxygen supply.
• Taken before exercise.
• E.g. Glyceryl trinitrate (GTN), Isosorbide mono/dinitrate.
BETA BLOCKERS
• Lower myocardial oxygen demand by reducing heart rate and blood
pressure.
• Can provoke bronchospasms in patients with asthma.
• E.g. Atenolol, Labetalol, Propranolol, Timolol, Bisoprolol.
CALCIUM CHANNEL BLOCKERS
• Inhibits the slow inward current caused by entry of extracellular calcium
through cell membrane of excitable cells results in decreasing myocardial
oxygen demand and lowering blood pressure.
• E.g. Verapamil, Diltiazem, Amlodipine, Nifedipine, Nicardipine.
OTHER DRUGS
• Nicorandil (Potassium channel activator)
• Ivabradine (Selective inhibitor of the sinus node) If, resulting in a decrease
in heart rate, maintains myocardial contractility, atrioventricular
conduction and ventricular repolarization, Particularly, indicated in patients
who have a contraindication or intolerance to beta-blockers.
• Trimetazidine (3-ketoacyl-CoA thiolase (KAT) inhibitor) which results in
decreased fatty acid oxidation in the myocardium, thus decreasing
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metabolic damage due to ischemia. It can be used in combination therapy
with other anti-anginal drugs).
TREATMENT OF MYOCARDIAL INFARCTION
• Oxygen to counteract the occurrence of hypoxia, pulmonary edema or
continuing myocardial ischemia.
• Intravenous diamorphine, sublingual glyceryl trinitrate or intravenous
glyceryl trinitrate or isosorbide dinitrate against pain and distress.
• Intravenous metoclopramide or prochlorperazine as antiemetics.
• Drugs used to limit infarct size: thrombolytics aspirin, heparin, beta-
blockers, ACE (angiotensin-converting enzyme) inhibitors or angiotensin II
receptor antagonists.
CONTINUOUS PREVENTIVE TREATMENT IN ANGINA
• Beta-blockers and oral long-acting nitrates.
• Verapamil: highly negative inotropic calcium channel blocker which reduces
cardiac output and slows heart rate. May precipitate heart failure, not to be
used in conjunction with beta-blockers.
• Beta-blocker + amlodipine/nifedipine, nicorandil.
PATIENT MONITORING
• Monitor blood pressure.
• Target total cholesterol level 5 mmol/L, low-density lipoprotein (LDL) 3
mmol/L.
• Monitor occurrence of diabetes.
HEART FAILURE
INTRODUCTION
HEART FAILURE
“Heart failure (HF) is a progressive clinical syndrome caused by inability of the
heart to pump sufficient blood to meet the body’s metabolic needs”
• Acute (following a heart attack or volume loading) or Chronic.
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UNDERLYING CAUSE
• Failure of the heart muscle.
• Sustained arrhythmias (atrial fibrillation).
• Failure of the heart valves.
LEADING CAUSE OF CHF
• Ischemic heart disease (IHD)
• Hypertension
­ Hypertension → Increased after-load → hypertrophy of the heart.
DEFINITIONS
CONGESTIVE HEART FAILURE
• Congestive heart failure (CHF) is a specific subset of HF characterized by left
ventricular systolic dysfunction & volume excess presenting as an enlarged,
blood congested heart.
AFTERLOAD
• Tension developed in the ventricular wall as contraction (systole) occurs.
Regulated by systemic vascular resistance (SVR) or impedance in ventricle
which is chiefly determined by arterial blood pressure (BP).
PRELOAD
• Forces acting on venous circulation to affect myocardial wall tension.
Elevated preload aggravates congestive failure.
CONTRACTILITY
• The inherent ability of myocardium to develop force (contract)
independent of preload or afterload. Contractility is synonymous with
inotropism.
EJECTION FRACTION
• Percent of LV volume expelled during systole. Normal 60% to 70%; <40%
indicates left ventricular systolic dysfunction.
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37. GM Hamad

CLASSIFICATION
LEFT-SIDED FAILURE
• Most common type & is often secondary to hypertension.
• Left ventricular (systolic) dysfunction with poor output leading to increased
left atrial & pulmonary venous pressure → pulmonary congestion & edema.
RIGHT-SIDED FAILURE
• Often due to chronic lung disease (cor pulmonale).
• Right ventricular output falls, leading to increased venous pressure, with
peripheral edema.
BIVENTRICULAR FAILURE
• Both main chambers are affected as left & right ventricular failure often
coincide (IHD may have affected both ventricles).
• Often left ventricular failure leads to pulmonary congestion, which in turn
impairs right ventricular function, causing failure on the right side.
NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION OF HEART
FAILURE
Class Characteristics
Class I No symptoms with ordinary physical activity (such as walking or
climbing stairs)
Class II Slight limitation with dyspnea on moderate to severe exertion
(climbing stairs or walking uphill)
Class III Marked limitation of activity, less than ordinary activity causes
dyspnea (restricting walking distance and limiting climbing to one
flight of stairs)
Class IV Severe disability, dyspnea at rest (unable to carry on physical
activity without discomfort)
CLASSIFICATION & ETIOLOGY OF LV DYSFUNCTION
Type of failure Characteristics
Contributing
factor
Etiology
Low-output,
systolic,
dysfunction
Hypo functioning left
ventricle, enlarged
heart, increased left
ventricular end
Decreased
contractility,
Increased
afterload.
Coronary ischemia, MI,
alcoholism, nutritional
deficiency,
Hypertension.
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38. GM Hamad

diastolic volume, EF <
40%, decreased
stroke volume.
Low-output,
diastolic
dysfunction
Normal LV
contractility, normal
size heart, stiff left
ventricle, impaired
left ventricular
relaxation & filling,
decreased left
ventricular end-
diastolic volume,
normal EF, decreased
stroke volume.
Thickened
left ventricle,
Stiff left
ventricle,
Increased
preload.
Coronary ischemia, MI,
hypertension,
Amyloidosis,
sarcoidosis, Na & H2O
retention.
PATHOPHYSIOLOGY
• For compensating of circulatory failure → activation of renin-angiotensin-
aldosterone system (RAAS) with increased release of anti-diuretic hormone
(ADH). Also, there is release of atrial natriuretic peptide (ANP) from the
dilated heart.
• Increased sympathetic & RAAS activities increase arterial vascular
resistance (afterload) & venous return (preload) thus increasing the
workload of the heart.
• The increased sympathetic activity will also attempt to increase the force of
cardiac contraction → cardiac arrhythmias.
• As a result of increased peripheral resistance → impaired renal function,
with additional salt & water retention → further RAAS activation.
• A consequence of these changes is edema (congestion) at different sites in
the body → hence the term is used Congestive Heart Failure.
• Neurohormonal activation also leads to monocyte dysfunction → increased
aldosterone activity leading to fibrosis & stiffening of cardiac muscle,
further impairing pump activity.
CLINICAL PRESENTATION
CARDIOVASCULAR-RELATED FEATURES
• Reduced EF (<45%) as identified on an echocardiogram.
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39. GM Hamad

• Hypotension leading to tiredness & possibly dizziness.
• Reduced urine flow.
• Cold peripheries.
• Breathlessness.
• Edema.
NON-SPECIFIC SYMPTOMS
• Fatigue, listlessness.
• Poor exercise tolerance.
• Weight loss or even weight gain due to edema.
DIAGNOSIS
Investigation Comment
Blood test Following assessments are usually performed:
• Blood gas analysis to assess respiratory gas
exchange.
• Serum creatinine and urea to assess renal function.
• Serum alanine and aspartate-aminotransferase plus
other LFTs.
• Full blood count to investigate possibility of anemia.
• Thyroid function tests to investigate possibility of
thyrotoxicosis.
• Serum BNP or NT pro-BNP to indicate likelihood of a
diagnosis of HF (screening test).
• Fasting blood glucose to investigate possibility of
DM.
12-lead ECG A normal ECG usually excludes the presence of LV systolic
dysfunction. Abnormal requires further investigation.
Chest radiograph A chest radiograph (X-ray) is performed to look for
enlarged cardiac shadow and consolidation in the lungs.
Echocardiography An echocardiogram is used to confirm the diagnosis of HF
and any underlying causes e.g. Valvular heart disease.
TREATMENT OF CHRONIC HEART FAILURE
TREATMENT GOALS
• Increase the quality of life.
• Avoid hospitalization.
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• Minimize adverse drug events.
• Increase survival time.
PHARMACOLOGICAL THERAPY
DIURETICS
• Indicated in both diastolic & systolic HF for patients with circulatory
congestion and/or cardiac distention.
• Thiazide diuretics (e.g. hydrochlorothiazide) are relatively weak and are
infrequently used alone in HF. However, thiazides or the thiazide-like
diuretic metolazone can be used in combination with a loop diuretic to
promote very effective diuresis.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
• Mixed preload & afterload properties + mild diuretic effects (aldosterone
inhibition). They are preferred over drugs like Digoxin.
• Choice of drug & dosing → efficient in systolic HF → initiate with short-
acting (captopril) switch to long acting.
• Monitor patient for hypotension, non-productive cough & hyperkalemia.
• Effect on renal function → improve renal function if Cardiac output is
increased.
• Monitor BP, BUN creatinine regularly.
• E.g. Captopril, Enalapril, Lisinopril.
ANGIOTENSIN-RECEPTOR BLOCKERS
• Improve exercise tolerance & EF.
• Dry cough is less but the effects of hypokalemia, BUN & creatinine are
equal to that of ACE-inhibitors.
• E.g. Candesartan, Valsartan, Losartan.
BETA-BLOCKERS
• Start with low initial dose followed by gradual increase after 1—2 weeks.
• Should be prescribed to patients with stable systolic HF.
• Transient bradycardia, fluid retention, hypotension & fatigue are common
during first 24—48hrs.
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• Carvedilol → a recently approved agent for HF. It has mixed alpha-blocker &
nonselective beta-blocker activity. Also has antioxidant effects. Start with
minimum dose & increase after 2 weeks.
• Metabolism → 2D6.
• Metoprolol.
• Propranolol → avoid in systolic HF. May be used in patients with diastolic HF
not responding to diuretics + ACE-inhibitors.
ALDOSTERONE ANTAGONISTS
• Spironolactone 25—50mg/day combined with loop-diuretics.
• Hyperkalemia → more prevalent with spironolactone when combined with
ACE-Is & aspirin.
• Hypokalemia treatment → K supplementation or K-sparing diuretics (until K
<3.5mEq/L) especially in patients taking Digoxin (average K intake 20—
60mEq/L /day). Chloride salt of K should be used.
DIGITALIS GLYCOSIDES
• Reduces symptoms of HF → combination of +ve ionotropic & other
neurohumoral actions.
CALCIUM CHANNEL BLOCKERS
• Systolic HF → Diltiazem & verapamil can increase serum digoxin levels and
have additive AV blocking effects.
• Amlodipine is safest in HF patients with concurrent angina.
• Diastolic HF → v\Verapamil alternative to beta-blockers.
TREATMENT OF ACUTE DECOMPENSATED HEART FAILURE
• Acute decompensated heart failure (ADHF) involves patients with new or
worsening signs or symptoms (often resulting from volume overload and/or
low cardiac output) requiring medical intervention, such as emergency
department visit or hospitalization.
TREATMENT GOALS
• The overall goal is to relieve symptoms while optimizing volume status and
cardiac output so the patient can be discharged in a stable compensated
state on oral drug therapy.
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42. GM Hamad

PHARMACOLOGICAL THERAPY
DIURETICS
• IV loop diuretics, including furosemide, bumetanide, and torsemide, are
used for ADHF, with furosemide being the most widely studied and used
agent.
VASODILATORS
• Venodilators reduce preload by increasing venous capacitance, improving
symptoms of pulmonary congestion in patients with high ventricular filling
pressures.
• Arterial vasodilators reduce afterload and cause a reflex increase in cardiac
output, which may promote diuresis via improved renal perfusion.
• Mixed vasodilators act on both arterial resistance and venous capacitance
vessels, reducing congestive symptoms while increasing cardiac output.
NITROGLYCERIN
• IV nitroglycerin is often preferred for preload reduction in ADHF, especially
in patients with pulmonary congestion.
• In higher doses, nitroglycerin displays potent coronary vasodilating
properties and beneficial effects on myocardial oxygen demand and supply,
making it the vasodilator of choice for patients with severe HF and ischemic
heart disease.
VASOPRESSIN ANTAGONISTS
• The vasopressin receptor antagonists currently available affect one or two
arginine vasopressin (AVP; antidiuretic hormone) receptors, V1A or V2.
• Stimulation of V1A receptors (located in vascular smooth muscle cells and
myocardium) results in vasoconstriction, myocyte hypertrophy, coronary
vasoconstriction, and positive inotropic effects. V2 receptors are located in
renal tubules, where they regulate water reabsorption.
• E.g. Tolvaptan, Conivaptan.
INOTROPES
• Low cardiac output in ADHF may worsen renal perfusion, resulting in
resistance to diuretic therapy. IV inotropes may improve peripheral
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43. GM Hamad

hypoperfusion and diuresis by improving central hemodynamics. However,
because of their adverse effect profile they should generally be reserved for
patients not responding to other modalities or those with clear evidence of
low cardiac output.
MILRINONE
• Milrinone inhibits phosphodiesterase III and produces positive inotropic
and arterial and venous vasodilating effects (an inodilator).
• During IV administration, milrinone increases stroke volume and cardiac
output with minimal change in heart rate.
Unit II: Pulmonary unit (Asthma e.g. acute, chronic, status asthamaticus,
childhood asthma, Pneumonia, COPD includes emphysema & chronic
bronchitis)
ASTHMA
DEFINITION
“Asthma, as defined by the Global Initiative for Asthma (GINA), is a
heterogeneous disease, usually characterized by chronic airway
inflammation”
• It is defined by a history of respiratory symptoms such as wheezing,
shortness of breath, chest tightness, and cough that vary over time and in
intensity, together with variable expiratory airflow limitation.
PATHOPHYSIOLOGY
• Variable degree of airflow obstruction (related to bronchospasm, edema,
and hypersecretion), bronchial hyperresponsiveness (BHR) and airway
inflammation.
• Inhaled allergens cause an early-phase allergic reaction characterized by
activation of cells bearing allergen-specific immunoglobulin E (IgE)
antibodies.
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• There is rapid activation of airway mast cells and macrophages, which
release pro-inflammatory mediators such as histamine and eicosanoids that
induce contraction of airway smooth muscle, mucus secretion, vasodilation,
and exudation of plasma in the airways.
• Plasma protein leakage induces a thickened, engorged, edematous airway
wall and a narrowing of the airway lumen with reduced mucus clearance.
• Histamine and other mediators of inflammation are released from mast
cells, for example:
­ leukotrienes, prostaglandins, bradykinin, adenosine and
prostaglandin generating factor of anaphylaxis, as well as various
chemotactic agents that attract eosinophils and neutrophils.
• Macrophages release prostaglandins, thromboxane and platelet-activating
factor (PAF). PAF appears to sustain bronchial hyperreactivity and cause
respiratory capillaries to leak plasma, which increases mucosal edema.
• PAF also facilitates the accumulation of eosinophils within the airways,
a characteristic pathological feature of asthma.
• Epithelial damage results and thick viscous mucus is produced that causes
further deterioration in lung function. Mucus transport is dependent on its
viscosity. If it is very thick, it plugs the airways, which also become blocked
with epithelial and inflammatory cell debris.
AUTONOMIC & NON-AUTONOMIC MECHANISM
• The airway is innervated by parasympathetic, sympathetic, and non-
adrenergic inhibitory nerves.
• Parasympathetic nerves result in release of Ach acting on bronchial M3-
muscarinic receptors → bronchoconstriction & increased mucus secretion.
• β2-receptors linked via cAMP → bronchodilatation.
• β2-receptors → no direct innervations but respond to circulating adrenaline
which stimulates bronchodilatation.
• In addition, the mucus glands contain β2-receptors → inhibit mucus
secretion.
• There is also limited number of sympathetic fibers which release nor-AD
acting on β2-receptors at parasympathetic ganglia to inhibit transmission.
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• Non-adrenergic Non-cholinergic (NANC) fibers → nitric oxide (NO) &
vasoactive intestinal polypeptide are inhibitory transmitters & substance-
P* is an excitatory transmitter.
• These sensory nerve fibers are thought to play a role in local reflex
responses to irritant stimuli.
CLINICAL PRESENTATION
• Persistent cough.
• Recurrent episodes of difficulty in breathing (dyspnea)
• Wheezing.
• Acute asthmatic attack requires hospitalization (peak flow rate <100L/min)
[pulse rate 110 beats/min]
• Low oxygen saturation (SpO2 < 92%) → patient become fatigued, cyanosed,
confused and lethargic.
• CO2 tension (PaCO2) is low in acute asthma.
• High PaCO2 level (hypercapnia) that does not diminish is a more severe
problem and indicates progression towards respiratory failure.
DIAGNOSIS
SPIROMETRY
• Assess lungs volume, air flow dynamics.
• Gives index about degree of obstruction & degree of reversibility.
FORCED VITAL CAPACITY (FVC)
• Total vol. of air expired.
• Normal adult value in males = 4—5L (age, gender & body weight
dependent).
FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1)
• The amount of air expired during the 1
st
second.
• FEV1 value in adult male = 3.2—4L (80% of FVC)
• The FEV1 is usually expressed as a percentage of the total volume of air
exhaled, reported as the FEV1/FVC ratio.
• Asthma → FEV1 is usually decreased, the FVC normal or slightly reduced and
the FEV1/FVC ratio decreased, usually < 0.7 measured by spirometer.
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PEAK EXPIRATORY FLOW RATE (PEFR)
• Maximum flow rate that can be produced during forced expiration
following a deep breath to full inspiration.
• Normal PEFR = 550—700L/min (adults) 150—220L/min (children)
• The diagnosis of asthma can be confirmed by measuring the response to a
bronchodilator or by examining a patient‘s day-to-day variation in PEF
readings. A diurnal variability of 60L/min (or more than 20%) is highly
suggestive of asthma.
CATEGORIES OF ASTHMA
• On the basis of severity
­ Mild intermittent
­ Mild persistent
­ Moderate persistent
­ Severe persistent
1. MILD INTERMITTENT ASTHMA
• With mild intermittent asthma, the symptoms are mild. This
classification means you will have symptoms up to two days per week or
two nights per month. This asthma type will usually not hinder any of
your activities and can include exercise-induced asthma.
SYMPTOMS
• Wheezing or whistling when breathing
• Coughing
• Swollen airways
• Development of mucus in the airways
2. MILD PERSISTENT ASTHMA
• If you have mild persistent asthma, your symptoms are still mild but
occur more than twice per week. For this type classification, you do not
have symptoms more than once per day.
SYMPTOMS
• Wheezing or whistling when breathing
• Coughing
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• Swollen airways
• Development of mucus in the airways
• Chest tightness or pain
TREATMENT
• At this asthma level your doctor may prescribe a low-dose inhaled
corticosteroid medication. An inhaled corticosteroid is taken by quickly
inhaling it. It is usually taken daily.
3. MODERATE PERSISTENT ASTHMA
• With moderate persistent asthma you will have symptoms once each
day, or most days. You will also have symptoms at least one night each
week.
SYMPTOMS
• Wheezing or whistling when breathing
• Coughing
• Swollen airways
• Development of mucus in the airways
• Chest tightness or pain
TREATMENT
• Slightly high doses of inhaled corticosteroids. Allergy medication if triggered
by allergies. Oral corticosteroids may also be added for people aged 50 and
older. A rescue inhaler.
4. SEVERE PERSISTENT ASTHMA
• If you have severe persistent asthma, you will have symptoms several
times during the day. These symptoms will occur almost every day. You
will also have symptoms many nights each week.
• Severe persistent asthma does not respond well to medications even
when taken regularly.
SYMPTOMS
• Wheezing or whistling sound when breathing
• Coughing
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• Swollen airways
• Development of mucus in the airways
• Chest tightness or pain
TREATMENT
• The medications used will include:
­ Inhaled corticosteroids — at a higher dose than with other asthma
types.
­ Oral corticosteroids — at a higher dose than with other asthma
types.
­ Rescue inhaler.
­ Medications that will help combat the cause or trigger.
TREATMENT
TREATMENT GOALS
• The GINA long-term goals for asthma management include:
­ Achieve good control of symptoms and maintain normal activity
levels.
­ Minimize future risk of exacerbations, fixed airflow limitation, and
side effects. For acute severe asthma, the primary goal is prevention
of life-threatening asthma by early recognition of signs of
deterioration and early intervention.
NON-PHARMACOLOGIC THERAPY
• Patient education is mandatory to improve medication adherence, self-
management skills, and use of healthcare services.
• Avoidance of known allergenic triggers can improve symptoms, reduce
medication use, and decrease BHR. Environmental triggers (e.g. animals)
should be avoided in sensitive patients, and smokers should be encouraged
to quit.
• Dehydration should be corrected.
PHARMACOTHERAPY
BETA-ADRENOCEPTOR AGONISTS
Short-acting Beta-adrenoceptor agonists
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• First choice.
• Act on bronchial smooth muscle to increase cAMP → rapid bronchodilation
& reversal of bronchospasm in early phase.
• Prolong usage → receptor down-regulation → less effective.
• Concomitant use of corticosteroids may reduce receptor down-regulation.
• E.g. Salbutamol, terbutaline.
Long-acting Beta-adrenoceptor agonists
• Rate of onset is slow b/c of lipophilic nature the molecules retained near
receptor for prolonged period → action persists.
• They are not used to reverse an attack but cause prolonged
bronchodilation.
• More effective than xanthines or cromones.
• E.g. Formoterol, Salmeterol.
CORTICOSTEROIDS
• Anti-inflammatory action via activation of intracellular receptors → altered
gene transcription.
• Decreased cytokine production & synthesis of lipocortin → inhibits
production of PGs & leukotrienes.
• Oral fungal infections → local immunosuppression.
• Laryngeal myopathy → hoarseness & bone resorption with increased doses.
• E.g. Beclomethasone, Budeunoside, Fluticasone, Prednisolone (oral).
XANTHINES
• Bronchodilators but not as effective as beta-agonists.
• Given orally (I.V aminophylline occasionally)
• They are Phosphodiesterase III & IV inhibitors & potentiate cAMP by
preventing its breakdown → bronchodilation.
• Blockade of adenosine receptors → bronchial smooth muscle relaxation.
• Anti-inflammatory action → reduction in mediator release.
• Narrow therapeutic index, CNS side-effects & nausea limit the use of
xanthines.
• E.g. Aminophylline, Theophylline.
MUSCARINIC M-RECEPTOR ANTAGONISTS
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• Given by inhalation.
• Blocks parasympathetic-mediated bronchoconstriction.
• They are of little or no value in the treatment of asthma (recent reports)
• E.g. Ipratropium.
LEUKOTRIENE RECEPTOR ANTAGONISTS
• New class of orally active drugs which block Leukotriene receptors and also
will oppose the bronchoconstriction & inflammatory action of Leukotrienes.
• E.g. Montelukast, Zafirlukast.
MONOCLONAL ANTIBODIES
• It is a monoclonal antibody.
• Novel agent has a role in the treatment- resistant asthma.
• It has been raised against IgE.
• E.g. Omalizumab
CROMONES
• Prevent both early & late phases.
• Uncertain actions but may include a reduction in sensory nerve reflexes,
stabilization of mast cells & decrease in release of PAF & cytokines.
• Only beneficial in children from 5—12years.
• Effective in exercise induced asthma.
• E.g. Nedocromil sodium, Sodium Cromoglicate.
STEP WISE MANAGEMNET OF ASTHAMA
STEP 1: MILD INTERMITTENT ASTHMA
• Inhaled short-acting β-2 agonist as required
STEP 2: REGULAR PREVENTER THERAPY
• Add inhaled steroid 200–800 μcg/day*
• 400 μcg is an appropriate starting dose for many patients
• Start a dose of inhaled steroid appropriate to severity of disease
STEP 3: ADD-ON THERAPY
1. Add inhaled long acting β2 agonist (LABA)
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2. Assess control of asthma:
­ Good response to LABA – continue LABA
­ Benefit from LABA but control still inadequate – continue LABA and
increase inhaled steroid dose to 800 μcg/day* (if not already on this
dose)
­ No response to LABA – stop LABA and increase inhaled steroid to 800
μcg/day*. If control still inadequate, institute trial of other therapies,
e.g. leukotriene receptor antagonist or SR theophylline.
STEP 4: PERSISTENT POOR CONTROL
• Consider trials of:
­ Increasing inhaled steroid up to 2000 μcg/day*
­ Addition of a fourth drug e.g. leukotriene receptor antagonist, SR
theophylline, β2 agonist tablet.
STEP 5: CONTINUOUS OR FREQUENT USE OF ORAL STEROIDS
• Use daily steroid tablet in lowest dose providing adequate control.
• Maintain high dose inhaled steroid at 2000 μcg/day*
• Consider other treatments to minimize the use of steroid tablets
• Refer patient for specialist care.
PNEUMONIA
INTRODUCTION
• Pneumonia is an infection in one or both lungs.
• Pneumonia causes inflammation in the alveoli.
• The alveoli are filled with fluid or pus, making it difficult to breathe.
DEFINITION
“Inflammation and consolidation of lung tissue due to an infectious agent”
• COSOLIDATION = ‘Inflammatory induration of a normally aerated lung due
to the presence of cellular exudative in alveoli.
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TYPES OF PNEUMONIA
COMMUNITY ACQUIRED (CAP)
• Pneumonia developing in patients with no contact to a medical facility.
HOSPITAL ACQUIRED (HAP)
• Pneumonia developing within 48 hours after hospital admission.
VENTILATOR ASSOCIATED (VAP)
• Pneumonia developing within 48 – 72 hours after intubation and
mechanical ventilation.
PATHOPHYSIOLOGY
• Microorganisms gain access to the lower respiratory tract by three routes:
they may be inhaled as aerosolized particles, they may enter the lung via
the bloodstream from an extrapulmonary site of infection, or aspiration of
oropharyngeal contents may occur.
• Lung infections with viruses suppress the bacterial clearing activity of the
lung by impairing alveolar macrophage function and mucociliary clearance,
thus setting the stage for secondary bacterial pneumonia.
• The most prominent pathogen causing community-acquired pneumonia in
otherwise healthy adults is S. pneumoniae. Other common bacterial causes
are H. influenza, the “atypical” pathogens including M. pneumoniae,
Legionella species, Chlamydophila pneumoniae, and a variety of viruses.
• Anaerobic bacteria are the most common etiologic agents in pneumonia
that follows the gross aspiration of gastric or oropharyngeal contents.
DIAGNOSIS
SPUTUM
• Gram Staining
• AFB
• Giemsa or methenamine silver stain
• KOH mount
• Culture
X RAY
• Homogenous opacity with air bronchogram.
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CT THORAX
• Seldom used.
INVESTIGATIONS
• Complete white blood count
• Blood Sugar
• Electrolytes
• Creatinine
• Blood culture
• Screening for retro (ICTC)
• Oxygen saturation by pulse
oximetry
• ABG
• USG Chest
• Mantoux
CLINICAL PRESENTATION
SIGNS AND SYMPTOMS
• Abrupt onset of fever, chills, dyspnea, and productive cough.
• Rust-colored sputum or hemoptysis.
• Pleuritic chest pain.
PHYSICAL EXAMINATION
• Tachypnea and tachycardia.
• Dullness to percussion.
• Increased tactile fremitus, whisper pectoriloquy, and egophony.
• Chest wall retractions and grunting respirations.
• Diminished breath sounds over affected area.
• Inspiratory crackles during lung expansion.
CHEST RADIOGRAPH
• Dense lobar or segmental infiltrate.
LABORATORY TESTS
• Leukocytosis with predominance of polymorphonuclear cells.
• Low oxygen saturation on arterial blood gas or pulse oximetry.
TREATMENT
OUTPATIENTS TREATMENT (EMPIRICAL)
• Previously healthy and no antibiotics in past 3 months:
­ A macrolide (clarithromycin or azithromycin) or Doxycycline.
• Comorbidities or antibiotics in past 3 months:
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­ Respiratory fluoroquinolone (moxifloxacin, levofloxacin) or β-lactam
(high-dose amoxicillin or amoxicillin/clavulanate).
INPATIENTS
NON-ICU
• A respiratory fluoroquinolone (moxifloxacin, levofloxacin)
• β -lactam (cefotaxime, ceftriaxone, ampicillin) plus a macrolide (oral
clarithromycin or azithromycin)
ICU
• β-lactam plus Azithromycin or a fluoroquinolone.
PSEUDOMONAS
• An antipneumococcal, antipseudomonal β-lactam (piperacillin/tazobactam,
cefepime, imipenem, meropenem) plus fluoroquinolones.
• Above β-lactams plus an aminoglycoside and azithromycin.
• Above β-lactams plus an aminoglycoside plus an antipneumococcal
fluoroquinolone.
METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS
• If MRSA, add linezolid or vancomycin.
COMPLICATIONS
• Lung abscess
• Para-pneumonic effusions
• Empyema
• Sepsis
• ARDS, Respiratory failure
• Circulatory failure
• Renal failure
• Multi-organ failure
• Metastatic infections (meningitis, endocarditis, arthritis)
COURSE
• Most healthy people recover from pneumonia in one to three weeks, but
pneumonia can be life-threatening.
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• The mortality rate associated with community-acquired pneumonia (CAP) is
very low in most ambulatory patients and higher in patients requiring
hospitalization, being as high as 37 percent in patients admitted to the
intensive care unit (ICU).
CHRONIC OBSTRUCTIVE PULMONARY
DISEASE
DEFINITION
“Chronic obstructive pulmonary disease (COPD) is characterized by progressive
airflow limitation that is not fully reversible”
• Two principal conditions include:
CHRONIC BRONCHITIS
• Chronic or recurrent excess mucus secretion with cough that occurs on
most days for at least 3 months of the year for at least 2 consecutive years.
EMPHYSEMA
• Abnormal, permanent enlargement of the airspaces distal to the terminal
bronchioles, accompanied by destruction of their walls, without fibrosis.
PATHOPHYSIOLOGY
AIRWAYS
• Chronic inflammation.
• Increased numbers of goblet cells.
• Mucus gland hyperplasia.
• Fibrosis.
• Narrowing and reduction in the number of small airways.
• Airway collapse due to the loss of tethering caused by alveolar
wall destruction in emphysema.
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LUNG PARENCHYMA
• Emphysema affects the structures distal to the
terminal bronchiole, consisting of the respiratory
bronchiole, alveolar ducts, alveolar sacs, and
alveoli, known collectively as the acinus.
SUBTYPES OF EMPHYSEMA
Centrilobular emphysema (Proximal acinar)
• Abnormal dilation or destruction of the respiratory
bronchiole, the central portion of the acinus.
• It is commonly associated with cigarette smoking.
Panacinar emphysema
• Refers to enlargement or destruction of all parts of the
acinus.
• Seen in alpha-1 antitrypsin deficiency and in smokers.
Paraseptal emphysema
• Distal acinar - the alveolar ducts are predominantly
affected.
PULMONARY VASCULATURE
• Intimal hyperplasia and smooth muscle hypertrophy or hyperplasia thought
to be due to chronic hypoxic vasoconstriction of the small pulmonary
arteries.
• Destruction of alveoli due to emphysema can lead to loss of the associated
areas of the pulmonary capillary bed and pruning of the distal vasculature.
CLINICAL PRESENTATION
SYMPTOMS OF COPD
• The characteristic symptoms of COPD are chronic and progressive dyspnea,
cough, and sputum production that can be variable from day-to-day.
• Dyspnea: Progressive, persistent and characteristically worse with exercise.
• Chronic cough: May be intermittent and may be unproductive.
• Chronic sputum production: COPD patients commonly cough up sputum.
Normal Acinus
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OTHER CLINICAL FEATURES
• Wheezing.
• Chest tightness.
• Weight loss.
• Respiratory infections.
PHYSICAL EXAMINATION
• Physical examination is normal in most patients
in milder stages. When airflow limitation
becomes severe, patients may have cyanosis of
mucosal membranes, development of a “barrel
chest” due to hyperinflation of the lungs,
increased resting respiratory rate, shallow
breathing, pursing of lips during expiration, and
use of accessory respiratory muscles.
DIAGNOSIS
• Diagnosis is based in part on patient symptoms and history of exposure to
risk factors such as tobacco smoke and occupational substances.
• Classification of disease severity is based on assessment of airflow
limitation by spirometry, measurement of symptom severity, and
assessment of exacerbation frequency.
SPIROMETRY
• The presence of airflow limitation should be confirmed with spirometry.
The forced expiratory volume after 1 second (FEV1) is reduced except in
very mild disease. The forced vital capacity (FVC) may also be decreased.
The hallmark of COPD is reduced FEV1: FVC ratio to less than 70%.
CHEST X-RAY-CHRONIC BRONCHITIS
• No apparent abnormality or thickened and increased lung markings are
noted.
CHEST X-RAY EMPHYSEMA
• Marked over inflation is noted with flattened and low diaphragm.
• Intercostal space becomes widen.
• A horizontal pattern of ribs.
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• A long thin heart shadow.
• Decreased markings of lung peripheral vessels.
CT (COMPUTED TOMOGRAPHY)
• Greater sensitivity and specificity for emphysema.
• For evaluation of bullous disease.
LABORTORY EXAMINATION
BLOOD EXAMINATION
• In exacerbation or acute infection in airway, leukocytosis may be detected.
SPUTUM EXAMINATION
• Streptococcus pneumonia.
• Hemophilus influenzae.
• Moraxella catarrhalis.
• Klebsiella pneumonia.
ARTERIAL BLOOD GAS MEASUREMENT
• Significant changes in arterial blood gases (ABG) are not usually present
until FEV1 is less than 1 L. At this stage, hypoxemia and hypercapnia may
become chronic. Hypoxemia usually occurs initially with exertion but
develops at rest as the disease progresses.
• PaO2 < 8.0 kPa with or without PaCO2 > 6.7 kPa when breathing room air
indicates respiratory failure.
TREATMENT
TREATMENT GOALS
• Prevention of further progress of disease.
• Preservation and enhancement of pulmonary functional capacity.
• Avoidance of exacerbations in order to improve the quality of life.
PHARMACOTHERAPY
BRONCHODILATORS
• Bronchodilators are central to the symptomatic management of COPD.
• Improve emptying of the lungs, reduce dynamic hyperinflation and improve
exercise performance.
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• Three major classes of bronchodilators:
B2 - agonists
• Short acting: Salbutamol & terbutaline.
• Long acting: Salmeterol & formoterol.
Anticholinergic agents
• Ipratropium, tiotropium.
Theophylline
• A weak bronchodilator, which may have some anti-inflammatory
properties.
GLUCOCORTICOIDS
• Regular treatment with inhaled glucocorticoids is appropriate for
symptomatic patients with an FEV1 < 50% predicted and repeated
exacerbations.
• Chronic treatment with systemic glucocorticoids should be avoided because
of an unfavorable benefit-to-risk ratio.
COMBINATION THERAPY
• Combination therapy of long acting ß2-agonists and inhaled corticosteroids
show a significant additional effect on pulmonary function and a reduction
in symptoms.
• Mainly in patients with an FEV1 < 50% predicted.
PHOSPHODIESTERASE INHIBITORS
• Roflumilast (Daliresp) is a phosphodiesterase 4 (PDE4) indicated to reduce
risk of exacerbations in patients with severe COPD associated with chronic
bronchitis and a history of exacerbations.
OTHER PHARMACOLOGIC TREATMENTS
• Influenza vaccines can reduce serious illness. Pneumococcal
polysaccharide vaccine is recommended for COPD patients 65 years and
older and for COPD patients younger than age 65 with an FEV1 < 40%
predicted.
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• The use of antibiotics, other than for treating infectious exacerbations of
COPD and other bacterial infections, is currently not indicated.
OXYGEN THERAPY
• Oxygen → 15 h/d.
• Long-term oxygen therapy (LTOT) improves survival, exercise, sleep and
cognitive performance in patients with respiratory failure.
• The therapeutic goal is to maintain SaO2 ≥ 90% and PaO2 ≥ 60mmHg at sea
level and rest.
OTHER TREATMENTS
• Pulmonary rehabilitation.
• Nutrition.
• Surgery:
­ Bullectomy.
­ Lung volume reduction surgery.
­ Lung transplantation.
COMPLICATIONS
• Pneumothorax.
• Cor pulmonale.
• Exacerbations of COPD.
• Respiratory failure.
COPD COMORBIDITIES
• COPD patients are at increased risk for:
­ Cardiovascular diseases.
­ Osteoporosis.
­ Respiratory infections.
­ Anxiety and Depression.
­ Diabetes.
­ Lung cancer.
­ Bronchiectasis.
• These comorbid conditions may influence mortality and hospitalizations
and should be looked for routinely and treated appropriately.
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Unit III: Gastroenterology unit (Ulcer, Liver cirrhosis, Portal
hypertension, Hepatitis, Diarrhea, Inflammatory bowel disease (IBD)

ULCER
DEFINITION
“An ulcer is localized erosion in stomach or duodenum”
OR
“A break in superficial epithelial cells penetrating down to muscularis mucosa”
DUODENAL VS GASTRIC ULCERS
Duodenal Gastric
Incidence More common Less common
Anatomy
First part of duodenum –
anterior wall
Lesser curvature of stomach
Duration Acute or chronic Chronic
Malignancy Rare Benign or malignant
CAUSES OF PEPTIC ULCER
• H. Pylori
• NSAIDs
• Smoking
• Alcohol
• Radiation therapy
• Stomach cancers
PATHOPHYSIOLOGY
There are two common forms of peptic ulcer disease: those associated with the
organism H. pylori and those associated with the use of aspirin and NSAIDs. Less
common is ulcer disease associated with massive hypersecretion of acid which
occurs in the rare gastrinoma (Zollinger–Ellison) syndrome.
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HELICOBACTER PYLORI
• Urease producing, gram negative bacillus, colonize in stomach.
• Weakens the protective mucous coating of stomach and duodenum thus
allowing the acid to pass through sensitive lining.
• H. Pylori is able to survive in stomach acid because it secretes enzymes that
neutralize acid.
INFECTS MUCOSA OF STOMACH
• H. Pylori converts urea into carbon dioxide and ammonia.
• Ammonia is alkaline so it neutralizes the acidity. Therefore, H. Pylori is able
to move down to the cells of stomach with the help of flagella.
• Once in contact with epithelial cells, H. Pylori adheres using
lipopolysaccharide.
• Then it secretes Cag A (cytotoxin-associated gene A) proteins and
vacuolating cytotoxins, such as Vac A.
• Cag A disrupts cell integrity and also stimulates production of interleukin 8
which attracts neutrophils towards stomach area, which produces
inflammation. (Inflammation causes more secretion of Hcl)
• Vac A causes apoptosis of stomach cells.
• Combination of Cag A and Vac A produces ulcer.
NSAIDs
• NSAIDs inhibit the enzymes Cyclooxygenase (which is involved in the
synthesis of inflammatory prostaglandins)
• This reduces the prostaglandins over long period of time.
• Normally, Prostaglandins gets secreted into stomach and duodenum where
they stimulate mucus and bicarbonate secretion, which promotes growth
of new epithelial cells of gastric lining.
• Reduced prostaglandins lead to gastric mucosa susceptible to damage and
ulcer.
PROTECTIVES FOR ULCER
• Prostaglandins
• Mucus
• Bicarbonate
• Mucosal blood flow
• Epidermal growth factor &
transforming growth factor.
AGGRESSIVE FOR ULCER
• Acid
• Pepsin
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• NSAIDs • Helicobacter Pylori
CLINICAL PRESENTATION
• Abdominal pain is the most frequent PUD symptom. Pain is often epigastric
and described as burning but can present as vague discomfort, abdominal
fullness, or cramping. Nocturnal pain may awaken patients from sleep,
especially between 12 am – 3 am.
• Pain from duodenal ulcers often occurs 1 to 3 hours after meals and is
usually relieved by food, whereas food may precipitate or accentuate ulcer
pain in gastric ulcers. Antacids provide rapid pain relief in most ulcer
patients.
• Heartburn, belching, and bloating often accompany pain. Nausea, vomiting,
and anorexia are more common in gastric than duodenal ulcers and may be
signs of an ulcer-related complication.
• Severity of symptoms varies among patients and may be seasonal,
occurring more frequently in spring or fall.
• Presence or absence of epigastric pain does not define an ulcer. Ulcer
healing does not necessarily render the patient asymptomatic. Conversely,
absence of pain does not preclude an ulcer diagnosis, especially in the
elderly who may present with a “silent” ulcer complication.
• Ulcer complications include upper GI bleeding, perforation into the
peritoneal cavity, penetration into an adjacent structure (e.g. pancreas,
biliary tract, or liver), and gastric outlet obstruction. Bleeding may be occult
or present as melena or hematemesis.
• Perforation is associated with sudden, sharp, severe pain, beginning first in
the epigastrium but quickly spreading over the entire abdomen. Symptoms
of gastric outlet obstruction typically occur over several months and include
early satiety, bloating, anorexia, nausea, vomiting, and weight loss.
DIAGNOSIS
• Physical examination may reveal epigastric tenderness between the
umbilicus and the xiphoid process that less commonly radiates to the back.
• Routine blood tests are not helpful in establishing a diagnosis of PUD.
Hematocrit, hemoglobin, and stool guaiac tests are used to detect bleeding.
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• Diagnosis of PUD depends on visualizing the ulcer crater either by upper GI
radiography or endoscopy. Endoscopy is preferred because it provides a
more accurate diagnosis and permits direct visualization of the ulcer.
• Diagnosis of H. pylori infection can be made using endoscopic or non-
endoscopic (urea breath test [UBT], serologic antibody detection, and fecal
antigen) tests.
• Testing for HP is only recommended if eradication therapy is planned. If
endoscopy is not planned, serologic antibody testing is reasonable to
determine HP status. The UBT and fecal antigen tests are the preferred non
endoscopic methods to verify HP eradication but must be delayed at least 4
weeks after completion of treatment to avoid confusing bacterial
suppression with eradication.
DIFFERENTIAL DIAGNOSES FOR EPIGASTRIC PAIN
SURGICAL
• Biliary colic, acute cholecystitis.
• Pancreatitis.
• Perforation of viscus.
• Acute appendicitis.
• Malignancy.
MEDICAL
• GORD
• MI
• PE
• Pneumonia
SYMPTOMS OF PUD
• Asymptomatic.
• Epigastric pain.
• Nausea.
• Oral flatulence, bloating, distension and intolerance of fatty food.
• Heartburn.
• Pain radiating to the back.
ALARMING SIGNS FOR EPIGASTRIC PAIN
• Chronic GI bleeding.
• Iron-deficiency anemia.
• Progressive unintentional weight loss.
• Progressive dysphagia.
• Persistent vomiting.
• Epigastric mass.
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• Patients aged 55 years and older with unexplained and persistent recent-
onset dyspepsia alone.
INVESTIGATIONS
H. PYLORI TESTING
• C-urea breath tests.
• Stool antigen tests.
• Serology.
• Endoscopy with biopsy.
C-Urea Breath Test
• Swallow urea labelled with uncommon isotope either carbon
14
or carbon
13

• In 10 – 30 mins, detection of isotope labelled carbon dioxide in exhaled
breath indicates that urea was split, thus, indicating urease is present in
stomach, hence H. Pylori bacteria present.
NSAIDs TESTING
• Stool antigen tests.
• Serology.
• C-urea breath tests.
­ Only +ve for H. Pylori.
• Endoscopy with biopsy.
­ If -ve for H. Pylori, then it is further investigated for NSAIDs.
TREATMENT
TREATMENT GOALS
• Overall goals are to relieve ulcer pain, heal the ulcer, prevent ulcer
recurrence, and reduce ulcer-related complications.
• In H. pylori-positive patients with an active ulcer, previously documented
ulcer, or history of an ulcer related complication, goals are to eradicate H.
pylori, heal the ulcer, and cure the disease with a cost-effective drug
regimen.
• The primary goal for a patient with an NSAID-induced ulcer is to heal the
ulcer as rapidly as possible.
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NONPHARMACOLOGIC TREATMENT
• Patients with PUD should eliminate or reduce psychological stress, cigarette
smoking, and use of NSAIDs (including aspirin). If possible, alternative
agents such as acetaminophen or a nonacetylated salicylate (e.g. salsalate)
should be used for pain relief.
• Although there is no need for a special diet, patients should avoid foods
and beverages that cause dyspepsia or exacerbate ulcer symptoms (e.g.
spicy foods, caffeine, and alcohol).
• Elective surgery is rarely performed because of highly effective medical
management.
• Emergency surgery may be required for bleeding, perforation, or
obstruction.
PHARMACOLOGIC TREATMENT
FOR H. PYLORI
Currently 8 H. Pylori Treatment Regimens have been approved by FDA
1. Omeprazole 40 mg QD + clarithromycin 500 mg TID x 2 weeks, then
omeprazole 20 mg QD x 2 weeks.
2. Ranitidine bismuth citrate (RBC) 400 mg BID + clarithromycin 500 mg TID x 2
weeks, then RBC 400 mg BID x 2 weeks.
3. Bismuth subsalicylate (Pepto Bismol®) 525 mg QID + metronidazole 250 mg
QID + tetracycline 500 mg QID* x 2 weeks + H2 receptor antagonist therapy
as directed x 4 weeks.
4. Lansoprazole 30 mg BID + amoxicillin 1 g BID + clarithromycin 500 mg TID x
10 days.
5. Lansoprazole 30 mg TID + amoxicillin 1 g TID x 2 weeks**
6. Ranitidine bismuth citrate 400 mg BID + clarithromycin 500 mg BID x 2
weeks, then RBC 400 mg BID x 2 weeks.
7. Omeprazole 20 mg BID + clarithromycin 500 mg BID + amoxicillin 1 g BID x
10 days (Triple Therapy)
8. Lansoprazole 30 mg BID + clarithromycin 500 mg BID + amoxicillin 1 g BID x
10 days.
FOR NSAIDs
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• NSAID-associated ulcers may be H. pylori positive. Although the presence of
H. pylori may enhance the efficacy of acid suppression, eradication is
generally recommended in infected patients with NSAID-associated ulcers
as it is difficult to differentiate between H. Pylori or NSAID as the cause of
the ulcer.
• If NSAIDs are discontinued, most uncomplicated ulcers heal using standard
doses of a PPI, H2-receptor antagonist, misoprostol or sucralfate.
PATIENT CARE
PATIENT EDUCATION AND COUNSELING
• It does not help to eat more often or increase the amount of milk and dairy
products you consume. These changes may even cause more stomach acid.
• Avoid foods and drinks that cause discomfort for you. For many people
these include alcohol, coffee, caffeinated soda, fatty foods, chocolate, and
spicy foods. Avoid eating late night snacks.
• Other things you can do to ease your symptoms and help healing include:
­ If you smoke or chew tobacco, try to quit. Tobacco will slow the
healing of your ulcer and increase the chance that the ulcer will come
back.
­ Try to reduce your stress level and learn ways to better manage
stress.
­ Avoid drugs such as aspirin, ibuprofen, or naproxen. Take
acetaminophen to relieve pain. Take all medicines with plenty of
water.
SUMMARY
• A peptic ulcer is a break in superficial epithelial cells penetrating down to
muscularis mucosa.
• Duodenal > gastric ulcers.
• Can be asymptomatic.
• H. Pylori is a predominant risk factor.
• H. Pylori diagnosed by c-urea breath test, stool antigen or if validated
serology, treated with PAC500 or PMC250 regime.
• Complications of PUD can lead to acute emergency of upper GI bleed.

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LIVER CIRRHOSIS
INTRODUCTION
• Consequence of chronic liver disease characterized by replacement of liver
tissue by fibrosis, scar tissue and regenerative nodules leading to
progressive loss of liver function.
“Pathological condition with the development of fibrosis to the point that there
is architectural distortion with formation of regenerative nodules”
• Due to chronic scarring and damage liver becomes fibrotic which is not
reversible that is why it is referred as cirrhosis “End stage”
• Cirrhosis is characterized histologically by regenerative nodules surrounded
by fibrous tissue.
TYPES
• Clinically two types:
1. COMPENSATED
­ Early symptoms, some fibrosis, liver functions.
2. DECOMPENSATED
­ Late symptoms, liver stops functioning.
PATHOPHYSIOLOGY
• Irreversible chronic injury of the hepatic parenchyma.
• Extensive fibrosis - distortion of the hepatic architecture.
• Formation of regenerative nodules.
CLINICAL PRESENTATION
• Testicular atrophy
• Jaundice
• Hepatomegaly
• Splenomegaly
• Xanthoma
• Parotid gland enlargement (salivary glands)
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• Spider angiomas
­ Spider angiomas is a type of telangiectasis (swollen blood vessels)
found slightly beneath the skin surface, often containing a central red
spot and reddish extensions which radiate outwards like a spider's
web.
• Palmar erythema
­ Palms become red and swollen.
• Gynecomastia
­ Increase in breast.
• Nail changes
­ Muehrcke's nails.
­ Terry’s nails.
• Fetor hepaticus
­ A condition seen in portal hypertension where portosystemic
shunting allows thiols to pass directly into the lungs.
• Asterixis
­ A tremor of the hand when the wrist is extended.
• Pigment gallstones
­ Pigment gallstones of bilirubin and calcium salts.
• Cruveilhier-Baumgarten murmur
­ There are prominent umbilical and paraumbilical
veins; auscultation over these vessels may reveal
a humming sound.
• Caput medusa
­ Also known as palm tree sign, is the appearance
of distended and engorged superficial epigastric
veins, which are seen radiating from the
umbilicus across the abdomen.
DIAGNOSIS
• LIVER FUNCTION TESTS (LFTS)
­ The enzyme tests.
­ Tests of synthetic function.
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• RADIOLOGIC MODALITIES
­ Can occasionally suggest the presence of cirrhosis, they are not
adequately sensitive or specific for use as a primary diagnostic
modality.
­ Major utility of radiography in the evaluation of the cirrhotic patient
is in its ability to detect complications of cirrhosis.
• LIVER BIOPSY
­ Obtained by either a percutaneous, trans-jugular, laparoscopic, or
radiographically guided fine-needle approach.
­ Sensitivity of a liver biopsy for cirrhosis is in the range of 80 to 100
percent depending upon the method used, and the size and number
of specimens obtained.
­ Liver biopsy is not necessary if the clinical, laboratory, and radiologic
data strongly suggest the presence of cirrhosis.
­ Liver biopsy can reveal the underlying cause of cirrhosis.
• MORPHOLOGIC CLASSIFICATION
MICRONODULAR CIRRHOSIS
• Uniform, small nodules up to 3 mm in diameter.
• Often caused by alcohol damage, hemochromatosis, cholestatic causes of
cirrhosis.
MACRONODULAR CIRRHOSIS
• Nodules larger than 3 mm.
• Believed to be secondary to chronic viral hepatitis.
CAUSES AND TREATMENTS
1. ALCOHOLIC CIRRHOSIS
DIAGNOSIS
• Clinical features + physical examination findings + laboratory studies.
• Liver biopsy, ultrasonography, CT.
CLINICAL FEATURES

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NON-SPECIFIC SYMPTOMS:
• Vague right upper quadrant
pain
• Fever
• Nausea and vomiting
• Diarrhea
• Anorexia
LATER, SPECIFIC COMPLICATIONS:
• Ascites
• Edema
• Bleeding (UDH)
• Jaundice/encephalopathy
• Incidentally at the time of
autopsy or elective surgery.
PHYSICAL EXAMINATION
• Palmar erythema
• Spider angiomas
• Parotid gland enlargement
• Digital clubbing
• Muscle wasting
TREATMENT
• Give up alcohol completely.
• Good nutrition and long-term medical supervision (folate, B6, Vitamin A,
mineral and element, Zinc)
• Glucocorticoids are occasionally used.
• Oral PENTOXIFYLINE decrease tumor necrosis factor alpha (TNF-α) and
other proinflammatory cytokines.
• Parenteral administration of inhibitors of TNF-α (INFLIXIMAB/ ETANERCEPT)
• Medication that reduce craving for alcohol Acamprosate calcium,
Disulfiram, Topiramate, Baclofen.
2. HEPATITIS B OR C CIRRHOSIS
CLINICAL FEATURES
• Fatigue
• Malaise
• Right upper quadrant pain

LABORATORY EVALUATION
• HCV-RNA, genotype
• AgHBS
• Anti HBS
• HBe Ag
TREATMENT
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• Lamivudine 100mg/day
• Entecavir 0.5mg/day
• Tenofovir
• Adefovir
• Interferon plus drugs for skin conditions.
3. AUTOIMMUNE HEPATITIS CIRRHOSIS
DIAGNOSIS
• Positive autoimmune markers ANA (antinuclear antibodies)
• ASMA (anti-smooth muscle antibody)
TREATMENT
• Corticosteroids (prednisolone 30 – 60 mg/day and tapered off over a period
of 3 months)
• Immune suppressant (azathioprine 50 mg/day)
• Liver transplant.
4. PRIMARY BILIARY CHOLANGITIS/CIRRHOSIS (PBC)
DIAGNOSIS
• It is characterized by portal inflammation and necrosis of cholangiocytes in
small and medium size bile ducts.
• Mostly in middle aged women.
CLINICAL PRESENTATION
• Lab findings: elevated bilirubin level, progressive liver failure.
• Physical examination: Jaundice, hepatomegaly, splenomegaly, ascites.
TREATMENT
• Ursodeoxycholic acid (UDCA) – naturally occurring bile acid.
• Liver transplant (Last Resort)
• Plasma pheresis (Filters blood to remove harmful antibodies)
• Rifampin (in controlling priuritis)
• Antihistamines
5. PRIMARY SCLEROSING CHOLANGITIS
DEFINITION
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• “Chronic cholestatic syndrome – diffuse inflammation, fibrosis involving the
entire biliary tree → obliteration of both intra and extrahepatic biliary tree,
leading to biliary cirrhosis/portal hypertension/liver failure”
CLINICAL FEATURES
• Fatigue profound and nonspecific
• Pruritus (Itch sensation that provokes the urge to scratch)
• Steatorrhea – fatty stool
• Deficiencies of fat – soluble vitamins
• Metabolic bone disease
LABORATORY FINDINGS
• Abnormal liver enzymes (ALP and ↑ AST, ALT)
• Albumin levels ↓
• TP ↑
DIAGNOSIS
• Colangiographic imaging-multifocal stricturing and beading.
• MRCP (Magnetic resonance cholangiopancreatography)-initial evaluation.
• ERCP (Endoscopic retrograde cholangiopancreatography)-whether or not a
dominant stricture is present.
TREATMENT
• UDCA high dose (20mg/kg/day)
• Endoscopic dilatation of strictures
• Liver transplantation (LT); Cholangiocarcinoma
6. HEMOCHROMATOSIS
DEFINITION
• “Inherited disorder of iron metabolism that results in a progressive increase
in hepatic iron deposition which, over time, can lead to a portal-based
fibrosis progressing to cirrhosis/liver failure/hepatocellular cancer”
• ↑ Transferrin saturation.
• ↑ Ferritin level.
TREATMENT
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• Treatment is straight forward with regular therapeutic phlebotomy.
7. WILSON’S DISEASE
DEFINITION
• “Inherited disorder of copper homeostasis with failure to excrete excess
amounts of copper, leading to accumulation in the liver”
DIAGNOSIS
• Ceruloplasmin levels – store and carries copper in liver.
• 24-hours urine copper levels.
• Liver biopsy.
PHYSICAL EXAMINATION
• KAYSER-FLEICHER corneal ring.
TREATMENT
• Copper chelating medication (D-PENICILLAMINE/TRIENTINE/Zn)
8. ALFA1-AT DEFICIENCY
DEFINITION
• “Inherited disorder that causes abnormal folding of the alfa1-AT Protein
leading to failure of secretion of that protein from the liver”
• α1-antitrypsin (A1AT) is a protein belonging to the serpin superfamily. It is
encoded in humans by the SERPINA1 gene. As a type of enzyme inhibitor, it
protects tissues from enzymes of inflammatory cells, especially neutrophil
elastase, and has a reference range in blood of 0.9–2.3 g/L but the
concentration can rise many folds upon acute inflammation.
DIAGNOSIS
• Determining of alfa1 AT levels/ genotype.
• Liver biopsy.
TREATMENT
• LT is curative.
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TREATMENT OF COMPLICATIONS OF CIRRHOSIS
1. BLEEDING FROM VARICES IN OESOPHAGUS
• Varices form due to backup of blood from the scarred liver that causes the
veins in the wall of the esophagus to enlarge and bleed.
TREATMENT
• Taking Beta Blockers:
­ Propranolol
­ Nadolol
­ Carvedilol
2. ASCITES
• Fluid leaks out into the belly and begins to fill it up. This can make the
abdomen (belly) enlarge like a balloon filled with water.
TREATMENT
• Diuretic therapy ("Water Pills")
­ Spironolactone 100 mg – 400 mg.
­ Furosemide 40 mg – 160 mg.
• Paracentesis (Tap)
­ Paracentesis is the draining of fluid out of the abdomen with a
needle.
­ This is done using local anesthetic (lidocaine).
• Spontaneous bacterial peritonitis
­ This condition occurs when the ascites fluid becomes infected and
can be life threatening.
­ 2
nd
generation cephalosporin-CEFOTAXIM 4g/day.
3. HEPATIC ENCEPHALOPATHY
• Hepatic encephalopathy is a decline in brain function that occurs as a
result of severe liver disease. In this condition, liver cannot adequately
remove toxins from blood. This causes a buildup of toxins in
bloodstream, which can lead to brain damage.
TREATMENT
• Lactulose syrup daily.
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• Antibiotics rifaximin and neomycin.
4. HEPATOCELLULAR CARCINOMA
• Patients with cirrhosis have a markedly increased risk of developing
hepatocellular carcinoma.
• Symptoms are largely due to mass effect from the tumor:
­ Pain, early satiety, obstructive jaundice, and a palpable mass.
• Serum AFP greater than 500 micrograms/l in a patient with cirrhosis are
virtually diagnostic.
• Median survival following diagnosis is approximately 6 to 20 months.
PROGNOSTIC TOOLS
• MELD (model for end-stage liver disease)
• Identify patients whose predicted survival post-procedure would be three
months or less.
• MELD = 3.8[serum bilirubin (mg/dL)] + 11.2[INR] + 9.6[serum creatinine
(mg/dL)] + 6.4
LIVER TRANSPLANTATION
• Liver transplantation is the definitive treatment for patients with
decompensated cirrhosis. Depends upon the severity of disease, quality of
life and the absence of contraindications.
• Minimal criteria for listing cirrhotic patients on the liver transplantation list
include:
­ A child-Pugh score 7
­ Less than 90 percent chance of surviving one year without a
transplant.
­ An episode of gastrointestinal hemorrhage related to portal
hypertension.
­ An episode of spontaneous bacterial peritonitis.
VACCINATIONS
• Hepatitis A and B.
• Pneumococcal vaccine.
• Influenza vaccination.
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PORTAL HYPERTENSION
INTRODUCTION
“Portal hypertension is an increase in the blood pressure within a system of
veins called portal venous system”
• Veins coming from stomach, intestine, spleen and pancreas merge into
portal vein which takes it to liver.
• If vessels in the liver are blocked due to liver damage, blood cannot flow
properly through liver.
• As a result, high pressure in the portal system develops.
• Portal hypertension is a pressure in the portal venous system that is at least
5 mm Hg higher than the pressure in the inferior vena cava.
• This increase in pressure is harmful as it may lead to development of large
swollen veins (varices) within esophagus, stomach, rectum or umbilical
area.
CAUSES
• Liver cirrhosis.
• Parasitic infection.
• Blood clots in portal vein.
• Blockage of vein that carry blood from liver to heart.
LIVER ANATOMY
• Upper right quadrant
• 4 lobes / 8 segments
• 1800g in men / 1400g in women
• Largest vein → Portal vein (splenic + mesenteric)
• Portal vein supplies 70% of blood flow to liver.
PATHOPHYSIOLOGY
• There are many causes of portal hypertension including etiologies above
the liver, within the liver, and below the liver.
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1. SUPRAHEPATIC CAUSES
• Suprahepatic abnormalities leading to portal hypertension include cardiac
disease, hepatic vein etiology, and inferior vena cava thrombosis or webs.
• Liver fibrosis can result from suprahepatic disease, and cirrhosis can also
develop late in the disease course.
2. HEPATIC CAUSES
• Cirrhosis is the most common cause of portal hypertension.
• Cirrhosis is caused due to:
­ Hepatitis B or C.
­ Hemochromatosis.
­ Alcohol consumption.
­ Drug induced liver diseases.
3. INFRAHEPATIC CAUSES
• Alterations of portal venous blood flow can also lead to portal
hypertension.
• Splenomegaly and portal vein thrombosis are examples of infrahepatic
causes of portal hypertension.
CLINICAL PRESENTATION
CLINICAL FEATURES
• Splenomegaly
• Gynecomastia
• Caput medusae
• Edema of the legs
SYMPTOMS
• Gastrointestinal hemorrhage
• More advanced liver disease:
­ Ascites
­ Jaundice
­ Coagulopathy
­ Spider angioma
­ Hepatic encephalopathy
• Splenomegaly
• Hepatomegaly
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• Portal vein thrombosis
• Dilated abdominal wall veins
DIAGNOSIS
Portal hypertension can be diagnosed in several ways.
1. CLINICAL DIAGNOSIS
• Clinical diagnosis can be made in the setting of end-stage liver disease
and in the presence of ascites and/or varices.
2. SUBCLINICAL DIAGNOSIS
• Subclinical portal hypertension is much more difficult to diagnose, but
low platelet levels, a large portal vein, and splenic enlargement on
imaging studies are suggestive.
3. WEDGED HEPATIC VEIN PRESSURE
• Direct or indirect measurements of the portal vein may be accomplished
using wedged hepatic vein pressure or splenic pulp pressure, but these
methods are relatively invasive. Wedged hepatic venous pressure
(WHVP) is measured by inflating a balloon at the catheter tip, thus
occluding a hepatic vein branch.
• Measurement of the WHVP provides a close approximation of portal
pressure. Splenic pulse pressure is measured using laparoscopy.
4. IMAGING STUDIES
• Duplex doppler ultrasonography is a noninvasive, low-cost method of
diagnosis that provides specifics regarding the direction and velocity of
portal flow.
• CT (Computed tomography)
• MRI (Magnetic resonance imaging)
5. ENDOSCOPIC DIAGNOSIS
• Gastrointestinal endoscopy allows the physician to visualize and biopsy
the mucosa of the upper gastrointestinal tract including the esophagus,
stomach, and duodenum.
• Portal pressure gradient (PPG) value is measured using invasive
methods.
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TREATMENT
• Treatment of portal hypertension is aimed at prevention of complications.
TREARMENT GOAL
• The main goal of therapy is to decrease portal pressures. This is generally
difficult to achieve and adequately maintain.
1. ASCITES
• The most important aspect in treating ascites is to restrict sodium to less
than 2 g per day.
• Diuretic therapy: Loop diuretics + Spironolactones.
2. VARICES
• Acute bleeding from varices or nonvariceal sites in patients with portal
hypertension requires prompt and appropriate measures to control
bleeding and prevent recurrent episodes.
MEDICAL THERAPY
• β-blockers: (Propranolol)
• Vasopressin (to reduce blood flow)
• Somatostatin 50 micro-organisms IV (to sop variceal bleeding)
• Antibiotics (to target gram negative bacteria)
ENDOSCOPIC THERAPY
• Treatment options include Sclerotherapy, banding of esophageal varices
and balloon tamponade to control bleeding.
SCLEROTHERAPY
• The use of sclerotherapy, or injection of a sclerosing agent directly into
and around the varices. The technique consists of injecting 1–10 mL of
sclerosing agent into the varix beginning at the gastroesophageal
junction and circumferentially into all columns.
• After the initial sclerotherapy session, subsequent sessions are scheduled
with the intent to completely obliterate the varices.
• Common side effects include tachycardia, chest pain, fever, and
ulceration at the injection site.
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BANDING
• Acute variceal hemorrhage is ideally managed by variceal ligation with
elastic rings, commonly called banding.
• This method is performed endoscopically and is safe and effective. This
technique employs insertion of rubber band ligation into esophagus with
suction device which sucks the varices.
BALLOON TAMPONADE
• Balloon tamponade is useful to control variceal bleeding through
compression.
• Use of one of three commercially available balloons to tamponade
bleeding esophageal or gastric varices can be employed when medical
management has not been successful, and endoscopic management has
failed or is unavailable.
SHUNTING PROCEDURES
• Nonsurgical Trans jugular Intrahepatic Portal-Systemic Shunt (TIPSS)
• Trans jugular intrahepatic portal-systemic shunting is a radiologic
procedure that has become very popular as an alternative method of
controlling acute bleeding, especially if gastric varices are present.
• The procedure is done for dilation of tract. First, access to the hepatic vein
is obtained through the right internal jugular vein. A needle is passed
through the liver parenchyma into the portal vein, followed by dilation of
the tract and subsequent placement of a metal stent. The stent is then
dilated to achieve a portal to hepatic vein gradient of less than 10 mmHg.
SURGICAL SHUNTS
• The aim of surgical shunting in portal hypertension is threefold:
1) To reduce portal venous pressure.
2) To maintain hepatic and portal blood flow.
3) To try to reduce or not complicate hepatic encephalopathy.
LIVER TRANSPLANTATION
• Liver transplantation is the only effective treatment for end-stage liver
disease. This option offers excellent patient survival and rehabilitation.
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HEPATITIS
INTRODUCTION
“Hepatitis is inflammation of the liver caused by a virus or a toxin”
• The major hepatotrophic (feed on liver) viruses responsible for viral
hepatitis are hepatitis A, hepatitis B, hepatitis C, delta hepatitis, and
hepatitis E.
CLINICAL COURSE OF VIRUS-RELATED LIVER DISEASE







GENERAL PATHOPHYSIOLOGY
• Each of the hepatitis viruses cause similar liver damage.
• The inflammatory process is activated throughout the whole liver, and
hepatocytes are destroyed by cytotoxic cytokines and natural killer cells,
both parts of the inflammatory process.
• Cellular necrosis takes place, if inflammation affects the periportal areas,
cholestasis, or the interruption of the flow of bile takes place.
• The liver is usually able to repair itself and regain complete function if no
other complications occur.
• The antigen-antibody complexes that are formed from the interaction of
the immune system with the infection circulate throughout the body, which
activates the complement system.
• The person feels malaise, rash, arthritis, fever and angioedema from this
activation. Abnormal proteins are also produced in the blood.
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HEPATITIS A
• Self-limiting, acute viral infection, rarely fatal.
• Incubation period 15 – 50 days.
• Spread through fecal-oral route, person to person contact, ingestion of
contaminated food or water.
• Children at higher risk – mostly asymptomatic.
• Mostly linked to poor socioeconomic status.
• Rarely spread through blood transfusion.
PATHOPHYSIOLOGY
• RNA virus.
• Stable in harsh environment.
• For inactivation – heating of food at 85℃ (185℉) for 1 minute or treatment
with sodium hypochlorite in 1:100 dilution.
• Multiple genotypes exist – type I and III most common.
• Infection is usually acute, self-limiting – absorption from the intestine
resulted into circulation.
• Replication of virus in hepatocytes and gastrointestinal epithelial cells.
• New viral particles are released into the blood and secreted into the bile by
the liver.
CLINICAL PRESENTATION
SIGNS AND SYMPTOMS
• Phase 1 (viral replication phase) – Patients are asymptomatic during this
phase; laboratory studies demonstrate serologic and enzyme markers of
hepatitis.
• Phase 2 (prodromal phase) – Patients experience anorexia, nausea,
vomiting, alterations in taste, arthralgias, malaise, fatigue, urticaria, and
pruritus, and some develop an aversion to cigarette smoke. When seen by a
health care provider during this phase, patients are often diagnosed as
having gastroenteritis or a viral syndrome.
• Phase 3 (icteric phase) – Patients may note dark urine, followed by pale-
colored stools; in addition to the predominant gastrointestinal (GI)
symptoms and malaise, patients become icteric and may develop right
upper quadrant pain with hepatomegaly.
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• Phase 4 (convalescent phase) – Symptoms and icterus resolve, and liver
enzymes return to normal.
PHYSICAL EXAMINATION
• Icteric sclera, skin and secretions.
• Mild weight loss of 2-5 kg.
• Hepatomegaly.
DIAGNOSIS
• Hepatocellular degeneration (due to immune mediated injury)
• Hepatocyte regeneration
• Inflammatory infiltrate
• HAV – RNA serum for 17 days
• IgM (Anti HAV) → for detection
• IgG (Anti HAV) → for immunity
ABNORMAL LAB REPORTS
• Elevated ALT, AST, Bilirubin, Prothrombin time, Urinary urobilinogen, ALP.
TREATMENT
• Supportive care.
• Mainly Non-Pharmacologically treated.
• Active immunity can be achieved through vaccination (HAVRIX, VAQTA,
AVAXIM)
HEPATITIS B
• Double strand DNA with partial single strand virus.
• 7 genotypes of HBV exist (A to H), Genotype C is the most important type.
TRANSMISSION
• HBV is transmitted sexually, parenterally, and perinatally.
• In areas of high HBV prevalence, perinatal transmission from mother to
infant is most common, whereas in areas of intermediate prevalence,
horizontal transmission contact, both homosexual and heterosexual, and
injection-drug use are the predominant forms of transmission in low-
endemic countries.
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• The virus is detectable in moderate quantities in semen, vaginal fluid, and
saliva, and is present in low concentrations in urine, feces, sweat, tears, and
breast milk.
• Transmission can occur through contact with infected body fluids in the
absence of blood, as the virus may be stable in the environment for a
number of days.
PATHOPHYSIOLOGY – LIFE CYCLE
ATTACHMENT
• The virus gains entry into the cell by binding to receptors on the surface of
the cell and entering it by endocytosis.
• HBV initially binds to heparin sulfate proteoglycan.
PENETRATION
• Following endocytosis, the virus membrane fuses with the host cell's
membrane, releasing the nucleocapsid into the cytoplasm.
UNCOATING
• Because the virus multiplies via RNA made by a host enzyme, the viral
genomic DNA has to be transferred to the cell nucleus.
• Capsid is transported on the microtubules to the nuclear pore. The core
proteins dissociate from the partially double stranded viral DNA, which is
then made fully double stranded (by host DNA polymerase) and
transformed into covalently closed circular DNA (cccDNA) that serves as a
template for transcription of four viral mRNAs.
REPLICATION
• The largest mRNA, (which is longer than the viral genome), is used to make
the new copies of the genome and to make the capsid core protein and
the viral RNA-dependent-DNA-polymerase.
ASSEMBLY
• Four viral transcripts undergo additional processing and go on to form
progeny virions which are released from the cell or returned to the nucleus
and re-cycled to produce even more copies.
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RELEASE
• The long mRNA is then transported back to the cytoplasm where the virion
P protein synthesizes DNA via its reverse transcriptase activity.
MAIN ANTIGEN CAUSING HBV
• The HBsAg is the most abundant of the three surface antigens and is
detectable at the onset of clinical symptoms.
• Its persistence past 6 months after initial detection corresponds to chronic
infection and poses an increased risk for cirrhosis, hepatic decompensation,
and Hepatocellular carcinoma (HCC).
FACTORS ASSOCIATED WITH HBV
• Male sex
• Alcohol use
• Age at diagnosis
• Infection with genotype C
• Persistence of HBV serum DNA
• Frequency of severe hepatic flares
• Severity of liver disease and diagnosis
• Coinfection with HCV, Delta hepatitis or HIV
• Laboratory/ physical findings of abnormal liver function
CLINICAL PRESENTATION
SIGNS AND SYMPTOMS
• Easy fatigability, anxiety, anorexia and malaise.
• Ascites, jaundice, variceal bleeding, and hepatic encephalopathy can
manifest with liver decompensation.
• Hepatic encephalopathy is associated with the hyperexcitability, impaired
mentation, confusion, obtundation and eventually coma.
• Vomiting and seizures.
PHYSICAL EXAMINATION
• Asterixis.
• Spider angioma.
• Icteric sclera skin and secretion.
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• Decreased bowel sounds increased abdominal girth and detectable fluid
wave.
LABORATORY TESTS
• Presence of hepatitis B surface antigen for at least 6 months.
• Elevated ALT, AST levels moderately.
• HBeAg → Anti HBe
• HBsAg → Anti HBs
• HBcAg → Anti HBc IgM, IgG
• HBV DNA
• Liver biopsy is for pathologic classification as chronic persistent hepatitis,
chronic active hepatitis, or cirrhosis.
CIRRHOSIS
• Cirrhosis - liver attempts to regenerate while in an environment of
persistent inflammation.
• Continued alcohol consumption exacerbates hepatocellular damage.
• In compensated cirrhosis, patients are either asymptomatic or have mild
symptoms of epigastric pain and dyspepsia.
• During cirrhosis, the liver enters a cycle of ongoing liver damage, fibrosis,
and attempts at regeneration.
HEPATOCELLULAR CARCINOMA
• HBV is a well-known risk factor of Hepatocellular carcinoma.
• The development of HCC can be insidious, in the absence of cirrhosis or in
the presence of clinically silent, compensated cirrhosis.
• Many patients with HCC have no signs of decompensated cirrhosis.
TREATMENT
TREATMENT GOALS
• The goals of therapy are to suppress HBV replication and prevent disease
progression to cirrhosis and HCC. The loss of HBsAg is becoming an
increasingly more important goal in therapy.
• Some patients with chronic HBV infection should be treated.
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• Recommendations for treatment consider the patient's age, serum HBV
DNA and ALT levels, and histologic evidence and clinical progression of the
disease.
NON-PHARMACOLOGICAL TREATMENT
• Avoid alcohol
• Should be vaccinated
• Avoid Sexual and household contacts
• Consult doctor before any medication
PHARMACOLOGICAL TREATMENT
INTEFERON
• IFN-α2b therapy was the first approved therapy for treatment of HBV and
improves long-term outcomes and survival.
• Acting as a host cytokine, it has antiviral, antiproliferative, and
immunomodulatory effects in chronic HBV.
• Duration of therapy is finite – optimal duration is unclear – 12 months
duration is associated with sustained viral response. Therapy inconvenience
include thrice daily injections.
• Has been replaced by peg-interferon – ease of administration and less side
effects. Not routinely used in decompensated cirrhosis – better results in
compensated.
Side effects of Peginterferon therapy
­ Fatigue
­ Fever
­ Musculoskeletal pain
­ Headache
­ Nausea
­ Depression
LAMIVUDINE
• Lamivudine, a nucleoside analog, has antiviral activity against both HIV and
HBV.
• It is dosed at 100 mg daily; the optimal duration of treatment is unknown.
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• In both HBe Ag-positive and negative patients, lamivudine demonstrates
profound viral suppression.
ADEFOVIR
• The drug acts by inhibiting HBV DNA polymerase.
• It is dosed at 10 mg daily for 1 year.
• A 48-week course of treatment is effective in improving histologic findings,
reducing serum HBV DNA and ALT levels, and increasing HBe Ag
seroconversion in both HBe Ag-negative and positive patients.
ENTECAVIR
• Entecavir is a guanosine nucleoside analog that acts by inhibiting HBV
polymerase.
• An oral agent, it is more potent than lamivudine in suppressing serum HBV
DNA levels and is effective in lamivudine-resistant HBV.
• The drug is dosed at 0.5 mg daily in treatment-naive or non–lamivudine-
resistant infections and at 1 mg daily in lamivudine-refractory patients.
TREATMENT ALGORITHM FOR CHRONIC HBV WITH CIRRHOSIS





HEPATITIS C
• HCV is the most common blood-borne pathogen and is most often acquired
through injection drug use, coinfection with sexually transmitted diseases,
multiple sexual partners.
ETIOLOGY
• HCV is a single-stranded RNA virus notable for lacking a proofreading
polymerase and enabling frequent viral mutations.
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• 6 major genotypes, genotypes are further classified into subtypes (a, b, c,
etc.), genotype 1 and 2 are common with genotype 1 most common.
• Infections caused by these genotypes lead to cirrhosis, end-stage liver
disease (ESLD), or Hepatocellular carcinoma (HCC).
TRANSMISSION
• Sexual
• Vertical (mother-to-infant)
• Percutaneous exposure to blood
RISK FACTORS FOR CHRONIC HEPATITIS C (CHC)
• Black race
• Male gender
• Low family income
• 10 lifetime sexual partners
• High-school education or less
• Incarceration (30% are HCV Ab+)
• History of illicit drug use other than marijuana.
CDC SCREENING GUIDELINES
• Risk-based screening for those who:
1. Are infected with HIV.
2. Ever injected illegal drugs.
3. Were ever on chronic hemodialysis.
4. Children born to HCV-positive women.
5. Received blood/organs before July 1992.
6. Received clotting factors made before 1987.
7. Have evidence of liver disease (elevated ALT level).
8. Are healthcare and public safety workers after needle stick/mucosal
exposure to HCV-positive blood.
PATHOPHYSIOLOGY
• During the early phases of infection, natural killer cells are activated as HCV
RNA levels rapidly rise.
• A combined effort of HCV specific CD4 and CD8 T lymphocytes and
interferon co-expression decrease viral replication.
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• The eradication of HCV by cytotoxic T lymphocytes may occur either as a
result of induced apoptosis by infected hepatocytes or by the release of
interferon to stifle viral replication.
• The HCV RNA levels plateau at 105 to 107 international units/mL.
• Rising ALT levels indicate hepatic injury and cell necrosis.
• Approximately one-third of adults will experience some mild and
nonspecific symptoms, including fatigue, anorexia, weakness, jaundice,
abdominal pain, or dark urine
• Up to 85% of acutely infected patients will go on to develop a chronic HCV
infection, defined as persistently detectable HCV RNA for 6 months or
more.
• Additional symptoms include right upper quadrant pain, nausea, or poor
appetite.
HCV LIFE CYCLE
• The HCV lifecycle begins with the attachment of a virion to its specific
receptors on hepatocytes: the high-density lipoprotein receptor, scavenger
receptor class B type I, tetraspanin CD81, tight junction protein claudin-1,
and occludin are the known cellular receptors initiating the attachment
step of HCV infection.
• Viral internalization is through endocytosis of the bound virion in a clathrin-
coated endosome, and fusion of viral and endosomal membranes and that
the nucleocapsid is released into the cytoplasm.
• The virus is then uncoating to free its genomic RNA, and the HCV genomic
RNA is used both for polyprotein translation and replication in the
cytoplasm.
• Replication of HCV takes place in membranous webs associated with the
NS4B protein and cellular endoplasmic reticulum (ER).
• HCV replication is catalyzed by the NS5B protein. NS4B initiates the
formation of replication complex that supports HCV replication.
• The viral RNA-dependent RNA polymerase first copies the positive sense
RNA into a negative-sense RNA intermediate and then copies the negative-
sense RNA into more positive sense RNA.
• The core protein, however, remains within the cytoplasm after cleavage
from E1, E1 and E2 are embedded in the ER membrane, and their
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extracellular domains are glycosylated. Nascent genomes can then be
translated, further replicated or packaged within new virus particles.
• New virus particles are thought to bud into the secretory pathway and are
released at the cell surface.
WHO HEPATITIS C SCREENING, CARE AND TREATMENT GUIDELINES






DIAGNOSIS
• For many patients, a diagnosis of hepatitis C is incidental.
• Some patients are diagnosed after persistently abnormal transaminases.
• Unfortunately, those patients who present with symptoms typically have
advanced disease.
• A diagnosis of chronic HCV is confirmed with a reactive enzyme
immunoassay for anti-HCV.
• Testing for anti-HCV is not routinely recommended because of the low
prevalence of HCV in the general population and the nonspecificity of the
test.
LAB TESTS
• Anti HCV, Enzyme immunoassay (HCV RNA PCR assay)
METAVIR LIVER BIOPSY SCORING SYSTEM
METAVIR
Stage
F0 F1 F2 F3 F4
Definition
No
fibrosis
Portal fibrosis
without septa
Portal fibrosis
with septa
Numerous
septa without
cirrhosis
Cirrhosis
TREATMENT
• Before therapy is initiated, quantitative HCV testing, genotyping, and a liver
biopsy are performed.
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• Quantitative amplification assays for HCV RNA are performed in patients
who are candidates for therapy to obtain baseline information on the viral
load.
• A baseline HCV RNA level serves as a prognostic indicator for response and
is used to monitor virologic response once therapy is initiated.
• Genotyping is also necessary for treatment candidates because response to
therapy and duration of therapy vary depending on the infecting genotype.
• Liver biopsy is used to determine histologic grade and stage and to guide
therapy.
NON-PHARMACOLOGICAL THERAPY
• All chronic HCV patients should be vaccinated against hepatitis A and B.
• Lifestyle changes are an important factor in reducing health consequences
in hepatitis C.
• Avoiding alcohol, smoking, illicit drugs.
PHARMACOLOGICAL THERAPY
ASSESSING FOR HCV TREATMENT: All adults and children with chronic HCV
infection, including people who inject drugs, should be assessed for antiviral
treatment.
1. Treatment with pegylated interferon and ribavirin: Pegylated interferon in
combination with ribavirin is recommended for the treatment of chronic
HCV infection rather than standard non-pegylated interferon with ribavirin.
2. Treatment with telaprevir or boceprevir: Treatment with the direct-acting
antivirals telaprevir or boceprevir, given in combination with pegylated
interferon and ribavirin, is suggested for genotype 1 chronic HCV infection
rather than pegylated interferon and ribavirin alone.
3. Treatment with sofosbuvir: Sofosbuvir, given in combination with ribavirin
with or without pegylated interferon (depending on the HCV genotype), is
recommended in genotypes 1, 2, 3 and 4 HCV infection rather than
pegylated interferon and ribavirin alone (or no treatment for persons who
cannot tolerate interferon).
4. Treatment with simeprevir: Simeprevir, given in combination with
pegylated interferon and ribavirin, is recommended for persons with
genotype 1b HCV infection and for persons with genotype 1a HCV infection.
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DIRECT ACTING ANTIVIRALS (DAA)
• DAAs are considered pangenotypic when they achieve high treatment
efficacy across all six major HCV genotypes.
1. Sofosbuvir/velpatasvir
• Good efficacy in infections with genotypes 1–6, HIV/HCV coinfection,
persons on opioid substitution therapy (OST) and persons with
compensated or decompensated cirrhosis.
2. Sofosbuvir/velpatasvir/voxilaprevir
• Generally considered for use in the retreatment of HCV-infected persons
who previously failed a DAA regimen.
3. Glecaprevir/pibrentasvir
• Good efficacy in infections with genotypes 1–6, compensated cirrhosis,
including in persons with renal insufficiency and end-stage renal disease.
4. Sofosbuvir/daclatasvir
• Good efficacy of the combination of daclatasvir and sofosbuvir in
infections with genotypes 1–4, persons with decompensated liver
disease, liver transplant recipients and those with HIV/HCV coinfection.
Also effective in infections with genotypes 5 and 6.
CURRENTLY AVAILABLE PANGENOTYPIC DAAS FOR THE TREATMENT OF HCV
INFECTED PERSONS WITHOUT CIRRHOSIS
HCV infected persons without cirrhosis
Glecaprevir/pibrentasvir Sofosbuvir/daclatasvir Sofosbuvir/velpatasvir
8 weeks 12 weeks 12 weeks

CURRENTLY AVAILABLE PANGENOTYPIC DAAS FOR THE TREATMENT OF HCV
INFECTED PERSONS WITH COMPENSATED CIRRHOSIS
HCV infected persons with compensated cirrhosis
Glecaprevir/
pibrentasvir
Sofosbuvir/
daclatasvir
Sofosbuvir/daclatasvir
Sofosbuvir/
velpatasvir
12 weeks 24 weeks
12 weeks may be
considered in countries
where genotype 3
distribution is known
12 weeks

CONTRAINDICATIONS TO HEPATITIS C VIRUS COMBINATION THERAPY
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• Autoimmune hepatitis.
• Patients on hemodialysis.
• Decompensated liver disease.
• Patients with creatinine clearance < 50ml/min.
• Patients with ischemic cardiovascular or cerebrovascular disease.
• Women who are pregnant or patients whose female partners are pregnant.
HEPATITIS SEROLOGIES
Virus Acute Infection Chronic Infection Immunity
Hepatitis A Anti-HAV IgM --- Anti-HAV IgG
Hepatitis B
HBsAg
Anti-HBc IgM
HBsAg
Anti-HBc IgG
HBsAg
Anti-HBs
Hepatitis C Anti-HCV Anti-HCV ---
TESTS FOR HEPATITIS
Virus Tests Significance
A
Anti HAV IgM Acute infection
Anti HAV IgG
Previous infection and long-term
immunity or immunization.
B
HBsAg
Current infection, positive in chronic
carriers.
Anti HBs
Indicate previous infection with
hepatitis B or immunization.
HBeAg
Indicates high infectivity, present in
acute active infection.
Anti HBe Indicates previous infection.
HBcAg Ongoing infection with hepatitis B.
Anti HBc IgM Acute infection.
Anti HBc IgG
Indicate previous infection or ongoing
infection with hepatitis B.
HBV DNA
Indicate active ongoing viral replication.
Best indicator of viral replication.
C
Anti HCV
Marker for acute or chronic infection
with HCV.
Enzyme immunoassay Used in initial screening for HCV
HCV RNA PCR assay Indicate active ongoing viral replication
LABORATORY TEST INTERPRETATION
Test Abnormal findings Etiology
Transaminases AST, ALT Increased in acute phase, decreases
as jaundice disappears.
Liver cell injury.
ALP Moderately increased.
Impaired excretory function of
the liver.
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Serum proteins (albumin,
globulin)
Normal or increased.
Impaired clearance of the
liver.
Serum bilirubin Increased. Liver cell damage.
Urinary urobilinogen
Increased 2 – 5 days before jaundice. Diminished reabsorption of
urobilinogen.
Prothrombin time Prolonged.
Decreased absorption of
vitamin K in intestine with
decreased production of
prothrombin by liver.
DIARRHEA
DEFINITION
“Diarrhea is defined as the increased passage of loose or watery stools relative
to the person's usual bowel habit”
TYPES OF DIARRHEA
• Watery Diarrhea: 3 or more liquid or watery stools in 24 h.
• Dysentery: Presence of blood and/or mucus in stools.
• Persistent Diarrhea: Diarrhea lasting for 14 days or more.
CAUSES








PATHOPHYSIOLOGY
• Disorders affecting either the small or large bowel can lead to diarrhea.
• There are numerous causes of diarrhea, but in almost all cases, this
disorder is a manifestation of one of the four basic mechanisms:
Diarrhoea
Persistent
Multiple
cause
Dysentery
BacillaryAmoebic
Watery
CholeraE. coliRotavirus
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1. OSMOTIC DIARRHEA
• Absorption of water in the intestines is dependent on adequate
absorption of solutes. If excessive amounts of solutes are retained in the
intestinal lumen, water will not be absorbed, and diarrhea will result.
• Osmotic diarrhea typically results from one of two situations:
­ Ingestion of a poorly absorbed substrate, examples include
mannitol or sorbitol, Epson salt (MgSO4) and some antacids
(MgOH2).
­ Malabsorption: Inability to absorb certain carbohydrates.
2. SECRETARY DIARRHEA
• This type of diarrhea occurs when secretion of water into the intestinal
lumen exceeds absorption.
• Secretory diarrhea associated with cholera.
­ The responsible organism, Vibrio cholerae, produces cholera
toxin, which strongly activates adenylyl cyclase, causing a
prolonged increase in intracellular concentration of cyclic AMP
within crypt enterocytes.
­ This change results in prolonged opening of the chloride channels
that are instrumental in secretion of water from the crypts,
allowing uncontrolled secretion of water.
­ Additionally, cholera toxin affects the enteric nervous system,
resulting in an independent stimulus of secretion.
• E. coli induces the same series of steps.
• In addition to bacterial toxins, a large number of other agents can
induce secretory diarrhea by turning on the intestinal secretory
machinery, including: some laxatives hormones secreted by certain
types of tumors, a broad range of drugs (e.g. some types of asthma
medications, antidepressants, cardiac drugs), certain metals, organic
toxins, and plant products (e.g. arsenic, insecticides, mushroom toxins,
caffeine).
• In most cases, secretory diarrheas will not resolve during a 2-3 day fast.
3. INFLAMMATORY AND INFECTIOUS DIARRHEA
• Disruption of the epithelium of the intestine due to microbial or viral
pathogens is a very common cause of this diarrhea.
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• Destruction of the epithelium results not only in exudation of serum and
blood into the lumen but often is associated with widespread
destruction of absorptive epithelium. In such cases, absorption of water
occurs very inefficiently and diarrhea results.
• Examples of pathogens frequently associated with infectious diarrhea
include:
­ Bacteria: Salmonella, E. coli, Campylobacter
­ Viruses: Rotaviruses, coronaviruses, parvoviruses, norovirus
­ Protozoa: Coccidia species, Cryptosporium, Giardia
­ Age < 2 years: Rotavirus
­ Age 2-5 years: Cholera; E. coli; Shigellosis
­ All ages: E. coli; Campylobacter
• The immune response to inflammatory conditions in the bowel
contributes substantively to development of diarrhea.
• Activation of white blood cells leads them to secrete inflammatory
mediators and cytokines which can stimulate secretion, in effect
imposing a secretory component on top of an inflammatory diarrhea.
4. DIARRHEA ASSOCIATED WITH DERANGED MOTILITY
• In order for nutrients and water to be efficiently absorbed, the intestinal
contents must be adequately exposed to the mucosal epithelium and
retained long enough to allow absorption.
• Disorders in motility than accelerate transit time could decrease
absorption, resulting in diarrhea.
COMMON CAUSES OF DIARRHEA
COMMON CAUSES OF DIARRHEA – BACTERIA
• Several types of bacteria consumed through contaminated food or water
can cause diarrhea:
­ Vibrio cholera
­ Shigella
­ Escherichia coli
­ Salmonella
­ Staphylococcus
­ Clostridium difficile
COMMON CAUSES OF DIARRHEA – VIRUS
• Infection with the rotavirus is the most common cause of acute diarrhea in
children.
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• Rotavirus diarrhea usually resolves in 3 to 7 days but can cause problems
digesting lactose for up to a month or longer.
­ Rotavirus
­ Adenoviruses
­ Astroviruses
COMMON CAUSES OF DIARRHEA – PARASITE
• Parasites can enter the body through food or water and settle in the
digestive system.
­ Entamoeba histolytica
­ Cryptosporidium
­ Isospora
COMMON CAUSES OF DIARRHEA – OTHERS
• Metabolic disease
­ Hyperthyroidism
­ Diabetes mellitus
­ Pancreatic insufficiency
• Food allergy
­ Lactose intolerance
• Antibiotics
• Irritable bowel syndrome
SIGNS & SYMPTOMS
• Diarrhea may be accompanied by cramping, abdominal pain, nausea, an
urgent need to use the bathroom, or loss of bowel control.
• Some infections that cause diarrhea can also cause a fever and chills or
bloody stools.
DEHYDRATION
• Diarrhea can cause dehydration. Loss of electrolytes through dehydration
affects the amount of water in the body, muscle activity, and other
important functions.
• Dehydration is particularly dangerous in children, older adults, and people
with weakened immune systems.
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• Dehydration must be treated promptly to avoid serious health problems,
such as organ damage, shock, or coma.
SIGNS OF DEHYDRATION IN INFANTS AND YOUNG CHILDREN
• High fever.
• No tears when crying.
• Dry mouth and tongue.
• Listlessness or irritability.
• No wet diapers for 3 hours or
more.
• Sunken eyes, cheeks, or soft
spot in the skull.
SIGNS OF DEHYDRATION IN ADULTS
• Thirst
• Fatigue
• Dry skin
• Dizziness
• Light-headedness
• Dark-colored urine
• Less frequent urination than
usual.
ASSESSMENT OF DEHYDEATION
Dehydration
Mild Moderate Severe
Appearance Irritable, thirsty Irritable, very thirsty
Lethargy, coma, or
unconscious.
Anterior Fontanelle Normal Depressed Markedly depressed
Eyes Normal Sunken Sunken
Tongue Normal Dry Very dry, furred
Skin Normal Slow retraction Very slow retraction
Breathing Normal Rapid Very rapid
Pulse Normal Rapid and low volume Feeble or imperceptible
Urine Normal Dark Scanty
Weight loss < 5% 6 - 9% 10% or more

TREATMENT
• When people are dehydrated, their skin does not flatten back to normal
right away after being gently pinched and released.
• Although drinking plenty of water is important in preventing dehydration,
water does not contain electrolytes.
• Adults can prevent dehydration by also drinking liquids that contain
electrolytes, such as fruit juices, sports drinks, caffeine-free soft drinks, and
broths.
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• Children with diarrhea should be given oral rehydration solutions such as
Pedialyte, Naturalyte, Infalyte, and Ceralyte to prevent dehydration.
WHEN TO SEE A DOCTOR
CHILDREN
• Children with any of the following symptoms should see a health care
provider:
­ Signs of dehydration
­ Diarrhea for more than
24 hours
­ Fever of 102 degrees or
higher
­ Stools containing blood
or pus
ADULTS
• Adults with any of the following symptoms should see a health care
provider:
­ Signs of dehydration
­ Severe pain in the
abdomen or rectum
­ Fever of 102℉ or higher
­ Diarrhea for more than 2
days
SIGN/SYMPTOMS OF CHOLERA
DIARRHEA
• Rice-watery stool
• Marked dehydration
• Projectile vomiting
• No fever
• Shock, unconsciousness
• Scanty urine
SIGN/SYMPTOMS OF E. COLI
DIARRHEA
• Yellow watery stools
• Dehydration moderate to
severe
• Fever– often of moderate
grade
• Mild abdominal pain
SIGN/SYMPTOMS OF ROTAVIRUS DIARRHEA
• Prodromal symptoms: fever, cough, and vomiting preceding diarrhea.
• Stools are watery or semi-liquid; the color is greenish or yellowish– typically
looks like yoghurt mixed in water.
• Mild to moderate dehydration.
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SIGN/SYMPTOMS OF SHIGELLOSIS DIARRHEA
• Frequent passage of scanty amount of stools, mostly mixed with blood and
some mucus
• Moderate to high grade fever
• Severe abdominal cramps
• Tenesmus– pain around anus during defecation
• Usually no dehydration
SIGN/SYMPTOMS OF AMEBIASIS DIARRHEA
• Lower abdominal cramp
• Mild grade fever
• No dehydration
• Offensive and bulky stools containing mostly mucus and sometimes blood.
TRANSMISSION
• Most of the diarrheal agents are transmitted by the fecal-oral route.
• Cholera: water-borne disease; transmitted through water contaminated
with feces.
• Some viruses (such as rotavirus) can be transmitted through air.
• Nosocomial transmission is possible.
• Shigellosis (blood dysentery) is mainly transmitted person-to-person.
Shigellosis is a water-washed disease; transmitted more when there is
scarcity of water.
SEASONALITY
Disease Common season
Cholera diarrhea
Rotavirus diarrhea
Shigellosis diarrhea
Winter
Winter
Dry summer
DIAGNOSE CAUSE OF DIARRHEA
STOOL CULTURE
• A sample of stool is analyzed in a laboratory to check for bacteria, parasites,
or other signs of disease and infection.
BLOOD TESTS
• Blood tests can be helpful in ruling out certain diseases.
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FASTING TESTS
• To find out if a food intolerance or allergy is causing the diarrhea, the
doctor may ask a person to avoid foods with lactose, carbohydrates, wheat,
or other ingredients to see whether the diarrhea responds to a change in
diet.
SIGMOIDOSCOPY OR COLONOSCOPY
• These tests may be used to look for signs of intestinal diseases that cause
chronic diarrhea.
LABORATORY DIAGNOSIS
• Stool microscopy
• Dark field microscopy of stool for cholera
• Stool cultures
• ELISA for rotavirus
• Immunoassays, bioassays or DNA probe tests to identify E. coli strains.
TREATMENT: 3 DS
• Dehydration correction– replace the loss of fluid and electrolytes.
• Diet: Start food as soon as possible.
• Drug:
­ Tetracycline/ciprofloxacin for cholera
­ Selexid for shigellosis
­ Metronidazole for amebiasis
COMPLICATIONS
WATERY DIARRHEA
• Dehydration
• Electrolyte imbalances
• Tetany
• Convulsions
• Hypoglycemia
• Renal failure
DYSENTERY
• Electrolyte imbalances
• Convulsions
• Toxic megacolon
• Protein losing enteropathy
• Arthritis
• Perforation
ACUTE DIARRHEA
• 14 days in duration.
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• Persistent diarrhea — more than 14 days in duration.
• Chronic — more than 30 days in duration.
• Agents that commonly cause acute gastrointestinal illness:
­ Bacteria
▪ Salmonella
▪ Campylobacter
▪ Escherichia coli
▪ Clostridium
difficile
­ Viruses
▪ Rotavirus
▪ Calicivirus
▪ Adenovirus
▪ Astrovirus
­ Protozoa
▪ Cryptosporidium
▪ Cyclospora
▪ Entamoeba
histolytica
DIAGNOSTIC APPROACH
• Careful history to determine the duration of symptoms.
• The frequency and characteristics of the stool.
• Evidence of extracellular volume depletion (e.g. Decreased skin turgor,
orthostatic hypotension).
INDICATIONS FOR DIAGNOSTIC EVALUATION
• Bloody diarrhea
• Severe abdominal pain
• Temperature 38.5ºC (101.3ºF)
• Profuse watery diarrhea with signs of hypovolemia.
• Passage of many small volume stools containing blood and mucus.
• Recent use of antibiotics or hospitalized patients.
• Passage of 6 unformed stools per 24 hours or a duration of illness > 48
hours.
OBTAIN STOOL CULTURES
• Immunocompromised patients, including (HIV).
• Patients with more severe, inflammatory diarrhea.
• Patients with comorbidities that increase the risk for complications.
• Patients with underlying inflammatory bowel disease in whom the
distinction between a flare and superimposed infection is critical.
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ENDOSCOPY
• Endoscopy is uncommonly needed in the diagnosis of acute diarrhea. It
may be helpful in the following settings:
­ Distinguishing inflammatory bowel disease from infectious diarrhea.
­ Diagnosing C. difficile infection.
TREATMENT
1. ORAL REHYDRATION SOLUTIONS
• Those with more than eight stools per day, volume depletion, symptoms
for more than one week.
2. EMPIRIC ANTIBIOTIC THERAPY
• Those with moderate to severe travelers' diarrhea as characterized by
more than four unformed stools daily, fever, blood, pus, or mucus in the
stool.
• Oral fluoroquinolone (ciprofloxacin 500 mg twice daily, norfloxacin 400
mg twice daily, or levofloxacin 500 mg once daily) for three to five days
to eradicate bacterial infection.
• Azithromycin (500 mg PO once daily for three days) and Erythromycin
(500 mg PO twice daily for five days) are alternative agents particularly if
fluoroquinolone resistance is suspected.
3. SYMPTOMATIC THERAPY
• The antimotility agent loperamide (Imodium) may be used for the
symptomatic treatment of patients with acute diarrhea in whom fever is
absent or low grade and the stools are not bloody. The dose of
loperamide is two tablets (4 mg) initially, then 2 mg after each unformed
stool, not to exceed 16 mg/day for 2 days.
• Diphenoxylate (Lomotil) is an alternative agent. The dose of
diphenoxylate is two tablets (4 mg) four times daily for 2 days.
• Bismuth subsalicylate (Pepto-Bismol) used in patients with significant
fever and dysentery, conditions in which loperamide should be avoided.
The dose of bismuth subsalicylate is 30 mL or two tablets every 30
minutes for eight doses.
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CHRONIC DIARRHEA
DEFINITION
• Chronic diarrhea is defined as loose stools that last for at least four weeks.
This usually means three or more loose stools per day.
SYMPTOMS
• The main symptom of chronic diarrhea is loose or watery stools that persist
for weeks.
• These stools may or may not be accompanied by a sense of urgency.
• Patient may have other symptoms as well, such as:
­ Abdominal cramps
­ Bloating
­ Nausea
CAUSES
• Inflammatory conditions that can cause loose, watery stools include
ulcerative colitis and Crohn’s disease.
• These conditions can also cause bloody stools and abdominal pain.
• A stool sample, which examines feces, may reveal elevated white blood
cells. This can be a sign of inflammation in body or bacteria or parasites in
stool. The latter can also cause loose stools.
• This sample may also reveal fat in stool, which can indicate chronic
pancreatitis (damage to the pancreas from prolonged inflammation) or
celiac disease.
• Diet can also play a role in chronic diarrhea. Certain ingredients speed up
the rate of digestion, causing food to pass rapidly through the colon.
Common culprits include milk and artificial sweeteners (sorbitol and
fructose).
• Other causes of chronic diarrhea may include:
­ Diabetes
­ Alcohol abuse
­ Gluten insensitivity
­ Medications: NSAIDs, antibiotics, antacids.
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TREATMENT
• Anti-diarrheal medications are a short-term remedy for diarrhea. While
they may relieve symptoms, they should not be used on an ongoing basis.
• Other medications which may help include:
­ Antibiotics: for infections that are causing diarrhea.
­ Codeine-containing medications: which can reduce watery and loose
stools.
­ Over-the-counter medications: to slow down the passage of stool
through the digestive tract, including bismuth (Pepto-Bismol) and
loperamide (Imodium).
­ Bile acid binding resins (cholestyramine, colestipol, colesevelam)
­ Octreotide: to treat diarrhea in patients with carcinoid syndrome or
VIPoma, chemotherapy-induced diarrhea.
­ For small volume watery diarrhea and fecal incontinence, fiber
supplementation.
­ Oral calcium supplementation also may treat mild chronic diarrhea.
­ Bismuth subsalicylate is a frequently used over-the-counter
treatment for diarrhea.
­ Crofelemer, a chloride channel antagonist, is approved for the
treatment of HIV-associated diarrhea but may be of use in a variety
of diarrheal diseases.
­ Alosetron: a serotonin type 3 antagonist that slows colonic transit
and increases fluid absorption.
DIETARY RECOMMENDATIONS
• Adequate nutrition during an episode of acute diarrhea is important to
facilitate enterocyte renewal if patients are anorectic.
• A short period of consuming only liquids will not be harmful.
• Boiled starches and cereals (e.g. potatoes, noodles, rice, wheat, and oat)
with salt are indicated in patients with watery diarrhea; crackers, bananas,
soup, and boiled vegetables may also be consumed.
EATING, DIET, AND NUTRITION
• Until diarrhea subsides, avoiding caffeine and foods that are greasy, high in
fiber, or sweet may lessen symptoms. These foods can aggravate diarrhea.
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• Some people also have problems digesting lactose during or after a bout of
diarrhea.
• Yogurt, which has less lactose than milk, is often better tolerated. Yogurt
with active, live bacterial cultures may even help people recover from
diarrhea more quickly.
• As symptoms improve, soft, bland foods can be added to the diet, including
bananas, plain rice, boiled potatoes, toast, crackers, cooked carrots, and
baked chicken without the skin or fat.
• For children, the health care provider may also recommend a bland diet.
Once the diarrhea stops, the health care provider will likely encourage
children to return to a normal and healthy diet if it can be tolerated.
• Infants with diarrhea should be given breast milk or full-strength formula as
usual, along with oral rehydration solutions.
INFLAMMATORY BOWEL DISEASE
INTRODUCTION
• It includes a group of chronic disorders that cause inflammation or
ulceration in large and small intestines.
“Inflammatory bowel disease (IBD) is a term used to describe two main
diseases: ulcerative colitis and Crohn’s disease which cause inflammation of the
bowel”
• This inflammation is thought to be due to dysfunction of your immune
system and is not due to an infection.
ULCERATIVE COLITIS
• Ulcerative colitis causes inflammation of only the
inner lining of the colon and rectum (large bowel).
• When only the rectum is involved it is sometimes
called ulcerative proctitis or just proctitis.
• When the entire colon is involved it is sometimes
called pan-colitis.
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CROHN’S DISEASE
• Crohn’s disease causes inflammation of the full
thickness of the bowel wall and may involve any part of
the digestive tract from the mouth to the anus.
• Most frequently the ileum, which is the last part of the
small bowel, the colon or both are involved.
• These patterns of disease location are referred to as
ileitis, colitis and ileo-colitis, respectively.
ETIOLOGY
INFECTIOUS
• Virus
• Bacteria
GENETICS
• Metabolic defects
• Connective tissue disorders
ENVIRONMENTAL FACTORS
• Diet
• Smoking (CD)
IMMUNE DEFECTS
• Altered host susceptibility
• Immune mediated mucosal
damage
PSYCHOLOGICAL FACTORS
• Stress
• Trauma/emotional
PATHOPHYSIOLOGY
• In individuals with IBD, trigger factors typically cause a severe, prolonged
and inappropriate inflammatory response in the gastro-intestinal tract and
the ongoing inflammatory reaction leads to an alteration in the normal
architecture of the digestive tract.
• Genetically susceptible individuals seem unable to downregulate immune
or antigen non-specific inflammatory responses.
• It is thought that chronic inflammation is characterized by increased activity
of effector lymphocytes and pro-inflammatory cytokines that override
normal control mechanisms.
• Others, however, have suggested that IBD may result from a primary failure
of regulatory lymphocytes and cytokines, such as interleukin-10 and
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transforming growth factor-β, to control inflammation and effector
pathways.
• In Crohn's disease, it is also thought that T-cells are resistant to apoptosis
after inactivation.
• Th1 cytokine activity is excessive in CD and increased expression of
interferon-γ in the intestinal mucosa.
• Production of IL-12 are features of immune response in CD.
• Tumor Necrosis Factor-α is a cytokine increased in mucosa and intestinal
lumen of patients with IBD.
• Antineutrophil cytoplasmic antibodies are found in high percentage of UC
patients than in CD.
• Non-pathogenic bowel flora appears to be an essential factor.
CLINICAL PRESENTATION
ULCERATIVE COLITIS
• The presentation of ulcerative colitis is highly variable.
• Symptoms may range from mild abdominal cramping with frequent small-
volume bowel movements to profuse diarrhea.
• Most sufferers experience intermittent bouts of illness after varying
intervals of no symptoms.
• Mild disease, which afflicts two-thirds of patients, has been defined as ≤ 4
stools daily, with or without blood, with no systemic disturbance and a
normal ESR.
• Patients with moderate disease have more than 4 stools per day but with
minimal systemic disturbance.
• In severe disease → patient has more than six stools per day with blood,
with evidence of systemic disturbance as shown by fever, tachycardia,
anemia, or ESR > 30.
• Fulminant disease.
SIGN AND SYMPTOMS OF ULCERATIVE COLITIS
• Diarrhea
• Tenesmus
• Weight loss
• Abdominal cramping
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• Fever and tachycardia in severe disease
• Frequent bowel movements, with or without blood.
LAB TESTS
• Increased platelets
• Increased C reactive proteins
• Decreased hematocrit/hemoglobin
• Increased erythrocyte sedimentation rate
• Leukocytosis and hypoalbuminemia with severe disease.
CROHN’S DISEASE
• Similar to ulcerative colitis, the presentation of CD is also highly variable.
• A single episode may not be followed by further episodes, or the patient
may experience continuous, unremitting disease.
• A patient may present with diarrhea and abdominal pain or a perirectal or
perianal lesion.
• The course of Crohn’s disease is characterized by periods of remission and
exacerbation.
• Some patients may be free of symptoms for years, while others experience
chronic problems in spite of medical therapy.
SIGNS AND SYMPTOMS
• Fistula
• Weight loss
• Steatorrhea
• Hematochezia
• Abdominal pain
• Malaise and fever
• Frequent bowel movements.
LAB TESTS
• Increased ESR
• Increased CRP
• Increased white cell count.
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CLINICAL DIFFERENCES
Features/Symptoms Ulcerative Colitis Crohn’s Disease
Diarrhea Very Common Fairly Common
Tenesmus More common Less common
Fever, Malaise Uncommon Common
Fistulae Absent Common
Weight loss Fairly Common Common
Rectal bleeding Very common Fairly Common
Abdominal Pain Varies Common
Malnutrition Fairly Common Common
Abdominal tenderness Maybe present Common
Dehydration Very Common Common
Anemia Present Present
Extraintestinal
manifestation
Present Present

COMPLICATIONS

Colon Cancer.
Skin, eyes,
joints
Inflammation.
Arthritis.
Malnutrition.
Ulcers.
Liver disease.
Toxic
megacolon
Bowel
Obstruction.
Fistula.
Anal Fissure
Blood Clots.
Sclerosing
cholangitis.
Perforated
Colon.
Severe
Dehydration.
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EXTRA-INTESTINAL COMPLICATIONS
DIAGNOSIS
ENDOSCOPY
COLONOSCOPY
• Doctor view entire colon using a thin, flexible, lighted tube with camera.
Can do a biopsy.
FLEXIBLE SIGMOIDOSCOPY
• Doctor uses a slender, flexible, lighted tube for rectum and sigmoid.
UPPER ENDOSCOPY
• Examine the esophagus, stomach and first part of the small intestine
(duodenum).
Diagnostic Findings Ulcerative Colitis Crohn’s Disease
Terminal ileum
involvement
Seldom Commonly
Colon Involvement Always Usually
Rectum Involvement Usually Seldom
Involvement Around
Anus
Seldom Common
Joints and bones
•Arthropathies
(Pauciarticulardisease)
•Osteopenia, potentially
leading to osteoporosis.
Skin
•Erythema nodosum
•Pyoderma gangrenosum
•Sweet's syndrome
Eye
•Episcleritis
•Scleritis
•Uveitis
•Conjunctivitis
Hepatobiliary
•Gallstones and sclerosing
cholangitis.
•Fatty liver, pericholangitis,
chronic active hepatitis
and cirrhosis.
Thromboembolic
•Pulmonary embolism
Anemia
•Microcytic anemia
•Normocytic anemia
•Folate, iron, vitamin B12
malabsorption.
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Bile Duct Involvement Higher Rate
No increase in rate of
PSC
Endoscopy Continuous Ulcer
Deep geographic and
snake like ulcers
Inflammation Depth Shallow, mucosal
Transmural, deep into
tissues
Granulomas on Biopsy
Non-peri-intestinal crypt
granuloma not seen
May have non-
necrotizing non-peri-
intestinal crypt
granulomas

RADIOLOGY
• X-ray of your abdominal area to rule out serious complications, such as a
perforated colon.
• Computed tomography (CT scan) and magnetic resonance imagery (MRI)
for locating and defining fistulae and abscesses in active Crohn’s disease.
LABORATORY FINDINGS
• Tests for anemia.
• Fecal occult blood test.
• Raised erythrocyte sedimentation rate (ESR), platelet count and C-reactive
protein (CRP).
TREATMENT
TREATMENT GOALS
• Resolution of acute inflammatory processes, resolution of attendant
complications (e.g., fistulas or abscesses), alleviation of systemic
manifestations (e.g., arthritis), maintenance of remission from acute
inflammation, or surgical palliation or cure.
NON-PHARMACOLOGICAL TREATMENT
NUTRITIONAL SUPPORT & LIFESTYLE
• Probiotic.
• Stress (Exercise)
• Enteral nutrition and Total parenteral nutrition.
• Small meals, Drink plenty of liquids, Multivitamins.
• Low fiber diet, low lactose diet, low fat diet, Fish Oil, Turmeric.
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SURGERY
• For ulcerative colitis, colectomy maybe indicated for long standing disease
(> 8-10 years)
• For crohn’s disease, not as well established and surgery is usually reserved
for the complications of the disease. There is a high recurrence rate.
PHARMACOLOGICAL TREATMENT
ULCERATIVE COLITIS
MILD TO MODERATE DISEASE
• Oral Sulfasalazine 4-8 g/day or mesalamine derivative, or topical
mesalamine or steroids for distal disease.
• Sulfasalazine instituted at 500 mg/day and increased every few days up to
4 g/day or the maximum tolerated.
• Oral mesalamine reasonable alternatives to sulfasalazine for treatment as
better tolerated.
MODERATE TO SEVERE DISEASE
• Steroids when unresponsive to maximal doses of oral and topical
mesalamine. Oral Prednisone 40 to 60 mg daily.
• Infliximab is used who are unresponsive to steroids or other
immunosuppressive agent.
SEVERE OR INTRACTABLE DISEASE
• Requires hospitalization, medication via parenteral route.
• IV Hydrocortisone 300 mg daily or methylprednisolone 60 mg once daily is
first-line agent.
• Patients who are unresponsive to IV corticosteroids after 3-7 days receives
Cyclosporine (4 mg/kg/day IV) or Infliximab.
MAINTENANCE OF REMISSION
• Oral Sulfasalazine, mesalamine and balsalazide are all effective for
maintenance (Dose 2 to 2.4 g/day).
• Steroids do not have a role in remission. Should be gradually withdrawn
after remission.
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CROHN’S DISEASE
• Sulfasalazine is more effective when Crohn’s disease involves the colon.
• Mesalamine derivatives (such as Pentasa or Asacol) release in the small
bowel may be more effective than sulfasalazine for ileal involvement.
• Oral corticosteroids such as prednisone 40-60 mg/day are first line
therapies for moderate to severe CD.
• Budesonide 9 mg daily is a viable first-line option for patients with mild to
moderate ileal or right-sided disease.
• Metronidazole 10-20 mg/kg/day maybe useful with colonic or ileocolonic
involvement, perianal disease, or those unresponsive to sulfasalazine.
• Azathioprine (2-3 mg/kg/day) & Mercaptopurine (1-1.5 mg/kg/day) are
effective in maintaining steroid-induced remission.
• Cyclosporine is (7.9 mg/kg/day) not recommended except for patients with
symptomatic and severe perianal or cutaneous fistulas.
• Methotrexate (25 mg/week) has efficacy for induction and maintenance
therapy. The risks are bone marrow suppression, hepatotoxicity, and
pulmonary toxicity.
• Infliximab (5 mg/kg/day infusion for 8 weeks) is used for moderate to
severe active Crohn’s disease in patients failing immunosuppressive
therapy.
• Adalimumab The typical dosage is 160 mg subcutaneously, 80 mg
subcutaneously at week 2, 40 mg subcutaneously every other week
thereafter.
MAINTENANCE OF REMISSION
• Prevention of recurrence of disease is clearly more difficult with Crohn’s
disease than with ulcerative colitis.
• Sulfasalazine and oral mesalamine derivatives are effective in preventing
acute recurrences in quiescent Crohn’s disease.
• Budesonide is considered for steroid dependent patient for maintenance
therapy for up to 1 year.
• Azathioprine and Mercaptopurine are effective in maintaining remission.
• Methotrexate, the TNF-α inhibitors are effective in maintaining remission
in CD.
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OTHER MEDICATIONS
• NSAIDS
• Multivitamins
• Anti-diarrheal
• Iron Supplements
• Fish Oil (Omega-3 fatty acids)
• Calcium and Vitamin D Supplements.
ADRS ASSOCIATED WITH IBD TREATMENT
SALFASALAZINE
• Dose-related side effects
­ GI disturbances such as nausea, vomiting, diarrhea, or anorexia,
headache and arthralgia.
­ Inhibits folic acid absorption so patient should receive oral folic acid
supplementation.
• Non–dose-related adverse effects
­ Common → Rash, fever, or hepatotoxicity most commonly
­ Relatively uncommon but serious reactions → bone marrow
suppression, thrombocytopenia, pancreatitis, interstitial nephritis,
and hepatitis.
GLUCOCORTICOIDS
• Hypertension
• Osteoporosis
• Hyperglycemia
• Adrenocortical suppression
• Reduced resistance to infection
• Fluid retention and electrolyte disturbances.
IMMUNOSUPRESSANTS
• Pancreatitis
• Lymphomas
• Bone marrow suppression.
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PATIENT PROFILE AND PATIENT COUNSELING
PATIENT PROFILE
• It is a record of information of a patient’s drug therapy that has direct
impact on patient care by enhancing the pharmacist’s ability to optimize
therapeutic outcome in efficient manner.
• Note: Patient profile can be patient medication profile or patient disease
profile. The former primarily focusses on the information about medication
of patients including past and present medicines the patient is taking and
the latter primarily focusses on the information about patient’s disease
progression. Basically, patient profile is a better terminology that contains
all the information including medication as well as disease progression.
• The purpose of patient profile is to provide a summary of patient’s
complete medical picture that enables the healthcare workers to manage
the therapy for individual patient. It helps in clinical decision making for the
effective therapy that rationalizes therapeutic outcome.
• Patient profile is prepared by a process called history taking.
TAKING CASE HISTORY
INTRODUCTION
• Medication history may be defined as the comprehensive statement of
facts pertaining to past and present health and drugs used, gathered ideally
from the patient, by directed questioning and organized under the different
headings.
• It includes taking of the past and current medication history of the patient
both for the prescription and non-prescription drugs. Determining drugs
allergies, noting the side effects, toxicity, incorrect drug administration and
any specific problem associated with the drug use fall under this heading.
• An account of past diseases, injuries, treatments, and other strictly medical
facts are included here.
• There are different perspectives of history taking of the patients.
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• This helps in establishing the safety of the medicines prescribed to the
patient.
• The purpose of the medication profile is to document the medication
history and the use of medicines by the patient.
APPROACH TOWARDS TAKING MEDICATION HISTORY
• Pharmacists are more oriented towards the drugs while taking history of
the patient. The patient’s medication history must be noted by the
pharmacist, which should include the followings:
­ Medications being taken while admitted, Medications taken during
recent past, OTC drugs used, Lab tests performed.
­ The essential information required includes:
▪ Patient details name, address, telephone number, date of
birth, previous diseases and the treatment received including
drugs which were ineffective, incidence of allergy to a
particular drug or group of drugs, idiosyncratic reactions or
side effects.
­ This helps in establishing the safety of the medicines prescribed to
the patient. The purpose of the medication profile is to document
the medication history and the use of medicines by the patient.
MAINTAINING MEDICATION PROFILE
• Medication profile must be maintained for almost all patients; inpatients
and those ambulatory patients who are receiving routine care from the
institution. Its uses are as follows:
­ To promote safe and rationale use of drugs.
­ To detect and help prevent potential drug interactions.
­ To detect and help prevent ADRs.
­ To detect and help prevent IV additive incompatibilities.
­ To detect drug induced lab test abnormalities.
­ To detect possible drug induced diseases.
­ To help detect and prevent potential drug toxicities.
MEDICATION HISTORY SAMPLE


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Patient Profile
Name: --------------
Date: ---------------
Age: ----------------
Address: -----------
Sex: --------------
Height: ----------
Weight: ---------

Chief complaints (C/C)

History of Present Illness (HPI)

Past Medical History (PMH)

Family History (FH)

Social History (SH)

Medication History (MH)

Physical Examination

Investigations

Diagnosis

Treatment

PATIENT COUNSELING
INTRODUCTION
• Traditionally pharmacists have always given advice on the proper use of
medicines. However, with the production of newer dosage forms this has
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gained more popularity since the patients prescribed will almost certainly
require newer information from pharmacists on their method of use and
the dosage regimen. In addition, many medicines interact with other drugs
both OTC and prescription and/ or with food and drink. Thus, if patients are
to get the best out of their medicines, they need to know how to correctly
use/ administer them in a safe manner as possible, with knowledge about
side effects, interactions, etc.
• Patient counseling refers to the process of providing information, advice
and assistance to help the patients use their medications appropriately. It is
more about giving information and guidance on the medicines to the
patients and allowing the patient to make informed decisions but with the
interest of the patient uppermost.
• BNF counseling needs to be related to the age, experience, background and
understanding of the individual patient. The pharmacists should ensure
that the patient understands how to take or use the medicine and how to
follow the correct dosage schedule. Any effects of the medicine on driving
or work, any foods or medicines to be avoided, and what to do if a dose is
missed, should be explained. Other matters, such as the possibility of
staining of the clothes or skin by a medicine should also be mentioned. For
some preparations, there should be a special need for counseling, such as
an unusual method or time of administration or a potential interaction with
a common food or domestic remedy.
AIM OF PATIENT COUNSELING
• The aims of patient counseling in addition to the provision of advice from
the pharmacist could be to:
­ Encourage the patients to identify any problems they perceive with
medicines and any solutions to these problems.
­ Encourage patients to develop their own action plan for taking/ using
medicines correctly.
­ Gain an understanding of the patient’s perspective.
­ Respect the patient’s beliefs and be non-judgmental of their use or
non-use of medicines.
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INFORMATION TO BE INCLUDED IN COUNSELING
• Each situation and each patient will have different information needs, but
as a general summary, no patient who has been given medication should
leave a community or hospital pharmacy without knowing:
­ How to take or use the medicine? When to take or use the medicine?
­ How much to take or use the medicine?
­ How long to continue to take or use the medicine?
­ What to expect, e.g. immediate relief, no effect for several days?
Why the medicine is being taken or used?
­ What to do if something goes wrong, e.g. if a dose is missed?
­ How to recognize the side effects and minimize their incidence?
What type of lifestyle changes to be made?
­ What type of dietary changes to be made?
STAGES IN THE COUNSELING PROCESS
• If the counseling is approached in a structured manner, it becomes a
success. The followings are the stages of counseling:
­ Recognizing the need for counseling, assessing and prioritizing the
needs.
­ Specifying the assessment methods to be used, Implementation.
­ Assessing the success of the process.
AIDS TO COUNSELING
• Patient information leaflets (PILs), warning cards and placebo devices are
all useful devices while giving advice to the patients. Many drugs also have
patient information leaflets along with the drug. These PILs should be used
while counseling where appropriate and important points should be
highlighted. Placebo devices e.g. inhalers, patches, etc. can be used to
demonstrate a particular technique and to check the patient’s ability to use
the devices. Leaflets on how to use eye drops, eardrops, eye ointment,
pessaries, suppositories, nebulizer are available.
• Counseling may be thought as a method of relieving distress undertaken by
the means of a dialogue between the two people. Its main aim is to help
the patients find their own solutions to the problems while being supported
to do so and being guided for appropriate advice.
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• The physician normally instructs the patients for the proper use of
medications prescribed. However, it has been observed that the physician’s
chamber is not very fit for counseling purpose since the patient is sick,
anxious for his/her illness, and finds difficulty in understanding the
physician and only a few questions back about the things are not sufficient
to understand the whole case. Thus, only a few people are able to leave the
physician’s chamber having understood properly the mode of use of the
medicines prescribed to them.
• Therefore, pharmacists are made to counsel the patients where they feel
much comfortable and that he/she can be explained in non- professional
terms such that he/she understands the things said. It may be noted that
counseling was earlier discouraged as per the code of ethics. It was later
adopted in the USA in 1969. Now, pharmacists should counsel each patient
with their full ability and thus serve as an essential health care practitioner.
The pharmacists should be responsible if the patient suffers any harm due
to inadequate patient counseling. Counseling techniques are useful in
history taking, assessing and ensuring compliance.
TECHNIQUES OF COUNSELING
• These are:
­ Information giving.
­ Patient focused discussion.
­ Problem solving.
SOME DRUGS AND THE TYPES OF SIDE EFFECTS THAT OCCUR
• Some drugs cause side effects that can be minimized by good management.
Drug Side effect Precaution
Chlorpromazine Photosensitivity Use sunscreen
NSAIDs GI disturbances Take with food
Tamoxifen Nausea Take at bedtime

• Some drugs have S/Es, which require the patient to be warned for their
information and benefit.
Drug Side effect
CNS drugs Drowsiness
Rifampin Colored urine
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• Some drugs have S/Es that need monitoring.
Drug Side effect
Penicillamine Blood and urine tests to get done
Chloroquine Ocular tests to get done

• Some drugs have S/Es that require immediate reporting to the prescriber.
Drug Side effect
Gold therapy Sore throat, breathlessness, rashes
Aminoglycosides Bleeding, bruising

ADMINISTRATION TECHNIQUES OF SOME DOSAGE FORMS
• Here is given some points regarding administration technique of some of
the dosage forms to make the process appropriate into the following
headings:
EYE DROPS
• Wash hands thoroughly.
• Do not touch the tip of the container with fingers or any other
body part while opening or administering the drug. Ensure
adequate lightening. Read the label carefully.
• Assume comfortable position. Look upwards, pull down the
lower eyelid to form a pouch or space between the eyeball and
the eyelid, but do not press the eyeball.
• Bring the container as close as possible to the pouch and instill
recommended number of medications into there. Close the eye gently for a
couple of minutes, apply gentle pressure to the canthus for 1-2 minutes.
Remove the excess medicine from the eyes by a tissue paper or a clean
piece of cloth.
• If more than one medicine is to be used, give at least five minutes between
the two administrations. Wash hands thoroughly again.
• Sometimes patients may also need to be explained if the medication causes
some irritation and which, if persists for a long time, the prescriber or the
pharmacist should be consulted.
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EYE OINTMENT
• Wash hands thoroughly. Ensure adequate lightening. Read the
label carefully.
• Assume comfortable position. Take out the lid of the ointment.
Tilt the head back. Pull down the lower eyelid to form a pouch or
space between the eyeball and the eyelid, but do not press the
eyeball.
• Bring the container as close as possible to the pouch and gently
squeeze a 1cm line of ointment along the inside of the lower eyelid, taking
care not to touch the eye or eyelashes with the tip of the tube.
• Blink the eyes to spread the ointment over the surface of the eyeball. (The
vision may be blurred while opening eyes, the blurring will clear off after a
few moments if keeps blinking.)
• Do not rub the eyes. Wipe away any excess ointment with a clean tissue.
Repeat this procedure for the other eye if you have been advised to do so,
Replace the lid of the tube. Wait for about half-an-hour before using the
next ointment if to be used, to allow the first to be absorbed into the eye.
• Wait for five minutes before applying the eye ointment if eye drop also is to
be used.
• Note: Normally eye ointments are used at bedtime.
EAR DROPS
• Wash hands thoroughly. Hold the container in hands for
sometimes to warm the drops a bit. Lie down on one side or tilt
the head sideways.
• Gently pull the ear lobe up and back to expose the ear canal, use
the other hand to squeeze the bottle. Instill the recommended
number of drops.
• Keep the head tilted sideways for several minutes. Allow a gap of about five
minutes if more than one medicine is to be used. Wait for about five
minutes before turning for another ear.
• Use cotton wool to close the ear canal only if mentioned in the label or
indicated by the physician. Wash hands thoroughly again.
• Note: It may be necessary to warn the patients that burning or stinging
sensation might occur.
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NASAL SPRAY
• Wash hands thoroughly. Shake the bottle. Blow the
nose to make nostrils clear. Take out the lid of the
bottle. Tilt the head slightly forward.
• Close one nostril by gently pressing against the side of
the nose with finger. Insert the tip of the nasal spray
into the other nostril and start to breathe in slowly
through the nose. While the patient is still breathing
in squirt one spray into the nostril keeping the bottle upright.
• Remove the spray from the nostril and breathe out through the mouth. Tilt
the head backwards to allow the spray to drain into the back of the nose,
repeat step seven if a second dose is required in the same nostril.
• Repeat this procedure for the other nostril if advised, Replace the lid on the
bottle.
Important Instructions:
• Some nasal sprays give an unpleasant taste as they drain into the back of
the throat. A drink of water or other liquid will help to take this taste away.
• Decongestant nasal sprays should not be used for longer than a week, as
this can cause rebound congestion. (Rebound congestion also known as
Rhinitis medicamentosa, is a condition of rebound nasal congestion
brought on by extended use of topical decongestants (e.g., Oxymetazoline,
Phenylephrine, Xylometazoline, and Naphazoline nasal sprays) that work by
constricting blood vessels in the lining of the nose.)
NASAL DROPS
• Wash hands thoroughly. Blow the nose gently. Tilt
the head backwards in a sitting position or while
lying down put a pillow under the shoulders.
• Squeeze the rubber bulb on the bottle and
withdraw the required amount of medicine on the
dropper. Insert the dropper about 1 cm into the
nostril and instill the recommended number of
drops.
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• Tilt gently from the head side to side to distribute drugs evenly. After a few
minutes sit upright, the drops may trickle into the pharynx, Repeat the
same procedure for another nostril.
• Clean the dropper using boiled water. Wash hands thoroughly again.
SUPPOSITORY
• Wash the hands thoroughly. If the suppository is soft,
hold it under cool water or place it in a refrigerator for a
few minutes to harden it before removing the wrapper.
• Remove the suppository from the pack with clean hands,
Moisten the suppository with cold water. Lie on side with
lower leg straightened out and upper leg bent forward
towards the stomach.
• Lift upper buttock to expose the rectal area. Insert the suppository, pointed
end first, with the finger until it passes the muscular sphincter of the
rectum, about half to one inch in infants and one inch in adults. (If not
inserted past this sphincter, the suppository may pop out.)
• Hold buttocks together for a few seconds. Remain lying down for about 5
minutes to avoid having the suppository come out. Wash hands thoroughly.
Important Instructions:
• Avoid the bowel movement for one hour.
• Store suppositories in a cool place and avoid melting; refrigerate them if so
labeled.
METERED DOSE INHALER (MDI)
• Wash the hands properly. Take the inhaler and shake
it well. Remove the mouthpiece cover and hold the
inhaler in upright position with the thumb on the
base and two fingers on the top of the canister.
Breathe out gently from the mouth.
• Place the mouthpiece on the mouth and close the lip
around, breathe in slowly and press canister to
release the dose. Remove the inhaler, hold the
breath for 10 seconds at least and to breathe out slowly.
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• Administer another dose after one minute with the same procedure from
step two to the last step. Gargle properly with lukewarm water. Replace the
mouthpiece cover after cleansing with lukewarm water.
ROTAHALER WITH ROTACAP
• Wash the hands properly. Hold the
rotahaler vertically. Take out the rotacap
from the container and insert it into the
raised square hole of the rotahaler.
• Press firmly the placed rotacap such that
the top end of the rotacap is leveled with
the top of the hole and one half of the
rotahaler is rotated to make rotacap into
two halves. Breathe out through the
mouth.
• Place the mouthpiece on the mouth, close the lip around, Breathe in rapidly
and deeply. Remove the inhaler, hold the breath for 10 seconds at least and
breathe out slowly, Gargle properly with lukewarm water.
• Wash the device properly with lukewarm water.
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CLINICAL TRIALS OF DRUG SUBSTANCES


CLINICAL TRIAL
The word clinical trial is made up of two words, clinical and trials.
Clinical means.
­ Observation and treatment of actual patients
­ Connected with a clinic
­ Direct observation of patient
­ Dispassionate
Trial means.
­ Test of performance
­ Examination of evidence by a competent tribunal.
­ Test of patience.

Clinical Trials can be defined as,
• “Prospective or behavioral research studies on human subjects with the
aim to answer specific questions regarding biomedical or behavioral
interventions (vaccines, drugs, treatments, novel modalities of known
interventions).
WHO DEFINITION
• “A clinical trial is any research study that prospectively assigns human
participants or groups of humans to one or more health-related
interventions to evaluate the effects on health outcomes.”
• It is Research studies to examine how well medical approaches work in
people.
HISTORY
• The first systematic clinical trial was done by James Lind in 1747. It was a
survey.
• In 1920’s Sir Ronald A. Fisher gave the idea of randomization, replication,
blocking and factorial evaluation.
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• In 1930’s British Medical Research council recognized the importance of
clinical trials and established Therapeutic Trial Committee.
AIM OF CLINICAL TRIALS
• The aim of trials is to ask specific clinically relevant scientific questions in an
attempt to find better ways to prevent, screen or treat a disease. Also, to
compare new treatment with the existing ones.
• The aim is to find the best ways to:
­ To prevent disease and reduce the number of people who become ill.
­ To treat illness to improve survival or increase the number of people
cured.
­ To improve the quality of life for people living with illness, including
reducing symptoms of disease or the side effects of other
treatments, such as cancer chemotherapy.
­ Diagnose diseases and health problem.
IMPORTANCE OF CLINICAL TRIALS
The importance of clinical trials can be understood by following points
1. Clinical trials are the best way to compare different approaches to
preventing and treating illness and health problems.
2. Health professionals and patients need the evidence from trials to know
which treatments work best.
3. Without trials, there is a risk that people could be given treatments which
have no advantage, waste resources and might even be harmful.
4. TREATMENT APPROVAL
­ Many treatments that are now in common use in health care were
tested in clinical trials.
5. EARLY ASSESSMENT
­ Some types of clinical trial are designed to look at a treatment at an
early stage of its development.
6. CONTINUITY
­ Researchers and regulators will look at the information they have
gathered and decide whether it is safe and appropriate to continue
the development of that treatment.
7. CHECK
­ If treatment has no benefits or has serious side effects, it may not be
developed further.
8. DETECTION OF BENEFITS AND RISKS
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­ During the later stages of development of a treatment, researchers
will report on the benefits and risks so that doctors can decide
whether or how best to use it.
9. DECISION MAKING
­ It is important that the results of clinical trials are published so that
others can use the information to help them make decisions about
treatment and health care.
DESIGNING A CLINICAL TRIAL
1. CLINICAL TRIALS DESIGN THOUGHT PROCESS – HOMEWORK
• Clinical trials are designed by doctors and other clinical specialists with
input from a wide variety of people, including patients.
SYSTEMIC REVIEW
• First of all, they look carefully at the results of the trials that have already
been done to find out what is already known. This is called a Systematic
review. They work together to decide what questions need to be answered.
• A systematic review provides more accurate answers than individual trials
and also helps to identify important questions that still need to be
answered through further research.
• Doctors, nurses, patients and researchers work together with statisticians,
trial managers and representatives from pharmaceutical companies if
relevant, to design the best possible trial.
RESEARCH ETHICS COMMITTEE
• The design for the trial forms the basis of the Trial Protocol. When the trial
protocol is ready it is sent to a Research Ethics Committee, an independent
group of people that includes doctors, nurses, other medical staff,
members of the public and sometimes lawyers. They decide whether the
trial is ethical. In particular they check whether the potential benefits of a
new treatment are likely to outweigh the side effects.
• The ethics committee focuses that.
­ The information is provided to help people to decide whether they
want to participate in a trial, is clear and satisfactory.
­ The way in which people will be asked to take part in a trial
(recruited) is appropriate.
­ There will be compensation for people in the trial in the unlikely
event that something goes wrong.
­ Travel expenses will be offered to people who take part.
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­ The trial can only go ahead when it has been approved by an ethics
committee.
DESIGN OF A CLINICAL TRIAL
• A good clinical trial design controls or minimizes known or suspected
sources of bias and other errors. Therefore, clinical treatment/ device
effectiveness may be assessed clearly and objectively.
• Error is the result of our inability to accurately measure a variable.
­ Type I – detecting an effect when it is not present (false positives)
­ Type II – failing to detect the effect when it is present (false
negatives)
• BIAS results when any characteristic of the investigator, study population,
or study conduct interferes in a systematic way with the ability to measure
a variable accurately
­ SELECTION BIAS – difference in baseline characteristics of group
­ PERFORMANCE BIAS – difference in care that is provided
­ DETECTION BIAS – how outcomes are determined
­ ATTRITION BIAS – withdrawals
­ REPORTING BIAS – Reported and Unreported findings
2. THE TRIAL OBJECTIVE – STUDY QUESTION
• An effective and efficient design of a clinical investigation cannot be
accomplished without a clear and concise objective.
• Usually the study objective is posed as a research question, involving the
medical claims for the device or a medication.
• This research question should be formulated with extreme care and
specificity.
• A question such as "Is my drug safe and effective?" is far too general to
be meaningful. There two types of questions.
­ Primary questions – General questions and broad
­ Secondary questions – Derived from primary questions like adverse
effects, ancillary effects, natural history, interventions, response
variable etc.
WHAT IS A RESEARCH QUESTION?
• The researcher asks a very specific question and tests a specific hypothesis.
Broad questions are usually broken into smaller, testable hypothesis or
questions.
• Often called an objective or aim, though calling it a question tends to help
with focusing the hypothesis and thinking about how to find an answer.
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WHAT MAKES A POOR RESEARCH QUESTION?
• A question that matters to nobody, even you are hoping one emerges from
routine clinical records
­ the records will be biased and confounded
­ they will lack information you need to answer your question reliably,
because they were collected for another reason
• Fishing expedition/data dredging – gathering new data and hoping a
question will emerge.
WHAT MAKES A GOOD QUESTION?
• Feasible (answerable with a robust method)
• Interesting
• Novel
• Ethical
• Relevant
• FINER criteria
HOW TO FOCUS YOUR QUESTION
• Brief literature search for previous evidence
• Discuss with colleagues
• Narrow down the question – time, place, group
• What answer do you expect to find?
TURNING A RESEARCH QUESTION INTO A PROPOSAL
• Who am I collecting information from?
• What kinds of information do I need?
• How much information will I need?
• How will I use the information?
• How will I minimize chance/bias/confounding?
• How will I collect the information ethically?
MINIMISING BIAS AND CONFOUNDING
Variation - measurements are nearly always subject to random
variation. Minimise error by ensuring adequate sample size and
using statistical analysis.
Bias - caused by systematic variation/error in selecting patients,
measuring outcomes, analysing data – take extra care.
Confounding - factors that affect the interpretation of outcomes
e.g. people who carry matches are more likely to develop lung
cancer, but smoking is the confounding factor – so measure likely
confounders too.
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EXACTLY WHAT ARE YOU PLANNING TO DO?
PICO
P - Who are the patients or what is the problem?
I - what is the intervention or exposure?
C – What is the comparison group?
O - What is the outcome or endpoint?

More detail on PICO
Patients
• disease or condition
• stage, severity
• Demographic characteristics (age, gender, etc.)
Intervention
• type of intervention or exposure
• Dose, duration, timing, route, etc.
Comparison
• risk or treatment
• placebo or other active treatment
Outcome
• frequency, risk, benefit, harm
• dichotomous or continuous
• Type: mortality, morbidity, quality of life, etc.
3. SELECTION OF VARIABLES
• Clinical study involves two types of variables:
• Outcome variables
­ Outcome variables define and answer the research question and
should have direct impact on the claims for the medication.
­ These variables, also known as response, endpoint, or dependent
variables, should be directly observable, objectively determined
measures with minimal bias and error. They should be directly
related to biological effects of the clinical condition.
• Influencing variable
­ Influencing variables, are any aspect of the study that can affect
the outcome variables (increase or decrease) or can affect the
relationship between treatment and outcome.
­ These variables are also known as baseline variables, prognostic
factors, confounding factors, or independent variables.
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• Imbalances in comparison or treatment groups in influencing variables at
baseline can lead to false conclusions by improperly attributing an effect
observed in the outcome variable to an intervention when it was merely
due to the imbalance.
• Appropriate statistical testing of these baseline values should reveal any
significant imbalances between the two comparison groups before the trial
begins.
• Once the variables or factors to be included in the trial have been
identified, the selection of measurement methods becomes critical. The
most informative and least subjective methods (arising out of one’s
awareness, determined by mind) should be used.
­ Quantitative (continuous) variables are measures of physical dimension
(height, weight, circumference, area, etc.). The data which can be
measured.
­ Qualitative or categorical (discrete) variables are measures of distinct
states usually represented by whole numbers (alive or dead, healthy or
diseased, tumor classes, etc.). The data can be observed but not
measured.
• Quantitative data can contain more information than qualitative data, and
this generally allows for the use of more mathematically sophisticated and
statistically powerful analytical methods.
• However, there may be situations where qualitative data is most
appropriate or the only information available for a specific comparison, and
there are many powerful non-parametric or distribution-free techniques
available for these types of analyses.
Parametric Non-parametric
Assumed distribution Normal Any
Assumed variance Homogeneous Any
Typical data Ratio or Interval Ordinal or Nominal
Data set relationships Independent Any
Usual central measure Mean Median
Benefits
Can draw more
conclusions
Simplicity; Less affected
by outliers
Tests
Choosing
Choosing parametric
test
Choosing a non-
parametric test
Correlation test Pearson Spearman
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Independent measures,
2 groups
Independent-measures
t-test
Mann-Whitney test
Independent measures,
> 2 groups
One–way, independent
measures
ANOVA
Kruskal-Wallis test
Independent measures,
2 conditions
Matched-pair t-test Wilcoxon test
Independent measures,
> 2 conditions
One-way, repeated
Measures ANOVA
Friedman's test
4. STUDY POPULATION
• The study population should be a representative subset of the
population targeted for the medical treatment. The study population
should be defined before the trial by the development of severe, clear-
cut inclusion/exclusion criteria.
• Clinical experts in the field of the particular medical condition under
investigation should develop these criteria. These inclusion/exclusion
criteria will characterize the study population and, in this way, help to
define the intended treatment modalities.
• It is possible to narrowly define a study population such that it is rather
homogeneous in its composition.
­ The advantage of using a restrictive population is that it allows for
a smaller sample size in the clinical trial. That is, in homogeneous
populations, the variability in responses in general will be smaller
than in a more heterogeneous group, and this reduction in
variability, (all other critical factors being held constant), will
result in a corresponding decrease in the sample size required to
observe a specified significant difference between two groups.
­ The disadvantage is that it may limit generalization of the
approval to a narrow subset of the general population as defined
by the criteria.
• Thus, a sponsor should discuss how they intend to define the study
population with the reviewing committee before beginning the clinical
trial.
STUDY POPULATION ISSUES
Study population issue includes.
1. AGE: Preferable to impose upper limit on age to reduce comorbidities in
elderly and to reduce dropouts.
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2. GENDER: Women and men were essentially equally represented in clinical
trials in; endocrinology, pulmonary medicine, and special pathogens.
Women comprised less than half of the participants in four disciplines:
oncology, medical imaging, cardio-renal, and antiretroviral studies
3. SOCIOECONOMIC STATUS: Socioeconomic status also creates barriers to
research participation, for both social and logistical reasons.
Example: Homelessness, lack of transportation, and language barriers can
preclude reliable participation in a clinical trial.
4. COMORBID DISEASES: The presence of comorbid diseases is a rate-limiting
factor in study design.
Example: African Americans have the highest mortality rates and poorest
survival from cancer compared with other ethnic groups.
5. STUDY INCLUSION & EXCLUSION CRITERIA
• Inclusion criteria are characteristics that the prospective subjects must
have if they are to be included in the study.
• Exclusion criteria are those characteristics that disqualify prospective
subjects from inclusion in the study.
• Inclusion and exclusion criteria may include factors such as age, gender,
race, ethnicity, type and stage of disease, the subject’s previous
treatment history, and the presence or absence (as in the case of the
“healthy” or “control” subject) of other medical, psychosocial, or
emotional conditions. Healthy, or control, subjects may be defined as
those individuals who are free of certain specified attributes of non-
health.
• Inclusion/exclusion criteria should include an assessment of prognostic
factors for the outcome variable(s), since one or more of these variables
may influence the effectiveness of a treatment.
Example: Gender may be a prognostic factor for a particular disease
process.
• It seems reasonable to assess what role, if any, that gender might play in
treatment evaluation and then determine inclusion/exclusion criteria,
other design, and analytical considerations accordingly. Consideration
should also be given to patient age; concomitant disease, therapy or
condition (at both baseline and subsequent follow-up times); severity of
disease; and others.
POORLY JUSTIFIED REASONS FOR EXCLUSION
• Any criterion has a direct bearing on condition/intervention/results.
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STRONGLY JUSTIFIED REASONS FOR EXCLUSION
• Unable to provide informed consent
• Harmful effects of Placebo or intervention
• Lack of equipoise (intervention harmful)
• Effect of intervention difficult to interpret
POTENTIALLY JUSTIFIED REASONS FOR EXCLUSION
• Individual may not adhere
• Individual may not complete follow up
Example:
­ An example of inclusion criteria for a study of chemotherapy of
breast cancer subjects might be postmenopausal women between
the ages of 45 and 75 who have been diagnosed with Stage II breast
cancer.
An exclusion criterion for this study might be abnormal renal function tests, if the
combination of study drugs includes one or more that is nephrotoxic. In this case
it would be required to specify which tests of renal function are to be performed
to evaluate renal function and the threshold values that would disqualify the
prospective subject (e.g., serum creatinine above 1.9 mg/dl).
6. CONTROL POPULATION
• Every clinical trial intended to evaluate an intervention is comparative,
and a control exists either implicitly or explicitly.
• The safety and effectiveness of a treatment is evaluated through the
comparison of differences in the outcomes (or diagnosis) between the
treated patients (the group on whom the device/treatment was used)
and the control patients (the group on whom another intervention,
including no intervention, was used).
• A scientifically valid control population should be comparable to the
study population in important patient characteristics and prognostic
factors, i.e., it should be as alike as possible except for the treatment.
7. SAMPLE SIZE
• When planning a study, it is important to know how many individuals one
need for the study. A proper justification is required for a chosen sample
size. Sample size estimation depends upon.
• Type I error
• Type II error
• Statistical power
I. HYPOTHESIS TESTING
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• Type I and type II errors are related to statistical hypothesis
• Let us suppose.
Null Hypothesis (H0): Brand 1 is equal to Brand 2
Alternate Hypothesis (H1): Brand 1 is better than Brand 2
Error 1: Based on analysis it is concluded that Brand 1 is better than Brand
2, basically we reject H0. Knowing that Brand 1 is equal to Brand 2 (H0), we
are making an error here by rejecting H0. This is called as Type I error -
detecting an effect that is not present or incorrect rejection of a true null
hypothesis
Error 2: If analysis concludes that Brand 1 is equal to Brand2, we accept H0.
Knowing that Brand 1 is better than Brand 2 (H1) we are making an error
here by accepting H0. This is called as Type II error - failing to detect an
effect that is present or failure to reject a false null hypothesis
The Null hypothesis (H0) is a hypothesis which the researcher tries to
disprove, reject or nullify.
The Alternative hypothesis is what the researcher really thinks is the cause
of a phenomenon.
II. POWER ANALYSIS
• It helps a researcher to determine how big a sample size should be selected
for that experiment.
• Statistical power is the probability that a statistical analysis will be able to
catch false null hypotheses. This is another way of saying that the analysis
will not make a Type-II error.
• As power increase chances of type II error decreases. Power should not be
less than 80%. Type II error is directly proportional to sample size.
III. POWER CALCULATION
• Comparing two proportions
• A placebo-controlled randomized trial proposes to assess the effectiveness
of Drug A in curing infants suffering from sepsis. A previous study showed
that proportion of subjects cured by Drug A is 50% and a clinically
important difference of 16% as compared to placebo is acceptable. Level of
significance = 5%, Power = 80%, Type of test = two-sided
• Formula of calculating sample size is.
n = [(Zα/2 + Zβ)
2
× {(p1 (1-p1) + (p2 (1-p2))}]
(p1 - p2)
2

• Where,
­ n = sample size required in each group,
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­ p1 = proportion of subject cured by Drug A = 0.50,
­ p2 = proportion of subject cured by Placebo = 0.34,
­ p1 – p2 = clinically significant difference = 0.16
­ Zα/2 = This depends on level of significance, for 5% this is 1.96
­ Zβ = This depends on power, for 80% this is 0.84

• Based on above formula the sample size required per group is 146. Hence
total sample size required is 292.
Formula: Cochran
Prévalence based
n= t² x p(1-p)
m²
• Description:
n = required sample size
t = confidence level at 95% (standard value of 1.96)
p = estimated prevalence of malnutrition in the project area
m = margin of error at 5% (standard value of 0.05)
It has been estimated that roughly 30% (0.3) of the children in the project area
suffer from chronic malnutrition. This figure has been taken from national
statistics on malnutrition in rural areas. Use of the standard values listed above
provides the following calculation.
• n= 1.96² x 0.3(1-.3)
0.05²
• n = 3.8416 x 0.21
0.0025
• n = 0.8068
0.0025
• n = 322.72 ~ 323
RANDOMIZATION
• Assurance that subject populations are similar in test and control groups is
best attained by randomly dividing a single sample population into groups
that receive the test or control treatments.
• Randomization avoids systematic differences between groups with respect
to known or unknown baseline variables that could affect outcome.
Randomization also provides a sound basis for statistical inference.
BLINDING
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• The groups should not only be similar at baseline but should be treated and
observed similarly during the trial, except for receiving the test and control
drug.
• Clinical trials are often “double-blind” (or “double-masked”), meaning that
both subjects and investigators, as well as sponsor or investigator staff
involved in the treatment or clinical evaluation of subjects, are unaware of
each subject's assigned treatment.
• The purpose of blinding to minimize the potential biases resulting from
differences in management, treatment, or assessment of patients, or
interpretation of results that could arise as a result of subject or
investigator knowledge of the assigned treatment.
APPROPRIATE TRIAL CONDUCT
• Even where there is historical evidence of sensitivity to drug effects and the
new study is similar in design to the past studies, assay sensitivity can be
undermined by the actual conduct of the trial.
• To ensure assay sensitivity of a trial, its conduct should be of high quality
and the patients actually enrolled, the treatments (other than the test
treatment) actually given, and the assessments actually made, should be
similar to those of the trials on which the determination of historical
sensitivity to drug effects was based.
• There are many factors in the conduct of a trial that can reduce the
observed difference between an effective treatment and a less effective or
ineffective treatment and therefore may reduce a trial’s assay sensitivity,
such as:
1. Poor compliance with therapy
2. Poor responsiveness of the enrolled study population to drug effects
3. Use of concomitant non-protocol medication or other treatment that
interferes with the test drug or that reduces the extent of the
potential response
4. An enrolled population that tends to improve spontaneously, leaving
no room for further drug-induced improvement
5. Poorly applied diagnostic criteria (patients lacking the disease to be
studied)
6. Biased assessment of endpoint because of knowledge that all
patients are receiving a potentially active drug, e.g., a tendency to
read blood pressure responses as normalized, potentially reducing
the difference between test drug and control.
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ETHICS IN CLINICAL RESEARCH
Influential codes of ethics and regulations that guide ethical clinical research
include:
• Nuremberg Code (1947)
• Declaration of Helsinki (2000)
• Belmont Report (1979)
• CIOMS (2002)
• U.S. Common Rule (1991)
SOCIAL AND CLINICAL VALUE
• Answering certain questions will have significant value for society or for
present or future patients with a particular illness.
• An answer to the research question should be important or valuable
enough to justify asking people to accept some risk or inconvenience for
others. In other words, answers to the research question should contribute
to scientific understanding of health or improve our ways of preventing,
treating, or caring for people with a given disease.
• Only if society will gain useful knowledge — which requires sharing results,
both negative and positive — can exposing human subjects to the risk and
burden of research be justified.
SCIENTIFIC VALIDITY
• This includes considering whether the question researchers are asking is
answerable, whether the research methods are valid and feasible, and
whether the study is designed with a clear scientific objective and using
accepted principles, methods, and reliable practices.
• It is also important that statistical plans be of sufficient power to
definitively test the objective.
• Invalid research is unethical because it is a waste of resources and exposes
people to risk for no purpose
FAIR SUBJECT SELECTION
• The primary basis for recruiting and enrolling groups and individuals should
be the scientific goals of the study — not vulnerability, privilege, or other
factors unrelated to the purposes of the study.
• Consistent with the scientific purpose, people should be chosen in a way
that minimizes risks and enhances benefits to individuals and society.
• Groups and individuals who accept the risks and burdens of research
should be in a position to enjoy its benefits, and those who may benefit
should share some of the risks and burdens.
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• Specific groups or individuals (for example, women or children) should not
be excluded from the opportunity to participate in research without a good
scientific reason or a particular susceptibility to risk.
FAVORABLE RISK-BENEFIT RATIO
• Research risk – probability of harm or injury (physical, psychological, social
or economic)
• Research benefit – “something of health-related, psychosocial, or other
value to an individual research subject or something that will contribute to
the acquisition of knowledge. Money or other compensation for
participation in research is not considered to be a benefit but rather
compensation for research-related inconveniences.
• Uncertainty about the degree of risks and benefits associated with a drug,
device, or procedure being tested is inherent in clinical research —
otherwise there would be little point doing the research. And by definition,
there is more uncertainty about risks and benefits in early-phase research
than in later research.
• It is imperative that everything been done to minimize the risks and
inconvenience to research subjects, to maximize the potential benefits, and
to determine that the potential benefits to individuals and society
• Disclosure of risks and benefits
INDEPENDENT REVIEW
• International Council of Harmonization (ICH) designate Institutional Review
Board (IRB) to protect the rights, safety and well-being of humans involved
in a clinical trial by reviewing all aspects of the trial and approving its
startup. IRBs can also be called independent ethics committees (IECs).
• To minimize potential conflicts of interest – to ascertain that the study is
ethically acceptable, an independent review panel with no vested interest
in the particular study should review the proposal and ask important
questions, including:
­ Are those conducting the trial sufficiently free of bias?
­ Is the study doing all it can to protect research volunteers?
­ Has the trial been ethically designed and is the risk–benefit ratio
favorable?
IRB/IEC RESPONSIBILITIES BEFORE, DURING AND AFTER A TRIAL
• Before it is allowed to start enrolling patients in a clinical trial, the IRB/IEC
must review all study related materials in an initial review.
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• The IRB/IEC also performs periodic reviews – called continuing reviews –
throughout the trial’s duration. Continuing reviews may take place at least
once a year and include the entire trial, not just changes.
• The IRB/IEC may also ask for additional information regarding payments
and compensation to study participants, as well as the informed consent
process.
INFORMED CONSENT
• For research to be ethical, most agree that individuals should make their
own decision. This is done through a process of informed consent in which
individuals.
1. Are accurately informed of the purpose, methods, risks, benefits, and
alternatives to the research.
2. Understand this information and how it relates to their own clinical
situation or interests
3. Make a voluntary decision about whether to participate.
• Exceptions to the need for informed consent — for example, in the case of
a child, of an adult with severe Alzheimer’s, of an adult unconscious by
head trauma, or of someone with limited mental capacity. Ensuring that the
individual’s research participation is consistent with his or her values and
interests usually entails empowering a proxy decision maker to decide
about participation, usually based on what research decision the subject
would have made
RESPECT FOR POTENTIAL AND ENROLLED SUBJECTS
• Individuals should be treated with respect from the time they are
approached for possible participation—even if they refuse enrollment in a
study—throughout their participation and after their participation ends.
This includes:
­ Respecting their privacy and keeping their private information
confidential.
­ Respecting their right to change their mind, to decide that the
research does not match their interests, and to withdraw without
penalty.
­ Informing them of new information that might emerge in the course
of research, which might change their assessment of the risks and
benefits of participating.
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­ Monitoring their welfare and, if they experience adverse reactions,
untoward events, or changes in clinical status, ensuring appropriate
treatment and, when necessary, removal from the study.
­ Informing them about what was learned from the research. Most
researchers do a good job of monitoring the volunteers’ welfare and
making sure they are okay.
­ They are not always so good about distributing the study results.
­ If they do not tell you, ask.
STUDY DESIGN
TYPES OF RESEARCH DESIGNS
CROSS-SECTIONAL
• Data are collected from the population on one occasion only
• Data usually relate to a single point or period in time
RETROSPECTIVE
• Information usually relates to previous events
PREVALENCE
• Cross-sectional studies collecting data relating to current situations or
events
OBSERVATIONAL
• Comprises of descriptive, often frequency analysis of cross-sectional data
area
PROSPECTIVE
• Relating to future events
EXPLORATORY
• Commonly employ qualitative methodology and/or a mixture of
approaches and methods
HYPOTHESIS GENERATING
• Gives clues about important factors that may influence the behavior of
individuals or success of service of explain a phenomenon.
LONGITUDINAL
• Study follows up a sample of individuals or cases over a period of time
COHORT
• A group of individuals is followed for a given period
EXPERIMENTAL STUDY
• To test a hypothesis (RCT)
QUASI-EXPERIMENTAL DESIGN
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• If randomization is not possible (participants will necessarily be aware of
the groups they are in)
FEASIBILITY STUDY
• Small scale studies
• Aims to assess aspects of the efficacy or practicalities of an intervention
• Involves small number of selected settings and often focus on specific
features of the service that would be deemed essential for its success Case-
control study
• Hypothesis generating or hypothesis testing
• Identification of causative factors or explanatory variables that lead to a
particular outcome
CASE-STUDY
• Focuses on a single case or a small number of cases in order to examine
phenomena of interest
PILOT STUDIES
• Small studies that are designed to test the methods, procedures,
instruments and documentation for a larger study.
• Before embarking on a large-scale project, it is important to check that the
project is feasible and will provide the information required to answer the
research question.
PURPOSE
• To check that the methods and procedures are acceptable and feasible in
the settings
• To ensure that the chosen methods provide the data required.
CLINICAL STUDY TYPES

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EXPERIMENTAL STUDIES
• The hallmark – allocation or assignment of individuals is under control of
investigator – can be randomized.
• The key – investigator controls the exposure or the treatment and potential
unknown confounders through randomization.
• Properly executed experimental studies provide the strongest empirical
evidence.
• The randomization also provides a better foundation for statistical
procedures than do observational studies.
I. RANDOMIZED CONTROLLED CLINICAL TRIAL (RCT)
• A prospective, analytical, experimental study using primary data
generated in the clinical environment.
• Individuals similar at the beginning are randomly allocated to two or
more treatment groups and the outcomes the groups are compared
after sufficient follow-up time.
• Properly executed, the RCT is the strongest evidence of the clinical
efficacy of preventive and therapeutic procedures in the clinical setting.
PROS AND CONS OF THE RCT
• An experimental comparison study where participants are allocated to
treatment/intervention or control/placebo groups using a random
mechanism. Best for studying the effect of an intervention.
ADVANTAGES
­ unbiased distribution of confounders
­ blinding more likely
­ randomization facilitates statistical analysis
DISADVANTAGES
­ expensive: time and money
­ volunteer bias
­ ethically problematic at times
II. RANDOMIZED CROSS-OVER CLINICAL TRIAL
• A prospective, analytical, experimental study using primary data
generated in the clinical environment.
• Individuals with a chronic condition are randomly allocated to one of
two treatment groups, and, after a sufficient treatment period and often
a washout period, are switched to the other treatment for the same
period.
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• This design is susceptible to bias if carry over effects from the first
treatment occur.
• Alternative treatments for a chronically affected individual are
administered in a random sequence and the individual is observed in a
double-blind fashion to determine which treatment is the best.
PROS AND CONS OF CROSSOVER TRIAL
• A controlled trial where each participant has both therapies e.g. is
randomized to treatment A first then starts treatment B.
ADVANTAGES
­ all participants serve as own controls and error variance is reduced, thus
reducing sample size needed
­ all participants receive treatment (at least some of the time)
­ statistical tests assuming randomization can be used
­ blinding can be maintained
DISADVANTAGES
­ all participants receive placebo or alternative treatment at some point
­ washout period lengthy or unknown
­ cannot be used for treatments with permanent effects
III. RANDOMIZED CONTROLLED LABORATORY STUDY
• A prospective, analytical, experimental study using primary data generated
in the laboratory environment.
• Laboratory studies are very powerful tools for doing basic research because
all extraneous factors other than those of interest can be controlled or
accounted for (e.g., age, gender, genetics, nutrition, environment, co-
morbidity, strain of infectious agent).
• However, this control of other factors is also the weakness of this type of
study.
• If any interactions occur between these factors and the outcome of
interest, which is usually the case, the laboratory results are not directly
applicable to the clinical setting unless the impact of these interactions are
also investigated.
OBSERVATIONAL STUDIES
• The allocation or assignment of factors is not under control of investigator.
• For those questions where it would be unethical to assign factors,
investigators are limited to observational studies.
• Observational studies provide weaker empirical evidence than do
experimental studies because of the potential for large confounding biases
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to be present when there is an unknown association between a factor and
an outcome.
• The greatest value of these types of studies (e.g., case series, ecologic,
case-control, cohort) is that they provide preliminary evidence that can be
used as the basis for hypothesis in stronger experimental studies, such as
randomized controlled trials.
1. COHORT (PROSPECTIVE - LONGITUDINAL STUDY, RETROSPECTIVE) STUDY
• A prospective, analytical, observational study, based on data, usually
primary, from a follow-up period of a group in which some have had,
have or will have the exposure of interest, to determine the
association between that exposure and an outcome.
• Susceptible to bias by differential loss to follow-up, the lack of
control over risk assignment and thus confounder symmetry, and the
potential for zero time bias when the cohort is assembled.
• Cohort studies are stronger than case-control studies when well
executed but they also are more expensive.
• Cohort studies do not provide empirical evidence that is as strong as
that provided by properly executed randomized controlled clinical
trials.
PROS AND CONS OF COHORT STUDY
• Data obtained from groups who have already been exposed, or not
exposed, to the factor of interest. No allocation of exposure is made by the
researcher. Best for studying effects of risk factors on an outcome.
ADVANTAGES
­ Subjects in cohorts can be matched, which limits the influence of
confounding variables
­ Standardization of criteria/outcome is possible
­ Easier and cheaper than a randomized controlled trial (RCT)
DISADVANTAGES
­ Cohorts can be difficult to identify due to confounding variables
­ No randomization, which means that imbalances in patient characteristics
could exist
­ Blinding/masking is difficult
­ Outcome of interest could take time
2. CASE-CONTROL STUDY

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• A retrospective, analytical, observational study often based on secondary
data in which the proportion of cases with a potential risk factor are
compared to the proportion of controls (individuals without the disease)
with the same risk factor.
• The common association measure for a case-control study is the odds ratio.
• Commonly used for initial, inexpensive evaluation of risk factors - useful for
rare conditions or for risk factors with long induction periods.
• Unfortunately, due to the potential for many forms of bias in this study
type, case control studies provide relatively weak empirical evidence even
when properly executed.
PROS AND CONS OF CASE-CONTROL STUDY
• Patients with a certain outcome or disease and an appropriate group of
controls, without the outcome or disease, are selected (usually with some
matching) then information is obtained on whether the subjects have been
exposed to the factor under investigation.
ADVANTAGES
­ Good for studying rare conditions or diseases
­ Less time needed to conduct the study because the condition or disease
has already occurred
­ Let you simultaneously look at multiple risk factors
­ Useful as initial studies to establish an association
­ Can answer questions that could not be answered through other study
designs
DISADVANTAGES
­ Retrospective studies have more problems with data quality because they
rely on memory and people with a condition will be more motivated to
recall risk factors (also called recall bias).
­ Not good for evaluating diagnostic tests because it is already clear that the
cases have the condition and the controls do not.
­ It can be difficult to find a suitable control group
3. ECOLOGIC (AGGREGATE) STUDY
• An observational analytical study based on aggregated secondary data.
Aggregate data on risk factors and disease prevalence from different
population groups is compared to identify associations. Because all data
are aggregate at the group level, relationships at the individual level
cannot be empirically determined but are rather inferred from the
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group level. Thus, because of the likelihood of an ecologic fallacy, this
type of study provides weak empirical evidence.
• Common study design for toxin studies.
4. CROSS SECTIONAL STUDY
• Sociodemographic patterning of non- communicable disease risk factors
in rural India: a cross sectional study.
PROS AND CONS OF CROSS-SECTIONAL STUDY
• Examines the relationship between
• Diseases/other health related characteristics and
• Other variables of interest as they exist in a
• Defined population at one time. Exposure and outcomes both measured at
the same time. Quantifies prevalence, risk, or diagnostic test accuracy
ADVANTAGES
­ cheap and simple
­ ethically safe
DISADVANTAGES
­ establishes association at most, not causality
­ recall bias, social desirability bias
­ researcher’s (Neyman) bias
­ group sizes may be unequal
­ confounders may be unequally distributed
REPORTING STATEMENTS
• CONSORT for randomized controlled trials STARD for diagnostic accuracy
studies STROBE for observational studies PRISMA for systematic reviews of
trials MOOSE for meta-analyses of observational studies EQUATOR network
5. CROSS-SECTIONAL (PREVALENCE STUDY) STUDY
• A descriptive study of the relationship between diseases and other
factors at one point in time (usually) in a defined population. Cross
sectional studies lack any information on timing of exposure and
outcome relationships and include only prevalent cases.
CASE SERIES
• A descriptive, observational study of a series of cases, typically describing
the manifestations, clinical course, and prognosis of a condition.
• A case series provides weak empirical evidence because of the lack of
comparability unless the findings are dramatically different from
expectations.
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• Case series are best used as a source of hypotheses for investigation by
stronger study designs, leading some to suggest that the case series should
be regarded as clinicians talking to researchers.
• Unfortunately, the case series is the most common study type in the clinical
literature.
CASE REPORT
• Anecdotal evidence. A description of a single case, typically describing the
manifestations, clinical course, and prognosis of that case.
• Due to the wide range of natural biologic variability in these aspects, a
single case report provides little empirical evidence to the clinician. They do
describe how others diagnosed and treated the condition and what the
clinical outcome was.
FACTOR INFLUENCING OBSERVATIONAL STUDIES
Observational studies are affected by following.
­ Research question
­ Data availability
­ Settings
­ Time
­ Resources
DRUG TRIALS
Types of clinical trials
Why do researchers do different kinds of clinical studies?
There are different types of clinical trials.
• Natural history studies provide valuable information about how disease
and health progress.
• Prevention trials look for better ways to prevent a disease in people who
have never had the disease or to prevent the disease from returning. Better
approaches may include medicines, vaccines, or lifestyle changes, among
other things.
• Screening trials test the best way to detect certain diseases or health
conditions.
• Diagnostic trials determine better tests or procedures for diagnosing a
particular disease or condition.
• Treatment trials test new treatments, new combinations of drugs, or new
approaches to surgery or radiation therapy.
• Quality of life trials (or supportive care trials) explore and measure ways to
improve the comfort and quality of life of people.
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DRUG TRIALS
PHASE 0 (INVESTIGATIONAL NEW DRUG STUDIES)
Aim
• Micro-dosing to assess or obtained Pharmacokinetics & Pharmacodynamic
data in humans
• Micro dose: less than 1/100 of the dose to produce pharmacological effect
with a max dose of ≤ 100 micrograms
• No therapeutic or diagnostic intent
SAMPLE SIZE
• 10 – 15 (duration of participation usually less than 1 week)
DOSE
• Sub-therapeutic
MONITORING
• Clinical researcher
MICRO-DOSING:
• Could accelerate drug development without compromising clinical safety
• It helps in selecting better drug candidates by providing early human PK
and bio-availability data
ADVANTAGES
­ Less chances of ADRs
­ Short duration
­ Less no. of volunteers
­ Reduced cost of development
­ Reduced drug development time
LIMITATIONS
­ Only PK and PD – not safety and efficacy
­ Different kinetics between micro-dose and full dose cannot be estimated
­ Limited use for agents having Non-linear kinetics
PHASE I
­ First phase of human testing for safety, efficacy, tolerability and PK and PD
of drug.
AIM
• Safety, Pharmacokinetics and pharmacodynamics for dose ranging – to
determine maximum tolerable dose
• Single ascending dose study
• Multiple ascending dose study
• Food effects
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DURATION
• 6-12 months
• No blinding or open labelled
• Act as an interface between pre-clinical research and clinical drug
development
• No therapeutic benefits
• Can also include patients – cytotoxic drugs and AIDS therapy
SINGLE ASCENDING DOSE STUDIES
• Small group (3) are given single dose – observed and tested for period
• If no adverse effects – dose is escalated with 3 new subjects
• If toxicity observed – 3 more subjects are given the same dose
• If found toxic – dose is considered maximum tolerable dose
MULTIPLE ASCENDING DOSE STUDIES
• To understand the PK and PD of multiple doses
• Samples of blood are taken at various time points
• Analyzed for how drug is processed by the body
SAMPLE SIZE OR TARGET POPULATION
• 20 – 100, healthy volunteers
DOSE
• Sub-therapeutic but ascending – until toxicity is reached
MONITORING
• Clinical researcher
• Large numbers available
• Rapid recruitment
• Low subject risks
• Results not confounded by disease variables
• Improved compliance with protocols
• In case of ADR – greater chance of recovery
DISADVANTAGE
• Dose range of interest is appropriate to determine in patients than in
healthy volunteers
• Trial restricted to homogenous subjects
• Data extrapolated to heterogeneous population
SPECIAL POPULATION HEALTHY VOLUNTEERS
• Elderly > 65 years of age
• Women childbearing age
• Children – if NCE is proposed
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PHASE II – THERAPEUTIC EXPLORATORY TRIAL
AIM
• On patients to access safety and efficacy in humans
• At this point drug is considered ineffective
• First on patients
• Sample size or Target population 1000 – 2000 - patients
DOSE
• Therapeutic
MONITORING
• Clinical researcher
NOTES
• Most of the drugs fail at this phase
• Genetic testing is common
PHASE II
AIM
• Efficacy – primary objective
• Safety – secondary objective
• At this point drug is considered ineffective
DURATION
• 6 months to several years
• Optimum dose finding
• Dose efficacy relationship
• Therapeutic dose regimen
• Duration of therapy
• Frequency of administration
• Therapeutic window
SUB-TYPES
Phase IIA: to assess dosing requirements
Phase IIB: to assess efficacy
PHASE III
Therapeutic confirmatory
Large scale, multi-centered, randomized, controlled trials
TARGET POPULATION
• Several 100s to 3000
DURATION
• Can take long time - up to 5 years
AIM
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• To establish efficacy of the test drug against the standard established drug
• To determine optimal dose schedule as anticipated in clinical use
DOSE
• Therapeutic
MONITORING
• Clinical researcher, personal physician
NOTES
• Most of the drugs fail at this phase
• Genetic testing is common
PRE-REQUISITES
• There should be no gross ADRs
• Long term preclinical safety studies completed
­ Chronic toxicity
­ Reproductive toxicity
­ Carcinogenicity
MARKETING INPUTS FAVORABLE
• IRB approval obtained
SUB-TYPES
Phase IIIA: to get sufficient and significant data
• Prior NDA approval
• Generates safety and efficacy data
Phase IIIB: allows patient to continue treatment
Phase IIIB also called label expansion – to show that drug works for additional
types of patients/diseases beyond original use
• After NDA approval
• These may supplement or complete or complete the earlier trials or may be
directed to phase IV trial
Expert committee review of efficacy, safety and potential sales
Results determine the decision to file a new application to DRAP
NCE is now in the market – beginning of Phase IV trial
NDA – New Drug Approval
• Formal proposal to FDA
• Evidences should be provided to FDA
­ Drug is safe and effective
­ Benefits outweighs the risks
­ Proposed labeling is appropriate
• Contains all information from pre-clinical to phase III studies
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• Can be thousands of pages long
• Can take 2 – 3 years to review by FDA
PHASE IV – POST MARKETING SURVEILLANCE
AIM
• Done after drug has been marketed– drug use in public
• At this point drug is considered effective
• To detect rare ADRs
• Evaluation of overdose
• Identification of new indications
• Dose and dosage refinement – new dosage and duration
• Evaluation in different age groups and types of patients
• Drug usage in community
• Cost-benefit analysis
• Quality of life assessment
SAMPLE SIZE OR TARGET POPULATION
• Anyone seeking treatment from physician – no fixed duration and patient
population
Studies continue to collect data of about efficacy and side effects on various
population on long term usage
OBSERVATIONAL AND NON-EXPERIMENTAL IN NATURE
• Helps to detect rare ADRs and interactions
• Can explore new uses of drugs
• Periodic Safety Reports
­ Submitted by manufacturer after every 6 months for 2 yrs. and then
annually for next 2 yrs. after marketing approval
• In case of harmful effect drug can be withdrawn from the market
E.g. September 30, 2004, Merck withdrew Rofecoxib from market because
of risks of heart attack and stroke associated with long term use.
DOSE
• Therapeutic
MONITORING
• Clinical researcher, personal physician
NOTES
• Most of the drugs fail at phase II, III, & IV.
• Genetic testing is common.
DRUG TRIALS SUMMARY
Phase Aim Notes
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Phase 0
Pharmacodynamics
and
pharmacokinetics in
humans
Phase 0 trials are the first-in-human trials. Single sub-
therapeutic doses of the study drug or treatment are given
to a small number of subjects (10 to 15) to gather
preliminary data on the agent's pharmacodynamics (what
the drug does to the body) and pharmacokinetics (what the
body does to the drugs).
For a test drug, the trial documents the absorption,
metabolization, and removal (excretion) of the drug, and
the drug's interactions within the body, to confirm that
these appear to be as expected.
Phase 1
Screening for
safety.
Testing within a small group of people (20–80) to evaluate
safety, determine safe dosage ranges, and begin to identify
side effects.
A drug's side effects could be subtle or long term, or may
only happen with a few of people, so phase 1 trials are not
expected to identify all side effects.
Phase 2
Establishing the
efficacy of the drug,
usually against a
placebo.
Testing with a larger group of people (100–300) to see if it is
effective and to further evaluate its safety. The gradual
increase in test group size, allows less common side effects
to be progressively sought.
Phase 3
Final confirmation
of safety and
efficacy – standard
treatment
Testing with large groups of people (1,000–3,000) to
confirm its effectiveness, monitor side effects, compare it to
commonly used treatments, and collect information that
will allow it to be used safely.
Phase 4
Sentry studies
during sales.
Post marketing studies delineate additional information,
including the treatment's risks, benefits, and optimal use.
As such, they are ongoing during the drug's lifetime of
active medical use.
CONTINGENCY PLANS
• Patient management
• Evaluation and reporting to all relevant persons and groups
• Data monitoring plans
• Protocol amendment or study termination
DATA ANALYSIS
• Occurrence of event
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• Time to event
• Mean level of response
• Duration of response
• Intention-to-treat
• Explanatory
• Subgroups
• Adjusted vs. Unadjusted
CLINICAL PROTOCOL
BACKGROUND/JUSTIFICATION
• Where we are in the field
• What the study will add that is important
OBJECTIVES
• Primary hypothesis
• Secondary hypothesis
• Other
STUDY DESIGN AND METHODS
• Type of study, comparison
• Inclusion and exclusion criteria
• Description of intervention (what, how)
• Concomitant therapy
• Examination procedures (baseline, follow-up, outcome assessment)
• Intervention assignment procedure
MONITORING AND MANAGEMENT
• Data and safety monitoring
• Adverse event assessment, reporting
• Contingency procedures
• Withdrawal criteria
REGULAR FOLLOW UP
1. Routine Procedures (report forms)
I. Interviews
II. Examinations
III. Laboratory Tests
2. Adverse Event Detection/Reporting
3. Quality Assurance
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EMERGENCY TREATMENT
INTRODUCTION
Emergency Treatment
• First aid or other immediate intervention for accidents or medical
conditions requiring immediate care and treatment before definitive
medical and surgical management can be procured.
EMERGENCY MEDICINE
• The branch of medicine that deals with evaluation and initial treatment of
medical conditions caused by trauma or sudden illness.
• Emergency medicine, also known as accident and emergency medicine, is
the medical specialty concerned with caring for undifferentiated,
unscheduled patients with illnesses or injuries requiring immediate
medical attention.
GOLDEN HOUR
• A structured approach is considered a hallmark of the initial care of specific
medical emergencies.
• It facilitates optimal use of time and early recognition of deterioration,
especially in the so-called ‘golden hour’ which is the first hour after onset of
injury or illness when resuscitation could be most beneficial.
• This golden hour has been recognized in various emergencies such as
trauma, stroke, sepsis and shock.
ABCDE APPROACH
The approach to all deteriorating or critically ill patients is the same. The
underlying principles are:
• Use the Airway, Breathing, Circulation, Disability, Exposure (ABCDE)
approach to assess and treat the patient.
• Do a complete initial assessment and re-assess regularly.
• Treat life-threatening problems before moving to the next part of
assessment.
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• Assess the effects of treatment.
• Communicate effectively - use the Situation, Background, Assessment,
Recommendation (SBAR) or Reason, Story, Vital signs, Plan (RSVP)
approach.
• The aim of the initial treatment is to keep the patient alive and achieve
some clinical improvement. This will buy time for further treatment and
making a diagnosis.
• Remember – it can take a few minutes for treatments to work, so wait a
short while before reassessing the patient after an intervention.
• The Airway, Breathing, Circulation, Disability, Exposure (ABCDE) approach is
a systematic approach to the immediate assessment and treatment of
critically ill or injured patients.
• The approach is applicable in all clinical emergencies.
• Training of a systematic approach using the Airway Breathing Circulation
Disability Exposure (ABCDE) primary assessment in medical emergencies
has increased during recent years.
AIMS OF ABCDE APPROACH
• To provide life-saving treatment
• To break down complex clinical situations into more manageable parts
• To serve as an assessment and treatment algorithm
• To establish common situational awareness among all treatment providers
• To buy time to establish a final diagnosis and treatment.
WHICH PATIENTS NEED ABCDE?
• The ABCDE approach is applicable for all patients, both adults and children.
• The ABCDE approach should be used whenever critical illness or injury is
suspected.
• The ABCDE approach is also recommended as the first step in post
resuscitation care upon the return of spontaneous circulation.
• The ABCDE approach is not recommended in cardiac arrest
ABCDE PRINCIPLES
• With the ABCDE approach, the initial assessment and treatment are
performed simultaneously and continuously.
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• Even when a critical condition is evident, the cause may be elusive; in such
situations, life-saving treatment must be instituted before a definitive
diagnosis has been obtained.
• Early recognition and effective initial treatment prevent deterioration and
buys time for a definitive diagnosis to be made.
AIRWAY
• Untreated, airway obstruction causes hypoxia and risks damage to the
brain, kidneys and heart, cardiac arrest, and death.
• A reduced level of consciousness is a common cause of airway obstruction,
partial or complete.
• A common sign of partial airway obstruction in the unconscious state is
snoring.
• Untreated airway obstruction can rapidly lead to cardiac arrest.
BREATHING
• During the immediate assessment of breathing, it is vital to diagnose and
treat immediately life-threatening conditions.
e.g.
­ acute severe asthma,
­ pulmonary edema,
­ tension pneumo thorax
­ massive hemothorax.
CIRCULATION
• In almost all medical and surgical emergencies, consider hypovolemia to be
the primary cause of shock, until proven otherwise.
• Unless there are obvious signs of a cardiac cause, give intravenous fluid to
any patient with cool peripheries and a fast heart rate.
• Color changes, sweating, and a decreased level of consciousness are signs
of decreased perfusion.
• An intravenous access should be obtained as soon as possible, and saline
should be infused.
DISABILITY
• what is the level of consciousness?
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The level of consciousness can be rapidly assessed using the AVPU method,
where the patient is graded as:
­ Alert (A)
­ Voice responsive (V)
­ Pain responsive (P)
­ Unresponsive (U).
• Alternatively, the Glasgow Coma Score can be used.
GLASGOW COMA SCALE
• It is a neurological scale which aims to give a reliable and objective way of
recording the conscious state of a person for initial as well as subsequent
assessment.
• A patient is assessed against the criteria of the scale, and the resulting
points give a patient score:
­ Between 3 (indicating deep unconsciousness) and either 14 (original
scale) or 15 (more widely used modified or revised scale).
ELEMENTS OF THE SCALE
EYE OPENING RESPONSE
• Spontaneous--open with blinking at baseline 4 points
• To verbal stimuli, command, speech 3 points
• To pain only (not applied to face) 2 points
• No response 1 point
VERBAL RESPONSE
• Oriented 5 points
• Confused conversation, but able to answer questions 4 points
• Inappropriate words 3 points
• Incomprehensible speech 2 points
• No response 1 point
MOTOR RESPONSE
• Obeys commands for movement 6 points
• Purposeful movement to painful stimulus 5 points
• Withdraws in response to pain 4 points
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• Flexion in response to pain (decorticate posturing) 3 points
• Extension response in response to pain 2 points
• No response 1 point
EXPOSURE
• To examine the patient properly full exposure of the body may be
necessary. Respect the patient’s dignity and minimize heat loss.
• Signs of trauma, bleeding, skin reactions (rashes), needle marks, etc., must
be observed.
• Body temperature can be estimated by feeling the skin or using a
thermometer when available.
The ABCDE approach is a strong clinical tool for the initial assessment and
treatment of patients in acute medical and surgical emergencies, including both
prehospital first aid and in-hospital treatment.
ADDITIONAL INFORMATION
• Take a full clinical history from the patient, any relatives or friends, and
other staff.
• Review the patient’s notes and charts:
­ Study both absolute and trended values of vital signs.
­ Check that important routine medications are prescribed and being
given.
• Review the results of laboratory or radiological investigations.
• Consider which level of care is required by the patient (e.g. ward, HDU,
ICU).
• Make complete entries in the patient’s notes of your findings, assessment
and treatment. Where necessary, hand over the patient to your colleagues.
• Record the patient’s response to therapy.
• Consider definitive treatment of the patient’s underlying condition.
STROKE
Stroke involves abrupt onset of focal neurologic deficit that lasts at least 24 hours
and is presumed to be of vascular origin. Stroke can be either
• Ischemic or
• Hemorrhagic.
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ISCHEMIC STROKE
• An Ischemic Stroke occurs when a clot or mass, often a fatty plaque
deposit, clogs a blood vessel cutting off the blood flow to brain cells. It is
also called cerebral infarction.
HEMORRHAGIC STROKE
• A Hemorrhagic Stroke results from a weakened vessel that ruptures and
bleeds into the surrounding brain tissue.
• The blood accumulates and forms a bruise within the brain tissue,
compressing brain cells and causing them to die.
TRANSIENT ISCHEMIC ATTACK OR TIA
• A TIA or Transient Ischemic Attack produces stroke-like symptoms. A TIA is
caused by a clot; but unlike a stroke, the blockage is temporary and usually
causes no permanent damage to the brain. TIAs are often called “mini-
strokes”.
• TIA is a medical emergency.
Stroke is associated with a risk of morbidity and mortality.
Patients presenting with acute symptoms should be immediately transferred to
hospital for accurate diagnosis of stroke type, and urgent initiation of appropriate
treatment.
SIGNS AND SYMPTOMS
The five most common signs and symptoms of stroke are:
1. Sudden numbness or weakness of the face, arm, or leg.
2. Sudden confusion or trouble speaking or understanding others.
3. Sudden trouble seeing in one or both eyes.
4. Sudden dizziness, trouble walking, or loss of balance or coordination.
5. Sudden severe headache with no known cause.
Rapid diagnosis and treatment of acute ischemic strokes is essential to reduce
death and disability from stroke. That is why learning the FAST acronym is so
important:
• F = Face: Is one side of the face drooping down?
• A = Arm: Can the person raise both arms, and is one arm weak?
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• S = Speech: Is speech slurred or confusing?
• T = Time: Time is critical
TREATMENT
• Ensure adequate respiratory and cardiac support and determine quickly
from CT scan whether the lesion is ischemic or hemorrhagic.
• Evaluate ischemic stroke patients presenting within hours of symptom
onset for reperfusion therapy.
• Elevated blood pressure (BP) should remain untreated in the acute period
(first 7 days) after ischemic stroke to avoid decreasing cerebral blood flow
and worsening symptoms. BP should be lowered if it exceeds 220/120 mm
Hg or there is evidence of aortic dissection, acute myocardial infarction
(MI), pulmonary edema, or hypertensive encephalopathy.
• If BP is treated in the acute phase, short-acting parenteral agents (e.g.,
labetalol, nicardipine, nitroprusside) are preferred.
• Assess patients with hemorrhagic stroke to determine whether they are
candidates for surgical intervention.
• After the hyperacute phase, focus on preventing progressive deficits,
minimizing complications, and instituting secondary prevention strategies.
ISCHEMIC STROKE
• The 2018 comprehensive guideline updates guidance on which patients are
eligible to receive IV alteplase, mechanical thrombectomy and other stroke
treatments to reduce long-term morbidity.
• Alteplase IV r-tPA within 4.5 hours of stroke onset remains the standard of
care for most ischemic stroke patients, providing the opportunity for more
favorable outcomes.
• Patients eligible for IV alteplase should receive it, even if mechanical
thrombectomy is being considered.
• Mechanical thrombectomy using stent retrievers within up to 24 hours of
stroke onset may lead to faster and more complete reperfusion for certain
patients.
• In selected patients with AIS within 6-16 hours of last known normal who
have large vessel occlusion in the anterior circulation and have favorable
imaging studies, mechanical thrombectomy is recommended.
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• The benefits of both IV alteplase and mechanical thrombectomy are time
dependent.
• The earlier the treatment within the time window, the greater the benefit to
patients.
• ADHERENCE TO A STRICT PROTOCOL IS ESSENTIAL TO ACHIEVING
POSITIVE OUTCOMES
1. Activate the stroke team.
2. Treat as early as possible within 4.5 hours of onset.
3. Obtain CT scan to rule out hemorrhage.
4. Meet all inclusion and no exclusion criteria.
5. Administer alteplase 0.9 mg/kg (maximum 90 mg) infused IV over 1
hour, with 10% given as initial bolus over 1 minute.
6. Avoid anticoagulant and antiplatelet therapy for 24 hours.
7. Monitor the patient closely for elevated BP, response, and
hemorrhage,
• Aspirin 160 to 325 mg/day started between 24 and 48 hours after
completion of alteplase also reduces long-term death and disability.
• Treatment of elevated BP after ischemic stroke reduces risk of stroke
recurrence.
• Treatment guidelines recommend BP reduction in patients with stroke or
TIA after the acute period (first 7 days).
• Low-molecular-weight heparin or low-dose subcutaneous unfractionated
heparin (5000 units three times daily) is recommended for prevention of
deep vein thrombosis in hospitalized patients with decreased mobility due
to stroke.
HEMORRHAGIC STROKE
• There are no standard pharmacologic strategies for treating intracerebral
hemorrhage.
• Follow medical guidelines for:
­ Managing BP
­ Increased intracranial pressure
­ And other medical complications in acutely ill patients in
neurointensive care units.
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• SAH (Subarachnoid Hemorrhage) due to aneurysm rupture is often
associated with delayed cerebral ischemia in the 2 weeks after the bleeding
episode.
• Vasospasm of the cerebral vasculature is thought to be responsible for the
delayed ischemia and occurs between 4 and 21 days after the bleed.
• The calcium channel blocker nimodipine 60 mg every 4 hours for 21 days,
along with maintenance of intravascular volume with pressor therapy, is
recommended to reduce the incidence and severity of neurologic deficits
resulting from delayed ischemia.
SHOCK
• Shock is an acute state of inadequate perfusion of critical organs that can
lead to death if therapy is not optimal.
• Shock is defined as systolic blood pressure (SBP) less than 90 mm Hg or
reduction of at least 40 mm Hg from baseline with perfusion abnormalities
despite adequate fluid resuscitation.
TYPES OF SHOCK
The main types of shock include:
• Cardiogenic shock (due to heart problems)
• Hypovolemic shock (caused by too little blood volume)
• Anaphylactic shock (caused by allergic reaction)
• Septic shock (due to infections)
• Neurogenic shock (caused by damage to the nervous system)
CAUSES
1. Hypovolemic shock: due to a loss of intravascular volume
2. Cardiogenic shock: due to cardiac pump failure
3. Obstructive shock: due to obstruction to cardiac filling or emptying
4. Distributive shock: due to exaggerated peripheral vascular dilatation
CLINICAL PRESENTATION
PATIENTS WITH HYPOVOLEMIC SHOCK MAY HAVE
• Thirst
• Anxiousness
• Weakness
• Lightheadedness
• Dizziness
• Scanty urine output
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• Dark yellow urine.
SIGNS OF MORE SEVERE VOLUME LOSS INCLUDE
• Tachycardia (>120 beats/min)
• Tachypnea (>30 breaths/min)
• Hypotension (SBP <90 mm Hg)
• Mental status changes or unconsciousness
• Agitation, and Normal or low body temperature (in the absence of
infection) with cold extremities and decreased capillary refill.
• Serum sodium and chloride concentrations are usually high with acute
volume depletion.
• The blood urea nitrogen (BUN): creatinine ratio may be elevated initially,
but the creatinine increases with renal dysfunction.
• Metabolic acidosis results in elevated base deficit and lactate
concentrations with decreased bicarbonate and pH.
• Complete blood cell count (CBC) is normal in absence of infection.
• In hemorrhagic shock, the red cell count, hemoglobin, and hematocrit will
decrease.
• Urine output is decreased to less than 0.5 to 1 mL/h.
• With more severe volume depletion, dysfunction of other organs may be
reflected in laboratory testing (e.g., elevated serum transaminases levels
with hepatic dysfunction).
TREATMENT
GOALS OF TREATMENT
• The goal during resuscitation from shock is to achieve and maintain mean
arterial pressure (MAP) above 65 mm Hg while ensuring adequate
perfusion to critical organs.
• The ultimate goals are to prevent further disease progression with
subsequent organ damage and, if possible, to reverse organ dysfunction
that has already occurred.
GENERAL APPROACH
• Initiate supplemental O2 at the earliest signs of shock, beginning with 4 to
6 L/min via nasal cannula or 6 to 10 L/min by face mask.
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• Fluid resuscitation to maintain circulating blood volume is essential.
• If fluid administration does not achieve desired end points, pharmacologic
support is necessary with inotropic and vasoactive drugs.
• Supportive care measures include assessment and management of pain,
anxiety, agitation, and delirium.
FLUID RESUSCITATION FOR HYPOVOLEMIC SHOCK
CRYSTALLOIDS
• Crystalloid solutions (0.9% sodium chloride or lactated Ringer solution) are
the initial fluids of choice.
• Crystalloids are administered at a rate of 500 to 2000 mL/h, depending on
severity of the deficit, degree of ongoing fluid loss, and tolerance to
infusion volume.
• Usually 2 to 4 L of crystalloid normalizes intravascular volume.
ADVANTAGE
• Crystalloids can be rapidly and easily administered, are compatible with
most drugs, and have low cost.
DISADVANTAGE
• Their disadvantages include the need to use large fluid volumes and the
possibility that dilution of oncotic pressure may lead to pulmonary edema.
COLLOIDS
• Hydroxyethyl starch, dextran, and albumin possess the theoretical
advantage of prolonged intravascular retention time compared with
crystalloid solutions.
• However, colloids are expensive and have been associated with fluid
overload, renal dysfunction, and bleeding.
BLOOD PRODUCTS
• Some patients require blood products (whole blood, packed red blood cells,
fresh frozen plasma, or platelets) to ensure maintenance of O2 carrying
capacity, as well as clotting factors and platelets for blood hemostasis.
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PHARMACOLOGICAL THERAPY FOR SHOCK
HYPOVOLEMIC SHOCK
• Inotropic agents and vasopressors are generally not indicated in initial
treatment of hypovolemic shock (if fluid therapy is adequate), because the
body’s compensatory response is to increase CO and peripheral resistance
to maintain BP.
• Use of vasopressors in lieu of fluids may exacerbate this resistance to the
point that circulation is stopped. Therefore, vasoactive agents that dilate
peripheral vasculature such as dobutamine are preferred if blood pressure
is stable and high enough to tolerate the vasodilation.
• Vasopressors are only used as a temporizing measure or last resort when all
other measures fail to maintain perfusion.
SEPTIC SHOCK
• Initial hemodynamic therapy for septic shock is administration of IV fluid
(30 mL/kg of crystalloid), with the goal of attaining CVP 8 to 12 mm Hg or
15 mm Hg in mechanically ventilated patients or patients with abdominal
distention or preexisting ventricular dysfunction.
• Crystalloids are preferred over colloids unless patients are at risk for
adverse events from redistribution of IV fluids to extravascular tissues or
are fluid restricted.
• Norepinephrine is the preferred initial vasopressor in septic shock not
responding to fluid administration.
• Epinephrine may be added in cases where there is suboptimal
hemodynamic response to norepinephrine.
• Phenylephrine may be tried as the initial vasopressor in cases of severe
tachydysrhythmias.
• Dobutamine is used in low CO states despite adequate fluid resuscitation
pressures.
• Vasopressin may be considered as adjunctive therapy in patients who are
refractory to catecholamine vasopressors despite adequate fluid
resuscitation.
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• Dosage titration and monitoring of vasopressor and inotropic therapy
should be guided by clinical response, the goals of early goal-directed
therapy, and lactate clearance.
• Vasopressor/inotrope therapy is continued until myocardial depression
and vascular hypo-responsiveness (i.e., blood pressure) of septic shock
improve, usually measured in hours to days. Discontinuation of therapy
should be executed slowly with careful monitoring.
1. NOREPINEPHRINE
• It is first-line therapy for septic shock because it effectively increases
MAP.
• Norepinephrine infusions are initiated at 0.05 to 0.1 mcg/kg/min and
rapidly titrated to preset goals of MAP (usually at least 65 mm Hg),
improvement in peripheral perfusion and/or achievement of desired
oxygen transport.
• Norepinephrine 0.01 to 2 mcg/kg/min improves hemodynamic
parameters to “normal” values in most patients with septic shock
exceeding those recommended by most references frequently are
needed in critically ill patients with septic shock to achieve
predetermined goals.
2. PHENYLEPHRINE
• In sepsis, it improves MAP by increasing cardiac index through enhanced
venous return to the heart (increase in CVP and stroke index) and by
acting as a positive inotrope.
• Phenylephrine 0.5 to 9 mcg/kg/min, used alone or in combination with
dobutamine or low doses of dopamine, improves blood pressure and
myocardial performance in fluid-resuscitated septic patients.
3. EPINEPHRINE
• It is an acceptable choice for hemodynamic support of septic shock
because of its combined vasoconstrictor and inotropic effects, but it is
associated with tachydysrhythmias and lactate elevation.
• As a result, it is considered an alternative agent.
• Infusion rates of 0.04 to 1 mcg/kg/min alone increase hemodynamic and
oxygen-transport variables to supranormal values without adverse
effects in septic patients without coronary artery disease.
4. DOPAMINE
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• Dopamine is generally not as effective as norepinephrine and
epinephrine for achieving goal MAP in patients with septic shock.
• Dopamine doses of 5 to 10 mcg/kg/min increase cardiac index by
improving contractility and heart rate, primarily from its β1 effects.
• Its clinical use frequently is hampered by tachycardia and
tachydysrhythmias, which may lead to myocardial ischemia.
5. DOBUTAMINE
• Dobutamine is an inotrope with vasodilatory properties (an
“inodilator”). It is used to increase the cardiac index, typically by 25%
to 50%.
• Dobutamine should be started at dosages ranging from 2.5 to 5
mcg/kg/min.
6. VASOPRESSIN
• Vasopressin produces rapid and sustained improvement in
hemodynamic parameters at dosages not exceeding 0.04 units/min.
• It should be used with extreme caution in septic shock patients with
cardiac dysfunction.
7. CORTICOSTEROIDS
• Corticosteroids can be initiated in septic shock when adrenal
insufficiency is suspected, when vasopressor dosages are escalating,
or when weaning of vasopressor therapy proves futile.
• Adverse events are few because corticosteroids are administered for
a short time, usually 7 days.
• Acutely, elevated BUN, white blood cell count, and glucose may
occur.
• In general, treatment of septic shock with corticosteroids improves
hemodynamic variables and lowers catecholamine vasopressor
dosages with minimal to no adverse effect on patient safety.
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DRUG INTERACTIONS
WHY STUDY DRUG INTERACTIONS
• Ideal drug still to be discovered that do not interact with food or other
drugs.
• Drugs are consumed by humans having:
­ Genetic variability
­ Food, lifestyle and environment
­ Herbs
REASONS OF DDI
• Drug interactions happens because of:
­ Genetic variability
­ Lack of knowledge about the drug, patient disease patho-physiology
­ Out of accidental misuse
­ It occurs when a patient’s response to a drug is modified by food,
nutritional supplements, formulation excipients, environmental
factors, other drugs or disease.
DEFINITION
• It is the modification of the effect of one drug (the object drug) by the prior
concomitant administration of another (precipitant drug).
• Interactions between drugs (drug–drug interactions) may be beneficial
(ketoconazole increase bioavailability of midazolam, ketoconazole reduce
cyclosporin dose 50 – 80%, Nifedipine + Propranolol) or harmful.
DDI’S AND PROBABLE RESPONSES
• A drug interaction is a pharmacological response which cannot be
explained by the action of a single drug but may be due to two or more
drugs acting simultaneously but the effects of a drug may also be changed
by the presence of food, drink or by some environmental chemical agent.
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• The outcome of a drug interaction may be harmful if the interaction results
in increased efficacy or toxicity of one or more drugs. However, reduction
in efficacy due to a drug interaction can sometimes be just as harmful.
INTERACTIONS MAY BE
ADDITIVE OR SYNERGISTIC (INCREASED EFFECTS)
• Potentiation e.g. combination antibiotics (beneficial)
• Toxicity e.g. diuretics and NSAIDs, worsening renal impairment
(undesirable)
ANTAGONISTIC (LESSENED EFFECT)
• Antagonism e.g. antidote for overdose (beneficial)
• Loss of effect e.g. carbamazepine reducing warfarin’s blood thinning effect
(undesirable)
Alteration of effects of one or more drugs or the production of idiosyncratic
effects.
When a therapeutic combination could lead to an unexpected change or
complication in the condition of the patient, this would be described as an
interaction of potential clinical significance.
CLINICAL RELEVANCE
• The clinical relevance of drug interactions is evident that up to 8% of
hospital admissions are due to adverse drug reactions and over 20% of
these are due to drug interactions.
DRUG INTERACTION CONSIDERATION
• When prescribing multiple drugs
• Patient’s food and lifestyle pattern
• Genes and Environment
• Drug interactions should be considered both in the differential diagnosis of
symptoms (for interactions that have already occurred) and when
prescription changes are made (for potential interactions).
• Software checkers for drug interactions are widely available but have
limited clinical utility.
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MAGNITUDE OF THE PROBLEM
• For example, amongst the macrolide class, while erythromycin and
clarithromycin inhibit CYP3A4 leading to interactions with other drugs,
Azithromycin does not.
• Likewise, while ketoconazole interacts with lovastatin and simvastatin and
raises their plasma levels it does not do so with rosuvastatin or pravastatin.
CHANCES OF DDI’S
• A study has pointed out that when 2 drugs are used in combination the
interaction potential is 5-6%, that goes up to 50% with 5 drugs and when 8
drugs or more are co-prescribed the potential may even reach 100%.
REDUCTION OF DRUG INTERACTIONS
• Patient harm from drug interactions can be reduced by:
1. Using a personal formulary – using few drugs and knowing them well.
2. Recognizing drugs that are major perpetrators of interactions.
3. Recognizing narrow therapeutic index drugs as vulnerable to
interactions.
4. Applying clinical pharmacology principles.
5. Comprehensive knowledge of the disease pathophysiology and Drug
PK and PD parameters.
RISK FACTORS
1. Poly pharmacy
2. Multiple prescribers
3. Multiple pharmacies
4. Genetic make up
5. High risk patients (age, patients with renal and hepatic impairment)
6. Specific population (females, elderly, obese, malnourished, critically ill
patient, transplant recipient)
7. Specific illness (Hepatic disease, Renal dysfunction)
8. Narrow therapeutic index drugs (Cyclosporine, Digoxin, Insulin, Lithium,
Antidepressant, Warfarin)
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CORE CONCEPTS
1. P450 SYSTEM
• A set of enzymes (usually hepatic, but not always) metabolize a wide array
of endogenous and exogenous substrates in order to detoxify them and
then eliminate them from the body.
• Involved in phase I, or oxidative, metabolism, as opposed to phase II
conjugation.
• There are more than 40 P450 enzymes.

2. SUBSTRATE
• “The agent that is metabolized by an enzyme into a metabolic end product
is called substrate.”
• Deactivation of the agent is a preparation, for elimination from the body.
• In the rare case of “pro drugs,” these agents are initially inactive and rely on
enzymes to be metabolized into active compounds.
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3. INHIBITOR
• Competitive inhibition - when two substrates compete for the same
substrate binding site(s) on an enzyme. The competitive inhibitor binds so
avidly to the substrate binding site that it effectively displaces the other
substrate(s), but the enzyme otherwise functions normally.
• Noncompetitive, or allosteric inhibition - when an agent binds to a non-
substrate binding site on an enzyme. It renders the enzyme less efficient in
metabolizing all substrates of that enzyme.
Example:
­ Paroxetine Is added to Nortriptyline.
▪ Nortriptyline is a 2D6 substrate (Sawada and Ohtani 2001), and
paroxetine is a 2D6 inhibitor (von Moltke et al. 1995).
▪ The addition of paroxetine impairs the ability of 2D6 to
metabolize nortriptyline, leading to an increase in the blood
level of nortriptyline.
4. INDUCERS
• “An agent that causes the liver (or other target organ) to produce more of
an enzyme, leading to increased metabolism of the substrates.”
• No more intrinsically active than otherwise; there is just more of it.
• In the concept of enzymatic stimulation, which is being considered for 3A4,
the enzyme is rendered more efficient, aside from its quantity in the liver
and/or gut. The introduction of inducers leads to increased metabolite
formation and more rapid depletion of substrate(s).
• Induction of P450 enzymes can be evident within several days but generally
takes 2 – 3 weeks to reach full effect.
• Example:
­ Carbamazepine Is Added to Haloperidol.
▪ Carbamazepine induces 3A4, 1A2, and phase II glucuronidation
(Hachad et al. 2002; Lucas et al. 1998; Parker et al. 1998, Spina
et al. 1996), and haloperidol is metabolized by 3A4, 2D6, 1A2,
and phase II glucuronidation (Desai et al. 2001; Kudo and
Ishizaki 1999).
▪ This increase in the available amounts of 3A4 and 1A2 (and
possibly particular UGTs as well) leads to more efficient
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metabolism of the haloperidol and a resulting decrease in the
blood level of haloperidol. This may lead to clinical
decompensation (Hesslinger et al. 1999).
5. VARIABILITY
• Inter-individual variability in enzymatic efficiency (10- to 30-fold differences
in 3A4 function).
• Trends within specific ethnic groups.
­ “Poor metabolizers” or “polymorphic” for the specific P450 enzymes
in question – lack copied of P450 genes.
­ “Ultra-rapid metabolizers” individuals who have extra copies of P450
genes.
­ Metabolically normal individuals (called “extensive metabolizers”)
can functionally be converted to “poor metabolizers” if exposed to
inhibitor of specific P450 enzyme - as long as they are exposed to
that agent.
• Example:
­ CYP2D6
I. Poor metabolizers
• White 6 – 10%
• Asians 2%
• Afro-Americans more than 10%
II. Ultra-rapid metabolizers
• Middle eastern
• North Africans
• Conversely, individuals exposed to an inducer may function as ultra-rapid
metabolizers for that P450 enzyme.
• Poor metabolizers/polymorphic individuals will generally have much higher
blood levels of a substrate at a given dose than will extensive metabolizers.
Although this is counterintuitive, the rate at which poor metabolizers /
polymorphic individuals metabolize a substrate of that enzyme is not
influenced by introducing an inhibitor of that enzyme. There is no way to
become an “ultra-poor metabolizer,” the inhibitor is redundant.
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6. P-GLYCOPROTEIN (P-GP)
• One of a super-family of transporters that line the gut and the blood-brain
barrier. It plays a central role in determining to what degree various
substances are absorbed into or excreted from the body.
• P-glycoprotein is an extruding transporter, designed to remove substances
from enterocytes back into the gut lumen, or from the brain back into the
blood.
• P-glycoprotein has substrates, inhibitors, and inducers.
­ P-glycoprotein inhibitors antagonize this process and lead to
retention of P-glycoprotein substrates.
­ P-glycoprotein inducers increase the amount of active P-glycoprotein
and thus lead to more extrusion of P-glycoprotein substrates.
P-gp Substrate P-gp Inhibitors P-gp Inducers
Digoxin Cyclosporine A Phenytoin
Loperamide Ketoconazole Carbamazepine
Vinblastine Ritonavir Rifampicin
Quinidine Verapamil
Reserpine
7. UGTS (URIDINE 5-DIPHOSPHATE GLUCURONOSYL TRANSFERASES)
• A family of enzymes that perform phase II conjugative metabolism
(glucuronidation), which usually follows the phase I oxidative metabolism
performed by P450 enzymes or other oxidative metabolic steps.
• This system functions quite similarly to the P450 system, with several
enzymes that also have alpha-numeric labels (1A4, 2B15, etc.), with each
enzyme having its own substrates, inhibitors, and inducers.
UGTs Substrates UGTs Inhibitors UGTs Inducers
Acetaminophen Atazanavir Nicotine
Losartan Gemfibrozil Carbamazepine
Fluvastatin
Morphine
Simvastatin
OUTCOMES OF DRUG INTERACTIONS
1. Loss of therapeutic effect
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2. Toxicity
3. Unexpected increase in pharmacological activity
4. Beneficial effects e.g. additive & potentiation (intended) or antagonism
(unintended).
5. Chemical or physical interaction e.g. I.V incompatibility in fluid or syringes
mixture.
DRUGS MOST LIKELY TO PRECIPITATE INTERACTIONS
• Highly protein bound; Aspirin & Phenylbutazone
Object Drug Precipitating Drug Effect
Aspirin Antacids Reduced aspirin levels
Anti-diabetic Aspirin (large doses) Reduced blood sugar
Corticosteroids Aspirin (large doses)
Reduced corticosteroid
levels
Furosemide Aspirin Risk of acute renal failure

Object Drug Precipitating Drug Effect
Azapropazone Phenylbutazone Reduced glucose levels
Warfarin Phenylbutazone
Increased anti-coagulant
effects

• Drugs that stimulate the metabolism of other drugs such as phenytoin,
carbamazepine, rifampicin and griseofulvin.
Object Drug Precipitating Drug Effect
Phenytoin Acetaminophen Reduced acetaminophen
Phenytoin Amiodarone
Reduced amiodarone
levels
Phenytoin Ketoconazole
Reduced plasma levels of
ketoconazole
Cimetidine Carbamazepine Increased CZP levels
Macrolides Carbamazepine Increased CZP levels
Rifampicin Calcium channel blockers Reduced levels of CCBs
Rifampicin B-blockers (propranolol)
Reduced levels of
Propranolol
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• Drugs that inhibit the metabolism of other drugs which include allopurinol,
cimetidine, metronidazole, ketoconazole, chloramphenicol, quinolones and
MAO inhibitors.
• Drugs that alter renal elimination like diuretics and probenecid.
DRUG INTERACTIONS TYPES
• Drug-drug interactions
• Drug-disease interactions
• Drug-Food interactions
• Drug-Herb interactions
• Drug-Environment interactions
• Several ways that a drug may interact
­ Pharmacokinetic
­ Pharmacodynamic
­ Synergistic
­ Antagonistic
MECHANISM OF DRUG INTERACTION
1. Pharmacokinetics involve the effect of a drug on another from the point of
view that includes absorption, distribution, metabolism and excretion.
2. Pharmacodynamics are related to the pharmacological activity of the
interacting drugs e.g. synergism, antagonism, altered cellular transport,
effect on the receptor site.
1. PHARMACOKINETIC DRUG INTERACTIONS
• Potential Mechanisms of Drug Interactions Involving Absorption and
Distribution.
­ Absorption (passive diffusion, active transport, facilitated transport,
ion-pair transport and endocytosis)
▪ Altered gastric pH
▪ Chelation of compounds
▪ Adsorption of compounds
▪ Altered gastric emptying
▪ Altered intestinal motility
▪ Altered intestinal blood flow
▪ Altered active and passive intestinal transport
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▪ Altered intestinal cytochrome P450 isozyme activity
▪ Altered intestinal P-glycoprotein activity
­ Distribution
▪ Altered protein binding
­ Metabolic biotransformation
▪ Altered liver P450 enzyme activity
▪ Phase II reactions (glucuronidation)
­ Excretion or Elimination
▪ Altered GFR
▪ Alteration in urinary pH
▪ Alteration in active secretion
2. PHARMACODYNAMIC DRUG INTERACTIONS
• Interactions between agonists and antagonists at drug receptors.
• To avoid interactions; inter and intra patient variations in disposition of a
drug must be taken into consideration in choosing a treatment regime
IMPORTANT CONSIDERATIONS OF DRUG INTERACTIONS
• Prescribed dose and its compliance, the actually administered dose, its rate
and extent of absorption, plasma concentration, Tmax, AUC, distribution,
metabolism, the rate of elimination (t
1/2
), drug concentration at the site of
action, genetic variations and the effect of the drug at the receptor.
• The major determinants of the disposition of many drugs are the
physiological and pathological variations in organ function.
PHARMACOKINETIC DRUG INTERACTION
• In general, pharmacokinetic interactions are considered clinically significant
when at least a 30% change is seen in Cmax, Tmax and AUC.
A. ALTERED GIT ABSORPTION
• Changes in absorption of a drug more than 20% may be considered
significant. The nonionized form of a drug is more lipid soluble and more
readily absorbed from GIT than the ionized form does.
A. ALTERED PH
• Basic drugs are more soluble in acidic fluids, and acidic drugs are more
soluble in basic fluids.
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• Example:
­ Antacids transiently raise gastric pH by 1 – 2 units for ½ – 2 hours.
­ H2-antagonists (Cimetidine) dose – dependently maintain gastric pH
above 5.0 for many hours.
­ Proton pump inhibitors (Omeprazole) dose – dependently raise
gastric pH above 5.0 for up 19 hours.
• The concomitant administration of these compounds leads to significant
alterations in the extent of absorption of basic compounds such as certain
azole – antifungals and β-lactam antibiotics.
• pH has certain clinical implications as it can result in a significant reduction
in the absorption of ketoconazole and itraconazole which are insoluble in
water and are only ionized at low pH.
• Therefore, these drugs must be separated by at least 2 hours in the time of
administration of both.
Example 1. Antacids

• Hence, gastric acidity plays an important part in this interaction.
• Weak acids need to be absorbed at a low pH. Raising the pH with antacid
medication considerably hinders absorption. Likewise, salicylic acid
absorption is greater at low pH.
• Other Drugs influenced by the changes in the pH include
­ Glipizide
­ Glyburide
­ Cefuroxime
­ Cefpodoxime
B. CHELATION
• Chelation or formation of insoluble complexes or when drugs are bound to
resins that bind to bile acids.
• This interaction can however be avoided if the interval between the
medications is at least 2 – 3 hours.
• Example:
­ Complexes with quinolones
▪ Di or tri valent cations (Mg and Al) can form complexes with 4-
oxo and 3-carboxyl groups of quinolones. Resulting in decrease
in AUC up to 30-50%.
altered pH
Decrease the tablet dissolution
of Ketoconazole (acidic)

pH
Example 2. H2 Antagonists
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­ Tetracycline with Iron
▪ Tetracycline AUC can decrease up to 80%.
­ Kaolin-pectin and Digoxin
▪ Kaolin-pectin suspensions in diarrheal disorders bind digoxin,
when co-administered reducing its absorption by 30-50%.
­ Resins affecting drug absorption
▪ Resins like cholestyramine and colestipol that sequester bile
acids in the gut bind to a number of drugs like digoxin,
levothyroxine, statins, valproic acid, steroids, loop diuretics
and warfarin reducing their absorption with resultant clinical
implications.
C. ANTIBIOTICS AND GI FLORA
• Antibiotics that alter gastrointestinal flora can reduce the rate of synthesis
of vitamin K with a resultant increase in the effect of oral anticoagulants
due to a competitive mechanism between them.
D. GASTRIC MOTILITY
• Drugs with anticholinergic properties like propantheline (for hyperhidrosis)
or those altering bowel motility like diphenoxylate (opioid agonist) may
affect the absorption of other drugs.
• Example:
I. Propantheline and Digoxin
▪ Propantheline increases the absorption of slow dissolving
Digoxin by 30% as the reduced gut motility allows a slow
dissolving Digoxin formulation more time to pass into solution
making a greater amount available for absorption but this
effect is not seen with fast dissolving tablets.
II. Metoclopramide and Digoxin
▪ Metoclopramide on the other hand produces the opposite
effects on motility allowing less time for digoxin absorption.
III. Prolonged stomach retention
▪ Can cause excessive degradation of acid-labile compounds,
such as penicillin and erythromycin
IV. Pro-kinetic agents
▪ Cisapride, metoclopramide, domperidone, may decrease the
absorption of poorly soluble drugs
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E. DRUG TRANSPORT
• P-glycoprotein (P-gp) which is a product of the normal expression of the
MDR1 gene and is expressed on the apical aspect of the enterocyte as well
as on the canalicular aspect of the hepatocyte, works as a ‘detoxification’
pump ejecting drugs that have diffused across the intestinal epithelial
barrier resulting in a reduction of the drug absorbed and greatly influenced
the bioavailability of some drugs.
• Other transporter proteins are OAT, OATP, OCT, MRP, BCRP, ABC-ATP, and
SLC. Induction or inhibition of these proteins also leads to drug interactions.
• Example:
I. Organic Anion Transporter (OAT)
▪ It is expressed in two major excretory organs – kidney and
liver. Classical OAT interactions include – inhibition of drug
excretion by OAT inhibitor that is Probenecid.
▪ Decreasing tubular secretion of drugs transported by OAT–fold
increase in cephalosporin AUC when given with probenecid.
II. Digoxin and P-glycoprotein
▪ Digoxin is not extensively metabolized, but it is transported by
the efflux pump P-gp that is expressed in excretory tissues,
kidney, liver and intestine.
▪ Rifampicin induces P-gp activity in the gut lining thereby
ejecting digoxin into the gut with resultant falls in its plasma
levels; on the other hand, Verapamil inhibits P-gp activity and
raises Digoxin levels.
▪ There is evidence that P-gp inhibition by quinidine may play an
important part in the absorption of digoxin in the small
intestine leading to increased plasma digoxin levels. Quinidine
is known to increase digoxin levels perhaps by reducing renal
excretion by 40 – 50% but the exact mechanisms are not clear
as there is also a biliary as well as an intestinal component of
excretion.
III. Breast cancer resistant protein (BCRP)
▪ It is expressed in liver, small intestine and placenta.
Anthracyclines, prazosin, topotecan, etoposide are its
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substrates. BRCP inhibitor GF120918 increased bioavailability
of topotecan up to 97%.
IV. Bile salt exporter pump (BSEP)
▪ It has been shown to transport pravastatin. Clinical significance
is evident from hepatotoxicity caused by troglitazone – leading
to its withdrawal.
F. DRUG DISTRIBUTION INTERACTION
• Of the many plasma proteins interacting with drugs, the most important
are:
­ Albumin
­ α1-acid glycoprotein
­ Lipoproteins
• Acidic drugs are usually bound more extensively to albumin, while basic
drugs are usually bound more extensively to α1-acid glycoprotein,
lipoproteins, or both.
• Only unbound drug is available for passive diffusion to extravascular or
tissue sites and typically determines drug concentration at the active site
and thus its efficacy.
• Albumin represents the most prominent protein in plasma, it is synthesized
in the liver and distributed in both plasma and extracellular fluids of skin,
muscles and various tissues. Intestinal fluid albumin concentration is about
60% of that in the plasma.
• Since albumin has five binding sites (i.e., for warfarin, benzodiazepines,
digoxin, bilirubin and tamoxifen), the main characterized are the site I and
II.
Site I Site II
Chlorothiazide Ketoprofen
Phenytoin Ibuprofen
Glibenclaamide Indomethacin
Naproxen Nimesulide
Salicylate Dicloxacilline
Nimesulide
Diclofenac
Sulphamidics
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Valproic acid
Fluoroquinolones
• Drugs that are more likely to displace other drugs from protein binding sites
include NSAID’s, phenylbutazone, salicylic acid, and sulfonamides.
• This type of interaction is common in hypoalbuminemia as patients
manifesting this condition will have more free or active drug available.
• Susceptible drugs likely to have clinically significant interactions are those
that are: 90% or more protein bound, those bound to tissues or having a
small volume of distribution, having a low therapeutic index, low hepatic
extraction ratios.
• Interactions of drugs can also be induced due to increases of decreases
distribution of the drug in the body fluid.
• Example:
I. Warfarin and Diclofenac
▪ A typical pharmacological displacement can be observed when
warfarin and diclofenac are coadministered.
▪ Warfarin and diclofenac have same affinity for albumin,
therefore the administration of diclofenac to a patient treated
chronically with warfarin results in displacement of latter from
its binding site.
▪ The increase in plasma concentration of free warfarin causes
the development of serious hemorrhagic reactions.
II. Isotretinoin & Hypoalbuminemia
▪ It is 99.9% protein bound drug. A patient suffering from
hypoalbuminemia, will have more free and active drug
available.
III. Gentamycin and Frusemide
▪ Gentamycin is well distributed in extracellular fluid any
reduction in ECF induced by frusemide reduces the volume of
distribution of gentamycin increasing its serum levels with the
clinical implication of nephrotoxicity and ototoxicity.
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G. DRUG METABOLISM INTERACTION
• Most drugs need to reach a receptor site in order to exert their systemic
effect and need to be lipid soluble so as to be able to penetrate the lipid
plasma membrane barrier.
• The lipid soluble drugs further need to be converted into a water-soluble
form to be excreted chiefly by the renal route and the chief role of
metabolism is to enable these processes in two phases.
Phase I (CYP 450) Phase II
Oxidation
• Hydroxylation
• Dealkylation
• Sulfoxidation
Reduction
Hydrolysis
Conjugation
• Glucuronidation
• Acetylation
• Glycine
• Sulfation
A. PHASE I METABOLISM
• In phase I, oxidation/reduction reactions convert the drugs into a more
polar form.
• Phase I reactions are catalyzed by a family of mixed function oxygenases
called the ''Cytochrome P 450" class, expressed chiefly within the
microsomal smooth endoplasmic reticulum hepatocytes and to a lesser
extent in other cells.
• The CYP450 complex is essential for metabolism of drugs and interactions -
out of 50 enzymes in this class, each encoded by a different gene, just 6 of
them (CYP1A2, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5)
together account for 90- 95% of biotransformation; with the 3A4 and 2D6
sub families being responsible for a large number of clinically important
interactions.
• However, there is a considerable variability in enzyme activity between
patients due to medical, environmental, nutritional and genetic
polymorphisms, reasons with polymorphism being especially significant for
CYP2D6, CYP2C9, and CYP2C19 and CYP3A4
• Example: 20% of Asians are poor metabolizers of drugs dependent on
CYP2C19 metabolism such as phenytoin, omeprazole phenobarbitone and
other drugs; only 2% of the same population exhibits a variant of CYP2D6
with low activity.
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• The clinical implication of this polymorphism is exemplified by omeprazole,
where poor metabolizers having higher drug levels with standard dosages
had markedly higher cure rates 100% than their EM counterparts Clinically
significant interactions however, are caused chiefly by Phase I reactions as
most of the metabolism occurs in the liver via the P450 enzymes, rather
than phase II metabolism.
• Although significant metabolism takes place in the liver, other organs like
the kidney and gut are also involved.
Isoenzymes Percentage Substrate
CYP1A2 17% Olanzapine, Theophylline
CYP2C9/19 26% Phenytoin, Warfarin
CYP2D6 2 – 4%
Codeine, Desipramine,
Tramadol
CYP2E1 9 – 10% Chlorzoxazone, Ethanol
CYP3A4 35 – 45%
Diazepam, Triazolam,
Quinidine
EFFECT OF ENZYME INHIBITION ON DRUG METABOLISM
• Inhibitors compete with other drugs for a particular enzyme thus affecting
the optimal level of metabolism of the substrate drug that then
accumulates in the body resulting in toxicity.
­ Extent of Inhibition and its effect on AUC and Clearance
▪ Strong inhibitors achieve a 5-fold increase in plasma AUC or an
80% decrease in clearance, while moderate inhibitors lead to a
2-fold increase in AUC and 50-80% decrease in clearance of the
substrate drug.
­ Effect of inhibition on duration
▪ Conversely inhibition of CYP enzymes tends to be rapid with
maximum effect occurring when steady state concentrations
of the inhibitor drug are established. However, if the t½ of the
affected drug is long it may take a week to reach steady state
levels.
▪ This inhibition leads to decreased metabolism of drugs acted
upon by the enzyme, prolonging its t½ and reducing clearance,
thereby increasing plasma levels that lead to interactions.
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MECHANISMS OF INHIBITION
Enzyme inhibition can result in sudden catastrophic drug interactions.
Reversible Inhibition
• It is the most common. Reversible inhibition occurs when compounds
quickly form weak bonds with CYP isozymes without permanently disabling
them.
­ Competitively (competition for the same binding site between
inhibitor and substrate)
­ Non-competitively (inhibitor binds at a site on the enzyme distinct
from the substrate).
• Potent inhibitors are of major concern e.g. Itraconazole for CYP3A4.
Irreversible Inhibition (or suicide inhibition)
• Occurs with the CYP-mediated formation of a reactive metabolite. This
metabolite can covalently and irreversibly bind to the catalytic site residue
and permanently inactivate the enzyme for subsequent reactions.
• The extent of the clinical importance of this reaction depends on the total
amount of CYP isozyme present the total amount of inhibitor to which the
isozyme is exposed, and the rate of new isozyme synthesis.
Inhibition by Oxidative processes
• Clinically relevant interactions of inhibited drug metabolism occurring
through oxidative processes include:
­ Inhibition of warfarin metabolism by phenylbutazone, cimetidine,
chloramphenicol, and metronidazole resulting in increased
therapeutic levels and toxicity
­ Inhibition of theophylline metabolism by quinolones and macrolides
resulting in increased therapeutic levels and toxicity.
­ Inhibition of phenytoin by isoniazid resulting in increased therapeutic
levels and toxicity
• CYP1A2 inhibitors can increase the risk of toxicity from theophylline or
clozapine; CYP2C9 that of phenytoin and warfarin; while CYP3A4 inhibition
results in the hazards of toxicity of a larger number of drugs like
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carbamazepine, lovastatin and simvastatin, rifabutin, cisapride, cyclosporin,
ergot, protease inhibitors and vinca alkaloids.
Inhibition and Pro-drugs
• Pro-drugs require enzyme activation to produce their effect, hence enzyme
inhibition results in a reduced activity of the drug.
• Example: The analgesic effect of codeine results from its conversion to
morphine by CYP2D6, hence its inhibition decreases codeine’s therapeutic
effect.
• Other inhibitory interactions utilizing different pathways include
Azathioprine and 6MP that are metabolized by Xanthine oxidase, which is
inhibited by allopurinol and the interaction of MAO inhibitors with tyramine
rich products such as cheese that precipitate hypertension.
Isozymes Substrates Inhibitors Inducers
Cyp1A2 Warfarin Cimetidine Phenytoin
Cyp2B6 Bupropion Thiotepa Rifampin
Cyp2C9 Phenytoin Isoniazid Rifampin
Cyp2C19 Diazepam Ketoconazole N/A
Cyp2D6 Metoprolol Cimetidine N/A
Cyp2E1 Ethanol Disulfiram INH
Cyp3A4,5,7 Terfenadine Erythromycin Phenytoin

Inhibitors of Hepatic isozymes
1A2 2C9/19 2D6 3A4
Fluvoxamine Amiodarone Fluoxetine Erythromycin
Cimetidine Fluconazole Paroxetine Azole antifungal
Ciprofloxacin Fluvastatin Quinidine Nefazodone
Fluoxetine Ritonavir Clarithromycin
Isoniazid Bupropion Ritonavir
Sertraline Cimetidine Cimetidine
Omeprazole
Cimetidine

EFFECTS OF ENZYME INDUCTION ON DRUG METABOLISM
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• An increase in CYP activity through induction is less of an immediate
concern than inhibition because induction occurs gradually rather than
rapidly and generally leads to compromised therapeutic goals rather than
profound toxicity.
Slower than Inhibition
• Induction of CYP isoenzymes is achieved slowly by drugs like rifampicin,
phenytoin, carbamazepine, barbiturates, glutethimide, troglitazone,
rifabutin, griseofulvin and St John’s Wort, by increasing the amount of
endoplasmic reticulum in liver cells and by increasing the content of
CYP450.
• An increase of 50-fold is considered clinically significant.
• Administration of these drugs increases the expression of genes such as
MDRI over a fortnight and results in clinically significant interactions by
decreasing the plasma levels of co administered drugs such as warfarin,
ketoconazole, itraconazole, quinidine, verapamil, mexiletine, low dose oral
contraceptives, prednisolone and theophylline.
CYP1 induction
• Induction of the CYP1 family by cigarette smoke, charcoal-broiled foods,
indoles (found in broccoli, cauliflower, cabbage, Brussels sprouts, kale,
watercress), and Omeprazole occurs primarily by substrate binding to the
Ah-receptor (dioxin receptor).
• This complex subsequently binds with a receptor-nuclear translocator,
enters the hepatocyte nucleus, and binds with regulatory deoxyribonucleic
acid (DNA) sequences to enhance gene transcription and stabilize mRNA.
CYP3 induction
• Investigators have established that a human orphan nuclear receptor,
termed the pregnane X receptor (PXR), binds to a response element in the
CYP3A4 promoter region. PXR is activated by a range of drugs known to
induce CYP3A4 expression (i.e., rifampicin, clotrimazole, etc.). PXR is
expressed most abundantly in the liver but is also present in the small
intestine and colon.
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• Inducers, on the other hand stimulate the production of the CYP isoform,
thus increasing the rate of metabolism and enabling substrate drug to clear
out of the system faster. This decreases its response, rendering the drug
ineffective, as it does not remain in the system long enough.
• Enzyme induction does not occur quickly, usually taking a week or two as its
maximal effect depends on enzyme synthesis and t
1/2
of the inducing drug.
• Example:
­ Phenobarbitone with its long t
1/2
may require a longer time, while
rifampicin with its short t
1/2
can manifest its effects within 24 hours.
• The process of P450 enzyme induction gets initiated by an increase in the
expression of the enzyme chiefly via increased transcription or decreased
degradation. Drugs or food gets bound to and activates several xenobiotic
receptors e.g. the Pregnane X receptor after entering the liver cells, which
then heterodimerizes with the Retinoid X receptor (RXR) to form a complex
with coactivators to initiate transcription of the P450 enzyme.
• Enzyme inducing drugs can also increase the activity of phase II metabolism
processes such as glucuronidation.
• Precaution:
­ Once the drugs responsible for induction are stopped their effects
take an equally long time to disappear and this can result in major
toxicity if the dose of a low therapeutic index coadministered drug
that has been stabilized in the presence of an inducer is suddenly
stopped; such as is seen in the case of warfarin, digoxin etc.
1A2 2C9/19 2D6 3A4
Smoking Rifampin None Carbamazepine
Omeprazole Phenobarbital Phenytoin
Phenytoin Phenytoin Rifampin
Phenobarbital
St. John’s wort

B. PHASE II METABOLISM
• Phase II reactions provide another set of mechanisms involving
conjugation / hydrolysis with substances like glucuronic acid and
glucuronyl transferase for modifying drugs into inactive compounds to
enable their excretion.
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• The group of Phase II isozymes consists of uridine 5-diphosphate (UDP)-
glucuronosyl transferases, sulfotransferases, acetyltransferases,
glutathione-S-transferase, and methyl transferases.
• Many of these families of enzymes are still growing in complexity, and
drug interactions involving these isozymes are under investigation.
H. DRUG ELIMINATION REACTION
• Drugs that are chiefly excreted by the kidneys can get involved in drug
interactions by different mechanisms such as Competition at active
transport sites, or alterations in Glomerular Filtration, passive renal tubular
reabsorption or active secretion and urinary pH.
• Example: The interaction between quinidine and digoxin is of definite
clinical importance and is extremely well documented, resulting not only
from quinidine reducing the renal excretion of digoxin by 50%, but also by
non-renal mechanisms, that includes reduction of about 50% in digoxin
excretion in bile as well as by its P-gp mediated inhibition of transcellular
transport and also inhibition in the gut.
1. GLOMERULAR FILTRATION RATE
• Rates of glomerular filtration can be affected by changes in renal blood
flow, cardiac output, and extent of protein binding.
• With highly protein-bound drugs (e.g. > 80%), a significant increase in
the unbound fraction can lead to an increase in glomerular filtration and
subsequent increased drug elimination.
• Conversely, with transporter saturation and renal elimination at
maximal, elimination rates may decrease significantly with increased
free drug.
2. TUBULAR SECRETION
• It occurs in the proximal tubules (a portion of renal tubules). The drug
combines with a specific protein to pass through the proximal tubules.
• When a drug has a competitive reactivity to the protein that is
responsible for active transport of another drug. This will reduce such a
drug excretion increasing its concentration and hence its toxicity.
• The most common renal drug interactions occur at the transport site of
tubular secretion. Sharing the same proximal tubular active transport
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system, many organic anionic and cationic drugs and metabolites
compete with each other for secretion.
• Example: A classic example of this interaction, used long ago
intentionally for therapeutic benefit, is the combination of probenecid
and penicillin to increase antibiotic serum concentrations.
• Examples of other anti-infectives that may exhibit interactions by this
mechanism include the sulfonamides, penicillins, and zidovudine.
• P-Glycoprotein has been identified in the apical membrane of the
proximal tubule and can transport a large variety of drugs into the
lumen. A number of experimental drug interaction investigations have
implicated the inhibition of renal p-glycoprotein to an increase in plasma
drug concentrations.
• Quinolones, macrolides, and azole antifungals demonstrate affinity for
renal P-glycoprotein and can potentially contribute to significant drug
interactions.
3. TUBULAR REABSORPTION
• Excretion and reabsorption of drugs occur in the tubules by passive
diffusion which is regulated by concentration and lipid solubility.
Reabsorption of drugs from the tubular lumen involves both passive
diffusion and active transport processes. Only non-ionized compounds
are passively reabsorbed for the renal tubule.
• Thus, manipulating urinary pH can alter the reabsorption of weak
organic acids and bases.
• Renal clearance of weak organic bases (pKa = 7–10) is increased with
urine acidification (i.e. by salicylates and ascorbic acid) and decreased
with urine alkalinization (i.e. by antacids, calcium carbonate, thiazide
diuretics, and sodium bicarbonate).
• Generally, these interactions are not clinically significant because few
drugs can have altered urinary excretion to a large enough extent to
affect plasma half-life.
• Example:
­ Renal elimination of weak organic acids (nitrofurantoin,
sulfonamides, aminoglycosides, and vancomycin) is increased with
urine alkalinization and decreased with urine acidification.
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­ Salicylates have been shown to reduce the renal clearance of
methotrexate leading to its toxicity.
­ The other interaction involves the excretion of lithium which gets
altered by diuretics and NSAID’s that inhibit renal tubular
reabsorption leading to compensatory reabsorption of lithium
with consequent toxicity.
­ Cimetidine also competes with metformin, (both being cationic
drugs) for elimination by renal tubular secretion.
• Changes in the pH of urine that alter the excretion of weakly acidic or basic
drugs can lead to interactions by affecting their ionization and
consequently affecting the reabsorption of drugs that are subject to passive
reabsorption from renal tubules.
­ The implication of this mechanism is reflected in the treatment of
salicylate or amphetamine poisoning by alkalinizing with antacids or
acidifying the urine, respectively.
­ Ascorbic acid and other acidifying drugs can result in increasing
phenobarbitone levels.
PHARMACODYNAMIC INTERACTIONS
• These interactions generally involve additive, synergistic or antagonistic
effects of drugs acting on the same receptors or physiological systems.
• Pharmacodynamic interactions are common but not always recognized.
• One drug may alter the normal physiological environment whereby it can
increase or decrease the effects of another drug as is exemplified by the
interaction produced by diuretic induced hypokalemia with the concurrent
use of digoxin that results in digoxin toxicity.
• In a similar situation of diuretic usage concurrently with anti-arrhythmic like
quinidine or sotalol a much more serious toxicity in the form of Torsade de
pointes can occur resulting in fatal ventricular arrhythmias.
• It means alteration of the dug action without change in its serum
concentration by pharmacokinetic factors.
• Example:
Propranolol + verapamil Synergistic or additive effect

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Synergism means 1+1=3
Additive means 1+1=2
Potentiation means 1+0=2
Antagonism means 1+1=0 or 0.5
POTENTIATION
• Potentiation occurs when two drugs are taken together and one of them
intensifies the action of the other. This could be expressed by a +b = B. As
an example, Phenergan(R), an antihistamine, when given with a painkilling
narcotic such as Demerol(R) intensifies its effect, there by cutting down on
the amount of the narcotic needed.
SYNERGISM
• Synergism is similar to potentiation. If two drugs are taken together that
are similar in action, such as barbiturates and alcohol, which are both
depressants, an effect exaggerated out of proportion to that of each drug
taken separately at the given dose may occur. This could be expressed by
1+1= 5. An example might be a person taking a dose of alcohol and a dose
of a barbiturate.
ADDITIVE EFFECT
• Additive effect is the term used when two or more drugs are taken at the
same time and the action of one plus the action of the other results in an
action as if just one drug had been given. This could be represented by
1+1= 2. An example would be a barbiturate and a tranquilizer given
together before surgery to relax the patient.
EXAMPLES
• Nephrotoxicity with synergism
­ Likewise, the simultaneous use of two nephrotoxic drugs can
aggravate renal damage, where the dose of either drug may have
been insufficient to produce toxicity - Amphotericin and pentamidine
administered concomitantly result in nephrotoxicity.
• Bone marrow suppression with synergism
On the other hand
Effect at the receptor site
• Antiadrenergic
• Anticholinergic
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­ Ganciclovir and Zidovudine given together increase the risk of bone
marrow depression.
• Hyperkalemia
­ The simultaneous prescription of potassium supplements to patients
already on spironolactone or triamterene and those on ACE inhibitors
leads frequently to severe hyperkalemia.
• Blood pressure
­ NSAID’s especially the Cox-2 inhibitors that would normally increase
blood pressure tend to inhibit the hypotensive action of diuretics,
ACEI’s and beta blockers.
• Synergistic ototoxicity
­ Aminoglycoside + frusemide
ANTAGONISM
• While the effects of benzodiazepines get inhibited with the concurrent
administration of theophylline.
• However, a few antagonistic reactions can actually be beneficial such as the
reversal of the effects of opium alkaloids with naloxone.
INDIRECT EFFECTS
• Certain pharmacodynamic interactions occur indirectly wherein the toxic or
therapeutic effects of either drug are not related directly and seem to act
on separate parts of a common process; e.g. warfarin could be involved in
an indirect interaction with aspirin when other drugs such as dipyridamole,
salicylates or phenylbutazone reduce platelet aggregation or in cases of
thrombocytopenia.
• NSAID’s can cause gastric ulcer and patients having concomitant warfarin
therapy run a risk of greatly increased bleeding.
DRUG-NSAID PD INTERACTIONS

Object Drug Interacting Drug Outcome
Antihypertensives NSAIDs ↑ BP
Corticosteroids NSAIDs ↑ Risk of PUD
Diuretics NSAIDs ↓ Diuretic effect
Triamterene Indomethacin ↑ K
+

Warfarin NSAIDs ↑ Anticoagulant effect
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DRUG-DRUG PD INTERACTIONS

Object Drug Interacting Drug (s)
ACE-I K
+
& K
+
sparing diuretics
ACE-I K
+
& K
+
sparing diuretics
Beta blockers Verapamil
Digoxin Diuretics
MAOI SSRI, Dextromethorphan, Pseudoephedrine, Anorexiants
Meperidine MAOI
Hydroxyine Thioridazine

PHYSIOLOGICAL FACTORS AFFECTING DRUG INTERACTIONS
• Gender/Growth Hormone
• Development/aging
• Inflammation/infection
• Thyroid hormone
• Stress
• Insulin/diabetes
• Liver disease
• Renal disease
DRUG INTERACTION EVALUATION
• Retrospectively
• Prospectively
• Experimentally
DRUG DISEASE INTERACTIONS
• Drug – disease interactions tend to occur when a:
1. Medication has the potential to worsen a disease.
2. The effect a drug has in certain patients may be unexpected not
related to the drug per se but because of the patient’s disease
pattern.
3. Certain drugs are capable of exacerbating acute and chronic diseases.
e.g. beta blockers are known to precipitate asthma, C.O.P.D. and
peripheral vascular disease 29,30 and can also blunt the signs of
hypoglycemia.
4. Certain beta blockers and the calcium blocker verapamil by virtue of
their negative inotropic and chronotropic effects have the potential
to precipitate C.H.F.
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ENVIRONMENT INDUCED INTERACTION
• They are chiefly due to smoking that entails both pharmacokinetic and
pharmacodynamic reactions. The carcinogenic polycyclic aromatic
hydrocarbons in tobacco smoke are potent inducers of the
CYP4501A1/1A2/and possibly 2E1 enzymes.
• PK interactions with smoking occur with drugs like caffeine, clozapine,
olanzapine, theophylline, haloperidol and imipramine that are substrates of
CYP1A2.
• The chief PD interactions are seen with O.C.’s that lead to serious CVS
consequences and with inhaled steroids, whose efficacy gets reduced.
DRUG – FOOD INTERACTION
• The myth that natural products, not being drugs, are completely safe
creates a need for responsible, public/physician education especially as
they are widely used by our rural/semi-urban populace.
• Hence, the need to be cognizant of these interactions and as a large
number do not inform the physicians about their intake, the potential and
true incidence of these interactions is largely unknown.
­ It reduces absorption of digoxin, lowering its blood levels
­ Amplifies action of clopidogrel increasing risk of bleeding.
­ It has synergistic effects with SSRI’s and Zolpidem, increasing
serotonin levels in brain leading to “Serotonin Syndrome”
­ By enhancing expression of intestinal P-gp and CYP3A4 it impairs
absorption and stimulates metabolism of cyclosporine, resulting in
sub-therapeutic levels.
EXAMPLES
1. As many cancer patients use alternative medicines with their
chemotherapy, unexpected toxicities, lowered plasma levels lead to under-
treatment. As treatment failure is common in cancer patients the
implication of the herb’s contribution to the failure is likely to be missed.
2. One of the most clinically significant interactions with tyramine rich foods
like cheese, bananas, chocolate, wine etc. occurs when they are
concurrently used with MAO inhibitors resulting in hypertensive crises
occasionally.
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ROLE OF PHARMACIST IN MANAGEMENT OF DRUG INTERACTION
• The pharmacist, along with the prescriber has a duty to ensure that
patients are aware of the risk of side effects and a suitable course of action
should they occur. With their detailed knowledge of medicine, pharmacists
have the ability to relate unexpected symptoms experienced by patients to
possible adverse effects of their drug therapy. The practice in clinical
pharmacy also ensures that drug interactions are minimized by avoiding
drugs with potential side effects in susceptible patients. Thus, pharmacist
has a major role to play in relation to prevention, detection, and reporting
drug interactions.
MANAGEMENT OPTIONS OF DRUG INTERACTION INCLUDE
AVOIDING THE COMBINATION ENTIRELY
• For some drug interactions, the risk always outweighs the risk, and the
combination should be avoided. Because drug classes are usually
heterogeneous with regard to drug interactions (as described above) one
can often select a no interacting alternative for either the object drug or
the precipitant drug.
ADJUSTING THE DOSE OF THE OBJECT DRUG
• Sometimes, it is possible to give the two interacting drugs safely as long as
the dose of the object drug is adjusted.
SPACING DOSING TIMES TO AVOID THE INTERACTION
• For some drug interactions involving binding in the gastrointestinal tract, to
avoid the interaction one can give the object drug at least 2 h before or 4 h
after the precipitant drug. In this way, the object drug can be absorbed into
the circulation before the precipitant drug appears.
MONITORING FOR EARLY DETECTION
• In some cases, when it is necessary to administer interacting drug
combinations, the interaction can be managed through close laboratory or
clinical monitoring for the evidence of the interaction.
PROVIDE INFORMATION ON PATIENT RISK FACTORS THAT INCREASES THE
CHANCE OF AN ADVERSE OUTCOME
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• It is clear from the clinical experience of physicians and pharmacists as well
as published studies that most patients who take interacting drug
combinations do not manifest adverse consequences.
IMPROVE COMPUTERIZED SCREENING SYSTEMS
• It is clear that computerized drug interaction screening systems have not
been as successful as one hoped.
• Excessive number of drug interactions on the systems: Many pharmacists
find that computerized drug interaction screening systems detect a large
number of DDIs of questionable clinical significance.
DRUG CLASS DIFFERENCES NOT HANDLED CORRECTLY
• Almost all drug classes interact heterogeneously, because individual
members of a drug class are often not metabolized by the same
cytochrome P450 isozymes or ABC (ATP-binding cassette) transporters as
other members of the class. The statins are a good example, because
simvastatin and lovastatin are extensively metabolized by CYP3A4,
atorvastatin is moderately metabolized by CYP3A4, fluvastatin is
metabolized by CYP2C9, and pravastatin and rosuvastatin are not
metabolized by cytochrome P450 isozymes. Thus, combining all members
of this drug class together is rarely justified when considering drug
interactions.
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ADVERSE DRUG REACTIONS AND
PHARMACOVIGILANCE
INTRODUCTION & DEFINITIONS
• There should be a basic and clear idea of side-effects and the adverse drug
reactions.
SIDE EFFECTS
• “Expected, well known reaction resulting in little or no change in patient
management”
• Example: Drowsiness or dry mouth due to administration of certain
antihistamines, or nausea associated with certain anticancer drugs.
OR
• “An effect with a predictable frequency and an effect whose intensity and
occurrence are related to the size of the dose”
ADVERSE DRUG REACTIONS
ACCORDING TO WHO
• “Any response to a drug which is noxious, unintended and occurs at doses
used for prophylaxis, diagnosis or therapy of disease, or for the modification
of physiological function”
ACCORDING TO FDA
• “A serious drug event (events relating to drugs and devices) as one in which,
the patient outcome is death, life threatening, hospitalization, disability, or
congenital anomaly, or required intervention to prevent permanent
impairment or damage”
ACCORDING TO (ASHP)
• “ASHP (American Society of Hospital System Pharmacists) defines a
significant ADR as any unexpected, unintended, undesired, or excessive
response to a drug that requires:
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1. Discontinuing the drug (therapeutic or diagnostic)
2. Changing the drug therapy
3. Modifying the dose (except for minor dosage adjustments)
4. Necessitates admission to a hospital
5. Prolongs stay in a health care facility
6. Necessitates supportive treatment
7. Significantly complicates diagnosis
8. Negatively affects prognosis
9. Results in temporary or permanent harm, disability, or death.
ACCORDING TO KRACH AND LASANGA
• “Any response to a drug that is noxious and unintended, and that occurs at
doses used in humans for prophylaxis, diagnosis, or therapy, excluding
failure to accomplish the intended purpose”
ADDITIONAL INFORMATION
• Drug withdrawal, drug-abuse syndromes, accidental poisoning, and drug-
overdose complications should not be defined as ADRs
• It is important also to avoid confusion with the term adverse drug event
(ADE).
• An ADR is an adverse outcome in a patient that is attributed to a
suspected action of a drug Whereas an ADE is an adverse outcome in a
patient, which occurs after the use of a drug, but which may or may not be
linked to use of the drug.
• It therefore follows that all ADRs are ADEs, but that not all ADEs will be
ADRs.
• This distinction is important in the assessment of the drug safety literature
because the term ADE can be used when a causal link between a drug
treatment and an adverse outcome has not been proven.
• The suspicion of a causal relationship between the drug and the adverse
effect is central to the definition of an ADR.
INCIDENCE
• ADRs are very common in everyday medical practice.
• USA—account for 3—7% of all hospitalization.
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• Prospective Study—ADRs occurred during 10—20% of hospitalizations
(10—20% were severe)
• Incidence of deaths: 0.5—0.9%
• Australian study (2003)
­ 2067 Adults 20—67 years = 14.7% systemic adverse reactions to one
or more drugs
• Pakistan—unfortunately, no data available.
CAUSES OF ADRs
• Drug overdose
• Drug side effects
• Drug interactions
• Polypharmacy
FACTORS AFFECTING SUSCEPTIBILITY OF ADRs
KEY FACTORS
• Awareness of the factors increasing the risk of ADRs.
• Informing prescribing decision → reducing burden on individual patient.
• Risks vary dependent on the population exposed and individual
characteristics of patients.
• Some reactions may be unseen in some populations, outside of susceptible
subjects.
• Other reactions may follow a continuous distribution in the exposed
population.
AGE
• Elderly patients more prone (age-related decline in metabolism and
elimination of drugs).
• Co-morbidities.
• Children: differ from adults.
• Neonatal differences in body composition, metabolism and other
physiological parameters → increase the risk of specific ADRs.
• Higher body water content can increase the volume of distribution for
water-soluble drugs, reduced albumen and total protein may result in
higher concentrations of highly protein-bound drug.
• Immature blood-brain barrier → increase sensitivity to drugs e.g. morphine.
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• Differences in drug metabolism and elimination and end organ responses
can also increase the risk.
• Older children and young adults → susceptible to ADRs e.g. increased risk of
extrapyramidal effects associated with metoclopramide.
• The use of aspirin restricted under the age of 12 (association with Reye’s
syndrome.
GENDER
• Women may be more susceptible.
• Certain ADRs that appear to be more common in women than men e.g.
impairment of concentration and psychiatric adverse events associated
with anti-malarial Mefloquine are more common.
• High susceptibility to drug-induced torsade de pointes (ventricular
arrhythmia linked to ventricular fibrillation & death).
CO-MORBIDITIES AND CONCOMITANT MEDICINES USE
• Reduction in hepatic and renal functions substantially increase the risk of
ADRs.
• Co-morbidities such as: CF, DM, PVD, COPD, Rheumatological, hepatic,
renal and malignancies → predisposing factors to ADRs (Ph-kinetic & Ph-
dynamic changes).
ETHNICITY
• Inherited traits of metabolism such as CYP450 genotype involved in drug
metabolism has varied distribution among people of differing ethnicity.
• E.g. CYP2C9 alleles associated with poor metabolism can affect warfarin
metabolism → increased risk of toxicity (occurs more frequently in white
than in black individuals).
• Increased risk of angioedema with ACE-Is in black population.
• In Asians increased risk of myopathies by using rosuvastatin.
• CNS ADRs associated with mefloquin in white and black people compared
with Chinese and Japanese.
PHARMACOGENETICS
• Genetic variations influence individual’s response to drug.
• Polymorphisms code for drug transporters, drug-metabolizing enzymes and
drug receptors.
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• ADRs may be avoided with the knowledge of a patient’s genetic
susceptibility.
• Major genetic variations are found in Cytochrome CYP450 group of
isoenzymes → inadequate responses to drug therapy or increased risk of
ADRs.
• Clinically significant genetic variations have been seen in CYP2D6, CYP2C9,
CYP2C19 and CYP3A5.
• CYP2C9 accounts for 20% of variations in Metabolism.
• Warfarin (high inter-individual variability)
• CYP2C9 metabolizes warfarin and vitamin K epoxide reductase (VKOR),
target of warfarin anticoagulant activity → genetic variations in VKORC 1
gene, which encodes VKOR, influences warfarin dosing threefold greater
extent than CYP2C9 variants (FDA warning → lower initial dose in
individuals with certain genetic variations).
PHARMACOGENETIC SUCCESS STORY
• Abacavir (Nucleoside analogue reverse transcriptase inhibitor) [NRTI] →
Hypersensitivity skin reaction associated with patients being treated for HIV
infection, Symptoms include fever, rash, arthralgia, headache, vomiting and
other GIT and respiratory disturbances.
• Research revealed strong predictive association with human leukocyte
antigen HLA-B* 5701 allele in Caucasian and Hispanic patient.
• HLA-B* 5701 screening result in substantial fall in incidence of
hypersensitivity reactions
ERYTHROCYTE GLUCOSE-6-PHOSPHATASE DEHYDROGENASE (G6PD) DEFICIENCY
• Sex-linked inherited enzyme deficiency → susceptibility to hemolytic
anemia in patients with low levels of G6PD → predisposing patients to
hemolysis with oxidant drugs e.g. primaquine, sulphonamides,
nitrofurantoin etc.
PORPHYRIAS
• Heterogeneous group of inherited disorders of haem biosynthesis →
transmitted as autosomal dominants (exception of rare congenital
porphyrias).
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• Some of the commonly prescribed agents may precipitate life-threatening
attacks—triggering factors include alcohol and changes in sex hormone
balance.
• Acute prophyrias—patients develop abdominal and neuropsychiatric
disturbances excreting in urine excessive amounts of porphyrin precursors
5-aminolaevulinic acid (ALA) and porphobilinogen.
IMMUNOLOGICAL REACTIONS
• Immune system recognizes drugs as foreign substances → Allergic
reactions.
• Smaller molecules (<600Da) can bind with proteins to trigger an immune
response or larger molecules can trigger immune response directly.
• Immune response is not related to pharmacological action of the drug and
prior exposure to drug is required.
• Immunological reactions are often distinct and recognizable responses.
• Allergic reactions → rash, serum sickness, angioedema, life threatening
bronchospasm, hypotension associated with anaphylaxis.
CLASSIFICATION OF ADRs
WHO / FDA CLASSIFICATION OF ADRs
RAWLINS–THOMPSON CLASSIFICATION
• TYPE – A REACTIONS
• TYPE – B REACTIONS

1. TYPE – A REACTIONS
• Qualitatively normal but augmented
• Unrelated to the primary therapeutic effects (intended effects)
• Predictable from pharmacology of a drug
• Dose dependent
• Do not usually cause serious illness
• Identified before a drug is marketed.
• Some have latency e.g. teratogenicity.
2. TYPE – B REACTIONS
• Usually due to “Hypersensitivity” & “Idiosyncratic”, mechanisms.
• Bizarre effects that are unpredictable on the basis of drug’s known
pharmacology.
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• Unrelated to dose.
• Although rare but cause serious illness and death.
• Account for many drug withdrawals from the market e.g. Lipobay, been
withdrawn from market.
Thin line between side effects & ADRs. The clinical trials evaluate most common
ADRs i.e. Type-A Reactions. Many type-B reactions are evaluated after a drug is
available for widespread use. Continuous post marketing surveillance is often
required before many type-B reactions can be identified.
EXTENDED RAWLINS-THOMPSON CLASSIFICATION OF ADRs
Type Type of effect Features Examples
A Augmented
Common
Predictable
Dose-dependent
Low morbidity
Low mortality
Bradycardia associated
with beta-blockers
B Bizarre
Uncommon
Unpredictable
Not dose-dependent
High morbidity
High mortality
Anaphylaxis associated
with Penicillin
C Chronic
Uncommon
Related to the cumulative dose
Hypothalamic pituitary
adrenal axis suppression
by corticosteroids
D Delayed
Uncommon usually dose-
related
Occur or become apparent
sometime after use of the
drug
Carcinogenesis
E End of Therapy
Uncommon
Occur soon after withdrawal
of drug
Opiate withdrawal
syndrome
F Failure of Therapy
Common
Dose-related
Often caused by drug-
interactions
Failure of oral
contraceptive in presence
of enzyme inducers

DoTS SYSTEM OF CLASSIFICATION
• Based on Dose relatedness, Timing and Patient Susceptibility.
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• Examine the various factors, describe a reaction and influence an individual
patient’s susceptibility.
• DoTS considers → dose of the drug → as many ADRs are related to the drug
used.
• E.g. Increasing the dose of cardiac glycoside will increase the risk of digitalis
toxicity.
• DoTS → reactions are divided into
­ Toxic effects = effects related to the use of drugs outside of their
usual therapeutic dosage.
­ Collateral effects = effects occurring within the normal therapeutic
use of the drug.
­ Hyper-susceptibility reactions = reactions occurring in the sub-
therapeutic doses in susceptible patients.
• The most important aspect of DoTS classification system is susceptibility
which includes factors such as genetic predisposition, age, sex, altered
physiology, disease and exogenous factors such as drug interactions.
• EXAMPLES
• Osteoporosis due to corticosteroids: this reaction occurs at therapeutic
doses, usually after some months of treatment. Females and older people
are at the greatest risk.
­ Dose: collateral effect
­ Time: late
­ Susceptibility: age, sex.
• Anaphylaxis due to penicillin: this reaction can occur with very small doses
and within minutes of taking the first dose of a course, but true anaphylaxis
only occurs when the drug (or a closely related agent) has been used
previously. Hence, it would be classified as:
­ Dose: hyper susceptibility
­ Time: first dose
­ Susceptibility: requires previous sensitization.
THE DoTS SYSTEM
Dose relatedness Time relatedness Susceptibility
Toxic effects: ADRs that
occur at doses higher
Time-dependent
reactions: ADRs that
Raised susceptibility may
be present in some
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212. GM Hamad

than the usual
therapeutic dose.
Collateral effects: ADRs
that occur at standard
therapeutic doses.
Hyper susceptibility
reactions: ADRs that
occur at sub-therapeutic
doses in susceptible
patients.
occur at any time during
treatment.
Time-dependent
reactions: Rapid
reactions occur when a
drug is administered too
rapidly.
Early reactions: occur
early in treatment then
tolerance develops.
Intermediate reactions:
occur after some delay,
but if reaction does not
occur after a certain
time, little or no risk
exists.
Late reactions: risk of
ADR increases with
continued-to-repeated
exposure, including
withdrawal reactions.
Delayed reactions: occur
sometime after
exposure, even if the
drug is withdrawn before
the ADR occurs.
individuals, but not in
others.
Factors include: genetic
variation, age, sex,
altered physiology,
exogenous factors
(interactions) and
disease.

CLASSIFICATION BASED ON THE INTENSITY
• Mild: Do not require an antidote, therapy, or prolongation of
hospitalization.
• Moderate: Require change in dose but not necessarily cessation of the drug
or may require prolong hospitalization or require special treatment.
• Severe: Potentially life threatening, requiring discontinuation of drug,
specific treatment of the adverse reaction.
• Lethal: Directly or indirectly contribute to the death.
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213. GM Hamad

MECHANISM OF ADVERSE DRUG REACTIONS
MECHANISM OF TYPE – A ADRs
• Individual response has great variations.
• Manifestations
­ Different doses required to produce pharmacologic effects &
different response to defined doses.
DOSE-RELATED EFFECTS
• Variations may be due to factors / causes like:
­ Pharmaceutical
­ Pharmacokinetics
­ Pharmacodynamics
­ Pharmacogenetics
­ Underlying disease
­ Sometimes the combination of all the above factors
1. PHARMACEUTICAL CAUSES
• Variations in dosage form (different quantities of drug / A.I. may be
present)
Example
• In 1983 rate-controlled preparation of Indomethacin was withdrawn from
the market after being reported for GI bleeding & hemorrhage caused by
rate-controlled formulation.
• The dosage form was not properly / uniformly formulated and due to high
concentration of AI → caused local GI irritation.
2. PHARMACOKINETIC CAUSES
• Quantitative alteration
­ Absorption
­ Distribution
­ Metabolism
­ Elimination
• Result → Exaggerated response OR Therapeutic failure.
i. ABSORPTION
• Differences in both rate and extent of drug absorption.
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214. GM Hamad

Factors affecting extent of absorption
• Dosage
• Pharmaceutical factors
• GI motility
• Absorptive capacity of GI mucosa
• First pass metabolism in the liver
Factors affecting rate of absorption
• Rate of gastric emptying (orally administered drug)
­ Nature of gastric contents
­ Disease
­ Concomitant drug
• Result → Decreased therapeutic efficacy OR Therapeutic failure.
ii. DISTRIBUTION
• Distribution to various organs & tissues may be affected by:
­ Regional blood flow
­ Plasma protein binding
• The clinical significance of such reactions is unclear.
iii. ELIMINATION
• Most drugs are metabolized in the liver either excreted in the bile or
through urine.
• Changes in the elimination mechanism are most important cause of Type-A
ADRs.
• Reduced Elimination → Accumulation of drug.
• Increased concentration of drug in plasma & tissues → Toxicity.
• Enhanced Elimination → Therapeutic failure.
Renal Excretion
• Impaired glomerular filtration → reduced elimination of drug through
kidneys in urine.
• Renal disease like in geriatrics & neonates → liable to develop Type-A ADRs.
• Drugs with nephrotoxic potential:
­ Digoxin
­ ACE inhibitors
­ Aminoglycoside antibiotics
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215. GM Hamad

­ Class-I Antiarrhythmics (disopyramide, flecainide)
­ Cytotoxic agents
iv. DRUG METABOLISM
• Phase I (cleavage phase)
• Phase II (synthetic / conjugation phase)
• Inter-individual differences or alteration in the rate at which drugs are
metabolized result in variations in elimination rate → genetic variations &
environmental influences.
• Reduced rate → drug accumulation.
• Enhanced rate → therapeutic failure.
• Inter-individual variations → genetics & environmental factors → applied to
­ Oxidation
­ Hydrolysis
­ Acetylation
• Competition for glucuronidation may occur when two drugs metabolized by
this pathway are given concurrently.
Microsomal oxidation
• Drug oxidation → smooth endoplasmic reticulum (SER) in hepatocytes by
CYP-450 enzyme system.
• 4 main subfamilies of CYP450 are responsible for 90% of drug metabolism
i.e. CYP1, CYP2, CYP3, CYP4.
• They are Further subdivided into isozymes i.e. CYP1A2, CYP2C9, CYP2C19,
CYP2D6, CYP3A3 & CYP3A4.
• CYP2D6 → most extensively studied isozyme (predominantly involved)
• Genes that code for specific enzyme can vary between individuals &
sometimes ethnic groups.
• Poor Metabolizer → decreased First-pass metabolism & increased plasma
levels → exaggerated response to Debrisoquine resulting in postural
hypotension.
• Rapid Metabolizer → extensive first-pass metabolism → require increased
doses for usual response.
• Example
­ The antidepressants Nortriptyline & Desipramine are metabolized by
similar mechanism to those of Debrisoquine and as a result the
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216. GM Hamad

steady state of these drugs are dependent on the individual’s
phenotype → the enzyme showing polymorphism in this case is
Debrisoquine hydroxylase or CYP2D6.
­ About 6% of white people have this enzyme inactive.
­ Increased chances of ADRs with those drugs which are substrate for
CYP2D6.
­ Clinical problems arise → co-administration of drugs that inhibit or
compete for CYP2D6.
­ As a result of the competition for the same enzyme → Drugs become
functionally inactive.
Hydrolysis
• Hydrolysis is genetically determined (individual variations)
• Suxamethonium apnea → is best known example of individual variations in
drug hydrolysis.
• The neuromuscular blocking effects of suxamethonium are usually short
lived → drug is rapidly inactivated in plasma by hydrolysis catalyzed by
Pseudocholinesterase.
• Individuals homozygous for atypical gene may develop prolonged
neuromuscular blockade.
• Suxamethonium apnea may also be prolonged in individuals who are
heterozygous for the gene.
Acetylation
• Drugs metabolized by acetylation
­ Dapsone, isoniazid, hydralazine, phenelzine, procainamide, &
sulphonamides.
• Slow-acetylators & Rapid-acetylators → Under genetic control.
• The variability due to differences in the activity of liver enzyme N-
acetyltransferase.
• In the UK, half the population are rapid-acetylators. The incidence in higher
in Japanese & Canadian.
• Slow-acetylators have increased risk to develop type-A ADRs.
• Examples:
­ Isoniazid induced peripheral neuropathy
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217. GM Hamad

­ Hematologic effects of Dapsone
­ Hydralazine & Procainamide → greater risk of developing Systemous
Lupus-Erythmatosus (SLE)
Glucuronidation
• Morphine, paracetamol & ethinylestradiol → eliminated by glucuronidation
conjugation.
• Glucanosyltransferases exist in multiple forms with many drugs acting as
substrate.
• This enzyme is also inducible → adm. of inducing agent can lead to loss of
efficacy e.g. oral contraceptives.
3. PHARMACODYNAMIC CAUSES
• DOSE DPENDENCE
­ Increasing size of the dose increases the effect e.g. increasing dose of
Benzodiazepines → affect would last longer.
• AGONISM.
• ANTAGONISM.
MECHANISM OF TYPE-B ADRs
• Usually due to “Hypersensitivity” & “Idiosyncratic” mechanism.
• Bizarre effects that are unpredictable on the basis of drug’s known
pharmacology.
• Unrelated to dose.
• Although rare but cause serious illness and death.
• Cause may be pharmaceutical or Pharmacokinetic or may lie in the target
organ or tissue response.
i. PHARMACEUTICAL CAUSES
• Presence of degradation product of active ingredients.
• Poor quality or degraded excipients & other compounds as coloring agents,
preservatives & antioxidants may be responsible for many of the type-B
reactions.
• Action of synthetic by-product of A.I.
• Administration of degraded product may either lead to therapeutic failure
or toxic or potentially lethal consequences.
• Example:
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218. GM Hamad

­ Used as a solvent in Sulfanilamide elixir.
­ Decomposition product Diethyl glycol → caused 105 deaths in USA in
1937.
­ The use of degraded excipients in susceptible patients e.g. asthmatics
or neonates → change in the bioavailability of the drugs like Digoxin,
Phenytoin.
­ Potentially fatal syndrome of Eosinophilia & Myalgia associated with
L-tryptophan due to its contamination.
ii. PHARMACOKINETIC CAUSES
• No documented evidence for type-B reactions caused by Pharmacokinetic
factors.
• Bioactivation of drugs to yield reactive species responsible for a significant
properties of Type-B ADRs.
• The binding may result in either direct or immune-mediated toxicity.
• Examples:
­ Tacrine → Hepatotoxicity
­ Clozapine → Agranulocytosis
­ Halothane → Hepatotoxicity
­ Carbamazepine → Allergic reaction
• Susceptible people may be over-reactive or under-reactive.
• Specific bioactivation pathway rendering the people more responsive to
haptogens or immunogens.
iii. PHARMACODYNAMIC CAUSES
• Individual patients vary widely in their response to drugs.
• Factors → Age, gender, body weight, disease state & concurrent drug
therapy.
• Qualitative differences in the target organ response to drugs may be
considered as genetic, immunological, neoplastic or teratogenic
CAUSES OF ABNORMAL DRUG RESPONSE
GENETIC
• Idiosyncratic mechanism → due to qualitative abnormality in patients.
• They are tended to form a “Dustbin” for ADRs cannot be classified under
any other heading.
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219. GM Hamad

• This situation is now being classified & underlying mechanisms are better
understood & it is becoming apparent that many have a genetic basis.
ERYTHROCYTES GLUCOSE 6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)
• Responsible for qualitative difference in the response to drugs.
• Affects 100—400 Million people worldwide.
• G6PD is required for the stability of RBCs.
• Individuals with sex-linked deficiency in this enzyme have weak RBC-
membrane & are predisposed to the hemolytic action of oxidant drugs e.g.
Primaquine, Sulphonamides, Sulphones and Nitrofurantoin.
• There are many variants of G6PD not all are associated with drug induced
hemolysis:
­ African type G6PD (A) is characterized by mild enzyme deficiency.
­ Mediterranean type → characterized by severe enzyme deficiency.
Drugs Avoided in G6PD Deficiency
• Dapsone
• Methylthionium chloride (methylene blue)
• Primaquine
• Quinolones (ciprofloxacin, nalidixic acid, nor-floxacin, ofloxacin)
• Sulphonamides (co-trimoxazole)
REACTIONS OCCURRING IN SUSCEPTIBLE SUBJECTS
• Drug Intolerance a low threshold to normal pharmacological action.
• Drug Idiosyncrasy genetically determined, qualitatively abnormal drug
reaction related to metabolite or enzyme deficiency.
• Drug Allergy hypersensitivity recurrence on re-exposure.
• Pseudo allergic Reaction as a result of histamine—lacking immunologic
specificity.
MEDICATION ERRORS
• Medication error is a mistake in prescribing, dispensing and administration
of drugs.
• Types of Medication Errors
­ Prescribing
­ Omission
­ Wrong time
­ Unauthorized drug
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220. GM Hamad

­ Improper dose
­ Wrong dosage form
­ Improper dose
­ Wrong drug preparation
­ Wrong administration
technique
­ Compliance / Non-
compliance
IDIOSYNCRASY
• Unusual response to a drug due to genetic abnormality.
• Drug interacts with some unique feature of the individual, not found in
majority subjects, and produces the uncharacteristic reaction.
Example
• Isoniazid: N-Acetylation affects the metabolism of isoniazid.
• Slow N-Acetylation: Isoniazid is more likely to cause peripheral neuritis.
• Fast N-Acetylation: Cause hepatotoxicity in this group.
ALLERGIC DRUG REACTIONS
• The immune system is able to recognize drugs as foreign substances,
leading to allergic reactions.
• Smaller drug molecules (<600 Da) can bind with proteins to trigger an
immune response, or larger molecules can trigger an immune response
directly.
• The immune response is not related to the pharmacological action of the
drug and prior exposure to the drug is required.
• Immunological reactions are often distinct recognizable responses. Allergic
reactions range from rashes, serum sickness and angioedema to the life-
threatening bronchospasm and hypotension associated with anaphylaxis.
Patients with a history of atopic or allergic disorders are at higher risk.
• Immunological (hypersensitivity) reactions are split into four main types.
CLASSIFICATION OF IMMUNOLOGICAL REACTIONS
Classification Mechanism Symptoms /signs Examples
Type I
(immediate)
Drug/IgE complex
to mast cells
release of
histamine and
leukotrienes.
Pruritis, urticaria,
bronchoconstriction,
angioedema,
hypotension, shock.
Penicillin
anaphylaxis
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221. GM Hamad

Type II
(cytotoxic)
IgG and
complement
binding to RBCs.
Cytotoxic T-cells
lyse the cell.
Hemolytic anemia,
thrombocytopenia
Cephalosporins,
Penicillins,
Rifampicin

Type III
(immune
complex)
Drug antigen and
IgG or IgM form
immune complex,
attracting
macrophages and
complement
activation

Cutaneous
vasculitis, serum
sickness

Chlorpromazine,
Sulphonamides.
Type IV (delayed
type)
Antigen
presentation with
major
histocompatibility
complex protein
to T-cells and
cytokine and
inflammatory
mediator release.
Usually occur after
7-20 days. Macular
rashes and organ
failure including
Stevens-Johnson
syndrome and toxic
epidermal
necrolysis.
Neomycin,
Sulphonamides.
MUTAGENECITY AND CARCINOGENICITY
• Capacity of a drug to cause genetic defects and cancer, respectively.
• Chemical carcinogenesis generally takes several (10 - 40) years to develop.
• Unpredictable.
EXAMPLE
• Estrogen- Endometrial carcinoma.
• OCP- Ca cervix, breast Ca.
• Iron S/C or I/M – blackening of area – increase incidence of sarcoma (cause
is unknown).
• Anticancer drug.
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222. GM Hamad

TERATOGENICITY
• Capacity of a drug to cause foetal abnormalities when administered to the
pregnant mother.
• Drugs can affect the fetus at 3 stages:
­ Fertilization and implantation (Conception to 17 days): failure of
pregnancy which often goes unnoticed.
­ Organogenesis (18 days to 55 days): most vulnerable period,
deformities are produced.
­ Growth and development (>56 days): developmental and functional
abnormalities can occur.
▪ Example
• Thalidomide → Phocomelia, multiple defects.
• Anticancer drugs → Cleft palate, hydrocephalus, multiple
defects.
DRUGS KNOWN TO BE TERATOGENIC
• Anticancer drugs – Methotrexate – multiple deformity.
• Steroid – cleft palate and other.
• Oral anticoagulants – bony abnormality (Hypoplastic nasal structures), optic
atrophy, mental retardation.
• Oral hypoglycemic agents - multiple deformity.
• Androgenic hormone – virilization, hermaphrodite, lid retraction.
• Tetracycline – inhibit bony growth.
ASSESSMENT OF LIKELIHOOD OF ADRS
• When an ADR is suspected following factors should be taken into account:
­ Full history of patient
­ Past & present drug history (OTC, herbal, homeopathic or any other
drugs)
­ Nature of the reaction
­ Timing of symptoms or events
▪ It is relatively easy to recognize an ADR that occurs soon after
drug administration.
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PHARMACOVIGILANCE
• Pharmacovigilance is concerned with the detection, assessment and
prevention of adverse effects or any other possible drug-related problems,
with the ultimate goal of achieving rational and safe therapeutic decisions
in clinical practice.
IDENTIFICATION OF ADRs
• Establish causal relationship between a specific drug and a clinical event.
• Recognition of features.
• Patient should be informed about possible ADRs and how to recognize
them.
• Patient should be asked to report any unexpected symptoms, which may
develop while taking that drug or within a month or so of its
discontinuation.
• Assessment → whether ADRs are definite, probable or possible due to the
drug.
DETECTION & MONITORING OF ADRs
POST-MARKETING SURVEILLANCE
• Methods most commonly adopted during post-marketing surveillance.
1) Case Reports
2) Cohort Studies
3) Case-control Studies
4) Spontaneous Reporting Schemes

1. CASE REPORTS
• Detection of new and serious reactions, particularly Type-B reactions.
• This involves publication of case reports, or case series of ADRs in
medical literature.
• Case reports are vital in alerting the professionals to several adverse
reactions, such as, “Halothane induced Hepatitis”.
2. COHORT STUDIES
• Study the fate of a large group of patients taking a particular drug.
• Compare adverse event rates in group of patients taking drug of intent,
with a comparative group.
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• These studies include:
­ Ad-hoc investigations to investigate specific problems.
­ Prescription Event Monitoring (PEM)
3. CASE- CONTROL STUDIES
• Valuable information on the incidence of Type B reactions & association
between drug & disease.
• Comparison of drug usage between a group of patients with a particular
disease and control group who are similar in confounding factors but do
not have the disease.
• Confirms whether or not a drug causes a given reaction once suspicion
has been raised.
4. SPONTANEOUS REPORTING SCHEMES
• Spontaneous reporting systems collect data about suspected ADRs in a
central database.
• Cases are not collected in a systematic manner, but accumulate through
reports submitted spontaneously by people who make a connection
between a drug and suspected drug-induced event.
• Many countries have established a system for adverse drug reaction
reporting.
• The physicians are asked to report all suspected serious reactions to any
drug or newer products.
Advantages
• Relatively cheap to administer.
• Follows a product throughout its life.
• Accept reports to over-the-counter medication and herbal treatments.
Disadvantages
• Passive surveillance systems, which rely on the ability of health
professionals to recognize possible ADRs and to distinguish these from
symptoms related to underlying disease.
• Only a suspicion of a causal link between a drug and an adverse event is
required, not confirmation of the association.
• Inability to quantify the risk.
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• Such systems supply a numerator (the number of reports) but estimates of
the incidence of reactions cannot be made because the population exposed
to the drug cannot be ascertained accurately.
• Only a minority of reactions are reported.
i. SIGNAL DETECTION
• A signal can be described as a possible causal relationship between an
adverse event and a drug, which was previously unknown.
• Statistical approaches scan the data accumulated through spontaneous
reports for ‘drug–adverse event pairs’ that are disproportionately
present within the database as a whole.
• Such calculations can be run automatically by modern computer
systems, providing the opportunity to scan large databases for potential
signals of new ADRs.
• Only rarely will a signal provide such strong evidence that a restriction
on use of the drug or its withdrawal is immediately required.
• Confounding factors such as particular groups of patients being
‘channeled’ into receiving a drug can influence reporting the strength of
the signal also depends on the quality of the individual spontaneous
reports.
ii. CAUSALITY ASSESSMENT
• The assessment of whether a drug is responsible for a suspected ADR is
of great importance in both the regulatory environment and within the
pharmaceutical industry.
• Reporters to spontaneous reporting schemes are requested to submit
suspected ADRs and such reports contain variable levels of information
For example, since re-challenge with the suspected drug is often
ethically unacceptable, very few reports contain such information.
• Often causality is difficult to prove in pharmacovigilance and a high
degree of suspicion may be all that is necessary for regulatory action.
iii. COMMITTEE ON SAFETY OF MEDICINES
• Responsible for ADR reporting & monitoring.
• CSM reporting scheme provides valuable early warnings & enables the
study of factors associated with them.
iv. YELLOW CARD SCHEME / SYSTEM
• Capable of detecting both rare and common reactions.
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• Cost effective.
• It should be available in every health care facility.
v. PAKISTANI PERSPECTIVE
• It is unfortunate that in Pakistan there is considerable under reporting of
reactions.
MOH Pakistan Initiative ADR- Reporting
• In October 2000, Ministry of Health Pakistan, developed & distributed a
comprehensive ADR reporting form to all the health care institutions →
failure due to non-compliance.
• In 2016 the DRAP established a portal and form for reporting of ADRs.
• Main Aim:
­ To Centralize.
­ Regularize the mechanism of reporting ADRs.
EXPECTATIONS
• Valuable Database.
• Resource for implementation of corrective actions.
• With “Yellow Card System”, in place staff can be regularly updated on
compliance.
ADR MONITORING & REPORTING PROGRAM
• This program should encourage:
­ ADR surveillance.
­ Facilitate ADR documentation.
­ Promote reporting of ADRs.
­ Monitor the safety of drug use in high risk patients.
­ Stimulate the education of health professionals.
• ADR programs should focus on:
­ Identifying problems leading to ADRs.
­ Planning for positive changes.
­ Measuring the results of these changes.
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ROLE OF PHARMACIST IN ADR MONITORING
• Leadership in the development, maintenance and ongoing evaluation of
ADR programs.
• Approval of such programs through appropriate committees as, P&TC and
organization's administration.
PHARMACIST SHOULD FACILITATE
• Analysis of each reported ADRs
• Identification of drugs and patients at risk
• Development of policies & procedures for ADR monitoring
• Interaction between physicians, nurses and paramedics
• Educational purposes
• Publication of reports
PHARMACIST’S OBLIGATION
• Its Pharmacist’s responsibility and professional obligation to report any
suspected ADR.
• Pharmacist in an organized health care system should develop a
comprehensive, ongoing programs for reporting & monitoring of ADRs.
CONCLUSION
• ADRs are inevitable risk associated with use of modern medicines.
• Careful attention to dosage & factors like age, sex, renal and hepatic
functions will minimize the risk of type A reactions.
• The Pharmacist is well placed to assist in prevention, detection and
monitoring of ADRs.
• Responsibility of every health professional to evaluate the appropriateness
of a particular opinion or therapy in the context of the actual clinical
situation & with due consideration for any new development in the field.
• Strengthening the professional interaction between Physicians,
Pharmacists, Nurses & other allied health professionals.
THE CONCEPT OF SAFETY
• Safety can be defined as relative absence of harm.
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• When we say that a drug is ‘safe’, → mean that there is a low probability of
harm which, in the context of the disease being treated and the expected
benefits of the drug, can be considered acceptable.
• Disease context is important because patients with more serious illnesses
are much more likely to be prepared to accept potentially harmful
treatments than those who have minor or self‐limiting illnesses.
• Acceptability’ is a subjective judgment which ultimately is made by
comparing both the positive and the negative consequences of one course
of action (e.g. a drug) with another (which could be any form of treatment
or no treatment).
• Treatments previously considered acceptably safe may become ‘unsafe’ in
the light of new evidence or the discovery of safer alternatives.
• An example of the latter was the antihistamine terfenadine which was
widely used in the treatment of hay fever until the early 1990s.
• Fatal ventricular arrhythmias (prolonging the QT interval) → later developed
Fexofenadine.
MEASURING RISK
• To assess how safe something is we need to identify and measure the
risks of harm associated with it.
• Risk is the probability of an adverse outcome. It may be expressed in the
following terms:
­ Absolute Risk – An absolute risk must have a numerator and a
denominator, but it may be a proportion (e.g. 1 in 100) or a rate
which includes time (e.g. 1 in 100 per year). The null value (i.e. no
increased risk) is zero.
­ Relative Risk – A relative risk is a ratio and makes comparison with a
specified alternative (e.g. a twofold increase compared to no
treatment is a relative risk of 2). The null value is one.
­ Absolute risk provides more useful information than relative risk, but
the latter is often easier to measure.
THE RULE OF THREE
• A simple and useful tool when zero cases have been observed in a defined
population.
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• Simply dividing the size of population by 3 approximates an upper 95%
confidence limit.
• In practice, this is the highest value that, statistically, is reasonably likely to
represent the truth.
• For example: If 900 patients use a new antibiotic and 0 allergic reactions
occur, then it is statistically unlikely that such reactions will occur more
frequently than 1 in 300 patients (i.e. 1 in 900/3).
• The rule of three works very well provided the size of the population is
at least 30 and thus, in the context of drug safety, it usually is applicable.
SAFETY IN PRACTICE
• There are two basic components to safety:
1. Intrinsic Safety – Some drugs are intrinsically and obviously safer
than others at therapeutic doses. For example: the adverse reactions
produced by paracetamol compared with cytotoxic drugs.
2. User‐Dependent Safety – The safety of a drug can also depend on
how it is used. For example: monitoring white blood cell count in
users of clozapine can completely prevent reduction in white blood
cells to a level that would potentially have fatal consequences.
THE AMOUNT OF SAFETY KNOWLEDGE
• How much a drug has been studied.
• There are four basic categories in respect of amount of safety knowledge:
1. Well‐Established – Drugs that have been widely used for many (~
20+) years for which it is unlikely that completely unidentified safety
issues will emerge.
2. Established – Drugs for which there is a substantial body of evidence
of safety in clinical use but not enough to meet level 1.
3. Provisional – All newly authorized drugs until they have been used
fairly extensively in ordinary practice over a period of at least 5 years.
During this period, such drugs are normally under additional
monitoring and their safety in ordinary practice needs to be studied
proactively.
4. Limited – All investigational drugs and the following situations where
the drug might be authorized on limited safety information.
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DRUG TOXICITY
TOXICITY OF DRUGS
• Toxicity is the consequence of:
­ Interactions (drug-drug, drug-food)
­ Side effects
­ Adverse drug reactions (type-A, type-B)
• Related to the principal pharmacological action of the drug (predictable,
dose related) e.g. bleeding with anticoagulants.
• Unrelated to the principal pharmacological action of the drug (pt. factors)
e.g. liver damage with paracetamol.

TOXICITY TESTING
• Animal testing of new drugs.
• Wide range of tests in different species.
• Long-term administration of drugs.
• Regular monitoring—physiological & biochemical abnormalities.
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• Detailed postmortem examination—gross or histological abnormalities.
• Doses well above the expected therapeutic range are used.
• Determines which organ (s) or tissue (s) are likely TARGETS of toxicity.
RECOVERY STUDIES—ASSESSMENT
• Toxic effects are Reversible or Irreversible.
• More attention is given to Irreversible effects (carcinogenesis,
neurodegeneration etc.).
• Toxicities—range from negligible to severe precludes further development
of the compound/drug.
INTERMEDIATE LEVELS OF TOXICITY
• Acceptable for drugs intended for serious illnesses e.g. AIDS.
• Decision whether to continue development is often difficult.
SAFETY OF A DRUG
• The safety of a drug can only be established during use in humans.
MECHANISM OF TOXICITY—CELL DEATH
• Toxic concentration of drugs or drug metabolites can cause:
­ NECROSIS
­ APOPTOSIS (programmed cell death or cell suicide)
• Chemically active metabolites form covalent bonds with target molecules
or may interact by non-covalent bonds.
• Some drug/ metabolites do both.
• LIVER—major site of drug metabolism that is the reason of development of
‘Hepatotoxicity’.
• KIDNEYS—drugs & metabolites are excreted or reabsorbed making the
kidneys more susceptible towards development of toxicity ‘Nephrotoxicity’.
• HEART— ‘Cardiotoxicity’.
NON-COVALENT INTERACTIONS
• Cytotoxicity caused by:
1. Lipid peroxidation
2. Generation of toxic oxygen radicals
3. Reactions causing depletion of glutathione (GSH)
4. Modification of sulfhydryl groups
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1. LIPID PEROXIDATION
• Polyunsaturated lipids undergo peroxidation by reactive metabolites or
reactive oxygen species.
• Lipid per oxyradicals (ROO’) can produce lipid hydroperoxides (ROOH)---
producing further lipid per oxyradicals.
• Disruption of the lipid membrane—eventually result in the cell death by
action of lipid peroxidase with the proteins.
• Glutathione & Vitamin-E protect against lipid peroxidation.
2. TOXIC OXYGEN RADICALS
• Reduction of molecular oxygen to superoxide anion.
• This is followed by enzymatic conversion to hydrogen peroxide or
reactive spp. such as hydroperoxy (HOO’) & hydroxy radicals.
• These reactive oxygen spp. are highly cytotoxic.
3. DEPLETION OF GLUTATHIONE
• GSH-redox reaction is a protective cycle that minimizes the cell damage
• Depletion of GSH is known as OXIDATIVE STRESS.
• This is a disturbance in the pro-oxidant/antioxidant balance in the favor
of pro-oxidant state.
• GSH is normally maintained with its disulfide GSSG.
• Oxidizing spp. convert GSH to GSSG.
• GSH is regenerated by NADPH-dependent GSSG-reductase.
• When cellular levels of GSH fall to 20—30% --cellular defense against
toxic compound is impaired & cell death occurs.
4. MODIFICATION OF SH GROUPS
• Oxidizing spp alter the SH groups reversibly or by covalent interactions.
• SH have critical role in catalytic activity of enzymes—modification in of
SH groups result in inactivation.
• Cytoskeletal protein Actin, Glutathione reductase & Ca-transportation
ATPase in plasma membrane & ER are commonly affected by the
reactive oxygen spp.
• High levels of Ca cause the activation of degenerative enzymes i.e.
protein kinases (proteases, endonucleases) lead to the damage to the
cytoskeleton.
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COVALENT INTERACTIONS
• Targets to Covalent Interaction:
­ DNA
­ Proteins / peptides
­ Lipids
­ Carbohydrates
• Interaction with the DNA is the basic mechanism of action of mutagenic
chemicals.
GENERAL MECHANISM OF CELL DAMAGE & CELL DEATH
• Drug induced damage is often a result of reactive metabolites that interact
both by non-covalent and / or covalent interactions.
• Cell death is often self-inflicted via triggering of apoptosis.
• Usually Mutagenesis is the result of covalent interaction.
EXAMPLES
• Covalent bond formation between the metabolite of paracetamol (N-
acetyl-p-benzoquinone imine) & the target cell.
• Covalent binding to proteins—immunogens.
• Binding to DNA—mutagenesis.
• Some non-mutagenic chemicals also form covalent bonds resulting in the
cell damage.
• Cholinesterase inhibitors bind cholinesterase at the neuromuscular
junctions and cause the necrosis of the skeletal muscles.
HEPATOTOXICITY
• Hepatocytes are exposed to reactive metabolites produced by CYP-450
enzymes.
• Liver damage can be produced by general mechanism of cell injury e.g.
covalent & non-covalent.
• Some drugs can cause reversible cholestatic jaundice.
• Immunological mechanisms are sometimes implicated.
CLINICAL MANIFESTATION OF LIVER DAMAGE
• Hepatitis (inflammation of hepatocytes).
• Laboratory abnormalities (enzyme levels etc.).
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• Drugs Paracetamol, Isoniazid, Halothane, Phenytoin cause hepatotoxicity.
• Genetic differences in drug metabolism have been implicated (Isoniazid,
Phenytoin).
• Irreversible liver disease as Cirrhosis require extreme caution e.g. low dose
of Methotrexate for various autoimmune diseases.
• Reversible obstructive jaundice—Chlorpromazine & Androgens.
HEPATOTOXICITY CAUSED BY PARACETAMOL TOXIC DOSE
• Toxic dose of paracetamol (mixed function oxidases CYP450) [reactive
oxygen species].
• N-acetyl-p-benzoquinone imine (NAPBQI).
• This is formed by lipid peroxidation, SH depletion.
• Resulting in increased membrane permeability.
• Cell death occurs ultimately by the Oxidative stress.
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PHARMACOTHERAPY PLAN
1. DEVELOPMENT, IMPLEMENTATION AND MONITORING OF DRUG THERAPY PLANS
2. PHARMACOTHERAPY DECISION MAKING
DEVELOPMENT, IMPLEMENTATION AND
MONITORING OF DRUG THERAPY PLANS
PHARMACEUTICAL CARE
• Pharmaceutical care is a pharmacy practice that deals with the responsible
provision of drug therapy for the purpose of achieving definite outcomes
that improves a patient quality of life.
EXPECTED OUTCOMES
• Cure of a specific disease
• Alleviation or minimization of a patient’s symptoms
• Impede disease progression
• Disease prevention
GOALS
• Optimize the patient's health-related quality of life.
• Achieve positive clinical outcomes, within realistic economic expenditures.
DIFFERENCE B/W CLINICAL PHARMACY AND PHARMACEUTICAL CARE
Clinical Pharmacy Pharmaceutical Care
Place Clinical Setting Everywhere
Target Healthcare Providers Patients
Goal Clinical Outcomes,
Pharmacoeconomic
Outcomes
Patient Related
Outcomes
Time Discontinuous Continuous
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Global Benefits Specialization Futuristic and Holistic
PHARMACEUTICAL CARE PROCESS

Element Purpose
Assessment The main goal is to establish a full medication history and
highlight actual and potential drug-related problems.
Care Plan This should clearly state the goals to optimize care and the
responsibilities of both the pharmacist and the patient in attaining
the stated goals.
Evaluation This reviews progress against the stated patient outcomes.
ESSENTIAL COMPONENTS OF PHARMACEUTICAL CARE
1. Pharmacist-patient relationship.
2. Pharmacist’s workup of drug therapy (PWDT).
3. Documentation of pharmaceutical care.
1. PHARMACIST-PATIENT RELATIONSHIP
PROFESSIONAL RELATIONSHIP MUST BE ESTABLISHED AND MAINTAINED
• Interaction between the pharmacist and the patient must occur to assure
that a relationship based upon caring, trust, open communication,
cooperation, and mutual decision making is established and maintained.
• In this relationship, the pharmacist holds the patient's welfare paramount,
maintains an appropriate attitude of caring for the patient's welfare, and
uses all his/her professional knowledge and skills on the patient's behalf.
• In exchange, the patient agrees to supply personal information and
preferences, and participate in the therapeutic plan.
• The pharmacist develops mechanisms to assure the patient has access to
pharmaceutical care at all times.
Assessment
Care Plan
Evaluation
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PATIENT-SPECIFIC MEDICAL INFORMATION MUST BE COLLECTED, ORGANIZED,
RECORDED, AND MAINTAINED
• Pharmacists must collect and/or generate subjective and objective
information regarding the patient's general health and activity status, past
medical history, medication history, social history, diet and exercise history,
history of present illness, and economic situation (financial and insured
status).
• Since this information will form the basis for decisions regarding the
development and subsequent modification of the drug therapy plan, it
must be timely, accurate, and complete.
• Moreover, it must be organized and recorded to assure that it is readily
retrievable and updated as necessary and appropriate. Patient information
must be maintained in a confidential manner.
PATIENT-SPECIFIC MEDICAL INFORMATION MUST BE EVALUATED AND A DRUG
THERAPY PLAN DEVELOPED MUTUALLY WITH THE PATIENT
• Based upon a thorough understanding of the patient and his/her condition
or disease and its treatment, the pharmacist must, with the patient and
with the patient's other healthcare providers as necessary, develop an
outcomes-oriented drug therapy plan.
• In designing the plan, the pharmacist must carefully consider the psycho-
social aspects of the disease as well as the potential relationship between
the cost and/or complexity of therapy and patient adherence.
• Patient must be explained
i. Various pros and cons (i.e., cost, side effects, different monitoring
aspects, etc.) of the options relative to drug therapy.
ii. Instances where one option may be more beneficial based on the
pharmacist's professional judgment.
• Patient’s responsibilities must be carefully and completely explained to the
patient.
• Information should be provided to the patient at a level the patient will
understand.
• The drug therapy plan must be documented in the patient's pharmacy
record and communicated to the patient's other healthcare providers, as
necessary.
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THE PHARMACIST ASSURES THAT THE PATIENT HAS ALL SUPPLIES, INFORMATION
AND KNOWLEDGE NECESSARY TO CARRY OUT THE DRUG THERAPY PLAN
• Pharmacist providing Pharmaceutical Care must accept ultimate
responsibility for assuring that his/her patient has been able to obtain, and
is appropriately using, any drugs and related products or equipment called
for in the drug therapy plan.
• The pharmacist must also assure that the patient has a thorough
understanding of the disease and the therapy/medications prescribed in
the plan.
THE PHARMACIST REVIEWS, MONITORS, AND MODIFIES THE THERAPEUTIC PLAN
AS NECESSARY AND APPROPRIATE, IN CONCERT WITH THE PATIENT AND
HEALTHCARE TEAM
• Pharmacist is responsible for monitoring the patient's progress in achieving
the specific outcomes according to strategy developed in the drug therapy
plan.
• The pharmacist coordinates changes in the plan with the patient and the
patient's other healthcare providers as necessary and appropriate
• Patient progress is accurately documented in the pharmacy record and
communicated to the patient and to the patient's other healthcare
providers as appropriate.
• The pharmacist shares information with other healthcare providers as the
setting for care changes thus helping assure continuity of care as the
patient moves between the community setting, the institutional setting,
and the long-term care setting.
2. PHARMACIST WORK-UP OF DRUG THERAPY (PWDT)
• Provision of pharmaceutical care is centered around this, although the
methods used for this purpose may vary.
• Components are:
i. Data collection.
ii. Develop or identify the CORE pharmacotherapy plan.
iii. Identify PRIME Pharmacotherapy problems.
i. DATA COLLECTION
• Collect, synthesize & interpret relevant information.
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• Patient’s demographic data: age, sex, race etc.
• Pertinent medical information.
• Medical history (current & past)
• Family history.
• Dietary history.
• Medication history (prescription, OTC, allergies)
• Physical findings (weight, height, B.P)
• Lab results (serum drug levels, potassium levels, serum creatinine levels
relevant to drug therapy)
• Patient complaints, symptoms & signs.
ii. DEVELOP OR IDENTIFY THE CORE PHARMACOTHERAPY PLAN
CORE PHARMACOTHERAPY PLAN
• C = Condition of patient
­ it may include nonmedical conditions or need and is thus not a
reiteration of the current medical problem.
• O = Outcome desired for the condition or need
­ Patient outcomes (generally five category of patient outcomes)
▪ Mortality
▪ Morbidity
▪ Behavior
▪ Economic
▪ Quality of life
­ Therapeutic end points (surrogate markers; disease-oriented
evidence)
▪ A therapeutic end point represents the pharmacological or
therapeutic effects that is expected, ultimately, to achieve the
desired outcome.
▪ More than one end point is usually needed to achieve an
outcome-for example, both near normal glycemic control and
normalization of blood pressure are necessary to significantly
reduce the risk of ESRD.
• R = Regimen to achieve desired outcome
­ Therapeutic regimens
▪ Existing therapy
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▪ Initial therapy
­ Goal setting and behavior regimens
▪ Identify the type of new goal set, such as the following:
• Start a new positive action- exercise program
• Increase the frequency or intensity of a positive action-
drink 2 more cups of water
• Stop or decrease- stop smoking
• Continue an action that is perfect- continue to exercise
30 minutes a day, every day.
• E = Evaluation parameters
­ Efficacy parameters
­ Toxicity parameters
▪ ADRs
▪ Allergic reactions
▪ Toxicity not occurring
iii. IDENTIFY PRIME PHARMACOTHERAPY PROBLEMS
PRIME PHARMACOTHERAPY PROBLEMS
• P = Pharmaceutical Problems
­ Dose, route, duration, form, timing, frequency etc.
• R = Risk to Patient
­ Known contraindications
­ Hypersensitivity/allergy
­ Drug-induced problems
­ Common/serious ADRs
• I = Interactions (Drug-drug, drug-food, drug-disease, drug-lab, etc.)
• M = Mismatch (Drug without indication, indication without drug, actual
barriers to implement PCP)
• E = Efficacy issues (suboptimal selection of pharmacotherapy, minimal or
no therapeutic effectiveness, medication availability, compliance or
administration considerations)
3. DOCUMENTATION OF PHARMACEUTICAL CARE
• Formulate a FARM note or SOAP note to describe or document the
interventions needed or provided by pharmacist.
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FARM NOTE
• F = Findings
­ Patient specific information that leads to the identification of
pharmacotherapy problem or indication for pharmacist’s
intervention.
• A = Assessment
­ Pharmacist’s evaluation of the findings (severity, priority or urgency
of the problem, short-term and long-term goals of the intervention)
• R = Resolution
­ Actual or proposed action plans by the pharmacist. The intervention
options may include
▪ Counselling or educating the patient.
• Making recommendations for the patient and caregiver.
▪ Informing the prescriber.
• Making recommendation to the prescriber.
• With-holding medication or advising against use.
• M = Monitoring and follow up
­ The parameters and timing of the follow-up monitoring to assess the
safety, efficacy and outcome of the intervention.
­ It includes
▪ Parameters to be followed
▪ Intent of the monitoring
▪ Ways of the monitoring
▪ Frequency of the monitoring
▪ Duration of monitoring
▪ Anticipated or desired findings
▪ Decision points to alter therapy
SOAP NOTE
• This is used primarily by physicians.
• S = Subjective findings
­ Means only what the patient tells you (e.g., symptoms,
attributions, etc.) or what you know to have occurred in the past
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(e.g., a medication change you made based on a telephone
conversation with the patient)
• O = Objective findings
­ Includes results of physical examination and interval test data
• A = Assessment
­ Diagnosis or possible explanations for patient’s medical problem
• P = Plan
­ Drug regimen or surgical procedures.
CLINICAL SKILLS & PHARMACIST’S ROLE IN PHARMACEUTICAL CARE
1. PATIENT ASSESSMENT
• Physical assessment
• Barriers to adherence
• Psychosocial issues
2. EDUCATION & COUNSELING
• Interview skills
• Communication skills (e.g. empathy, listening, speaking or writing at
patient's level of understanding)
• Ability to motivate & inspire
• Develop & implement patient education plan based on an initial
education assessment
• Identification & resolution of compliance barriers
3. PATIENT SPECIFIC PHARMACIST CARE PLAN
• Recognition, prevention & management of drug interactions
• Pharmacology & therapeutics
• Interpretation of lab tests
• Knowledge of community resources, professional referrals
• Communication & support with community medical providers
4. DRUG TREATMENT PROTOCOL
• Develop & maintain (update) protocols
• Follow protocols as pharmacist-clinician
• Monitor, aggregate adherence to the treatment protocols e.g. drug
utilization evaluation, especially for managed care or health system
facility.
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5. DOSAGE ADJUSTMENT
• Identify patients at high risk for exaggerated or subtherapeutic
response.
• Apply pharmacokinetic principles to determine patient specific dosing.
6. PRESCRIPTIVE AUTHORITY
• In designated practice site and positions.
PHARMACEUTICAL CARE AS THE MODEL FOR PHARMACY PRACTICE
• The concepts, activities and services in pharmaceutical care form the
basis for provision of clinical services directly to, and for the benefit of
patient in all pharmacy practice settings.
• These settings include home health, hospital, ambulatory care, primary
care, consultation, long term care, and community pharmacy practice.
• Workflow, staffing patterns, processes, and pharmacy programs might
differ, but the core approach to patient care remains pharmaceutical
care in all settings.
PHARMACEUTICAL CARE: AN ONGOING PROCESS
• The patient profile must be revised and re-assessed each time a new drug is
­ Added to or deleted from the medication regimen.
­ A new disease or condition is diagnosed.
­ Patient undergoes other clinical intervention, such as surgery.
• When the patient returns to the pharmacy or is readmitted to the health
system facility.
• The pharmacist uses the patient profile, PWDT, and FARM notes as the
basis for ongoing pharmacists -patient interactions.
IMPORTANCE OF PHARMACEUTICAL CARE IN TODAY’S PHARMACY
PRACTICE
• The potential for medication errors is growing, and one professional group
must assume a primary role in addressing this issue rather than fragmented
efforts by various groups or individuals.
• Pharmacist is trained specifically to address these therapeutic issues.
• The number, complexity, and efficacy of prescription and non-prescription
drug products are increasing.
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• These challenges put the pharmacist in key position to combat these drug
therapy problems.
• Every encounter with patients, regardless of practice setting provides an
opportunity for pharmaceutical care.
PHARMACOTHERAPY DECISION MAKING
DEFINITION
• The process by which we utilize evaluative data, the patient’s individual
needs and clinical judgment to formulate the most appropriate treatment
strategies to achieve the desired outcomes.
ROLE OF DRUG THERAPY PRACTITIONER OVER DRUG THERAPY ADVISOR
• Final goal of clinical pharmacist is to ensure the
­ Safe
­ Effective
­ Economic use of drugs
• This includes assessment of:
­ Drug abuse
­ Drug misuse
­ Safe use in Geriatrics
­ Safe use in Pediatrics
­ Right route
­ Right dose
­ Right time
­ Right patient
­ Drug-drug interactions
­ Drug food interactions
­ Patient adherence or
response
­ Economic issues
­ Pharmacotherapy based
on determinants
­ Right time for post
exposure prophylaxis
­ Polypharmacy
management
­ Monitoring of lab values
­ Monitoring of hepatic
impairment
­ Monitoring of renal
impairment
­ Risk v/s benefit ratio
­ Medication history
­ Previous allergies
­ Patient profile
­ Co-morbidities
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­ Assessment of toxicity
profile
­ Assessment of side
effect profile
­ Comparative study of
drug
­ Rapid diagnostic
techniques
­ Assessment of culture
­ antibiograms
­ Sensitivity patterns
­ Resistance patterns
­ Need of initiation of drug
­ Diagnosis
­ Diagnostic steps
­ Response monitoring
­ Cure
­ Assessment of clinical
presentation of patient
­ Identification of
symptoms
­ Symptomatic relief
­ First line treatment
­ Recognition of cause
­ Monitoring of patient
specific parameters
­ Preferable option of
treatment
­ Particulate drug
treatment
­ Periodic monitoring of
patient
­ Management plans
­ Administration
guidelines
­ Guidelines based
treatment
­ Continuation therapy
PHARMCOTHERAPY DECISION MAKING STEPS
• Ensure evidence-based medicine.
• Steps of applying the evidence-based medicine process to a
pharmacotherapeutic decision.
• Identify elements essential to a well-formulated question.
• Assess well-formulated clinical question based on a patient problem.
• Identify searching strategies to improve retrieval of evidence.
• Assess advantages and disadvantages of different resources.
• Identify validity of a randomized controlled trial.
• Assess validity of a practical guideline.
• Assess validity of a systematic review.
• Assess validity of economic analyses.
• Monitor absolute risk reduction and increment.
• Assess the need of treatment.
• List patient-specific factors.
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IMPORTANCE OF PHARMACOTHERAPY DECISION MAKING
• Recognize information needs and convert them into answerable questions.
• Conduct efficient searches for the best evidence with which to answer
these questions.
• Critically appraise the evidence for its validity and usefulness.
• Apply the results to patient situations to best assist clinical decision making.
EVIDENCE BASED MEDICINE
• Optimal care for patients.
• STEPS IN EVIDENCE BASED MEDICINE
1. Formulate a clear question from a patient's problem.
2. Identify relevant information.
3. Critically appraise available evidence.
4. Implement the findings in clinical practice.
• Quality of evidence.
• Evidence based medicine strategies.
• Evidence based medicine is realistic.
GENERAL PROCESS OF PHARMACOTHERAPY DECISION MAKING
• Identifying and defining the problem.
• Suggesting and weighing solutions.
• Making a choice.
• Assessing the results of the choice.
PHARMACOTHERAPY DECISION MAKING APPROACHES
1. Clinical
2. Ethical
3. Managerial
4. Economic
5. Legal
STEPS IN PHARMACOTHERAPY DECISION MAKING WITH RESPECT TO
APPROACHES
CLINICAL
• Identify the real or potential drug therapy problem
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• Determine the desired therapeutic outcome
• Determine the therapeutic alternatives
• Design an optimal pharmacotherapeutic plan
• Identify monitoring parameters for the outcome
• Educate the patient Implement of the pharmacotherapeutic plan
ETHICAL
• Gather relevant facts from the law, code of ethics and professional
knowledge
• Prioritize and ascribe values of the various parties involved
• Generate options and evaluate their potential consequences
MANAGERIAL
• Identify and define the problem
• Develop alternative solutions
• Evaluate alternative solutions (certainty conditions, risk conditions,
uncertainty conditions)
• Select an alternative
• Implement decision
• Evaluate and control
ECONOMIC
• Identify and bound the decision
• Structure the decision
• Assess the probabilities of each option
• Value the outcome of each option
• Choose the option with the highest expected benefit or lowest expected
cost
LEGAL
• Identify and define the legal issue
• Undertake legal research on choice relevant laws and policies
• Apply and act in accordance with laws and policies
INTENDED OUTCOMES OF DECISION MAKING IN PHARMACOTHERAPY
APPROACH
• Best quality of clinical care.
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• Maximization of therapeutic effect.
• Adopting the most morally defensible choice.
• Adopting the most legally defensible choice.
• Making the most cost-effective choice.
• Adherence to laws and statuses.
• Sustainability of clinical perfection.
• Maximization of benefits of clinical goals.
• Overall, well-being.
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DRUG INDUCED DISEASES
1. DRUG INDUCED KIDNEY DISEASE
2. DRUG INDUCED LIVER DISEASE
DRUG INDUCED KIDNEY DISEASE
BACKGROUND
• The incidence of drug-induced nephrotoxicity has been increasing with the
ever-increasing number of drugs and with easy availability of over-the-
counter medication viz. nonsteroidal anti-inflammatory drugs (NSAIDs)
• For most patients suffering from drug induced nephropathy common risk
factors which precipitate the adverse effects include old age, volume -
depleted state, pre-existing renal dysfunction and coexisting use of other
nephrotoxins.
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RISK FACTORS
PATIENT RELATED RISK FACTORS
• Age, sex, race
• Pre-existent renal disease
• Specific disease (diabetes
mellitus, multiple myeloma,
proteinuric patients)
• Sodium-retaining states
(cirrhosis, heart failure,
nephrosis)
• Dehydration and volume
depletion
• Acidosis, potassium and
magnesium depletion
• Hyperuricemia, hyperuricosuria
• Sepsis, shock
• Renal transplantation
DRUG-RELATED FACTORS
• Inherent nephrotoxic potential
• Dose
• Duration, frequency and form of administration
• Repeated exposure
DRUG INTERACTIONS
• Combined or closely associated use of diagnostic or therapeutic agents with
added or synergistic nephrotoxic potential (e.g. Radiocontrast agents,
aminoglycosides, NSAIDs, cisplatin, ACEI)
CLINICAL PRESENTATION DIKD GENERAL
• The most common manifestation is a decline in GFR leading to a rise in Scr
and BUN.
SYMPTOMS
• Malaise, anorexia, vomiting, shortness of breath, or edema.
SIGNS
• Decreased urine output may be an early sign of toxicity, particularly with
radiographic contrast media, NSAIDs, and ACEIs, with progression to
volume overload and hypertension.
• PROXIMAL TUBULAR INJURY
­ Metabolic acidosis with bicarbonaturia.
­ Glycosuria in the absence of hyperglycemia.
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­ Reductions in serum phosphate, uric acid, potassium, and
magnesium as a result of increased urinary losses.
• DISTAL TUBULAR INJURY
­ Polyuria from failure to maximally concentrate urine.
­ Metabolic acidosis from impaired urinary acidification.
­ Hyperkalemia from impaired potassium excretion.
LABORATORY TESTS
• A change in Scr of at least 0.5 mg/dL for subjects with a baseline Scr <2
mg/dL and an increase of >30% for those with Scr >2 mg/dL, when
correlated temporally with the initiation of drug therapy is commonly
observed.
TYPES OF DRUGS INDUCING KIDNEY DISEASES
• Drug induced kidney disease or nephrotoxicity is a relatively common
complication of several diagnostic and therapeutic agents.
1. TUBULAR EPITHELIAL CELL DAMAGE
ACUTE TUBULAR NECROSIS
• Aminoglycoside antibiotics
• Radiographic contrast media
• Cisplatin, carboplatin
• Amphotericin B
OSMOTIC NEPHROSIS
• Mannitol
• Dextran
• IV immunoglobulin
2. HEMODYNAMICALLY MEDIATED KIDNEY INJURY
• Angiotensin-converting enzyme inhibitors
• Angiotensin II receptor blockers
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
3. OBSTRUCTIVE NEPHROPATHY
CRYSTAL NEPHROPATHY
• Sulfonamides • Methotrexate
NEPHROLITHIASIS
• Triamterene • Indinavir
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4. GLOMERULOPATHY
• NSAIDS, COX-2 inhibitor
• Gold
• Pencillamide
5. TUBULOINTERSTITIAL DISEASE
• NSAID
• Antibiotics
• Diuretics
• Proton pump inhibitors
6. RENAL VASCULITIS, THROMBOSIS, AND CHOLESTEROL EMBOLI
• Hydralazine
• Allopurinol
• Penicillamine
• Warfarin
• Thrombolytic agents
1. TUBULAR EPITHELIAL CELL DAMAGE
• Drugs that lead to renal tubular epithelial cell (RTEC) damage typically
do so via direct cellular toxicity or ischemia.
• Damage is most often localized in the proximal and distal tubular
epithelia and is termed ATN (Acute Tubular Necrosis) when cellular
degeneration and sloughing from proximal and distal tubular basement
membranes are observed.
Acute Tubular Necrosis
• Acute tubular necrosis is the most common presentation of DIKD in the
inpatient setting.
• The primary agents associated with this type of injury are aminoglycosides,
radiocontrast media, cisplatin, amphotericin B, foscarnet, and osmotically
active agents such as immunoglobulins, dextran and mannitol.
AMINOGLYCOSIDES
• Aminoglycosides are prototype drugs having nephrotoxicity as major side
effect.
• Number of patients developing nephrotoxicity increases with duration of
therapy reaching 50% with 14 days or more of therapy.
CLINICAL FEATURES
• Classically it presents as acute tubular necrosis which is generally milder
than oliguric ARF.
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• Gradual progressive rise in Scr and in CrCl after 6 to 10 days of therapy
• No oliguria >500 mL/day
• Magnesium wasting >10 to 30 mg
• Severe kidney injury does not usually develop.
FEATURES INCLUDE
• Non-oliguric ARF, proximal tubular dysfunction, enzymuria, proteinuria,
glycosuria, hypokalemia, hypocalcemia, hypomagnesemia.
• In over 50%, renal functions decline after completion of therapy.
• Recovery is slow and requires 4-6 weeks.
• Recovery is incomplete if pre-existing renal insufficiency exists. Some
patients may progress to chronic interstitial nephritis.
MECHANISM
• The drug is actively concentrated in the renal cortex and proximal tubular
cells achieve maximum concentration.
• After entering the cortical cells AMG bind to lysosomes with formation of
myeloid bodies/secondary lysosomes.
• ROS generation, Altered cell metabolism and membrane fluidity
­ Cellular dysfunction and death.
• PCT epithelial cell damage leading to obstruction of the tubular lumen
­ Back leakage of the glomerular filtrate across the damaged tubular
epithelium.
­ Reduction of GFR
• It is believed that the release of AMG into cytoplasm interferes with the
phosphatidyl-inositol pathway.
• Thus, momentary high drug concentrations as achieved immediately after
intravenous injection result in saturation of the uptake mechanism.
• Hence, multiple dosing is more deleterious than single dosing bolus
injection.
PREVENTION AND MANAGEMENT
• Use total dose as once daily dosing, and for shortest possible time in
empirical therapy.
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• Mostly subclinical toxicity and beyond detection as electrolyte imbalances
are subtle.
• Routine monitoring of SCr daily with calculation of dose on basis of
GFR/creatinine clearance, especially in elderly.
• Daily monitoring of serum Na
+
and K
+
.
• If SCr > 1.5 mg/dl stop the drug and consider alternate therapy.
• Monitor urine output and start adequate fluid and electrolyte therapy with
specific emphasis on K+ and NaCl as well as Ca
2+
and Mg
2+
replacement.
AMPHOTERICIN B
• It contains hydrophilic as well as lipophilic regions; allowing it to easily
mingle with cellular membranes, disrupting them and increasing their
permeability.
• Disruption of cell membranes leads to endothelial damage with
vasoconstriction of afferent and efferent arterioles, causing an acute fall in
GFR and an initial oliguric ARF in some patients.
• Tubular toxicity is related to direct effect on cellular membrane and also
medullary ischemia caused by sudden vasoconstriction.
• Recent studies show protective effect of pentoxiphylline which is a vascular
decongestant and antagonist to TNF-α, IL-1α.
• Am-B typically causes distal tubular dysfunction.
• Toxicity relates to cumulative dosage, starts from 300-400mg, 4g (at higher
doses 80% incidence)
PATHOGENESIS
• Increases tubular permeability.
­ Consequent increase in energy and oxygen requirements of epithelial
cells.
­ Reduced cellular oxygen delivery due to renal vasoconstriction.
­ Renal medullary tubular epithelial cell necrosis and kidney injury.
CLINICAL SPECTRUM OF AMPHOTERICIN NEPHROTOXICITY
1. Azotemia: It is almost universal with Am-B. GFR falls to 40% in first 2-3
weeks and stabilizes at 20-60% of normal throughout course of treatment;
normalizing on cessation of therapy. Cumulative doses of 3-4g have greater
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risk, implying a greater incidence with longer duration of therapy and
greater chances of irreversibility as well.
2. Inability to concentrate urine occurs universally within 1-2 weeks of therapy
even in absence of decrease in GFR and is not related to occurrence of
azotemia. It occurs due to failure of arginine-vasopressin (AVP) response on
medullary collecting tubule.
3. Electrolyte disturbance occurs as a consequence of distal tubulopathy with
predominantly Mg
2+
and K
+
loss is important as it may cause worsening of
renal function with impairment of concentration ability, urinary
acidification, renal insufficiency.
4. Renal tubular acidosis can occur at cumulative doses of 0.5-1 g but is
reversible.
RISK FACTORS
• Age - important risk factor and careful use of CCR for dose titration is
necessary for elderly.
• Preexisting kidney disease, large individual and cumulative doses, short
infusion times, volume depletion, hypokalemia, increased age, and
concomitant administration of diuretics.
PREVENTION
• Nephrotoxicity can also be minimized by limiting the cumulative dose,
increasing the infusion time, ensuring the patient is well hydrated, and
avoiding concomitant administration of other nephrotoxins.
MANAGEMENT
• Prevention is the key with risk factors for Am-B toxicity remain the same as
for any toxic nephropathy, but sodium deficiency is important especially in
patients on diuretics.
• Dopamine agonists - may exert protective role
• Salt supplementation - is the most effective measure in reducing incidence.
• A titer of normal saline infused prior and post Am-B significantly lowers
incidence of nephrotoxicity.
• Discontinuation and substitution of therapy
­ Daily monitoring of Renal function indices i.e. Scr and BUN
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­ Daily monitoring of serum magnesium, potassium, and calcium
concentrations.
LIPOSOMAL AMPHOTERICIN-B
• Liposomal compounds and lipid complexes reduce Am-B toxicity.
• The lipid complex is rapidly taken up by the reticuloendothelial system
thereby significantly increasing the tissue concentration in the liver, spleen
and lymphoid tissues.
• A higher total dose of 5 mg/kg/day compared to a maximum of 0.5 to 1.5
mg/kg/day with Am-B can be achieved without risking the renal tissue; and
the efficacy is similar.
• High cost is the disadvantage.
• Liposomal preparations should be used in patients with pretreatment renal
dysfunction (SCr > 3 mg/dl) and where use of alternative antifungals is not
feasible.
ANTI-NEOPLASTIC AGENTS
CISPLATIN
• Major side effects are nephrotoxicity and is irreversible in most cases.
• Toxicity is cumulative and dose-related (> 25-33 mg/m2/wk. predisposes to
nephrotoxicity).
• Nephrotoxicity is by acute tubular necrosis or tubulointerstitial process with
symptoms of azotemia and fluid loss.
• Biochemical tests usually show tubular proteinuria with prominent tubular
casts (aggregation of proteins).
• High BUN and Scr and low serum Na
+
, K
+
, Mg
2+
, Ca
2+
, PO
4-
occur due to
proximal tubular damage.
REDUCTION OF NEPHROTOXICITY
• Hypomagnesemia is severe.
• Damage typically occurs at the S3 portion (straight) of proximal tubule.
• Free radicals may play an important role.
• Prevention of toxicity is by avoidance of other nephrotoxic drugs like AMG.
• Begin diuresis after drug administration; maintaining urine output of 100
mL/hr. can decrease nephrotoxicity.
• Mannitol may also be helpful.
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• Administration is better tolerated if given by hypertonic saline which is also
be given 12 hours prior and 12 hours post-cisplatin dose.
• Sodium-thiosulfate i.e. has been tried with some success.
• It should be added if > 200 mg/m2 of cisplatin is used.
• Some other measures to reduce nephrotoxicity are methylprednisolone, N-
acetylcysteine and antioxidants.
2. HEMODYNAMICALLY MEDIATED KIDNEY INJURY
• Hemodynamically mediated kidney injury generally refers to any cause
of AKI resulting from an acute decrease in intraglomerular pressure,
including “prerenal” states leading to reduced effective renal blood flow
(e.g., hypovolemia and congestive heart failure) and medications that
affect the renin–angiotensin system.
• Drug-induced causes of hemodynamic kidney injury typically stem from
constriction of glomerular afferent arterioles and/or dilation of
glomerular efferent arterioles. ACEIs, angiotensin II receptor blockers
(ARBs), and NSAIDs are the agents that have been most commonly
implicated.
NSAIDS INDUCED NEPHROTOXICITY
INCIDENCE
• Overall incidence is 3%; but over-the-counter availability of these drugs
puts a large population at risk.
RISK FACTORS
• Conditions causing NSAID-induced hemodynamic deterioration of renal
function:
­ Higher than usual dose, volume depletion due to flow loss diarrhea,
congestive heart failure, nephrotic syndrome, cirrhosis particularly
with ascites, preexisting renal disease, third space fluid
sequestration, diuretic therapy, age > 65 years.
SYNDROMES OF NSAID NEPHROTOXICITY
• Acute effects. ARF
­ usually oliguric.
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• Acute interstitial nephritis (AIN) - Associated with heavy proteinuria (> 3
g/24 hr.).
­ usually non-oliguric.
­ rarely without proteinuria, takes weeks or months to resolve.
• Hyperkalemia.
• Sodium and water retention.
• Hypertension.
EFFECTS OF NSAIDS ON BLOOD PRESSURE
• Modest increase of mean arterial pressure (~6-8 mmHg) in all patients with
increase more in patients already hypertensive.
• Most vulnerable are patients on diuretics and/or β-blocker especially
patients on propranolol; but less vulnerability seen with calcium channel
blockers, direct vasodilators and clonidine.
• Effects in combination with ACE inhibitors are controversial and may cause
deterioration of renal function.
• Most vulnerable are patients with low renin hypertension i.e. elderly and
blacks.
CONCEPT OF RENAL SPARING NSAIDS
• Sulindac was previously considered as reno-protective since its hepatic
metabolite sulindac sulfoxide has shown to be least affecting the renal
cyclooxygenase system whereas the sulfide metabolite is active as a
vasoconstrictor.
• Present views suggest that kidney can activate the prodrug and lead to
vasoconstrictive renal failure usually after days or week.
CHRONIC KIDNEY DISEASE (CKD) AND NSAIDS
• Also known as “analgesic nephropathy”.
• It is chiefly a chronic interstitial nephritis (spaces between kidney tubules
become swollen) associated with capillary sclerosis of the vessels of renal
pelvis and renal papillary necrosis followed by calcification.
• It is due to medullary ischemia induced by loss of vasodilatory effects of
prostaglandins on vasa recta (arterioles of kidney).
• Long term toxicity of individual drugs is unknown and so are incidence and
prevalence in view of most drugs available over the counter.
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• Classically seen with consumption of any NSAID for over 20 years.
• The potential of CKD exists with use of analgesic mixture and is most well
studied with aspirin-codeine.
• Incidence is higher in females and in patients suffering from rheumatic
disorders and migraine.
• Diagnosis is difficult as there is lack of a simple non-invasive test that
reliably implicates analgesics as a cause of renal injury.
CLINICO-RADIOLOGICAL CRITERIA
• History of analgesic abuse (i.e. daily use of mixture of analgesic drugs for a
period not less than five years) with non-contrast CT scan of abdomen
showing the following:
1. Bumpy contour of the kidneys
2. Decreased length of both the kidneys
3. Papillary calcification
• 1 or 2 with 3 carries maximum specificity (100%) and sensitivity (94%) in
diagnosis.
PREVENTION AND MANAGEMENT
• It is one of the few CKDs which can be prevented, and early intervention
can prevent its progression.
• Stop NSAIDs if patients develop any evidence of renal insufficiency.
• Appropriate legislation to limit accessibility of all analgesics is required.
3. OBSTRUCTIVE NEPHROPATHY
• Numerous medications may cause obstructive nephropathy, or kidney
injury from deposition or precipitation within the renal tubules and/or
collecting system. For example, the precipitation of drug crystals in
distal tubular lumens can lead to intratubular obstruction, interstitial
nephritis, and occasionally superimposed ATN, collectively termed
crystal nephropathy.
SULFONAMIDES
• Use of sulfonamides has increased with advent of AIDS.
• Sulfadoxine + pyrimethamine combination is used in malaria.
SPECTRUM OF NEPHROTOXICITY
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260. GM Hamad

1. Acute interstitial nephritis (not common)
2. Necrotizing arteritis
3. ARF due to massive hemolytic anemia in G-6-PD deficient patients
4. ARF due to crystalluria (seen only with long-acting agents like
sulphadiazine)
SULFADIAZINE
• A prototype drug causing crystalluria and ARF.
• The overall incidence is 6%.
• Renal dysfunction starts after three weeks of commencing treatment in
AIDS patients and is related to the cumulative dose (> 84g), the acetylated
byproduct is toxic.
• Sulphadiazine has low solubility in acidic urine.
• Crystals of sulfadiazine and acetyl sulfadiazine are typically recognized by
examining the urine sediment where they resemble “sheaves of wheat”.
• As the crystals transmit through tubular lumen, they cause local abrasion
and chemical irritation of collecting duct epithelium followed by peritubular
hemorrhage, tubular necrosis and obstruction at any level from collecting
duct to bladder.
• Patient manifests with asymptomatic crystalluria and microhematuria,
gross hematuria, oliguria to anuria and post-renal ARF.
CYTOTOXIC AGENTS
CYCLOPHOSPHAMIDE
• Although primarily a myelotoxic drug, nephrotoxicity is known.
• At daily doses of more than 50 mg/kg hyponatremia is seen.
• Hyponatremia occurs due to impaired water excretion by antidiuretic effect
on distal nephron.
• The effect is transient and dissipates after 24 hrs. of discontinuation of
therapy.
• Hemorrhagic cystitis is a more common side effect of cyclophosphamide
and occurs in 9% of cases.
METHOTREXATE
• Effective chemotherapeutic agent
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261. GM Hamad

• Nephrotoxicity seen at doses greater than 1.5 g/m2/week.
• Mainly due to intratubular deposition of 7- hydroxy methotrexate leading
to crystalluria and features of non-oliguric renal failure.
• Element of direct tubular toxicity are ameliorated with folinic acid.
• High doses of methotrexate need routine monitoring of KFT for casturia
and tubular dysfunction.
• Rapid discontinuation reverses the abnormality.
• In patients with overt nephrotoxicity, anion binding resin and
hemoperfusion (filtering the blood extra-corporeally) therapy have been
tried with some success.
• High dose folinic acid at 200-400 mg i.v. four hourly has been shown also to
revert nephrotoxicity.
4. GLOMERULOPATHY
COX-2 SELECTIVE INHIBITORS
• COX-2 selective inhibitors were designed to counteract the gastrointestinal
toxicity considering COX-1 as a constitutive enzyme and COX-2, an inducible
enzyme (induced by inflammatory and mitogenic stimuli).
• COX-2 is now known to exist constitutively in renal tissue especially the
cells of the thick ascending loop of Henle and macula dense in humans as
well as in renal medulla interstitial cells and medullary collecting duct cells.
• Prostaglandins generated by COX-2 are involved in tubuloglomerular
feedback mechanism leading to afferent arteriolar vasoconstriction.
• In medulla COX-2 promotes diuresis and natriuresis.
• Expression of COX-2 is enhanced in low salt diet in the cortex while it is
increased in medulla with high salt diet.
• The former preserves renal function in volume depletion whereas the latter
promotes natriuretic and diuretic response during volume expansion.
• Given the role of COX-2 in renal function; same precautions need to be
taken with COX-2 inhibitors as is necessary for non-selective NSAIDs
5. TUBULOINTERSTITIAL DISEASE
NSAID-INDUCED TUBULOINTERSTITIAL NEPHRITIS
CLINICAL FEATURES
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262. GM Hamad

• Usually subacute to chronic course.
• Mostly seen with fenoprofen but all NSAIDs till date observed to cause.
• Mean period of development 5.4 months.
• Associated with heavy proteinuria (> 3.0 g/d) in 83% of cases.
• Fever, rash, eosinophilia rare (< 19%)
• Renal biopsy characteristically shows tubulo-interstitial infiltrate with some
fibrosis. Immunofluorescence shows variable staining for IgA, IgM and C3.
MECHANISIM
• Proposed mechanism is occurrence of delayed hypersensitivity response
with shunting of arachidonic acid metabolites to lipoxygenase pathway.
• Leukotrienes mediate chemotaxis for WBCs leading to cellular infiltrates (T-
cell and eosinophils).
• Isolated proteinuria - Isolated reports of proteinuria in absence of
tubulointerstitial damage occur; proteinuria reaching nephrotic range; and
minimal change disease on biopsy.
DRUG INDUCED LIVER DISEASES
BACKGROUND
• A drug-induced disease is the unintended effect of a drug, which results in
mortality or morbidity with symptoms sufficient to prompt a patient to
seek medical attention and/or require hospitalization.
• Disease can also occur from product impurities, as was the case with deaths
attributed to the use of contaminated heparin in 2008.
• Vigilance on the part of regulatory authorities, drug manufacturers,
clinicians, and patients are necessary to minimize the potential harm that is
inherent in drug use.
• Adverse Drug Reaction: The World Health Organization defines an adverse
drug reaction (ADR) as any noxious, unintentional, and undesired effect of a
drug, which occurs at doses used in humans for prophylaxis, diagnosis, or
therapy.
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• Adverse event (AE): Medical occurrence temporally associated with the use
of a medicinal product, but not necessarily causally related. The essential
difference from ADR is that AE need not be causally related to the drug in
use.
• Side effect: Unintended effect occurring at normal dose related to the
pharmacological properties.
BRIEF HISTORY
• In 1922, there was an enquiry into the jaundice associated with the use of
SALVARSAN, an organic arsenical used in the treatment of Syphilis.
• In 1937 in the USA, 107 people died from taking an elixir of sulfanilamide
that contained the solvent diethylene glycol.
• This led to the establishment of the Food and Drug Administration (FDA),
which was given the task of enquiring into the safety of new drugs before
allowing them to be marketed
• The major modern catastrophe that changed professional and public
opinion towards medicines was the thalidomide tragedy.
• The thalidomide incident led to a public outcry, used for sleep disorders in
post-war era, to the institution all round the world of drug regulatory
authorities, to the development of a much more sophisticated approach to
the preclinical testing and clinical evaluation of drugs before marketing, and
to a greatly increased awareness of adverse effect of drugs and methods of
detecting them.
DRUGS AND THE LIVER





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WHY STUDY DRUGS AND THE LIVER?
• Liver is a major bio-transforming and elimination organ
­ Barrier and “Garbage Disposal”
• Drug-drug interactions occur in liver
­ May increase toxicity or reduce effect
• Drugs cause liver damage
­ Mechanism and can it be predicted?
• Liver disease in turn alters drug disposal.
DRUG ABSORPTION BARRIERS
• Barriers to uptake of potentially undesirable chemicals/xenobiotics (an
eternal problem):
1. Gut mucosa
2. Liver
• Barrier consists of multiple steps.
• Not all xenobiotics are affected by each step.
HEPATIC CLEARANCE OF DRUGS
• Liver removal of drugs/xenobiotics from blood is termed hepatic clearance
(ClH)
• Hepatic clearance is actually a very complex process due to many steps.
• Can be simplified to three factors
­ Liver blood flow
­ Liver intrinsic clearance
­ Fraction of drug not bound to albumin
EFFECT OF EFFICIENT EXTRACTION BY HEPATOCYTES IN SERIES







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HIGH EXTRACTION DRUGS /XENOBIOTICS /ENDOGENOUS COMPOUNDS
• Nitroglycerine
• Lidocaine
• Propranolol
• Bile Acids
HIGH EXTRACTION DRUGS
• Drugs/xenobiotics rapidly cleared in a single pass through the liver.
• Consequences can be good or bad:
­ Oral administration of drugs/ xenobiotics is inefficient – must
administer IV/IM.
­ However, enterohepatic circulation of bile acids is efficient.
EFFECT OF LOW EXTRACTION BY HEPATOCYTES IN SERIES






LOW EXTRACTION DRUGS/ ENDOGENOUS COMPOUNDS
• Diazepam
• Phenytoin
• Theophylline
• Bilirubin
• These drugs are efficiently absorbed when given orally.
• Thus, bioavailability of orally administered drugs is high.
• Drug companies look for these types of products as pills are easy to take.
CATEGORIZATION OF DILD
PREDICTABLE
• Dose related
• Intrinsically hepatotoxic drugs
• Acute (hours)
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• Injury pattern is usually necrosis
• Clinically → Fulminant (Acute Hepatitis)
• Example: Acetaminophen
UNPREDICTABLE
• Not dose related
• Rare 0.01-1.0 %
• Weeks to months after ingestion of drug
• Idiosyncratic
o Immune mediated idiosyncrasy (Hypersensitivity)
­ Rash
­ Fever
­ Arthralgia
­ Eosinophilia
­ Example: Phenytoin, Sulfonamides, Valproate
o Metabolic idiosyncrasy (Production of toxic metabolites)
­ Example: INH, Ketoconazole, and Diclofenac
HISTOLOGICAL CLASSIFICATION
• Hepatocellular ------› Hepatocytes
• Cholestatic -------› Bile ducts or canaliculi
• Mixed
CATEGORIZATION ACCORDING TO TYPE OF REACTION
• Direct toxic reactions
• Idiosyncratic reactions
• Veno-Occlusive disease
• Allergic hepatitis
• Chronic hepatitis and cirrhosis
• Cholestatic reactions
• Granulomatous reactions
• Combined toxic/Allergic reactions
• Fatty liver /NASH (non-alcoholic steatohepatitis)
OTHER CLASSIFICATION
• DILI can also be classified as:
1. Immune mediated (allergic)
2. Non-immune mediated (non- allergic)
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• Immune-mediated idiosyncratic reactions can be characterized by presence
of:
­ Fever
­ Rash
­ Eosinophilia
­ Autoantibodies (such as antinuclear and smooth muscle antibodies).
• Severe cases may be accompanied by:
­ Stevens–Johnson syndrome.
­ Toxic epidermal necrolysis.
­ Hematological features such as:
▪ Granulocytopenia.
▪ Thrombocytopenia.
▪ hemolytic anemia.
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DIAGNOSIS OF (DILD)
1. SIGNS & SYMPTOMS
• High index of suspicion
• Abnormalities in hepatic associated enzymes
• Hepatitis like symptoms
• Jaundice
2. DRUG HISTORY
• Dose
• Duration of therapy
• Time between initiating therapy and the development of hepatic injury
(latency)
3. EXCLUSION OF OTHER CAUSES OF LIVER DISEASES
• Hepatitis B
• Hepatitis C
• Alcoholic liver diseases
• Nonalcoholic fatty liver diseases
• Hemochromatosis
4. TEMPORAL RELATIONSHIP
• Most cases of acute DILD occurring within 1 week to 3 months of exposure
• Positive response to discontinuing the agent (Dechallenge)
­ In acute hepatocellular injury
▪ 50% reduction in hepatic –associated enzymes after 2 weeks
▪ Return to normal by 4 weeks
­ In cholestatic injury
▪ May have prolonged recovery time
5. EXTRA-HEPATIC MANIFESTATIONS
• Hypersensitivity reactions
­ Fever
­ Rash
­ Arthralgias
­ Eosinophilia
• Unique clinical syndromes
RISK FACTORS FOR SUSCEPTIBILITY TO DILD
2%-5% of
general
population
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METHOTREXATE
• Alcohol
• Obesity
• D.M
• Chronic hepatitis
INH
• HBV, HCV, HIV
• Alcohol
• Older age
• Female
ACETAMINOPHEN
• Alcohol
• Fasting
• INH
VALPROATE
• Young age
• Anticonvulsants
DICLOFENAC
• Female
• Osteoarthritis
SULFONAMIDE
• HIV
• Slow acetylator
• Genetic defect in defense
ANTI-CONVULSATS
• Genetic defect in detoxification
RIFAMPICIN
• Slow acetylators
• INH
PYRAZINAMIDE
• Slow acetylators
• INH
CLINICAL PRESENTATION

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ACUTE HEPATOCELLULAR INJURY (DIRECT TOXIC REACTION)
CHARACTERIZED BY
• Marked elevation in ALT and AST
• Normal or minimally elevated alkaline phosphatase
• Bilirubin variably increased-----›worse prognosis.
COMPRISE 1/3 OF ALL CASES OF FULMINANT HEPATIC FAILURE IN THE US.
• 20% due to Acetaminophen
• 12%-15% due to other drugs
ALCOHOL
• AST is always 2-3 times higher than ALT
• AST remains less than 300 IU.
• ALT is almost always less than 100 IU.
TOWERING ELEVATION OF ALT&AST (5000-10000 IU)
• Drugs (acetaminophen)
• Differential:
­ Chemical toxins
­ Toxic Mushrooms
­ Shock liver
• Unusual with other causes of liver diseases including Viral Hepatitis.
EXAMPLES
ANESTHETICS
• Halothane
• Isoflurane
ANTIMICROBIALS
• INH
• Rifampin
• Ketoconazole
• Sulfonamides
ANTICONVULSANTS
• Phenytoin
• Valproic acid
• Carbamazepine
NSAIDS & ANALGESICS
• Acetaminophen
• Piroxicam, Diclofenac
• Sulindac
MISCELLANEOUS
• Labetalol
• Nicotinic acid
• Propylthiouracil

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ACETAMINOPHEN METABOLISM

ACETAMINOPHEN METABOLISM: HIGH DOSE

LIVER DAMAGE DUE TO TOXIC DOSES OF ACETAMINOPHEN
ACETOMINOPHEN HEPATOTOXICITY




Pericentral Hepatocyte necrosis
Portal
Tract
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CHOLESTATIC INJURY
DEFINITION
• Reduction in bile flow due to reduced secretion of bile or obstruction in
pathway.
BIOCHEMICALLY
• Elevated Alk phosphatase, Elevated bilirubin, Elevated GGT, Elevated 5 NT.
• Acute illness that subsides when the offending drug is withdrawn.
CLINICAL PRESENTATION
• Jaundice
• Dark urine
• Pruritis
SERUM ENZYME ELEVATIONS
• Prominence of alkaline phosphatase (Alk P) and GGT elevations of at least 3
times the upper limit of normal (ULN) with variable elevations in ALT, which
can be as high as 10 times ULN (400 U/L) early in the course of illness.
• The ALT divided by Alk P (both expressed as multiples of ULN) or the R ratio
should be less than 2.0, but may be higher at the time of onset, as the Alk P
usually rises during the first week or two of injury.
• Drug induced cholestatic hepatitis is typically more prolonged than acute
hepatocellular hepatitis due to medications, the serum enzymes decreasing
slowly with 50% fall within 4 to 12 weeks.
• Severe cholestatic drug induced liver injury can lead to vanishing bile duct
syndrome to variable degrees.
ELEMENTS IMPORTANT IN DIAGNOSIS OF CHOLESTATIC HEPATITIS DUE TO
MEDICATIONS INCLUDE
• Cholestatic pattern of serum enzyme elevations (R value <2), with Alk P
levels greater than 3 times ULN (>345 U/L) at the time of peak ALT or
bilirubin elevation
• Latency of 2 to 24 weeks
• Symptoms (if present) of dark urine or pruritus early during course
• Bilirubin >2.5 mg/dL
• If liver biopsy is obtained, changes of intrahepatic cholestasis with
inflammatory cells but mild to moderate focal hepatocellular necrosis
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• Exposure to an agent known to cause cholestasis.
TYPES OF CHOLESTASIS RESULTING FROM DRUGS

DRUGS CAUSING CHRONIC CHOLESTASIS AND THE VANISHING BILE DUCT
SYNDROME
ANTIBIOTICS
• Ampicillin
• Augmentin
• Clindamycin
• Erythromycin
• Organic arsenicals
• Septrin
• Tetracycline
• Thiabebdazole
• Troleandomycin
PSYCHOTROPIC
• Amitriptyline
• Barbiturates
• Carbamazepine
• Chlorpromazine
• Haloperidol
• Imipramide
• Phenothiazines
MISCELLANEOUS
• Aprindine
• Azathioprine
• Carbutamide
• Ciproheptadine
• Chlorthiazide
• cyamemazine
• Ibuprphen
• Cimetidine
• Prochlorperazine
• Terbinafine
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GRANULAMATOUS HEPATITIS
A form of hepatic injury characterized by:
• Fever
• Diaphoresis
• Malaise
• Anorexia
• Jaundice
• Rt upper quadrant discomfort
• Granuloma on liver biopsy
• Illness usually occurs within the
first 2 months of therapy
EXAMPLES
• Quinidine
• Carbamazepine
• Allopurinol
• Hydralazine
• Phenytoin
• Gold
• Mineral oil ingestion
• Phenylbutazone
DRUG INDUCED CHRONIC HEPATITIS
• Can resemble chronic active hepatitis including cirrhosis as well as a form of
chronic autoimmune hepatitis.
CHARACTERISTICS OF DRUG INDUCED AUTOIMMUNE HEPATITIS

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DRUGS LEADING TO A SYNDROME RESEMBLING TYPE I AUTOIMMUNE CHRONIC
HEPATITIS


HALOTHANE INDUCED AUTOIMMUNE LIVER DAMAGE
• Approximately 60% to 80% of halothane is eliminated unchanged by the
lungs, but a proportion is bio transformed by hepatic microsomal enzyme
CYP 2E1 to a trifluoroacetic acid which can be detected in the urine, but
which also can trifluoro acetylate hepatic proteins, some of which may be
immunogenic and induce cytotoxic reactions.
• The clinical pattern of injury is suggestive of an allergic hepatitis with rapid
onset of injury, fever, eosinophilia and accelerated and more severe injury
with reexposure.
• Patients with halothane hepatitis often have antibodies to trifluoro
acetylated proteins.
• On the other hand, the clinical and histological pattern of halothane hepatic
injury also resembles chloroform induced liver damage with centrilobular
somewhat bland necrosis, suggesting that toxic intermediates of reductive
halothane metabolism may cause the injury by direct injury
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MECHANISM OF DRUG INDUCED AUTOIMMUNE LIVER DISEASE HALOTHANE
HEPATITIS

• Halothane, sulfamethoxazole, carbamazepine, and nevirapine are
associated with autoimmune injuries.
• Stimulation of autoimmunity is often associated with fulminant
presentations.
OUTCOME AND MANAGEMENT
• Severity ranges from mild and transient aminotransferase elevations
without symptoms or other evidence of liver injury, to a self-limited
symptomatic acute hepatitis-like reaction, to a severe, acute hepatic
failure.
• The severity and prognosis may relate in part of patient age, being more
severe in the elderly and both milder and less common in children.
• Obesity may also be both a predisposing factor and predictor of outcome.
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• Chronic liver injury from repeated halothane exposure has been described,
but the injury does not appear to lead to a chronic hepatitis if the exposure
is terminated.
• Patients should be cautioned against future exposure to a fluorinated
hydrocarbon anesthetic such as isoflurane, enflurane, desflurane or
sevoflurane.
HY’S LAW
• 3 Components
­ Drug causes hepatocellular injury (↑ enzyme drug>control)
­ Among those with enzyme elevations >3x ULN, some with ↑ serum
total bilirubin >2x ULN, with no cholestasis (↔ alk phosphatase)
­ No other reason can be found to explain the combination.
• Requires clinical adjudication to determine probable cause of liver
dysfunction.
CLINICAL MANAGEMENT OF SUSPECTED DILI
• DRUG DISCONTINUATION
­ Automatically stopping drug with >3xULN increase may be
unnecessary.
▪ Liver can adapt and become tolerant
▪ Close observation warranted
• PREVENT PROGRESSION TO FUNCTIONAL IMPAIRMENT
• GENERALLY, D/C DRUG IF:
­ ALT/AST > 8x ULN
­ ALT/AST > 5x ULN for more than 2 weeks
­ ALT/AST >3x ULN and (total bili >2x ULN or INR > 1.5)
­ ALT/AST >3x ULN with symptoms
• FOLLOW-UP
­ Follow until enzymes return to normal or baseline
­ Symptoms and enzymes may progress even after discontinuation
▪ Bilirubin elevations usually follow enzyme elevations by days
to weeks
• RECHALLENGE
­ Can be considered
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­ Not for patients with significant ↑ enzymes (> 5x ULN)
­ Not for patients with accompanying signs of an immunologic reaction
GATHER MORE INFORMATION TO ASSESS CAUSALITY
• Evaluate alternative causes
­ Acute viral hepatitis
­ Alcoholic and autoimmune hepatitis
­ Biliary tract disorders
­ Cardiovascular causes
­ Other uncommon causes
• Drug/Exposure history
­ Dietary supplements, occupational exposure to toxic agents
VASCULAR INJURY
• May involve all of the vascular components of the liver, including the
sinusoids, hepatic veins, and hepatic arteries.
VENO-OCCLUSIVE DISEASE (VOD)
• May be caused by:
­ Toxic plant alkaloids (certain herbal tea)
­ A serious complication of bone marrow transplant
• Azathioprine is probably the culprit.
CLINICALLY PRESENTATION
• Mild viral-like illness →→ Fulminant hepatic failure
• Rapid weight gain
• Ascites
• Jaundice
• Evidence of portal
hypertension
NEOPLASTIC LESIONS
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DRUG LITERATURE UTILIZATION
DEFINITION
Drug information is the current, critically examined, relevant data about drugs &
drug use in a given patient or situation.
LEVELS OF INFORMATION
There are three levels of information:
• Current information
• Critically examined information
• Relevant information
1. CURRENT INFORMATION
• Use the most recent, up to date sources possible.
2. CRITICALLY EXAMINED INFORMATION
• Includes more than one source should be used when appropriate.
• The extent of agreement of sources should be determined, if sources do
not agree, good judgment should be used.
• The plausibility of information, based on clinical circumstances, should
be determined.
3. RELEVANT INFORMATION
• Must be prepared in a manner that applies directly to the circumstances
under consideration
e.g. patient parameters, therapeutic objectives, alternative approaches.
DRUG INFORMATION RESOURCES
There are three sources of drug information:
• Primary sources (journals)
• Secondary sources (indexing & abstracting services)
• Tertiary sources (textbooks)
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1. PRIMARY SOURCES
JOURNAL ARTICLES
Provide the most current information about drugs and ideally should be the
source for answering therapeutic questions. Enable pharmacist to:
• Keep abreast of professional news.
• How a second clinician handles a particular problem.
• Keep up with new developments.
• Enhance communication
• Obtain continuing education & sharing opinions.
PRIMARY LITERATURE
PRIMARY RESEARCH
• Journal articles that are:
­ Case reports
­ Drug studies
­ Original reports of data
• Meta-analysis.
• Unpublished studies
PRIMARY LITERATURE CONSIDERATIONS
• Evaluating the basics
­ Peer-reviewed
­ Journal reputation
­ Source of funding
• Digging deeper
­ Study methodology
­ Clinical relevance
­ Patient populations
ADVANTAGES
• Most current published source
• Tremendous range of information
• Personally, assess utility/validity
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DISADVANTAGES
• Overwhelming volume
• Interpretation of results
• Not yet vetted by experts
PEER-REVIEWED JOURNALS
• JAMA
• New England Journal of Medicine
• American Journal of Health-system Pharmacy
• Annals of Internal Medicine
NON-PEER REVIEWED JOURNALS
• Supplements
• Pharmacy Today
2. SECONDARY SOURCES
• Indexing & abstracting services are valuable tools for quick and
selective screening of primary literature for specific information, data,
citation and articles.
• In some cases, the sources provide sufficient information to serve as
references for answering drug information requests.
SECONDARY LITERATURE
Guides you to the primary and tertiary literature
• Indexing
­ Bibliographic info only
• Abstracting
­ Bibliographic citation plus brief summary of article or resource
Almost all are electronic format.
ADVANTAGES
• Simple search strategies
• Very current citation information
• Access point for tremendous amount of primary sources
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DISADVANTAGES
• Understanding coverage of the database
• Tweaking search strategies unique to each database
SECONDARY RESOURCES
• CLIN Alert
• EMBASE (Elsevier)
• International Pharmaceutical Abstracts (IPA)
• Iowa Drug Information System (IDIS)
• Journal Watch
• Lexis-Nexis
• MEDLINE / PubMed
3. TERTIARY SOURCES
• General reference textbooks can provide easy convenient access to a
broad spectrum of related topics.
• Background information drugs & diseases is often available.
TERTIARY LITERATURE
• Summarizes and interprets the primary literature
• Information generally well accepted
• Place to start for basic information and guidance
• Can inform your subsequent research
ADVANTAGES
• Convenient, accessible
• Often available online
• Review process of information is already done
DISADVANTAGES
• Lag time
• Not as complete
• Author’s interpretation
TEXTBOOKS
• Electronic also
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COMPENDIA
• Electronic also
FULL-TEXT COMPUTER DATABASES
• Internet
REVIEW ARTICLES
TERTIARY RESOURCES – DRUG DATABASES
• Online
­ Lexi Comp CRL
­ MICROMEDEX
­ Drug Facts and Comparisons
­ MD Consult
­ AHFS Drug Information
­ Epocrates
• Print
­ PDR (Physician’s Desk Reference)
TERTIARY RESOURCES - BOOKS PRINT BOOKS
• Remington’s
• Martindale
• Handbook of Nonprescription Drugs
• Redbook
• Drugs in Pregnancy & Lactation (aka: Brigg’s)
• Martindale: The Complete Drug Reference.
TERTIARY RESOURCES – OTHER
• UpToDate
• Pharmacist’s Letter
• Natural Medicines Comprehensive Database
• Ohio Administrative Code (pharmacy.ohio.gov)
• FDA.gov (Orange Book, Drugs@FDA)
• CDC.gov
• Professional Organizations
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• APhA’s MTM Central
• Manufacturer web sites
USING TERTIARY LITERATURE
1. Does author have expertise?
2. Is the information current?
3. Is the information supported with citations?
4. Does the resource contain relevant information?
5. Is the resource free of bias or errors?
6. Is it clear/concise/easy-to-use?
WHAT’S THE DIFFERENCE?
EASE OF USE
Tertiary Secondary Primary
MOST CURRENT
Primary Secondary Tertiary
ALTERNATE SOURCES OF DI
• Internet, Listservs, and medical news briefs
• Local and national professional organizations and meetings
• Pharmaceutical manufacturers
• Drug information and poison control centers
SEARCHING STRATEGIES
• Begin broad, then narrow your search
­ Start with tertiary sources
• Use “related articles”
­ Bibliographies
­ Secondary resource guides
• Always be sure to assess most up to date information available
­ Primary sources
STRATEGIES—EVALUATING INFORMATION REQUESTS
• It is important to obtain as many clues as possible about drug information
requests before beginning a literature search.
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• Ask important questions to an inquirer or evaluate before a manual or
computerized search.
• Talk with the inquirer: who is requesting the information & acquire any
necessary additional information.
STRATEGIES
DETERMINE REASONS FOR THE INQUIRY
• Find out where the inquirer heard or read about the drug.
• Is he or she taking medication? If so why?
• Determine if the inquirer has a medical condition.
• Ascertaining the reason for inquiry helps determine what additional
information should be provided.
CLARIFY THE DRUG’S IDENTIFICATION AND AVAILABILITY
Make sure that the drug in question is available and double check information
about the drug, such as:
• Correct spelling
• Generic or brand name drug
• Pharmaceutical company & country
• Prescription or non-prescription
• Dosage form and the purpose.
TO IDENTIFY OR ACCESS PRODUCT AVAILABILITY
• For drugs manufactured in Pakistan
­ Pharma guide
­ Drug Index
­ Pakistan National Formulary
• Martindale the Extra Pharmacopoeia
• PDR (Physician Drug Reference)
• Mosby’s Index
• British National Formulary (BNF)
• Drug Facts & Comparisons.
SEARCH STRATEGIES
• Determine whether a question is clinical or research related.
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• Define the questions as specifically as possible.
• Determine the type of information & how much is needed.
• Ascertain as much information as possible about the drug being questioned
& the inquirer's association with it.
• What is the indication for the prescribed drug?
• What is the age, sex & weight of the patient in question?
• Does the patient have any other medical conditions or renal or hepatic
disease?
• Is the patient taking any other medications?
• What drugs has the patient taken during the past 6 months & what were
the dosages?
• Signs & symptoms of a possible ADR.
• Signs & symptoms of drug interactions.
CLINICAL DRUG LITERATURE
INTRODUCTION
• A Clinical drug Literature is basically a document containing all the
information including (but not limited)
­ Adverse effects
­ Drug interactions
­ Uses
­ Teratogenicity
­ Stability
­ Compatibility
­ Product identification and
availability
­ Dosages and administration
­ Toxicity
­ Pharmacokinetics
­ Pharmacodynamics
­ Pharmacogenomics
­ Health related quality of life
­ Pharmacoeconomics
­ Efficacy
• Including the comparative efficacy among drugs in the same
pharmacological or chemical class as well as drugs from other classes.
• Accessing reviewing, analyzing, evaluating, and interpreting the clinical drug
literature are important responsibilities of the health care professional and
particularly for the pharmacists who are expert in the drugs.
• The advances in the computer technology, continual growth of internet and
widespread availability of databases, search capabilities have placed
unprecedented amounts of information into individual grasp.
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LITERATURE SEARCH
• The best way to find quality information is to carry out a literature search
on one or more databases and to download, copy or request relevant
current publications on the topic/s of interest.
Lexi - Comp® Online™
> 4,000 monographs of medications and nearly 30 fields with each drug
monograph
Information includes:
• Dosing
• Pharmacology
• Pharmacokinetics
• Pregnancy/lactation considerations
• Adverse reactions
• Drug interactions
• Nutrition/herb interactions
MICROMEDEX®
• Facts on drugs, teratogenicity, toxicology, and alternative medicine.
• On-line version of the Physicians’ Desk Reference.
• Very comprehensive and contains the following:
­ Dosing
­ Pharmacology
­ Pharmacokinetics
­ Drug interactions, cautions
­ Clinical applications
­ References
• Limitations: difficulty in finding information and frequency of updates.
RESEARCH LITERATURE REVIEW
• It is a systematic, explicit, and reproducible method for identifying,
evaluating and synthesizing the existing body of completed and recorded
work produced by researchers, scholars and practitioners.
STEPS IN LITERATURE REVIEW WRITING
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1. Selecting the research questions
2. Selecting the sources
3. Choosing search terms
4. Conducting the search
5. Applying practical screening criteria
6. Critically appraising the literature
i. Journals & articles
ii. Websites
POSSIBLE RESEARCH QUESTIONS
• Broad questions
­ What is the prevalence of bacterial meningitis?
• Narrow question
­ What costs are associated with hospitalization of bacterial
meningitis?
• Very narrow question
­ What strategies have been utilized in Saudi Arabia to reduce length
of stay for patients with bacterial meningitis?
LITERATURE REVIEW DATA SOURCES
Literature review data sources are:
• Online public bibliographic databases
• Commercial bibliographic databases
• Specialized bibliographic data bases
• Manual or “hand searches” of references lists
• “Gery literature”
• Web reports
• Expert opinions
BIBLIOGRAPHIC DATA BASES
• Medicine
­ PubMed (or Ovid MEDLINE), EMBASE, Cochrane Library, PsycINFO
• Multidisciplinary
­ Scopus
­ Web of science
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• Nursing and allied heath
­ CINAHL
WEBSITES
• It includes Associations, Organizations, & Government such as:
­ World health organization (WHO)
­ Health Canada
­ Canadian medical Association
­ National Health Service (NHS)
GERY LITERATURE
• Dissertations & Theses
• SCOPUS (Conference Proceedings)
• Web search engines
BREAKDOWN THE RESEARCH QUESTION
Select your database and breakdown the research question into concepts:
1. Identify subject headings (descriptors) of each concept
2. Identify text words for each concept.
• Use a “target article” to help identify search terms.
• Use a worksheet to keep track of your terms
Your database will determine your subject headings and operators (i.e. truncation
symbols)
KEY OPERATORS IN OVID
Operator Command Example
* Find alternative endings to this
word
Nurs* [will find nurse,
nursing, nurses]
.tw. Search for this term in the title and
abstract fields
Anxiety.tw.

adj Search for one term with x number
of terms for another
Patient adj3 anxiety [will
find patient within three
words of anxiety]
AND Find articles where both terms
appear
Smoking AND cessation
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OR Find articles where either term
appears
Smoking OR tobacco
SEARCHING DATABASES: BASIC BOOLEAN
• “AND”
­ Combines 2 terms (shrinks search)
­ Both words must be present in results.
­ Paroxetine AND Suicide.
• “OR”
­ Gives database more choices (broadens search)
­ Either word can be present in results.
­ Paroxetine OR Suicide.
• “NOT”
­ Limits search (removes undesired terms)
­ The first but not the second term will be present
in the results.
­ Paroxetine NOT Suicide.
LITERATURE EVALUATION
• While evaluating the drug literature one should be Critical. One must obtain
papers most relevant to one’s question.
• Among the skills of drug information is a knowledge of drug literature
evaluation which allows one to provide a critical analysis of the literature
have a better understanding of the studies done in health and medicine.
­ It is a key to provide a good quality answer to a requester.
­ Being able to separate good data from poor data is essential.
­ Knowing the limitations of any study can help in evaluation the
usability of its data.
• Drug information specialists will often use some standard questions to help
in this process. Several references provide guides to evaluate the medical
and pharmacy literature.
KEY QUESTIONS IN EVALUATION EVALUATING DRUG LITERATURE
• What is the value of the trial in terms of new knowledge?
• What is the overall quality of the data?
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• Does it adequately address the aims and objectives and support the
conclusions reached?
• Were the end points appropriately chosen, and were the data analysis
reliably performed?
• Are the interpretations and conclusions justified?
• Are the extrapolations reasonable?
• Are the results likely to affect clinical practice or other research activities?
• Overall, how much emphasis should be placed on the findings?
PUBLICATION BIAS
• Negative results do not (often) get published – if you want to carry out a
detailed or systematic review of a subject area, you might consider trying to
get hold of unpublished studies.
• Reviewers may be biased against unconventional vs. conventional
techniques (e.g. orthodox drug vs. alternative therapy)
AUTHORSHIP
• Are the authors based at the well-established Centre of excellence?
• Are there any issues of sponsorship or competing interests?
JOURNAL RANKING & IMPACT FACTOR
• Impact factor is
“a measure of the frequency with which the average article in a journal has
been cited in a particular year or period”
• The impact factor of a journal is linked to its popularity and accessibility.
Journals with high impact factors in a subject area are generally more highly
regarded.
ABSTRACT QUALITY
• Read the paper carefully; do not rely on the only abstract. Many abstracts
in peer reviewed journals have errors. The three common types of
inaccuracies are:
­ Data is inconsistent in abstract and body of the paper, tablets and
figures.
­ Data or information in the abstract do not appear elsewhere.
­ Conclusions in the abstract not substantiated in the paper itself.
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SEARCH STRATEGIES
1. Patient’s current medication status.
2. Patient has any underlying diseases.
3. How the patient being managed so far.
4. What is the stability of drug and how is compatibility of the drug with other
drugs?
5. Administration techniques.
GUIDELINES FOR RESPONSES TO DI REQUESTS
1. Responses to a member of public must take several ethical issues into
account:
­ Patient privacy must be protected
­ Professional ethics must be maintained.
­ Patient-physician relationship cannot be breached.
­ Response is not necessary if the inquirer intends to misuse or abuse
the information.
2. Organize information before attempting to communicate the response to
inquirer. Anticipate additional questions.
3. Inform the inquirer where the information was found.
4. Exercise caution with statements like “there are no reports in the
literature.”
“I recommend…”
5. Ask if the information that is provided answers the inquirer’s question.
RESOURCES (LATEST EDITIONS)
• Martindale: The Extra Pharmacopoeia
• Physician Desk Reference (PDR)
• British National Formulary (BNF)
• Mosby’s Drug Index
• Facts and Comparisons
• Mayo Clinic
• Remington Pharmaceutical Sciences.
• Pharma guide and Drug Index
• Different current journals
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ONLINE PHARMACEUTICAL CARE SERVICES
AND GLOBALIZATIONS
PHARMACEUTICAL CARE
Pharmaceutical Care is a patient-centered, outcomes oriented pharmacy practice
that requires the pharmacist to work in concert with the patient and the patient's
other healthcare providers to promote health, to prevent disease, and to assess,
monitor, initiate, and modify medication use to assure that drug therapy
regimens are safe and effective.
GOALS OF PHARMACEUTICAL CARE
The goal of Pharmaceutical Care is to optimize the patient's health-related quality
of life, and achieve positive clinical outcomes, within realistic economic
expenditures.
To achieve goals following should be done:
1. A professional relationship must be established and maintained.
2. Patient-specific medical information must be collected, organized,
recorded, and maintained.
3. Patient-specific medical information must be evaluated, and a drug therapy
plan developed mutually with the patient.
4. The pharmacist assures that the patient has all supplies, information and
knowledge necessary to carry out the drug therapy plan.
5. The pharmacist reviews, monitors, and modifies the therapeutic plan as
necessary and appropriate, in concert with the patient and healthcare
team.
PHARMACEUTICAL CARE SERVICES
• Community-Pharmacy orientation towards a patient-centered practice has
become the new paradigm of pharmacy practice, supported by the
development of a clinical role for community pharmacists and a more
active role for patients in their own disease management.
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• This new paradigm has led to the development of new “pharmaceutical
services” concepts.
• There are a number of different services performed by pharmacists in
different countries that match CP’s (community pharmacists) role in
primary healthcare.
• These services range from the traditional distribution services to more
advanced disease management services.
• Pharmaceutical services have been considered extremely valuable for
professionals, patients and healthcare systems, mainly due to a greater
efficiency and improvement in individual patient’s health related outcomes.
INFORMATION SYSTEM AND TECHNOLOGY
Good communication between professionals is essential in multidisciplinary
practice, making Information Systems and Technologies (IST) a prerequisite
underpinning healthcare services in future health systems.
eHEALTH
• The continuous development of IST led to the onset of eHealth, that can be
defined as:
“The utilization of IST to support health service provision, complying with
the needs of citizens, patients, health professionals and other providers”
• eHealth is the use of information and communication technologies (ICT) for
health.
• The eHealth unit works with partners at the global, regional and country
level to promote and strengthen the use of ICT in health development,
from applications in the field to global governance.
• eHealth is a relatively recent healthcare practice supported by electronic
processes and communication, dating back to at least 1999.
• It can also include health applications and links on mobile phones, referred
to as mHealth or m-Health.
• Since 2011, the increasing recognition of the need for better cyber-security
and regulation may result in the need for these specialized resources to
develop safer eHealth solutions that can withstand these growing threats.
• The term can encompass a range of services or systems that are at the edge
of medicine/healthcare and information technology, including:
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1. Electronic Health Record
2. Computerized Physician order entry (CPOE)
3. ePrescribing
4. Clinical Decision support system (CDSS)
5. Telemedicine
6. Consumer Health Informatics
7. Health knowledge Management
8. Virtual Health-care teams
9. mHealth
10. Health Informatics/ Health Information System
1. ELECTRONIC HEALTH RECORDS
• An electronic health record (EHR), or electronic medical record (EMR), is
the systematized collection of patient and population electronically stored
health information in a digital format.
• These records can be shared across different health care settings. Records
are shared through network-connected, enterprise-wide information
systems or other information networks and exchanges.
• EHRs may include a range of data, including demographics, medical history,
medication and allergies, immunization status, laboratory test results,
radiology images, vital signs, personal statistics like age and weight, and
billing information.
• EHR systems are designed to store data accurately and to capture the state
of a patient across time. It eliminates the need to track down a patient's
previous paper medical records and assists in ensuring data is accurate and
legible.
2. COMPUTERIZED PHYSICIAN ORDER ENTRY
• Computerized physician order entry (CPOE), sometimes referred to as
computerized provider order entry or computerized provider order
management (CPOM), is a process of electronic entry of medical
practitioner instructions for the treatment of patients (particularly
hospitalized patients) under his or her care.
• The entered orders are communicated over a computer network to the
medical staff or to the departments (pharmacy, laboratory, or radiology)
responsible for fulfilling the order.
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3. ePRESCRIBING
• Electronic prescribing or e-prescribing (e-Rx) is the computer-based
electronic generation, transmission and filling of a medical prescription,
taking the place of paper and faxed prescriptions. E-prescribing allows a
physician, pharmacist, nurse practitioner, or physician assistant to
electronically transmit a new prescription or renewal authorization to a
community or mail-order pharmacy.
4. CLINICAL DECISION SUPPORT SYSTEM
• It has been proposed by Robert Hayward of the Centre for Health Evidence:
"Clinical decision support systems link health observations with health
knowledge to influence health choices by clinicians for improved health care
“
• A clinical decision support system (CDSS) is a health information technology
system that is designed to provide physicians and other health
professionals with clinical decision support (CDS), that is, assistance with
clinical decision-making tasks
5. TELEMEDICINE
• Telemedicine is the use of telecommunication and information technology
to provide clinical health care from a distance. It has been used to
overcome distance barriers and to improve access to medical services that
would often not be consistently available in distant rural communities. It is
also used to save lives in critical care and emergency situations.
• These technologies permit communications between patient and medical
staff with both conveniences, as well as the transmission of medical,
imaging and health informatics data from one site to another.
• Early forms of telemedicine achieved with telephone and radio have been
supplemented with videotelephony, advanced diagnostic methods
supported by distributed client/server applications, and additionally with
telemedical devices to support in-home care.
6. CONSUMER HEALTH INFORMATICS
• Consumer health informatics (CHI) is a sub-branch of health informatics
that helps bridge the gap between patients and health resources. It is
defined by the American Medical Informatics Association as
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"the field devoted to informatics from multiple consumer or patient views".
• The Consumer Health Informatics Working Group (CHIWG) of the
International Medical Informatics Association (IMIA) define it as
"the use of modern computers and telecommunications to support
consumers in obtaining information, analyzing unique health care needs
and helping them make decisions about their own health"
7. HEALTH KNOWLEDGE MANAGEMENT
• An overview of latest medical journals, best practice guidelines or
epidemiological tracking (examples include physician resources such
as Medscape)
8. VIRTUAL HEALTH CARE TEAMS
• Virtual healthcare teams: consisting of healthcare professionals who
collaborate and share information on patients through digital equipment.
9. mHEALTH
• mHealth (also written as m-health) is an abbreviation for mobile health, a
term used for the practice of medicine and public health supported by
mobile devices.
• mHealth applications include the use of mobile devices in collecting
community and clinical health data, delivery of healthcare information to
practitioners, researchers, and patients, real-time monitoring of patient
vital signs, and direct provision of care (via mobile telemedicine).
10. HEALTH INFORMATICS/HEALTH INFORMATION SYSTEM
• Health informatics (also called health care informatics, healthcare
informatics, medical informatics, nursing informatics, clinical informatics, or
biomedical informatics) is information engineering applied to the field of
health care, essentially the management and use of patient healthcare
information. It is a multidisciplinary field that uses health information
technology (HIT) to improve health care via any combination of higher
quality, higher efficiency.
INFORMATION SYSTEM AND TECHNOLOGY
• IST in healthcare have been used primarily to improve administrative
management. However, implementation of eHealth services has the
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potential to promote a better access to information by patients and
providers, improve the quality, efficacy and safety of healthcare services,
and encourage healthier lifestyles.
• Investing in IST and modernizing the architecture of pharmacies is
considered as a necessary and critical step towards the diffusion of new
forms of practice. eHealth services may develop in the next few years to
harvest the full potential of CP, enhancing their role in the primary care
network and supporting their activities in chronic disease management.
• For prescribers and pharmacists, IT can enable the storage of structured
patient records, facilitate the electronic prescribing, dispensing and
administration of medicines, automate the handling of medicines in the
supply chain and provide tools for monitoring the efficacy and safety of
medicines in use.
• IT can therefore improve patient safety, enable professionals to provide
high quality care and help patients make the most of their medicines.
• Pharmacists are already using IT systems to support their daily work and,
when considering the IT requirements for emerging working practices,
pharmacists should consider what functions could be provided by systems
that they already use.
• For example, all pharmacies use pharmacy management systems for
medication records, dispensing, labeling, ordering and stock control.
However, many pharmacies do not use all of the available functionality of
their system, for example, modules to handle patient-centered services,
such as medicines use reviews or prescription interventions.
• Pharmacists should also make the most of services that are available in
their locality, for example, electronic prescription service.
• Adoption and use of EPS in areas where it is available has the potential to
make dispensing and reimbursement processes more efficient for
community pharmacists and the nomination process may help pharmacists
to secure prescription business.
• Access to patient record systems will assist pharmacists with professional
decision-making in providing patient-centered services.
• As pharmacists deliver more patient-focused services in future, they will
increasingly use national and local patient record services to do so.
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• The internet has been widely adopted for business and social
communications. In future, as internet use becomes universal, there may
be an increase in the number of internet pharmacies and use of the
internet to display and disseminate information on medicines and health
from pharmacies.
• Currently, secure web-based platforms are available from various providers
to support enhanced pharmacy services and public health initiatives. The
use of these will increase and also web platforms will be used as a
communication portal to make information available to pharmacists from
other care settings (e.g., hospital discharge information).
• Electronic prescribing (EP) systems automate prescribing, supply and
administration of medicines in hospitals, where they have been shown to
reduce medication errors and have a major impact on patient safety.
However, the effect on error reduction is dependent on system design and
a poorly implemented system can actually increase error rates.
GLOBALIZATION
• The processes of globalization have led to an increasingly interconnected
world, with both benefits and costs for health. The speed and ease of
shared information, advancements to health care delivery and health
policy, and the increased pace of discovery through international research
collaborations, can all facilitate improvements to health.
• A range of particular problems in medicines and health, such as counterfeit
and poor-quality antimalarial drugs, gaps in funding and immunization for
polio eradication, the expected increase in global cancer incidence rates,
and drugs for neglected tropical diseases also highlight the importance of
global perspectives on health. A lack of skilled professionals, in particular
net migration from ‘developing’ to ‘developed’ countries is also recognized
as a barrier to the delivery of effective health care around the world. Health
priorities, for which the supply and use of medicines is often central, must
increasingly be viewed from a global perspective.
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