02 Drug interactions for natural and product

DDI file for variant things and natural drugs

1. Ali Mohammed
Assistant Professor

2. Outcomes of drug interactions
1)Loss of therapeutic effect
2)Toxicity
3)Unexpected increase in pharmacological activity
4)Beneficial effects e.g additive & potentiation (intended)
or antagonism (unintended).
Definition;
It is the modification of the effect of one drug (the object drug ) by
the prior concomitant administration of another (precipitant
drug).

3. The modification in response may be Quantitative (In Intensity), i.e.
➢Increased or
➢Decreased
It may be qualitative
➢Abnormal or a different (New) type of response is produced.
•Possibility arises whenever a patient receives more than one drug,
and
•Chances increase with
–More number of drugs.
–Patient with multiple diseases
–Patient treated by multiple doctors
–Patients with compromised physiology
–Patients with extreme of age ( Elderly and Children)

4. Every Drug Interaction is Harmful ????
NO
•Several drug interactions are deliberately employed in therapeutics,
e.g.
–ACE inhibitors + diuretics to treat hypertension or
–Sulfamethoxazole + Trimethoprimto treat bacterial infection or
–Furosemide + amilorideto prevent hypokalaemia.

5. Drugs more likely to be involved in drug interactions
▪With Narrow therapeutic index (Low Safety Margin)
▪Aminoglycosides
▪Digitalis
▪Lithium
▪Affecting vital physiology of the body
▪Antihypertensive drugs
▪Anti-diabetic drugs
▪Anticoagulants
▪With high plasma protein binding capacity
▪NSAIDs
▪Warfarin
▪Sulfonylureas
▪Metabolized by Zero Order Kinetics or Saturation Kinetics
▪Phenytoin
▪Theophyllin

6. MECHANISM OF DRUG INTERACTIONS
•Drug interactions can be broadly divided into
–Pharmaceutical Interaction
•During dosage form preparation or at time of administrations.
•Dissolving the drug in solvent,
•Mixing drugs in powder, solution or injection forms.
–Pharmacokinetic (ADME)
•Absorption (Complex or Chelate formation, Altered stomach pH, Ionization,
GIT motility, First Pass Metabolism)
•Distribution(Protein binding)
•Metabolism( Enzyme induction/inhibition)
•Excretion(Altered pH, Ionization, Entero-hepatic recirculation)
–Pharmacodynamic ( At receptor or tissue level)
•e.g synergism.antagonism, altered cellular transport, effect on the
receptor site.

7. Pharmacokinetic interactions
•Pharmacokinetic drug–drug interactions can
be managed by recognizing drugs with a narrow
therapeutic index and the major perpetratorsof
altered drug metabolism.
•Any change in prescription should take
particular note of these two groups of drugs.

8. Pharmacokinetic interactions
1) Altered GIT absorption.
•Altered pH, Altered bacterial flora, formation of drug chelates or complexes,
drug induced mucosal damage and altered GIT motility.
Ex1., antiacids
pH
Decreasethe tablet dissolution
of Ketoconazole (acidic)
H2 antagonists
pH
Therefore, these drugs must be separated by at least 2h in the time of administration of
both .
Insoluble and poorly absorbed complexesin the gut
Example:-
Tetracyclines and calcium/iron salts, antacids or sucralfate
Phenytoin absorption is decreased by sucralfate
Minimized by administering the two drugs with a gap of 2-3 hours.

9. b) Altered intestinal bacterial flora ;
EX.,In 10% 0f patients receive digoxin…..40% or more
of the administered dose is metabolized by the intestinal flora
Antibioticskill a large number of the normal flora of the intestine
Increase digoxin conc.
and increase its toxicity
a)Altered pH;
The non-ionized form of a drug is more lipid
soluble and more readily absorbed from GIT than the
ionized form does.
Alteration in Entero-hepatic recirculation
•Antibiotics like Tetracyclines (Broad Spectrum) markedly reduce gut flora that
normally deconjugates oral contraceptive steroids secreted in the bile as glucuronides
and permits their Entero-hepatic recirculation. Contraceptive failurewhen
concurrent use of antibiotics due to lowering of the contraceptive blood levels.

10. c) Complexation or chelation;
EX1., Tetracyclineinteracts with ironpreparations
or
Milk (Ca
2+
) Unabsorpable complex
Ex2., Antacid (aluminum or magnesium) hydroxide
Decrease absorption of
ciprofloxacinby 85%
due to chelation

11. d) Drug-induced mucosal damage.
Antineoplastic agentse.g., cyclophosphamide
vincristine
procarbazine
Inhibit absorption
of several drugs
eg., digoxin
e) Altered motility
Metoclopramide (antiemitic)
Increase absorption of cyclosporine due
to the increase of stomach empting time
Increase the toxicity
of cyclosporine

12. 2) Displaced protein binding
It depends on the affinity of the drug to plasma protein.
The most likely bound drugs is capable to displace others.
The free drug is increased by displacement by another drug
with higher affinity.
Phenytoin is a highly bound to plasma protein (90%),
Tolbutamide (96%), and warfarin (99%)
Drugs that displace these agents are Aspirin
Sulfonamides
phenylbutazone

13. 3) Altered metabolism
The effect of one drug on the metabolism of the
other is well documented. The liver is the major site of drug
metabolism but other organs can also do e.g., WBC,skin,lung,
and GIT.
CYP450 familyis the major metabolizing enzyme
in phase I (oxidation process).
Therefore, the effect of drugs on the rate of metabolism
of others can involve the following examples.

14. EX1.,Enzyme induction
A drug may induce the enzyme that is responsible
for the metabolism of another drug or even itself e.g.,
Carbamazepine(antiepileptic drug ) increases its own
metabolism
Phenytoin increases hepatic metabolism of theophylline
Leading to decrease its level
Reduces its action
and
Vice versa
N.B enzyme induction involves protein synthesis .Therefore,
it needs time up to 3 weeks to reach a maximal effect

15. IMPORTANT MICROSOMAL ENZYME
INDUCERS (RBC)
•Barbiturates,
•Phenytoin
•Carbamazepine
•Rifampin
•Cigarette smoking
•Chronic alcoholism
•Pollutants

16. EX2.,Enzyme inhibition;
It is the decrease of the rate of metabolism of a drug by
another one.This will lead to the increase of the concentration
of the target drug and leading to the increase of its toxicity .
Inhibition of the enzyme may be due to the competition
on its binding sites , so the onset of action is short
may be within 24h.
N.B;When an enzyme inducer(e.g.carbamazepine) is
administered with an inhibitor(verapamil)
The effect of the
inhibitor will be
predominant

17. Ex.,Erythromycin inhibit metabolism of astemazole and terfenadine
Increase the serum conc.
of the antihistaminic leading to
increasing the life threatening
cardiotoxicity
EX.,Omeprazole
Inhibits oxidative
metabolism
of diazepam

18. SOME IMPORTANT INHIBITORS OF
METABOLISM OF MULTIPLE DRUGS
(MAO-QC)
•Macrolide antibiotics,
•Azole antifungals,
•Chloramphenicol,
•Omeprazole, SSRIs,
•HIV -protease inhibitors,
•Cimetidine,
•Quinolones (Ciprofloxacin)
•Metronidazole.
Risk of statin induced myopathy is increased by fibrates,
niacin, erythromycin, azole anti-fungalsand HIV -protease
inhibitors, due to inhibition of statin metabolism.

19. First-pass metabolism:
Oral administration increases the chance for liver
and GIT metabolism of drugs leading to the loss of a
part of the drug dose decreasing its action. This is
more clear when such drug is an enzyme inducer
or inhibitor.
EX., Rifampin lowers serum con. of verapamil level by
increase its first pass . Also, Rifampin induces the
hepatic metabolism ofverapamil

20. Prodrugs:
Some drugs rely on cytochrome P450 enzymes for mconversion
to their active form. As this is usually
dependent on a single enzyme pathway, prodrugs
are particularly vulnerable to changes in metabolism.
Inhibition of conversion from prodrug to active drug
may lead to inadequate concentrations of the active
drug and therapeutic failure. For example, tamoxifen
is metabolisedby CYP2D6 to its active form
endoxifen, and concomitant therapy with the strong
CYP2D6 inhibitor paroxetinehas been associated with
increased mortality in breast cancer

21. 4) Renal excretion:
•Active 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 con. and hence its toxicity.
EX.,Probenecid …..
Decreases tubular secretion of
methotrexate.

22. * Passive tubular reabsorption;
Excretion and reabsorption of drugs occur in the tubules
By passive diffusion which is regulated by concentration
and lipid solubility.
N.B., Ionized drugs are reabsorbed lower than non-ionized ones
Ex1.,Sod.bicarb.
Increases lithiumclearance
and decreases its action
Ex2., Antacids
Increases salicylates
clearance and decreases its
action

23. Pharmacodynamic interactions;
It means alteration of the dug action without change in its
serum concentration by pharmacokinetic factors.
EX., Propranolol + verapamil
Synergistic or additive
effect
Synergism means =1+1=3
Additive means= 1+1=2
Potentiation means= 1+0=2
Antagonism means 1+1=0 or 0.5
Effect at the receptor site
•Antiadrenegic
•anticholinergic
On the other hand

24. Pharmacodynamic interactions between drugs with additive
effects may be intentional, for example when combining
antihypertensives, or unintentional, for example serotonin
syndromecaused by adding tramadolto a selective serotonin
reuptake inhibitor (SSRI).
Conversely, combining drugs with opposing effectscan result in
loss of drug effect, for example reduced bronchodilation by a beta2
agonist prescribed with a non-selective beta blocker.

25. * Risk factors:
1)High risk drugs;these are the drugs that show a narrow
therapeutic index e.g., corticosteroids, rifampin,
oral contraceptives, quindine,lidoquine
2) High risk patients;these are the groups of patients
that should be treated with caution due to a specific
heath condition e.g., pregnant women, malignant cases,
diabetic patients, patients with liver or kidney disorders
asthmatic patients and cardiac disorders.

30. •Onset of drug interaction
It may be seconds up to weeks for example in
case of enzyme induction, it needs weeks for protein synthesis
, while enzyme inhibition occurs rapidly.
The onset of action of a drug may be affected by the half
lives
of the drugs e.g., cimitidineinhibits metabolism of
theophylline.
Cimitidinehas a long half life, while, theophyllinehas a short
one.
When cimitidineis administered to a patient regimen for
Theophylline,interaction takes place in one day.

44. Self-test decision support. questions
True or false?
•Drugs with high oral bioavailability are often affected by pharmacokinetic
drug interactions.
•Fluvoxamine is a strong inhibitor of cytochrome P450 2C19.

46. Fatal rhabdomyolysis following
voriconazole and simvastatin
•An 85-year-old woman presented with an acute onset of generalisedweakness and functional
decline. The patient had a history of insulin-requiring diabetes, hypercholesterolaemia,
hypertension, glaucoma and chronic kidney disease. She also had longstanding fungal keratitis (>60
days) which had been unsuccessfully treated with topical therapy.
•The patient’s chronic conditions were managed with multiple medications, including simvastatin 20
mg daily. She had started oral voriconazole, 200 mg twice a day, 32 days before her admission.
•The patient was observed in hospital for a few weeks. She was examined by two ophthalmology
senior house officers and an infectious diseases physician before a general physician made the
diagnosis of rhabdomyolysis.
•Blood tests showed a creatine kinase of 23 200 U/L (normal range 34–145), aspartate transaminase
1030 U/L (<31), alanine transaminase 393 U/L (<34) and creatinine 255 micromol/L (<110).
Sodium, potassium, prothrombin time and full blood count were normal.
•The rhabdomyolysis was suspected to be the result of a drug interaction between simvastatin and
voriconazole.1 Both drugs were ceased on day 20 of the patient’s admission and her blood tests
improved.
•Unfortunately, the woman’s clinical symptoms did not resolve and she died of respiratory failure
secondary to respiratory muscle weakness 10 days after the concurrent therapy was stopped.

47. Comment
•Simvastatin is a substrate of cytochrome P450 3A42 and voriconazole is a
known inhibitor of this enzyme. However, their interaction is not documented
specifically in key reference sources such as the Australian Medicines Handbook
or in the product information, although class interactions are detailed.2
•It is listed as an interaction in dispensing software. Throughout the admission,
the patient’s medication was reviewed by three different clinical pharmacists.

53. Which person has polypharmacy?
•Ms. A & Ms. B 80 yr-old ♀withsimilar support networks.
Health issues: stable CHF, OAB, GERD, Depression, OA,
insomnia, itchy skin.
Ms. A
9 meds
Ms. B
9 meds
B presents with: dry mouth, constipation, urine retention, confusion,
blurred vision
“I’m feeling good for my age”
“I’m forgetful. I have
dizziness and a fear of falling”
CrCl = 60 mL/min
CrCl = 30 mL/min

54. Two 80 yr-old females, Ms. A & Ms. B similar support networks,
stable CHF, OAB, GERD, Depression, OA, insomnia, itchy skin,
forgetfulness
Ms. Ahas CrCl60 mL/min
•Spironolactone 25mg daily
•Ramipril2.5mg daily
•Metoprolol25mg bid
•Mirabegron25mg daily
•Pantoprazole 20mg daily
•Escitalopram20mg daily
•Acetaminophen 500mg qid
•Melatonin 5mg qhs
•Cetirizine 10mg daily
Ms. B has CrCl= 30 mL/min
•Spironolactone 25mg daily
•Ramipril2.5mg daily
•Metoprolol25mg bid
•Oxybutynin 5mg bid
•Ranitidine 150mg bid
•Nortriptyline50mg qhs
•Naproxen 250mg bid
•Trazodone25mg qhs
•Hydroxyzine 25mg qhs
Anticholinergic Burden Scale
A= 1 B=11
3
3
1
3
1
1
Anticholinergic effects: dry mouth, constipation, urine retention,
confusion, blurred vision

55. Potentially Inappropriate Medications (PIM)
Explicit Criteria
•26 published PIM lists
1
–Beers, STOPP, McLeod
–Drugs to avoid
•categorically or based on disease, D-D interactions
•High alertmedications
–Anticholinergic activity, benzodiazepines, TCAs, warfarin,
NSAIDs, fluoxetine, digoxin, oxybutynin
•High alertpatients
–Impairments of renal function, cognition or the senses;
falls, hypotension, diabetes, PD, or poor nutrition
Eur J Clin Pharmacol 2018;74:679-700

60. What Can We Do?
1.High risk medications to avoid
2.Minimize prescriptions (decrease polypharmacy)
2. Accurate medication history
3. Discourage OTC medications that are on this list
4. Caution with herbal medications

61. High Risk Medications to Avoid
Class Medications
Sedatives benzodiazepines, Z-drugs, antipsychotics
Opioids morphine, hydromorphone, fentanyl patch
Anticholinergic loadTCA, antispasmodics,1
st
gen antihistamines,
Anticholinergic Cognitive Burden Scale (ACB)
AntihypertensivesACEI, ARBs,CCB, BB, diuretics
Antidepressants TCAs, fluoxetine
Anticoagulants warfarin, DOACs [dabigatran, apixaban, rivaroxaban,
edoxaban]
NSAIDs indomethacin, naproxen, celecoxib, diclofenac, ibuprofen
Urinary
antispasmodics
oxybutynin, tolterodine,fesoterodine
solifenacin, darifenacin, trospium
GI antispasmodichyoscyamine(Buscopan)

63. What Can We Do?
•Develop a systematic process for
development of standard set of drug drug
interactions for clinical decision support
•Electronic Medical Record Utilization
•uses First Data Bank for pharmacy review of drug interactions
•Physicians see absolute contraindications upon order entry (decision
made by Medical Staff)

64. What Can We Do?

65. Medication Appropriateness Index (MAI)
1.Is there an indication for the drug?
2.Is the medication effective for the condition
3.Is the dose correct?
4.Are the directions correct?
5.Are the directions practical?
6.Are there clinically significant drug-drug interactions
7.Are there clinically significant drug-disease interactions
8.Is there unnecessary duplication with other drugs?
9.Is the duration of therapy acceptable?
10.Is the drug the least expensive compared to others of equal utility?
Chief Question Officer (CQO)
Hanlon JT, et al. MAI J Clin Epidemiol. 1992;45:1045–51.

74. * Prevention of drug interaction
1)Monitoring therapy and making adjustments
2)Monitoring blood level of some drugs with narrow
therapeutic index e.g., digoxin, anticancer agents…etc
3)Monitoring some parameters that may help to
characterize the the early events of interaction
or toxicity e.g., with warffarinadministration, it
is recommended to monitor the prothrombin time
to detect any change in the drug activity.
4)Increase the interest of case reportstudies to
report different possibilities of drug interaction

75. ❑Drug interactions are an avoidable cause of patient harm.
❑Harm may occur due to either increased drug effect causing toxicity or
decreased drug effect leading to therapeutic failure.
❑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.
Patient harm from drug interactions can be reduced by:
•• using a personal formulary –using few drugs and knowing them well
•• recognisingdrugs that are major perpetrators of interactions
•• recognisingnarrow therapeutic index drugs as vulnerable to interactions
•• applying clinical pharmacology principles.

76. How to avoid unwanted drug–drug interactions in clinical practice
•The better your pharmacological knowledge, the easier it is! Prescribe few drugs
and know them well.
•We use five ‘rules’ to manage potential drug–drug interactions in clinical practice:
1. Any interactions between existing drugs in a given patient have already occurred.
Hence they are part of differential diagnosis.
2. Knowledge of the pharmacological effects of drugs and of patient physiology
together allows recognition of potential pharmacodynamic drug–drug interactions.
3. Drugs with a narrow therapeutic index are particularly susceptible to
pharmacokinetic drug–drug interactions (Table1).
4. A small number of drugs are important ‘perpetrators’ of pharmacokinetic drug–
drug Interactions
5. Starting or stopping a drug is a prescribing decision that may cause a drug
interaction.
•Monitoring patients for drug toxicity or loss of efficacy is part of routine care.
Checking for changes in symptoms, biomarkers of effect, or drug concentrations
soon after prescription changes helps identify drug interactions early and can
reduce harm.