PHYSIOLOGY OF RESPIRATION
•Respiration is the exchange of gases between the tissue of the body and
to outside environment.
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Breathing in of an air Respiratory tract
Uptake of oxygen from the lungs
Transport of oxygen through the body in
the blood stream
Utilization of oxygen in the metabolic
activities
Removal of carbon dioxide from the body.
Innervation of respiratory system
Parasympathetic supply
M3 receptors in smooth muscles and glands.
Bronchoconstriction
Increase mucus secretion
No sympathetic supplybut B
2receptors in smooth muscles and
glands.
Bronchodilation
Decrease mucus secretion
Asthma
Asthma is a chronic inflammatory disorder
of airways that result in airway
obstruction in response to external
stimuli.
It’s characterized by activation of mast cell,
infiltration of eosinophil, T2 helper cells,
Innate type 2 lymphocytes.
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Bronchial asthma
•Bronchial asthma is characterized by
hyperresponsivenessof tracheobronchial smooth
muscle to a variety of stimuli, resulting in narrowing
of air tubes, often accompanied by increased
secretion, mucosal edema and mucus plugging.
•Symptoms include dyspnoea, wheezing, cough
and may be limitation of activity.
•Infection, irritants, pollution, exercise, exposure to
cold air, psychogenic.
•Extrinsic asthma: It is mostly episodic, less prone
to status asthmaticus.
•Intrinsic asthma: It tends to be perennial, status
asthmaticus is more common.
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Bronchial asthma
•Acute Asthma. It is characterized by episodes
of dyspnoea associated with expiratory
wheezing.
•Chronic Asthma. There is continuous wheeze
and breathlessness on exertion; cough and
mucoid sputum with recurrent respiratory
infection are common.
•Status Asthmaticus (Acute Severe Asthma).
When an attack of asthma is prolonged with
severe intractable wheezing, it is known as
acute severe asthma.
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Pathophysiology
•Mast cells (present in lungs) and inflammatory cells
recruited as a result of the initial reaction produce a
multitude of mediators by the following processes
•Release of mediators stored in granules (immediate):
histamine, protease enzymes, TNF-a.
•Release of phospholipids from cell membrane followed
by mediator synthesis (within minutes): PGs, LTs, PAF.
•Activation of genes followed by protein synthesis (over
hours): Interleukins, TNFa.
•These mediators together constrict bronchial smooth
muscle, cause mucosal edema, hyperemia and
produce viscid secretions.
•All resulting in reversible airway obstruction.
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Airways of the asthmatic patients are characterized
by:
1.Inflammation
•Swelling
•Thick mucus production.
2.Bronchospasm
•constriction of the muscles around the airways,
causing the airways to become narrow.
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Symptoms of asthma
Asthma produces recurrent episodic attack of
Acute bronchoconstriction (immediate)
Shortness of breath
Chest tightness
Wheezing
Rapid respiration
Cough
Symptoms can happen each time the airways
are irritated.
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Anti asthmatic drugs:
1) Quick relief medications:
Bronchodilators used to relieve acute episodic
attacks of asthma.
2) Control therapy (prophylactic drugs):
anti-inflammatory drugs used to reduce the
frequency of attacks, and nocturnal awakenings.
Anti asthmatic drugs
Bronchodilators
(Quick relief medications)
treat acute attack of asthma
•Short acting 2-agonists
•Antimuscarinics
•Xanthine preparations
Anti-inflammatory Agents
(Prophylactic therapy)
reduce the frequency of attacks
•Corticosteroids
•Mast cell stabilizers
•Leukotrienes antagonists
•Anti-IgE monoclonal antibody
•Long acting ß2-agonists
Bronchodilators:
Abronchodilatoris a substance
thatdilatesthebronchiandbronchioles,decreasing
resistance in therespiratory airwayand increasing
airflow to thelungs.
Medicationsadministered for the treatment of
breathing difficulties.
They are most useful inobstructive lung diseases, of
whichasthmaandchronic obstructive pulmonary
diseaseare the most common conditions
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Bronchodilators
These drugs can produce rapid relief of
bronchoconstriction.
Bronchodilators:
2 -adrenoreceptor agonists
Antimuscarinics
Xanthine preparations
Mechanism of Action
direct
2stimulation stimulate adenyl
cyclase cAMP bronchodilation.
Increase mucus clearance by (increasing
ciliary activity).
Stabilization of mast cell membrane.
Non selective -agonists.
Epinephrine
•Potent bronchodilator
•Given subcutaneously, S.C.
•rapid action (maximum effect within 15 min).
•Has short duration of action (60-90 min)
•Drug of choicefor acute anaphylaxis (hypersensitivity
reactions).
Disadvantages
Not effective orally.
Hyperglycemia
Skeletal muscle tremor
CVS side effects:
tachycardia, arrhythmia, hypertension
Not suitable for asthmatic patients with hypertension
or heart failure.
Contraindications:
CVS patients, diabetic patients
Selective 2 –agonists
Are mainly given by inhalationby (metered
dose inhaler or nebulizer).
Can be given orally, parenterally.
Short acting ß2 agonists
e.g. salbutamol, terbutaline
Long acting ß2 agonists
e.g. salmeterol, formoterol
Nebulizer Inhaler
Short acting ß
2agonists
Salbutamol, inhalation, orally, i.v.
Terbutaline, inhalation, orally, s.c.
Have rapid onset of action (15-30 min).
short duration of action (4-6 hr)
used for acute attack of asthma (drugs of
choice).
Long acting selective ß
2 agonists
Salmeterol & formoterol
are given by inhalation
Long acting bronchodilators (12 hours) due to
high lipid solubility (creates depot effect).
are not used to relieveacute episodes of asthma
used for nocturnal asthma.
combined with inhaled corticosteroids to control
asthma (decreases the number and severity of
asthma attacks).
Advantages of ß
2agonists
Minimal CVS side effects
suitable for asthmatic patients with
CV disorders as hypertension or heart failure.
Disadvantages of ß
2agonists
Skeletal muscle tremors.
Nervousness
Tolerance (β-receptors down regulation).
Overdose may produce tachycardia due to
β
1stimulation.
Muscarinic antagonists
Ipratropium –Tiotropium
Act by blocking muscarinic receptors .
given by aerosol inhalation
Have delayed onset of action.
Quaternary derivatives of atropine (polar).
Does not diffuse into the blood
Does not enter CNS.
Have minimal systemic side effects
Ipratropiumhas short duration of action 3-5 hr
Tiotropium has longer duration of action (24 h).
Pharmacodynamics
Inhibit bronchoconstriction and mucus secretion
Less effective than β
2-agonists.
No anti-inflammatory action only bronchodilator
Uses
Main choice in chronic obstructive pulmonary
diseases (COPD).
In acute severe asthma combined with β
2agonists
& corticosteroids.
Never use as a rescue medication.
Pharmacokinetics
Theophylline is given orally
Aminophylline, is given asslow infusion
metabolized by Cyt P450 enzymes in liver
T ½= 8 hours
has many drug interactions
Enzyme inducers:
as phenobarbitone & rifampicin
↑ metabolism of theophylline → ↓ T ½.
Enzyme inhibitors:
as erythromycin
↓ metabolism of theophylline → ↑ T ½.
Uses
Second line drug in asthma (theophylline).
For status asthmatics (aminophylline, is given
asslow infusion).
Side Effects
Low therapeutic index(narrow safety margin)
monitoring of theophylline blood level is
necessary.
GIT effects:nausea & vomiting
CVS effects:hypotension, arrhythmia.
CNS side effects:tremors, nervousness,
insomnia, convulsion
Prophylactic therapy
Anti -inflammatory drugs include:
Glucocorticoids
Leukotrienes antagonists
Mast cell stabilizers
Anti-IgEmonoclonal antibody
e.g. omalizumab
Anti -inflammatory drugs:
(control medications / prophylactic
therapy)
↓ bronchial hyper-reactivity.
↓ reduce inflammation of
airways
↓ reduce the spasm of airways
Glucocorticoids
Mechanism of action
Anti-inflammatory action due to:
Inhibition of phospholipase A2
↓prostaglandin and leukotrienes
↓Number of inflammatory cells in airways.
Mast cell stabilization →↓histamine release.
↓capillary permeability and mucosal edema.
Inhibition of antigen-antibody reaction.
Upregulate β
2receptors(have additive effect to B
2
agonists).
Behavioral changes: depression
Bone loss (osteoporosis)due to
•Inhibit bone formation
•↓ calcium absorption from GIT.
Routes of administration
Inhalation:
e.g. Budesonide & Fluticasone, beclometasone
•Given by inhalation (metered-dose
inhaler).
•Have first pass metabolism
•Best choice in asthma, less side effects
Orally:Prednisone, methyl prednisolone
Injection:Hydrocortisone, dexamethasone
Glucocorticoids in asthma
Are not bronchodilators
Reduce bronchial inflammation
Reduce bronchial hyper-reactivity to stimuli
Have delayed onset of action (effect usually attained after
2-4 weeks).
Maximum action at 9-12 months.
Given as prophylactic medications, used alone or
combined with β
2agonists.
Effective in allergic, exercise, antigen and irritant-induced
asthma,
Systemic corticosteroids are reserved for:
•Status asthmaticus (i.v.).
Inhaled steroids should be consideredfor
adults,
children with any of the following features
•using inhaled β
2agonists three times/week
•symptomatic three times/ week or more;
•or waking one night/week.
Clinical Uses of glucocorticoids
1.Treatment of inflammatory disorders(asthma,
rheumatoid arthritis).
2.Treatment of autoimmune disorders(ulcerative
colitis, psoriasis) and after organ or bone marrow
transplantation as immunosuppressants.
3.Antiemetics in cancer chemotherapy.
Side effects due to systemic corticosteroids
•Adrenal suppression
•Growth retardation in children
•Susceptibility to infections
•Osteoporosis
•Fluid retention, weight gain, hypertension
•Hyperglycemia
•Fat distribution
•Cataract
•Psychosis
Inhalation has very less side effects:
•Oropharyngeal candidiasis (thrush).
•Dysphonia (voice hoarseness).
Withdrawal of systemic corticosteroids
•Abrupt stop of corticosteroids should be
avoided and dose should be tapered (adrenal
insufficiency syndrome).
Mast cell stabilizers
e.g. Cromoglycate -Nedocromil
act by stabilization of mast cell membrane.
given by inhalation (aerosol, nebulizer).
Have poor oral absorption (10%)
Pharmacodynamics
areNotbronchodilators
Noteffective in acute attack of asthma.
Prophylacticanti-inflammatory drug
Reduce bronchial hyper-reactivity.
Effective in exercise, antigen and irritant-
induced
asthma.
Children respond better than adults
Uses
Prophylactic therapy in asthma especially in
children.
Allergic rhinitis.
Conjunctivitis.
Side effects
Bitter taste
minor upper respiratory tract irritation
(burning sensation, nasal congestion)
Leukotrienes antagonists
Leukotrienes
synthesized by inflammatory cells found in
the airways(eosinophils, macrophages, mast
cells).
produced by the action of 5-lipoxygenase on
arachidonicacid.
Leukotriene B4: chemotaxisof neutrophils
Cysteinyl leukotrienes C4, D4 & E4:
•bronchoconstriction
•increase bronchial hyper-reactivity
•↑ mucosal edema, ↑ mucus secretion
Uses of leukotriene receptor antagonists
Noteffective in acute attack of asthma.
Prophylaxisof mild to moderate asthma.
Aspirin-induced asthma
Antigen and exercise-induced asthma
Can be combined with glucocorticoids (additive
effects, low dose of glucocorticoids can be
used).
Side effects:
Elevation of liver enzymes, headache, dyspepsia
Anti-IgE monoclonal antibody
e.g. Omalizumab
is a monoclonal antibody directed against human
IgE –given by injection (s.c.)
prevents IgE binding with its receptors on mast
cells & basophiles.
↓ release of allergic mediators.
Expensive-not first line therapy.
used for treatment of moderate to severe allergic
asthma which does not respond to high doses
ofcorticosteroids.
Drugs used in chronic obstructive pulmonary
disease (COPD)
•COPDis a chronic irreversible airflow
obstruction, lung damage and inflammation
of the air sacs (alveoli).
•Smoking is a high risk factor but air
pollution and genetic factors can contribute.
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Treatment:
•Inhaled bronchodilators
•Inhaled glucocorticoids
•Oxygen therapy
•Antibioticsspecificallymacrolides such
asazithromycinto reduce the number of
exacerbations.
•Lung transplantation
Inhaled bronchodilators in COPD
Inhaled antimuscarinics
Ipratropium & tiotropium.
are superior to β2agonists in COPD
β
2agonists
these drugs can be used either alone or combined
•salbutamol + ipratropium
•salmeterol + Tiotropium (long acting-less dose
frequency).
Summary
Drugs
Adenyl
cyclase
cAMP
–Short acting
–main choicein acute
attack of asthma
–Inhalation
B2 agonists
Salbutamol, terbutaline
Long acting, Prophylaxis
Nocturnal asthma
Salmeterol, formoterol
Blocks M
receprtors
Main drugs For COPD
Inhalation
Inhalation
Antimuscarinics
Ipratropium (Short)
Tiotropium (long)
Inhibits
phosphodi
esterase
cAMP
(orally)
(parenterally)
Xanthine derivatives
Theophylline
Aminophylline
Bronchodilators (relievers for bronchospasm)
Understanding the Common Cold
Most caused by viral infection
(rhinovirus or influenza virus—the “flu”)
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Understanding the Common Cold
Virus invades tissues (mucosa) of upper
respiratory tract, causing upper respiratory
infection (URI).
Excessive mucus production results from the
inflammatory response to this invasion.
Fluid drips down the pharynx into the
esophagus and lower respiratory tract,
causing cold symptoms: sore throat,
coughing, upset stomach.
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Understanding the Common Cold
Irritation of nasal mucosa often triggers the
sneeze reflex.
Mucosal irritation also causes release of
several inflammatory and vasoactive
substances, dilating small blood vessels in
the nasal sinuses and causing nasal
congestion.
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Treatment of the Common Cold
Involves combined use of antihistamines,
nasal decongestants, antitussives, and
expectorants.
Treatment is SYMPTOMATIC only, not
curative.
Symptomatic treatment does not eliminate
the causative pathogen.
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Cough:protective reflex which helps
to expel irritant matter from the
respiratory tract
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Antitussive Agents
Depress the area in CNS which controls the
cough refles
Stimulate the flow of respiratory secretions
Expectorants
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Expectorants
“Drugsthathelpinremovingsputumfromtherespiratorytract.
-eitherbyincreasingthefluidity(orreducingtheviscosity)of
sputumor
-increasingthevolumeoffluidsthathavetobeexpelledfrom
therespiratorytractbycoughing.”
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Expectorants: Mechanisms of
Action
Direct stimulation
or
Reflex stimulation
Final result: thinner mucus that is easier to remove
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Expectorants: Mechanism of
Action
Direct stimulation:
The secretory glands are stimulated directly
to increase their production of respiratory
tract fluids.
Examples: terpin hydrate, iodine-containing
products such as iodinated glycerol and
potassium iodide (direct and indirect
stimulation)
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Expectorants: Mechanism of
Action
Reflex stimulation:
Agent causes irritation of the GI tract.
Loosening and thinning of respiratory tract
secretions occur in response to this irritation.
Examples: guaifenesin, syrup of ipecac
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Expectorants: Drug Effects
By loosening and thinning sputum and
bronchial secretions, the tendency to cough
is indirectly diminished.
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Boththeactionandmechanismofexpectorantshavebeenquestioned
andremaincontroversial.However,thesemayserveaplaceborole
andhelpthepatient
•Ammonium chloride
•Potassium iodide
•Sodium iodide
placebois a simulated or otherwise medically ineffectual treatment for a disease
.
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80
Dose related side-effects
•Ifthepatientissensitive,doseofexpectorantishighenough,this
mayinducevomiting(emeticaction).
•Hence,itisadvisabletogivethedosesofexpectorantsthatcouldbe
tolerated(bythepatient)alongwithotherpharmaceuticalaids
(flavours,sweetners,etc.)andcoughsuppressants.
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Classification of Expectorants
•According the their mechanism of action…
(1) Sedative type
(2) Stimulant type
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Sedative expectorants
•Thesearestomachirritantexpectorantswhichareabletoproduce
theireffectthroughstimulationofgastricreflexes.
•e.g.
Bitter drugs –Ipecac, Senega, Indian Squill
Compounds –Antimony potassium tartrate,
Ammonium chloride, Sodium citrate,
Potassium iodide, etc.
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Stimulant type
•Thesearetheexpectorantswhichbringaboutastimulationofthe
secretorycellsoftherespiratorytractdirectlyorindirectly.
•Sincethesedrugsstimulatesecretion,morefluidinrespiratorytract
andsputumisdiluted.
•e.g. -Eucalyptus, lemon, anise
-Active constituents of oil like terpine hydrate,
anethole
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Ammonium chloride
•Assay:Itwaspreviouslyassayedbyprecipitationtitrationby
usingtheVolhard’smethod.
Now,itisassayedbyacid-basetitrationmethod.
•Uses:
(1)Itactsasmildexpectorantanddiaphoreticwhen
administeredinsmalldoses.
Itdoessoduetolocalirritationwhichproducesincreasing
secretionofrespiratorytract,andmakesthemucusless
viscous.NH
4ClandNH
4HCO
3arethereforeusedincough
preparations.
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Mucolytes
Mucolyticsare medicines that make the mucus
(sputum) less thick and sticky and easier to
cough up.
They are usually prescribed for people who have
a chronic (long-term) cough.
They work best if they are taken regularly.
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Anexpectorantincreases bronchial
secretionsand mucolyticshelp loosen thick
bronchial secretions.
Expectorantsreduce the thicknessorviscosity
of bronchial secretions thus increasing mucus
flow that can be removed more easily through
coughing.
Mucolyticsbreak down the chemical structure
of mucus molecules.
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Bronchitis is inflammation or swelling of the
bronchial tubes (bronchi), the air passages between
the nose and the lungs.
More specifically, bronchitis is when the lining of the
bronchial tubes becomes inflamed or infected.
Bronchitis is caused by viruses, bacteria, and other
particles that irritate the bronchial tubes.
Bronchitis
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Acute bronchitis
Acute bronchitisis a shorter illness that commonly follows a
cold or viral infection, such as theflu
Acute bronchitis usually lasts a few days or weeks
Chronic bronchitis
Chronic bronchitisis characterized by a persistent, mucus-
producing cough on most days of the month, three months of
a year for two successive years in absence of a secondary
cause of the cough.
TYPES OF BRONCHITIS
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Bronchial asthma
Types of Asthma based on clinical condition:
Mild episodic asthma:
Seasonal asthma:
Mild chronic asthma:
Moderate asthma with frequent exacerbations:
Severe asthma:
Status asthmaticus/Refractory asthma
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Inflammation or swelling of the bronchi
Coughing
Production of clear, white, yellow, grey, or green mucus
(sputum)
Shortness of breath
Wheezing
Fatigue
Fever and chills
Chest pain or discomfort
Blocked or runny nose
Signs &symptoms of bronchitis
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Antiasthmaticdrugsaremedicinesthat
treatorpreventasthmaattacks.
BRONCHODILATORS:
CORTICOSTEROIDS
1
ST
choice in patients with any degree of persistent asthma
ANTI Ig-E ANTIBODY: In moderate to severe asthma patients who are poorly
controlled with conventional therapy.
◦Reduces steriod requirements
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Decongestants
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Nasal Congestion
Excessive nasal secretions
Inflamed and swollen nasal mucosa
Primary causes:
–Allergies
–Upper respiratory infections (common cold)
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Decongestants
Two main types are used:
Adrenergics (largest group)
Corticosteroids
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Decongestants
Two dosage forms:
Oral
Inhaled/topically applied to the nasal membranes
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Oral Decongestants
Prolonged decongestant effects,
but delayed onset
Effect less potent than topical
No rebound congestion
Exclusively adrenergics
Examples:phenylephrine
pseudoephedrine (Sudafed)
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Topical Nasal Decongestants
Both adrenergics and steroids
Prompt onset
Potent
Sustained use over several days causes
rebound congestion, making the condition
worse
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Nasal Decongestants:
Mechanism of Action
Site of action: blood vessels surrounding
nasal sinuses
Adrenergics
–Constrict small blood vessels that supply
URI structures
–As a result, these tissues shrink and nasal
secretions in the swollen mucous membranes
are better able to drain
–Nasal stuffiness is relieved
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Nasal Decongestants: Drug
Effects
Shrink engorged nasal mucous membranes
Relieve nasal stuffiness
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