ANTIASTHMATIC ANTIASTHMATIC DRUGSDRUGS

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ASTHMAASTHMA

Asthma is a reversible obstruction of airflow through the airway. Asthma is a reversible obstruction of airflow through the airway. The airway resistance is increased and the patient has difficulty The airway resistance is increased and the patient has difficulty in breathing out. This is manifested as a decrease in the forced in breathing out. This is manifested as a decrease in the forced expiratory volume in 1 second (FEVexpiratory volume in 1 second (FEV11). Symptoms are:). Symptoms are:

Episodic wheezingEpisodic wheezing Episodic coughingEpisodic coughing BreathlessnessBreathlessness Chest tightnessChest tightness Rapid respirationRapid respirationAll the above symptoms are due to acute bronchoconstriction, an All the above symptoms are due to acute bronchoconstriction, an

increased viscid mucous secretion, inflammation of the increased viscid mucous secretion, inflammation of the bronchial wall & hyperplasia of smooth muscle cells. The bronchial wall & hyperplasia of smooth muscle cells. The bronchiole muscles also become hyperactive (hyperreactivity, bronchiole muscles also become hyperactive (hyperreactivity, hyperresponsiveness) and give an exagerated response to hyperresponsiveness) and give an exagerated response to stimuli. These effects are due to production of leucotrienes, stimuli. These effects are due to production of leucotrienes, cytokines, and migration of eosinophils, macrophages and cytokines, and migration of eosinophils, macrophages and lymphocytes. lymphocytes.

PATHOGENESIS & Tx STRATEGIESPATHOGENESIS & Tx STRATEGIES

PATHOGENESISPATHOGENESIS Tx STRATEGIESTx STRATEGIES

Bronchial Mucosal Bronchial Mucosal InflammationInflammation

InflammationInflammation-Anti-inflammatory Agents:Anti-inflammatory Agents:

-corticosteroidscorticosteroids-Leukotriene Leukotriene

antagonist/inhibitorantagonist/inhibitor-Inhibitor of mast cell Inhibitor of mast cell

degranulationdegranulation

BronchoconstrictionBronchoconstriction

(most easily reversed)(most easily reversed)

Bronchodilatation Bronchodilatation -BronchodilatorsBronchodilators

-Beta Beta agonists,PDEI,ipratropiumagonists,PDEI,ipratropium

MucusMucus Get rid of mucusGet rid of mucus

- Mucolytic & expectorant- Mucolytic & expectorant

THERAPY FOR ASTHMATHERAPY FOR ASTHMA

Short-term Short-term RelieversRelievers

-BronchodilatorsBronchodilators

e.g. Salbutamole.g. Salbutamol

Long-term Long-term ControllerController

(Reduce (Reduce symptoms & symptoms & prevent attacks)prevent attacks)

-Anti-inflammatoryAnti-inflammatory

e.g. Inhaled e.g. Inhaled Corticosteroid Corticosteroid

BRONCHODILATORSBRONCHODILATORS

ββ2 2 – adrenoceptor agonist – adrenoceptor agonist

short acting -short acting - Salbutamol (Albuterol) Salbutamol (Albuterol)

long acting, delayed onset – Salmeterol (not for acute attacklong acting, delayed onset – Salmeterol (not for acute attack))

MetylxanthineMetylxanthine

- Theophylline- Theophylline

- Aminophylline- Aminophylline

Antimuscarinic agentsAntimuscarinic agents

- Ipratropium bromide- Ipratropium bromide

ANTI-INFLAMMATORY AGENTSANTI-INFLAMMATORY AGENTS CorticosteroidsCorticosteroids

- Prednisolone – oral- Prednisolone – oral

- Hydrocortisone – IV- Hydrocortisone – IV

- Beclomethasone – inhalation- Beclomethasone – inhalation

- Budesonide - inhalation- Budesonide - inhalation Mast Cell StabilizerMast Cell Stabilizer

- Sodium cromoglycate – inhalation or aerosol- Sodium cromoglycate – inhalation or aerosol

Leucotriene Receptor AntagonistLeucotriene Receptor Antagonist

- Montelukast – oral- Montelukast – oral

Leucotriene Synthesis InhibitorLeucotriene Synthesis Inhibitor

- Zileuton - oral- Zileuton - oral

BRONCHODILATORSBRONCHODILATORS

Mechanism of actionMechanism of action of bronchodilatorsof bronchodilators

• cause bronchodilatation

• increase ciliary function

• block release of bronchoconstricting mediators from mast cells.

B2 Agonist Agent

Stimulate bronchial B2 adrenoceptors

ATP cAMP 5’- AMP

PhosphodiesteraseAdenyl cyclase

* B2 Agonist Agents & Methylxantine are not given together

Mechanism of actionMechanism of action of PDEIof PDEI

• cause bronchodilatation (major effect)

• increase mucociliary activity(questionable)

• block release of bronchoconstricting mediators from mast cells.

ATP cAMP 5’- AMP

PhosphodiesteraseAdenyl cyclase

Methylxanthine

* B2 Agonist Agents & Methylxantine are not given together

Mechanism of action of PDEI

Mechanism is unclear. One possible mechanism of

inhibition of PDE (see next slide) Blocks adenosine at adenosine

receptors. May have effect on cGMP

phosphodiesterase.

ββ2 2 – adrenoceptor agonists– adrenoceptor agonists

Prototype: Salbutamol (Albuterol): by inhalation for acute Prototype: Salbutamol (Albuterol): by inhalation for acute attacks. attacks. Fast OOA (effect maximal within 15-30 mins& short Fast OOA (effect maximal within 15-30 mins& short DOA (3-4 hrs). DOA (3-4 hrs).

Salmeterol. Not for acute attacks. Slow Salmeterol. Not for acute attacks. Slow OOA & long DOA (12 OOA & long DOA (12 hrs). Given b.d.regularly as adjuncts in patients whose asthma hrs). Given b.d.regularly as adjuncts in patients whose asthma is not controlled by oral glucocorticosteroids.is not controlled by oral glucocorticosteroids.

Mode of administrationMode of administration- Inhalation: aerosol, nebulizer- Inhalation: aerosol, nebulizer- Oral, parenteral (rare)- Oral, parenteral (rare)

Adverse effectsAdverse effects- CVS: tachycardia, arrhythmia, palpitation (unsubstantiated)- CVS: tachycardia, arrhythmia, palpitation (unsubstantiated)- Tremor: - Tremor: ββ2 2 effect on skeletal muscleeffect on skeletal muscle

Methylxanthine (PDEI)Methylxanthine (PDEI)

Xanthine drugs are theophylline, theobromine and caffeine.Xanthine drugs are theophylline, theobromine and caffeine.

Only theophylline (oral) was used clinically.Only theophylline (oral) was used clinically. Aminophylline (theophylline ethylenediamine,(IV)Aminophylline (theophylline ethylenediamine,(IV) Now replaced by beta agonists and corticosteroids. It has a Now replaced by beta agonists and corticosteroids. It has a

low therapeutic index. Blood level measurement is necessary. low therapeutic index. Blood level measurement is necessary.

Side effect on other systems.Side effect on other systems. CNS: stimulation causing insomnia, higher blood level - CNS: stimulation causing insomnia, higher blood level -

seizures leading to death.seizures leading to death. CVS: inotropic +ve & chronotrophic +ve (fatal arrhythmias)CVS: inotropic +ve & chronotrophic +ve (fatal arrhythmias) GIT: GIT: major side effect is nausea and vomiting, also causes major side effect is nausea and vomiting, also causes

gastric acid secretion.gastric acid secretion. Kidney: mild diuresis.Kidney: mild diuresis.

Methylxanthine-contMethylxanthine-cont

PharmacokineticsPharmacokinetics

- Oral, IV- Oral, IV- Metabolized- Metabolized- Narrow therapeutic Index (5-20 mg/l)- Narrow therapeutic Index (5-20 mg/l)- Different individual plasma conc.- Different individual plasma conc.- Toxic Effects:- Toxic Effects:

> 20 mg/l - GIT: anorexia, nausea, vomiting> 20 mg/l - GIT: anorexia, nausea, vomiting - CNS: headache, anxiety- CNS: headache, anxiety

> 40 mg/l – CNS: convulsion> 40 mg/l – CNS: convulsion - CVS: serious arrhythmias- CVS: serious arrhythmias

Muscarinic Receptor AntagonistMuscarinic Receptor Antagonist

Ipratropium bromide, a quaternary ammonium compoundIpratropium bromide, a quaternary ammonium compound

ACH + muscarinic receptor (MR) on hyperreactive bronchusACH + muscarinic receptor (MR) on hyperreactive bronchus causing bronchoconstriction.causing bronchoconstriction.

Mechanism of actionMechanism of action- It binds to ACH receptor (competitively) on the bronchioles, - It binds to ACH receptor (competitively) on the bronchioles, blocks the effect of ACH and causes bronchodilatation.blocks the effect of ACH and causes bronchodilatation.

Effective only where there is a parasympathetic component Effective only where there is a parasympathetic component involved in causing the bronchoconstriction.involved in causing the bronchoconstriction.

- does not dry airway secretion and interfere with mucociliary - does not dry airway secretion and interfere with mucociliary secretion.secretion.

PharmacokineticsPharmacokinetics- Inhalation (oral – not absorb via GIT)- Inhalation (oral – not absorb via GIT)- Elimination – lung (exhalation)- Elimination – lung (exhalation)

Adverse effectsAdverse effects- minimal muscarinic effects since given by inhalation and it is a - minimal muscarinic effects since given by inhalation and it is a quaternary ammonium compound.quaternary ammonium compound.

ANTI-INFLAMMATORY AGENTSANTI-INFLAMMATORY AGENTS

ANTIINFLAMMATORY: ANTIINFLAMMATORY: CORTICOSTEROIDSCORTICOSTEROIDS

MECHANISM OF ACTION:MECHANISM OF ACTION: have antiinflammatory effect by reversing oedema of have antiinflammatory effect by reversing oedema of

bronchiole mucosa, inhibiting release of leucotrines and bronchiole mucosa, inhibiting release of leucotrines and decreasing the permeability of capillaries.decreasing the permeability of capillaries.

decrease formation of cytokines, contributing in part to decrease formation of cytokines, contributing in part to antiinflammatory effect.antiinflammatory effect.

decrease the number and activity of oesinophils, macrophages decrease the number and activity of oesinophils, macrophages and T lymphocytes that are involved in airway inflammation. and T lymphocytes that are involved in airway inflammation. This is their most important action.This is their most important action.

Increase effect of beta 2 adrenoceptor agonists.Increase effect of beta 2 adrenoceptor agonists. Do not cause bronchodilation directly.Do not cause bronchodilation directly. Do not relieve acute asthma.Do not relieve acute asthma. Reduce bronchial hyperreactivity when inhaled for several Reduce bronchial hyperreactivity when inhaled for several

months.months. Reduce frequency of asthmatic attacks.Reduce frequency of asthmatic attacks.

ANTIINFLAMMATORY: CORTICO-STEROIDS.

Oral steroids cause serious side effects, so used only when symptoms of asthma worsen despite treatment with beta adrenoceptor agonists + inhaled steroids. Usually given for 7 to10 days,then tail off dose.

Inhalation steroids are used for regular therapy, best way to avoid systemic adverse effects. Given for 10- 12 weeks,then withdrawn to see response.

Inflammatory mediatorsInflammatory mediators

PHOSPHOLIPID IN CELL MEMBRANE

Phospholipase Enzyme

ARACHIDONIC ACID

Cyclooxygenase

Enzyme (COX)

Lipoxygenase Enzyme

PG LEUCOTRINE

Inflammatory mediatorsInflammatory mediators

PHOSPHOLIPID IN CELL MEMBRANE

Phospholipase Enzyme

ARACHIDONIC ACID

Cyclooxygenase

Enzyme (COX)

Lipoxygenase Enzyme

PG LEUCOTRINE

Corticosteroids

Adverse effects of corticosteroidsAdverse effects of corticosteroids

local(inhalation)local(inhalation)

- oral candiasis, hoarseness of voice- oral candiasis, hoarseness of voice

systemic (oral)systemic (oral)

- cataract, glaucoma,osteoporosis, - cataract, glaucoma,osteoporosis, peripheral myopathy, peripheral myopathy, depression,infections due to depression,infections due to decreased immunity. decreased immunity.

Drugs: beclomethasone, Drugs: beclomethasone, prednisolone,hydrocortisone, prednisolone,hydrocortisone, budesonide.budesonide.

ANTIINFLAMMATORY:ANTIINFLAMMATORY:CROMOLYN SODIUM,NEDOCROMILCROMOLYN SODIUM,NEDOCROMIL

MECHANISM OF ACTION:MECHANISM OF ACTION:

- ORIGINALLY THOUGHT TO PREVENT HISTAMINE RELEASE - ORIGINALLY THOUGHT TO PREVENT HISTAMINE RELEASE FROM MAST CELLS.FROM MAST CELLS.

- ALTERS FUNCTION OF DELAYED CHLORIDE CHANNELS - ALTERS FUNCTION OF DELAYED CHLORIDE CHANNELS RESULTING IN INHIBITION OF CELL ACTIVATION AND RESULTING IN INHIBITION OF CELL ACTIVATION AND PRODUCTION OF INFLAMMATORY MEDIATORS.PRODUCTION OF INFLAMMATORY MEDIATORS.

EFFECTS:EFFECTS:

NOT A BRONCHODILATOR, NOT USED FOR IMMEDIATE NOT A BRONCHODILATOR, NOT USED FOR IMMEDIATE EFFECTSEFFECTS

USED AS A PROPHYLACTIC DRUG ( INHALATION OR USED AS A PROPHYLACTIC DRUG ( INHALATION OR AEROSOL )TO DECREASE FREQUENCY/PREVENT AEROSOL )TO DECREASE FREQUENCY/PREVENT ASTHMATIC ATTACKS.ASTHMATIC ATTACKS.

ADVERSE EFFECTS:ADVERSE EFFECTS: NOT ABSORBED AT ALVEOLI, SO MINOR ADVERSE EFFECTSNOT ABSORBED AT ALVEOLI, SO MINOR ADVERSE EFFECTS

- THROAT IRRITATION, DRY MOUTH, BRONCHOSPASM, - THROAT IRRITATION, DRY MOUTH, BRONCHOSPASM, BITTER TASTE.BITTER TASTE.

ANTIINFLAMMATORY:LEUCOTRIENE LTB4 is a potent neutrophil and eosinophil

chemoattractants whose products proteases,platelet activating factor(PAF), eosinophil cationic protein (ECP) and major basic protein (MBP) are responsible for the symptoms of asthma.

LTC4 & LTD4 produce bronchoconstriction,bronchial hyperreactivity,mucosal oedema and mucus hypersecretion.

2 ways to decrease production of leucotriene is by inhibition of 5-lipooxygenase thereby preventing its synthesis (zileuton) and by blocking the leucotriene receptors (montelukast,zafirlukast).

Zileuton prevents the formation of LTB4 and the cysteinyl leukotrienes (LTC4 & LTD4 & LTE4).

Montelukast and zafirlukast blocks cysteinyl leukotriene receptors reversibly.

Leukotriene Receptor AntagonistLeukotriene Receptor Antagonist

Montelukast Montelukast Zafirlukast Zafirlukast

Blocks LT cysteinyl type Blocks LT cysteinyl type receptorsreceptors

LT EffectsLT Effects LT AntagonismLT Antagonism

Bronchus Bronchus inflammationinflammation

Bronchus Bronchus inflammationinflammation

Mucus secretionMucus secretion Mucus secretionMucus secretion

BronchoconstrictionBronchoconstriction BronchodilatationBronchodilatation

Leukotriene Receptor AntagonistsLeukotriene Receptor Antagonists

- not used for immediate bronchodilator effect.- not used for immediate bronchodilator effect.

- ability to cause bronchodilatation is lower than beta-- ability to cause bronchodilatation is lower than beta-agonistagonist

- very useful for aspirin induced asthma- very useful for aspirin induced asthma

- not used alone but in addition to beta agonists and - not used alone but in addition to beta agonists and corticosteroids.corticosteroids.

MONTELUKAST/ZAFIRLUKASTMONTELUKAST/ZAFIRLUKAST

PharmacokineticsPharmacokinetics - oral administration- oral administration

- Metabolism – liver- Metabolism – liver- Excretion – biliary- Excretion – biliary

Adverse effectsAdverse effects - occasional liver toxicity ( especially with - occasional liver toxicity ( especially with

zileuton)zileuton)- headache- headache- dyspepsia- dyspepsia

LEUKOTRIENE SYNTHESIS INHIBITORLEUKOTRIENE SYNTHESIS INHIBITOR

ZileutonZileuton

PharmacokineticsPharmacokinetics

- oral, good absorption- oral, good absorption

- metabolism – liver- metabolism – liver

- excretion – urine- excretion – urine

Adverse effectsAdverse effects

- headache- headache

- dyspepsia- dyspepsia

- hepatotoxic (rare)- hepatotoxic (rare)

LEUKOTRIENE SYNTHESIS INHIBITORLEUKOTRIENE SYNTHESIS INHIBITOR

PHOSPHOLIPID IN CELL MEMBRANE

Phospholipase Enzyme

ARACHIDONIC ACID

Cyclooxygenase

Enzyme (COX)

Lipoxygenase Enzyme

PG LEUCOTRINE

Given Orally – 4 times a day

LEUKOTRIENE SYNTHESIS INHIBITORLEUKOTRIENE SYNTHESIS INHIBITOR

PHOSPHOLIPID IN CELL MEMBRANE

Phospholipase Enzyme

ARACHIDONIC ACID

Cyclooxygenase

Enzyme (COX)

Lipoxygenase Enzyme

PG LEUKOTRINE

Given Orally – 4 times a day

• Zileuton

STATUS ASTHMATICUS (bronchospasm not reversed by usual measures) THIS CONDITION IS A MEDICAL

EMERGENCY AND CAN BE FATAL. PATIENT MUST BE ADMITTED TO HOSPITAL.

TREATMENT CONSISTS OF MECHANICAL INTERVENTION, SALBUTAMOL IN OXYGEN GIVEN BY NEBULISER AND I/V HYDROCORTISONE. THIS IS FOLLOWED BY A COURSE OF ORAL PREDNISOLONE.

OTHER DRUGS: ANTI-IgE MONOCLONAL ANTIBODIESOMALIZUMABINHIBITS BINDING OF IgE TO MAST

CELLS.MAY ALSO INHIBIT IgE SYNTHESIS BY B

LYMPHOCYTES.REDUCES THE FREQUENCY AND

SEVERITY OF ASTHMATIC ATTACKS.DECREASE CORTICOSTEROID

REQUIREMENTS.SEVERE ASTHMATICS RESPOND WELL.FOR SELECTED INDIVIDUALS BECAUSE

OF HIGH COST.

HAPPY STUDYING. REF: KATZUNG,LIPPINCOTT’S