Pharmacology Pharmacology departmentdepartment

FACULTY OF MEDICINES LAMPUNG UNIVERSITY

DRUGS USED IN ASTHMA

BRONCHODILATORS ANTI-INFLAMMATORY LEUKOTRIENE AGENTS ANTAGONISTS

β RELEASE LIPOXYGENASE RECEPTORAGONISTS INHIBITORS INHIBITORS INHIBITORS

MUSCARINIC STEROIDS ANTIBODIES ANTAGONISTS

METHLYXANTHINES SLOW ANTI- INFLAMMATORY DRUGS

BRONCHIAL ASTHMA

Airway inflammationEpisodic, reversible bronchospasmChronic inflammation that leads to

marked bronchial hyperreactivity

BRONCHIAL ASTHMA

BRO

NCH

IAL

ASTH

MA

Bronchial ToneBronchial Tone

ConstrictionConstriction

Leukotrienes

Adenosine

Acetylcholine

CAMP

ATP

PDEPDE

AMP

DilataDilatationtionACAC

BRONCHIAL ASTHMARelease of several mediators from IgE-

sensitized mast cells and other cells involved in immunologic responses

Mediators include LeukotrienesChemoattractantsCytokinesEnzymes

DRUGS USED IN ASTHMASTRATEGIES OF ASTHMA THERAPYACUTE ASTHMATIC ATTACKS

Treated promptly and effectively with bronchodilatorsβ2 agonistMuscarinic antagonistsTheophylline and its derivatives

DRUGS USED IN ASTHMASTRATEGIES OF ASTHMA THERAPYCHRONIC ASTHMA

Long term preventive treatment Requires control of inflammatory process in

the airwaysCorticosteroidsCromolyn

DRUGS USED IN ASTHMA BRONCHODILATORS ANTI-INFLAMMATORY LEUKOTRIENE

AGENTS ANTAGONISTS

β RELEASE LIPOXYGENASE RECEPTORAGONISTS INHIBITORS INHIBITORS INHIBITORS

MUSCARINIC STEROIDS ANTIBODIES ANTAGONISTS

METHLYXANTHINES SLOW ANTI- INFLAMMATORY DRUGS

DRUGS USED IN ASTHMABETA-ADRENOCEPTOR AGONISTSMechanism of action

Stimulate adenyl cyclase and increasing cAMP in smooth muscle cells bronchodilatation

Relaxation

Bronchial ToneBronchial Tone

ConstrictionConstriction

Leukotrienes

Adenosine

Acetylcholine

CAMP

ATP

PDEPDE

AMP

DRUGS USED IN ASTHMABETA-ADRENOCEPTOR AGONISTSMost important sympathomimetic used

to reverse asthmatic bronchoconstrictionAlmost given exclusively by inhalation

Decreases the systemic dose and adverse effects

Occasionally by nebulizer

DRUGS USED IN ASTHMABETA-ADRENOCEPTOR AGONISTSAlbuterol, terbutaline, metaproterenol

Short-actingDrug of choice for acute asthma

DRUGS USED IN ASTHMA

BETA-ADRENOCEPTOR AGONISTSSalmeterol and formoterol

Long-acting12 h or moreUsed for prophylaxis

DRUGS USED IN ASTHMA

BETA-ADRENOCEPTOR AGONISTSEpinephrine and isoproterenol

Still used occasionally Used for chronic obstructive pulmonary

disease (COPD) patients

DRUGS USED IN ASTHMABETA-ADRENOCEPTOR AGONISTSTOXICITY

Skeletal muscle tremorSignificant β1 effects (tachycardia) at high

clinical dosageArrhythmias may occur when used

excessively

DRUGS USED IN ASTHMABETA-ADRENOCEPTOR AGONISTSTOXICITY

Tolerance, tachyphylaxis (loss of responsiveness) is an unwanted effect

COPD patients often with concurrent cardiac disease may have arrhythmias at normal dosage

DRUGS USED IN ASTHMAMETHYLXANTHINESPurinePurine derivativesMOA

Inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP to AMP, thus increases cAMP

Anti-PDE effect requires high concentration of the drug

Relaxation

Bronchial ToneBronchial Tone

ConstrictionConstriction

Leukotrienes

Adenosine

Acetylcholine

CAMP

ATP

PDEPDE

AMP

DRUGS USED IN ASTHMAMETHYLXANTHINESFound in plants and provide the stimulant

effect of 3 common beveragesCaffeine (coffee)Theophylline (tea)Theobromine (cocoa)

DRUGS USED IN ASTHMAMETHYLXANTHINESTheophylline and several analogs

Orally active Available as salts and base

Slow-release theophylline For control of nocturnal asthmaMost important in clinical use

DRUGS USED IN ASTHMAMETHYLXANTHINESClearance varies

Highest in young adolescentsHigher in smokersConcurrent use of other drugs that inhibit or

induce hepatic enzyme

DRUGS USED IN ASTHMAMETHYLXANTHINESBronchodilation is the most important

therapeutic effectCNS stimulation, cardiac stimulation,

vasodilation and slight increase in BP (due to release of NE from adrenergic nerves

DRUGS USED IN ASTHMA

METHYLXANTHINESEliminated by Cytochrome P450-drug

metabolizing enzyme in the liverPentoxifylline

Used for treatment of intermittent claudication

DRUGS USED IN ASTHMAMETHYLXANTHINESTOXICITY

Common adverse effectsGI distressTremorInsomnia

DRUGS USED IN ASTHMAMETHYLXANTHINESTOXICITY

OverdosageSevere nausea and vomitingHypotensionCardiac arrhythmiasConvulsion

DRUGS USED IN ASTHMAMUSCARINIC ANTAGONISTSMOA

Competitively blocks muscarinic receptors in the airways

Prevents bronchoconstriction mediated by vagal discharge

Relaxation

Bronchial ToneBronchial Tone

ConstrictionConstriction

Leukotrienes

Adenosine

Acetylcholine

CAMP

ATP

PDEPDE

AMP

DRUGS USED IN ASTHMAMUSCARINIC ANTAGONISTSReverses bronchoconstrictionReverses bronchoconstriction

Useful in 1/3 to 2/3 of asthmatic patients (especially children)

No effect on the inflammatory aspects of asthma

Useful in many COPD patients More effective and less toxic than β

agonists

DRUGS USED IN ASTHMAMUSCARINIC ANTAGONISTSAtropineAtropine and other naturally-occurring

belladona alkaloids were used for asthma

DRUGS USED IN ASTHMAMUSCARINIC ANTAGONISTSIpatropiumIpatropium

Quaternary antimuscarinic drugDelivered to the airways by pressurized aerosol Have little systemic action

TiotropiumTiotropiumNewer longer-acting analog

DRUGS USED IN ASTHMAMUSCARINIC ANTAGONISTSTOXICITY

Delivered directly to the airway, minimally absorbed

Systemic effects are smallIn excessive dosage, minor atropine-like toxic

effects may occurDoes not cause tremor or arrhythmias

DRUGS USED IN ASTHMA

CROMOLYN AND NEDOCROMILNo bronchodilator action but can prevent

bronchoconstriction caused by a challenge with antigen to which the patient is allergic

DRUGS USED IN ASTHMACROMOLYN AND NEDOCROMILMOA

Decrease in the release of mediators (leukotrienes and histamine) from mast cells

Prevents both early and late responses to challenge

DRUGS USED IN ASTHMACROMOLYN AND NEDOCROMILCromolynCromolyn – prototype drug – prototype drugUnusual chemicalsExtremely insolubleMassive doses given orally or by

aerosol result in minimal systemic levels (local effects)

Given by aerosol for asthma

DRUGS USED IN ASTHMACROMOLYN AND NEDOCROMILFood allergy

Given orallyAsthma in childrenAsthma in children

Most important useHay feverHay fever

Nasal and eyedrop formulations

DRUGS USED IN ASTHMACROMOLYN AND NECRODOMILTOXICITY

Cough and irritation of the airway when given by aerosol

Drug allergy is rare

DRUGS USED IN ASTHMA BRONCHODILATORS ANTI-INFLAMMATORY

LEUKOTRIENE AGENTS ANTAGONISTS

β RELEASE LIPOXYGENASE RECEPTORAGONISTS INHIBITORS INHIBITORS INHIBITORS

MUSCARINIC STEROIDS ANTIBODIES ANTAGONISTS

METHLYXANTHINES SLOW ANTI- INFLAMMATORY DRUGS

DRUGS USED IN ASTHMACORTICOSTEROIDSMOA

Reduces the synthesis of arachidonic acid by phospholipase A2

Inhibit the expression of COX-2 (anti-anflammatory action)

Postulated that: this drugs increases the responsiveness of beta agonists in the airway

DRUGS USED IN ASTHMAArachidonic acidArachidonic acid

LipooxygenaseLipooxygenase CyclooxygenaseCyclooxygenase

HydroxypeptidaseHydroxypeptidase EndoperoxidaseEndoperoxidase

LeukotrienesLeukotrienes ProstacyclineProstacycline

Thromboxane A2Thromboxane A2

ProstaglandinProstaglandin

Membrane Lipid

Phospholipase Phospholipase A2A2

DRUGS USED IN ASTHMA

CORTICOSTEROIDSAll are potentially beneficial in severe

asthmaSystemic (oral corticosteroids)

Used chronically only if other therapies fail

DRUGS USED IN ASTHMACORTICOSTEROIDSLocal aerosol administration of surface

active corticosteroids are relatively safeBeclomethasoneBudesonideDexamethasoneFlunisolideFluticasoneMometasone

DRUGS USED IN ASTHMACORTICOSTEROIDSInhaled corticosteroids

Common first-line therapy for moderate to severe asthma

Appropriate (even in children) in cases of moderate asthma that does not fully respond to aerosol β agonist

DRUGS USED IN ASTHMACORTICOSTEROIDSPrednisolone and hydrocortisone

Intravenous For status asthmaticus

DRUGS USED IN ASTHMACORTICOSTEROIDSReduced activity of phospholipase

A2 Leukotrienes that result from the

synthesis of prostaglandins are potent bronchoconstrictors

DRUGS USED IN ASTHMACORTICOSTEROIDSEarly use may prevent the severe,

progressive inflammatory changes of long-standing asthma

DRUGS USED IN ASTHMACORTICOSTEROIDSTOXICITY

Changes on oropharyngeal flora result to candidiasis

For oral therapyAdrenal suppression can be reduced by

using alternate day therapy (give the drug in slightly higher dosage every other day)

DRUGS USED IN ASTHMACORTICOSTEROIDSTOXICITY

Systemic toxicitiesOccur if treatment is required for more

than 2 weeksRegular use of inhaled steroids cause

mild growth retardation in children

DRUGS USED IN ASTHMA

BRONCHODILATORS ANTI-INFLAMMATORY LEUKOTRIENE AGENTS ANTAGONISTS

β RELEASE LIPOXYGENASE RECEPTORAGONISTS INHIBITORS INHIBITORS INHIBITORS

MUSCARINIC STEROIDS ANTIBODIES ANTAGONISTS

METHLYXANTHINES SLOW ANTI- INFLAMMATORY DRUGS

DRUGS USED IN ASTHMALEUKOTRIENE ANTAGONISTSInterfere with the synthesis or action synthesis or action

of leukotrienesof leukotrienesNot as effective as corticosteroids in

severe asthma Not recommended for acute asthmaLow toxicity

DRUGS USED IN ASTHMAArachidonic acidArachidonic acid

LipooxygenaseLipooxygenase CyclooxygenaseCyclooxygenase

HydroxypeptidaseHydroxypeptidase EndoperoxidaseEndoperoxidase

LeukotrienesLeukotrienes ProstacyclineProstacycline

Thromboxane A2Thromboxane A2

ProstaglandinProstaglandin

DRUGS USED IN ASTHMALEUKOTRIENE ANTAGONISTSZileutonZileuton

Orally activeSelectively inhibits 5-lipoxygenase,

a key enzyme in the conversion of arachidonic acid to leukotrienes

DRUGS USED IN ASTHMALEUKOTRIENE ANTAGONISTSZileuton

Effective in Exercise- and antigen-induced

bronchospasmAspirin allergyToxicity include occasional elevation of

liver enzymes

DRUGS USED IN ASTHMALEUKOTRIENE ANTAGONISTSZafirlukast and montelukastZafirlukast and montelukast

Antagonist at the LTD4 leukotriene receptorOrally active

DRUGS USED IN ASTHMALEUKOTRIENE ANTAGONISTSEffective in preventing exercise-,

antigen-and aspirin-induced bronchospastic attacks

DRUGS USED IN ASTHMAAnti-IgE antibody

OmalizumabHumanized murine monoclonal

antibody to human IgEProphylactic management of asthmaGiven parenterally

DRUGS USED IN ASTHMAAnti-IgE antibody

Binds to IgE on sensitized mast cellsPrevents activation by asthma triggers Subsequent release of inflammatory

mediators

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