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Pharmacotherapy of Bronchial Asthma (BA)

By Dep of Pharmacology.

Dept of pharmacology , building 7 , G 755 ext 22330Profahmedali@hotmail.com

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Objectives To List drugs used for management of

asthma To discuss the clinical pharmacology

of bronchodilators To discuss the clinical pharmacology

of anti-inflammatory To understand the treatment strategy

for acute and chronic asthma

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1. To treat asthma acute attacks when they occur (Bronchodilators)

2. Controls inflammation and prevents chronic symptoms (long-term control medications)

Treatment Strategy:

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(19)

Clinician should be familiar with routes of administration & available dosage forms

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√√√√ Drugs used in treatment of BA:I. Bronchodilators

a) B2 -adrenoceptor agonists e.g:… albuterol , terbutaline ……….., ……………..

b) theophyllinec) Muscarinic antagonists e.g……ipratropium

bromide II. Corticosteroids

• inhalation … Beclomethazone, triamcinolone• systemic. e.g… prednisolone, methylprednisolone

………….III. Mast cell stabilizers e.g…Cromolyn & Nedocromil IVIV-leukotriene modifiers… Zileuton, Montelukast, zafirlukast, V-Anti –IgE antibody e.g………Omalizumab……..

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Short acting : albuterol , terbutaline ( onset 0.5 h , duration 3-4 hr )

Long acting : Salmitrol, formoterol ( slow onset, Duration up to 12 h )

Mechanism of action: Selectively activates B2 receptors , activate adenylyl cyclase (AC ) and increasing cAMP leading to smooth muscle relaxation and Bronchodilation.

Clinical uses:A. Inhaled short-acting agents are the drug of choice for

acute attack of asthma.B. Inhaled long-acting agents used for chronic treatment of

moderate to severe persistent asthma. • Used also for prevention of exercise induced asthma.

I- (a): β2 -adrenoceptor agonists

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Mechanism of action: still debates• inhibition of phosphodiesterase (PDE) enzyme this leads to increases cAMP ?? ?• block Adenosine receptor ?•Possible Anti-inflammatory effect ?Clinical uses:Sustained release preparations are used for chronic treatment of mild to moderate BA.Valuable in preventing nocturnal asthma. Valuable in developing counties ( low price ) Saudi national protocol : IV aminophylline 3rd line in Severe BA

1(-b )Theophylline

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Theophylline (ADE & limitations )

Narrow therapeutic range ( # 9-15 ug/ml )Variable clearance ( age, smoking, drugs, liver disease ) Adverse effects:

1. common ( within therapeutic range ): Gastric upsets & Insomnia2. Overdose : Slightly high level ( # >15-25 ug/ml ) Arrhythmias3. Toxicity : ( #> 30 ug/ml ) sever arrhythmia and seizures# these figures are approximate for illustration purpose., your are not requested to memorize.

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Quiz : what other clinical use of methylxanthins ? Caffeine citrate or theophylline for management of apnea of prematurity &

pentoxyifylline for intermittent claudicating

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Pharmacokinetics of theophylline Difficult. Narrow therapeutic window requires

monitoring of drug levels Certain disease states markedly increase half-life: CHF,

acute pulmonary congestion, cirrhosis. Smoking decreases half-life Peak serum levels in early AM best T/2 varies: with age Neonates, 20-36 hr

Children, 3.5 hrAdults, non smokers 6-9 hr Snooker 3-4 hr

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a quaternary derivative of atropine

Mechanism of action:•Muscarinic M3 blockade leads to smooth muscle relaxation.• it also decrease mucus secretion

Clinical uses:• its use is considered in severe BA • valuable in Chronic obstructive pulmonary disease (COPD).Adverse effects: nearly free of side-effects, : Quiz : Tiotropium ?

1( -c :)Muscarinic antagonists e.g Inhaled Iprartropium

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Mechanism of action: ( # broad anti-inflammatory action effect but not

bronchodilator ) • reduce synthesis of arachedonic acid by phosplipase A2 • subsequently decreases productions of prostaglandins

(PGs )& Leucotriens (LTs )• inhibit inflammatory cell migration and activation. • Decrease vascular permeability and extravasation.• Decrease eosinophil, basophil, lymphocyte

infiltration. • reduces airway hyper-responsiveness, • block late phase reaction to allergen.

II-Corticosteroids

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Inhaled agents: o Beclomethazone, triamcinolone,

- chronic treatment of moderate asthma that are not fully responsive to inhaled B2- agonists.

Systemic agents: o prednisolone, methylprednisolone

• for acute relief of severe BA + other drugs ( short acting B2-Adrenergic agonists , humidified oxygen etc ( see SNP last edition)

Clinical uses of corticosteroids

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Adverse effects of inhaled agents.• Hoarseness• Oropharyngeal

candidacies.• growth suppression

in children To minimize A& BSpacers improve delivery of inhaled glucocorticoids and are advised for virtually all patients. Rinsing the mouth after

inhalation can also decrease systemic absorption and the possibility of oropharyngeal candidiasis.

ADE of inhaled corticosteroids

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Short term steroid use• Reversible increases in glucose • fluid retention with weight gain • hypertension • decreases potassium • mood alterations including rare psychosis • peptic ulcers • InfectionsLong term steroid use• As those in short term use +• Height and growth, suppression• Suppression of immune system• cataracts, myopathy• aseptic necrosis of the femur,• Hirsutism, osteoprosis• Iatrogenic cushing syndrome• adrenal axis suppression,# Quiz What is the best corticosteroid regimen ?

Some Adverse effects of systemic steroids

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Chemistry & Administration Not absorbed orally , cromolyn is administered

by inhalation Mechanism of action:Cell membrane stabilization. Decrease mast cell

degranulation and release of mediators such as histamine that induce bronchospasm.

Clinical uses:

• Chronic treatment of mild persistant asthma. • Cromolyn can be used in children under 12 Y

but not nedocromil. • Used for prevention of Exercise induced

asthma• Allergic rhinoconjunctivitis.

Cromolyn, Nedocromil

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ZileutonMechanism of action:• Leukotriene B4 (LTB4) and the cysteinyl leukotrienes, LTC4 and LTE4, are products of the 5-lipoxygenase pathway of arachidonic acid metabolism.

• LTB4 is a potent chemoattractant for neutrophils and eosinophils, while cysteinyl leukotrienes constrict bronchiolar smooth muscle, increase endothelial permeability, and promote mucus secretion.

Zileuton inhibits 5-lipoxygenase enzyme, Decreases synthesis of all LTs , as a result LT-induced inflammation and bronchospasm are suppressed.

5-lipoxygenase inhibitor

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Clinical uses:Chronic treatment of mild to moderate persistent asthma.. Not used below 12 Y.

• approved for the prophylaxis of asthma

Adverse effects:1. Liver toxicity.

2. zileuton is inhibitors of cytochrome P450

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Mechanism of actionCompetitive antagonist for Cys-LT receptors Clinical usesChronic treatment of mild to moderate BA• approved for the prophylaxis of asthmaAdverse effects:• Elevations in serum hepatic enzymes• Churg-Strass syndrome (granulomatous vasculitis).• Zafirlukast is inhibitors of cytochrome P450

Montelukast, zafirlukast

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Omalizumab

Mechanism of action:A recombinant monoclonal antibody against IgE, selectively

binds IgE and thus reduces the availability of IgE to its receptors on mast cells and basophils. This suppresses degranulation.

Clinical uses: Chronic treatment of moderate to severe asthma. Used in patients above 12 Y who are inadequately controlled with inhaled corticosteroids.

Adverse effects:Anaphylactic & cancer ( 4/10.000 ) ??• Injection site reaction.• Infections: viral upper • respiratory infection.

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Step 1Mild Intermittent

No Daily Medication

Step 2 Mild Persistent

Preferred: Low-dose ICS

Step 3Moderate Persistent

Step 4Severe Persistent

Preferred:Moderate dose ICS + LABA or Medium-dose

ICS)+ LABA if needed(

High-dose ICS + LABA

+(systemiccorticosteroid

s if needed)

Recommendations for pharmacologic management of asthma in adults and children older than 5

All coming slides are for your knowledge but not the exam

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Students are required to read and study the treatment guidelines, and complete an evaluation.Assignment:1. Mention the short-acting symptomatic treatment and long acting preventive therapies of bronchial asthma.2. Treatment of status asthmaticus.

II- Readings:1. Lippencott’s illustrated pharmacology, Last edition.2. Basic and clinical pharmacology, Katzung, Last edition.3-USMLE Pharmacology, Last edition.III- Internetwww. Wikipedia.com

Assignments:

Triggers: Tobacco smoke. Infections such as colds, flu, or pneumonia . Allergens such as food, pollen, mold, dust mites, and

pet dander Exercise . Air pollution and toxins . Weather, especially extreme changes in temperature Drugs (such as aspirin, NSAID, and beta-blockers) Food additives (such as MSG) Emotional stress and anxiety . Singing, laughing, or crying . Smoking, perfumes, or sprays . Acid reflux .

05/03/23 PHYSIOLOGY PRESENTATION 25

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Examples of asthma triggering

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Minimizing Asthma Triggers

Use plastic mattress and pillow covers Weekly washing of bedding in hot water Animal dander control

Weekly bathing of the pet Keeping pets out of the bedroom Remove pet from the home

Cockroach control Hardwood flooring Avoid tobacco smoke Inhibit mite and mold growth by reducing humidity Do not be present when home is vacuumed