Anti-Asthma Drugs

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Bronchial asthma—it is a chronic inflammatory disease of the airways which is characterized by wheeze, breathlessness and hypersensitivity of the bronchus.

It may occur in response to stimuli such as—

1. Allergens

2. Environmental chemicals

3. Viruses

4. Others

 

Inflammatory mediators involved are—                                   

1. Histamine

2. Prostaglandin

3. Leukotriens

4. PAF

 

Type-1 allergic reaction—

Allergens→ stimulates B-lymphocytes→ converted into plasma cells→ produces antibody IgE→ fixed with the mast cell and mast cell becomes sensitive→ when allergens comes again degranulation of the mast cell occurs→ formation of the chemical mediators (Histamine, Interleukin, Bradykinin, Leukotriens C & D, PAF)→ some directly act on the bronchial smooth muscle cells and causes bronchospasm, other are responsible for inflammation.

The inflammation results in hyper-reactivity of the bronchial tree, oedema, exudation and narrowing of the lumen.

 

Types of asthma—Intrinsic and Extrinsic.

 

Classification of the anti-asthma drugs—

β2 receptor agonists

§    Salbutamol

§    Terbutalin

§    Femoterol

Anti-muscarinic drugs

§    Ipratropium bromide

§    Oxitropium

Xanthine derivatives

§    Theophylline

§    Aminophylline

Corticosteroids

§    Beclomethasone

§    Betamethasone

§    Prednisolone

Mast cell stabilizer

§    Sodium chromoglycate

§    Nedocromil sodium

Leukotrien pathway inhibitor

§    Zafirleukast

§    Zileuton

 

Approach to Treatment—

§    Prevention of the exposure to antigen

§    Reduction of bronchial inflammation and hyperactivity

§    Dilatation of the narrowed bronchi

 

Bronchodilators—

Sympathomimetics (β2 receptor agonist), Xanthine derivatives, Anti-cholinergics / muscarinics.

 

Sympathomimetic drugs—adrenalin is an agonist for the α1, α2, β1, β2 receptors. Binding with the β2 receptor it causes bronchodilatation but binding on the β1 receptors it causes ↑ HR, ↑ BP, ↑ O2 demand.

§    Non-selective—Epinephrine, Ephedrine, Isoproterenol {ephedrine causes tachyphylaxis / acute tolerance}

§    β receptor selective drugsIsopropanolol, Isoprenalin

§    β2 receptor selective—Salbutamol, Terbutaline, Femoterol

*** β receptors are also present in the peripheral vasculature, so long term use may cause hypotension.

 

The selective β2 agonists—

§    they can be given orally or inhalation

§    they act selectively on β2 receptors

§    they have long duration of action

§    bronchodilatation is maximal in 30 min when given by inhalation and persists for 2-3 hours

§    they produce less cardio-vascular side effects

§    orally they are given in doses of 4mg 3-4 times

 

Mechanism of Action—it acts in the following ways—

1. Salbutamol → Stimulates β2 receptors of the bronchial smooth muscle → Stimulation of the Adenylate Cyclase enzyme → Increased intracellular cyclic-AMP (also reduction of the intracellular calcium) → Smooth muscle relaxation → Bronchodilatation occurs.

2. Salbutamol → Acts on the β2 receptor of the mast cell → ↑ c-AMP production → Stabilization of the mast cell membrane → No Histamine release → No bronchoconstriction.

3. Salbutamol increases the muco-ciliary action of the lung.

4. Decreases micro-vascular permeability of the lung.

 

Xanthine derivatives—

Chemically they are purine having similar chemical structure with adenine and uric acid. Wide spreads pharmacological action so, not used. These drugs have low therapeutic index. Increases intra-cellular cyclic-AMP concentration within the bronchial smooth muscle cell.

Theophylline is the prototype, it is water insoluble but it’s salts are water soluble.

{Aminophylline—Theophylline Ethylene di-Amine}. Aminophylline is given with dextrose aqua.

 

Mechanism of Action of Theophylline—

1. Combines with the adenosine receptor (PI) and acts as antagonist of adenosine thus prevents it to cause contraction of the bronchial smooth muscle.

2. Combines and inactivates phospho-diesterase enzyme and degradation of the cyclic-AMP stops. C-AMP accumulates in the bronchial smooth muscle and causes bronchodilatation. C-AMP has negative effect on the release of the calcium from the endoplasmic reticulum.

 

Pharmacological effects—

Lung—bronchodilatation

CNS—cortical stimulation, excitement, ↓ mental exhaustion and fatigue. Loss of sleep. Stimulate medullary respiratory and vomiting center.

CVS—positive ionotropic and chronotropic effects. ↑ CO, ↑ HR, ↑ force of contraction. At large doses it causes cerebral vaso-constriction. In high leveltoxicity—cardiac arrhythmia, tachycardia

Kidney—diabetic action. ↑ renal blood supply and GFR. ↓ Na+ and other electrolyte absorption.

Skeletal muscle—diaphragmatic contraction is stimulated. ↓ fatigue of the skeletal muscle. Causes tremor.

GIT—↑ gastric acid secretion.

 

Loading dose—the dose which is given initially to attain a desired level in the plasma

Maintenance dose—to maintain the level

 

Adverse effects of Theophylline—

§    Therapeutic index is very low

§    Nausea, vomiting

§    Therapeutic blood level is 0.2-2mg/100ml

v     nausea, vomiting may appear in <2mg/100ml

v     convulsion in >4mg/100ml

v     cardiac arrhythmia may occur

(total dose should be given at least in 20min)

 

Indications—Bronchial asthma, COPD, apnea / preterm infant apnea.

 

Comparison between Salbutamol and Aminophylline as anti-asthma drug—

Points

Salbutamol

Aminophylline

Mechanism of Action

Selective stimulation of the β2 adrenoceptor of bronchial smooth muscle and causes bronchodilatation

Competitive inhibition of the bronchial adenosine receptors and causes bronchodilatation

Onset of action

Slower

Rapid

Duration of action

Longer

Shorter

Therapeutic index

Larger

Narrow

In acute asthma

Suitable in inhaler form

Suitable in IV form

Drug of choice

Mildest asthmatic with intermittent attack

Severe acute asthma and chronic asthma

Side effects

Tremor, headache, cardiac arrhythmia

Headache, vomiting

 

Anticholinergic drugs—Atropine is the prototype, cheap, causes bronchodilatation.

 

Mechanism of Action—

    Vagal nerve innervation→ acetyle choline→ muscarinic receptor→ bronchoconstriction

Anticholinergics act here by inhibiting the muscarinic receptors ↑

 

Adverse effects of Atropine—

o  Can cross the BBB and go to the CNS.

o  Mouth dryness.

o  Destroy the cilia of the respiratory tract—prone to infection.

 

Ipratropium Bromide (atropine methyl nitrate)—

Advantages—

o  Can reach in high doses in the bronchial airway.

o  Do not readily enter CNS.

o  Has less systemic effect.

o  Useful adjuvant to other drugs like Salbutamol

Disadvantages—

o  Cannot be given orally, only inhalation (expensive)

o  Bronchodilatation effect is not great

o  Full effect after long use

 

Anti-inflammatory drugs—

Glucocorticoids—

o  Phospholipase A2 blocker

o  Acts by inhibiting the PG secretion, no leukotriens secretion

o  Decrease permeability to capillaries—↓ exudation and transudation

 

Corticosteroids —anti-inflammatory drug (inhalation, tablet, IV).

Betamethasone

Beclomethasone

Inhaler / long acting

Prednisone

Prednisolone

Tablet / intermediate acting

Hydrocortisone

IV / short acting

 

 

 

 

 

 

*** cannot suddenly stop these drugs, tapering of the dose to avoid withdrawal syndrome and to avoid precipitating acute problems.

 

Function of Corticosteroids—

↑ neutrophil, RBC, platelet

↓ eosinophil, lymphocyte, monocyte

 

Monocyte→ IL1, TNF, Pyrogen

IL1→ ↑ fever, PAF, PG, Neutrophil and ↓ Lymphocytes

Lymphocyte→ IL2

IL2→ CD8, T-cell

T-Lymphocyte→ TNFα

(responsible for septicemic shock syndrome)

TNF→ Cytokinin

 

Mast cell stabilizer—Na-chromoglycate, Nedocromil-Na

o  Reduces the hyper-reactivity of the bronchial tree

o  Prevention of another attack

o  Prevents eosinophilic and neutrophilic chemotaxis

o  Stabilizes the mast cell of the bronchial airway

o  They should be given only by inhalation

o  Also reduce the irritation of airway nerve endings

o  No bronchodilator effects

o  As tablets in advance to minimize or reduce risk

 

Indication—

o  Prophylaxis in allergic bronchial asthma.

o  Allergic rhinitis

o  Allergic conjunctivitis

 

Leukotriens pathway inhibitor—leukotriens are produced from the action of 5-lipoxegenase on arachidonic acid by variety of cells like basophiles, eosinophils, monocytes etc.

 

They are of 2 categories—

o  5-lipoxegenase enzyme inhibitor (Zileuton)

o  LTD4 receptor antagonist (Zafirleukast, Monteleukast)

*** these drugs are effective when given orally and have important role in aspirin induced asthma.

 

Side-effects of inhalation—

a. Oropharyngeal candediasis (steroid causes immuno-suppresion)—advised for frequent mouthwash

b. Patient may have harshness / coarse voice

 

Side-effects of tablet—

Peptic ulcer, glaucoma, osteoporosis, hypertension, aggravation of diabetes mellitus.

 

Treatment steps—

1. Occasional use of short acting β2 agonists

2. Low dose inhaled steroids (or other anti-inflammatory drugs)

3. High dose of inhaled steroid or low dose inhaled steroid plus long acting inhaled β2 agonist

4. High dose inhaled steroids and regular bronchodilators

5. Addition of regular oral steroid therapy

 

Management of Acute Severe Asthma—the aim of management is to prevent death, to restore pulmonary function, to maintain optimum pulmonary function and to prevent early relapse.

 

Status Asthmaticus—acute emergency condition.

 

Immediate treatment in “Status Asthmaticus”—

1.      Oxygen—given at highest concentration possible

2.      High dose of inhaled β2 agonist—Salbutamol 2.5-5 mg as nebulizer and repeated every 30min

3.      Systemic corticosteroids—IV hydrocortisone or oral prednisolone (if patient can swallow)

4.      If severity persists then additional measurements used

5.      Monitoring of the patient  

 

***drug should not be used in bronchial asthma—Sedative.