2 Pathophysiology and Pharmacology of asthma

How is the immediate phase bronchospasm in asthma treated?

Bronchodilators:

• β2 agonists → relax airway smooth muscle

• Muscarinic antagonists → block bronchoconstriction

• Xanthines → bronchodilation via multiple mechanisms

What is the primary action of β2 adrenergic agonists in asthma?

• Bronchodilation

• Directly act on β2 receptors on bronchial smooth muscle → smooth muscle relaxation

• Mimic circulating adrenaline

What are additional effects of β2 adrenergic agonists?

• Decrease mucus secretion

• May inhibit mediator release from mast cells

What are the types and duration of inhaled β2 agonists?

• Short-acting: Salbutamol → lasts 4–6 hours

• Long-acting: Salmeterol → lasts ~12 hours

What are common side effects of inhaled β2 agonists?

• Tolerance (reduced response over time)

• Tremor

What is the stepwise mechanism of action of salbutamol and salmeterol on β2 adrenoceptors?

Step 1: Drug binds to β2 adrenoceptor (Gs-protein coupled) on bronchial smooth muscle
Step 2: Gs protein activated → stimulates adenylyl cyclase
Step 3: Adenylyl cyclase converts ATP → cAMP
Step 4: cAMP activates PKA (protein kinase A)
Step 5: PKA phosphorylates target proteins → smooth muscle relaxation → bronchodilation

What are the main effects of β2 adrenergic agonists in asthma? summary

• Direct action on β2 receptors on bronchial smooth muscle (mimics adrenaline)

• Increases cAMP → activates PKA

• Smooth muscle relaxation → bronchodilation

• Decreases mucus secretion

How do muscarinic antagonists cause bronchodilation?

Step 1: Block M3 receptors on bronchial smooth muscle
Step 2: Inhibit Gq → PLC → IP3/DAG → ↑Ca²⁺ pathway
Step 3: Prevent parasympathetic-mediated bronchoconstriction → bronchodilation.

How do muscarinic antagonists affect mucus secretion?

• Block M3-mediated mucus secretion from airway glands

• Result: decreased mucus production

What is an example of a muscarinic antagonist and how is it administered?

• Example: Ipratropium

• Given by inhalation

• Relatively non-selective but poor systemic absorption → few systemic side effects

How do Xanthines cause bronchodilation?

Step 1: Block (PDE) enzymes, especially PDE III and IV
Step 2: cAMP levels increase
Step 3: Smooth muscle relaxation → bronchodilation

How do Xanthines exhibit anti-inflammatory properties?

• PDE enzymes are involved in inflammatory processes

• Inhibition by Xanthines reduces inflammation in airways

Give an example of a Xanthine and its administration.

• Example: Theophylline

• Well absorbed orally

• Narrow therapeutic window → careful dosing required

What are the main side effects of Xanthines?

• Chronotropic / inotropic effects → tachycardia

• CNS stimulation → insomnia, tremor

• GI disturbances → nausea, vomiting

What is used to target the delayed inflammatory phase in asthma?

Glucocorticoids

How do glucocorticoids suppress inflammation in asthma?

• Inhibit transcription of phospholipase A2 → reduces production of inflammatory mediators:

  • LTC4, LTD4 → spasmogens

  • LTB4 → chemotaxins

  • PGE2, PGI2, cytokines → vasodilation & immune cell stimulation

• Suppress overall inflammatory response

What are examples of glucocorticoids used in asthma and how are they given?

• Beclomethasone → inhalation

• Prednisolone → oral (short-term use)

• Hydrocortisone → injection

• Effective in treating the delayed inflammatory phase

What are the side effects of glucocorticoids in asthma treatment?

• Oral candidiasis (mainly if inhaled)

• Typical glucocorticoid effects (Cushing-like syndrome) are less common due to minimal systemic absorption

What drugs target both the immediate and delayed phases of asthma?

• Chromolyn

• Cysteinyl leukotriene (CysLT₁) receptor antagonists

How does Sodium Cromolyn work in asthma/allergic conditions?

• Mast cell stabiliser → prevents release of histamine and other inflammatory mediators

• Inhibits airway hyper-responsiveness by depressing neuronal reflexes triggered by irritant receptors

What is the main clinical use of Sodium Cromolyn?

• Mainly used for allergic rhinoconjunctivitis

What are CysLT₁ receptor antagonists and their role in asthma?

• Block leukotriene-induced bronchospasm

• Target both immediate and delayed phases

• Effective for mild persistent asthma

• Less effective than glucocorticoids

• Example: Montelukast

How can β-adrenoreceptor antagonists affect patients with respiratory disease?

• Can precipitate severe or fatal asthma

• Non-selective β-blockers like propranolol are risky

• Hypertensive patients: prefer β1-selective blockers (e.g., atenolol)

How can ACE inhibitors affect patients with respiratory disease?

• Can induce cough

• Example: Captopril used for hypertension

• Mechanism: bradykinin accumulation

How can NSAIDs affect patients with respiratory disease?

• Can precipitate asthma attacks

• Example: Aspirin

• Mechanism: may increase leukotriene production