Pharmacology of Respiratory & GIT Drugs
This comprehensive unit covers two major organ systems. The Respiratory section covers drugs for Asthma (bronchodilators, anti-inflammatory agents), COPD (anticholinergics, combination inhalers), expectorants, antitussives, nasal decongestants, and respiratory stimulants. The GIT section covers the pharmacology of antiulcer agents (PPIs, H2 blockers, antacids, cytoprotectives), drugs for constipation and diarrhoea, appetite modulators, digestants, carminatives, and emetics/antiemetics.
Syllabus & Topics
- 1Asthma – Pathophysiology Overview: Asthma is a chronic inflammatory disease of airways characterized by: (1) Airway inflammation (mast cells, eosinophils, T-lymphocytes release inflammatory mediators). (2) Bronchospasm (smooth muscle contraction → airway narrowing). (3) Mucus hypersecretion. (4) Airway hyperresponsiveness (exaggerated bronchoconstriction to triggers). (5) Airway remodeling (chronic structural changes). Treatment targets both bronchoconstriction (relievers/bronchodilators) and inflammation (controllers/anti-inflammatory).
- 2Anti-Asthmatic Drugs – Bronchodilators (β₂-Agonists): Short-acting (SABA): Salbutamol (Albuterol), Terbutaline — for acute relief (‘rescue inhalers’). Onset: 5 min, duration: 4-6 h. Stimulate β₂-adrenoceptors → ↑cAMP → bronchial smooth muscle relaxation. Long-acting (LABA): Salmeterol, Formoterol — for maintenance (NEVER monotherapy, always with ICS). Duration: 12 h. Ultra-LABA: Indacaterol, Vilanterol — 24 h duration (once-daily COPD inhalers). ADR: tremor, tachycardia, hypokalemia.
- 3Anti-Asthmatic Drugs – Anticholinergics & Methylxanthines: Anticholinergics: Ipratropium bromide (short-acting), Tiotropium bromide (long-acting, 24 h). Block M₃ muscarinic receptors → ↓bronchoconstriction + ↓mucus secretion. More important in COPD than asthma. Methylxanthines: Theophylline (Aminophylline = theophylline + ethylenediamine for IV use). MOA: PDE inhibitor (↑cAMP), adenosine receptor antagonist, anti-inflammatory. Narrow therapeutic index (10-20 μg/mL). ADR: nausea, arrhythmias, seizures. Monitor blood levels.
- 4Anti-Asthmatic Drugs – Anti-Inflammatory (Controllers): Inhaled Corticosteroids (ICS): Beclomethasone, Budesonide, Fluticasone — MOST effective controller therapy. ↓inflammation, ↓eosinophils, ↓cytokines, ↓airway hyperresponsiveness. ADR: oral candidiasis, dysphonia (rinse mouth after use). Mast cell stabilizers: Cromoglycate (Cromolyn), Nedocromil — prevent mast cell degranulation. Prophylactic only (no acute relief). Leukotriene modifiers: Montelukast (LT receptor antagonist), Zileuton (5-LOX inhibitor) — oral, add-on therapy for mild asthma. Anti-IgE: Omalizumab — monoclonal antibody against IgE (severe allergic asthma).
- 5COPD Management: COPD = Chronic Obstructive Pulmonary Disease (emphysema + chronic bronchitis). Irreversible airflow limitation. Stepwise therapy: SABA/SAMA PRN → LABA or LAMA → LABA + LAMA → LABA + LAMA + ICS. Key drugs: Tiotropium (LAMA — cornerstone of COPD), Indacaterol (ultra-LABA), Roflumilast (PDE4 inhibitor — reduces exacerbations). O₂ therapy for hypoxia. Smoking cessation is the ONLY intervention that slows disease progression.
- 6Expectorants & Mucolytics: Expectorants: ↑volume of respiratory tract secretions → easier expectoration. Guaifenesin (most common OTC expectorant), Potassium iodide, Ammonium chloride. Steam inhalation is also expectorant. Mucolytics: break down mucus structure. N-Acetylcysteine (NAC — breaks disulfide bonds in mucus glycoproteins → ↓viscosity; also acetaminophen poisoning antidote), Bromhexine, Ambroxol (active metabolite of Bromhexine).
- 7Antitussives: Suppress cough reflex. Opioid antitussives: Codeine (most effective antitussive, but addictive — Schedule H), Pholcodine, Dextromethorphan (d-isomer of methylated codeine analog — no analgesic/addictive properties, OTC). Non-opioid: Noscapine (opium alkaloid but NO opioid activity), Benzonatate (local anesthetic that numbs stretch receptors in lung). Cough should NOT be suppressed when productive (with sputum) — only dry/irritating cough.
- 8Nasal Decongestants & Respiratory Stimulants: Decongestants: α₁-adrenergic agonists → vasoconstriction of nasal mucosal blood vessels → ↓edema → ↓congestion. Topical: Oxymetazoline, Xylometazoline (fast onset, BUT rhinitis medicamentosa/rebound congestion after >3-5 days). Systemic: Pseudoephedrine, Phenylephrine (slower onset, no rebound). Respiratory Stimulants (Analeptics): Doxapram (stimulates peripheral chemoreceptors + medullary respiratory center), Nikethamide, Caffeine citrate (neonatal apnea). Limited clinical use — mechanical ventilation is preferred.
- 9Antiulcer Agents – Pathophysiology: Peptic ulcer = erosion of GI mucosa due to imbalance between aggressive factors (HCl, pepsin, H. pylori, NSAIDs, stress) and protective factors (mucus, HCO₃⁻, prostaglandins, mucosal blood flow). H. pylori causes ~80% duodenal and ~60% gastric ulcers. Goal: ↓acid secretion + eradicate H. pylori + protect mucosa.
- 10Antiulcer – Proton Pump Inhibitors (PPIs): Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole. MOA: irreversibly inhibit H⁺/K⁺-ATPase (proton pump) — the final common pathway of acid secretion in parietal cells. Most potent acid suppressants (↓acid secretion ~95%). Prodrugs activated in acidic environment of parietal cell canaliculus. ADR: ↓B12, ↓Mg²⁺ (long-term), ↑fracture risk, C. difficile infection. H. pylori triple therapy: PPI + Clarithromycin + Amoxicillin (or Metronidazole) × 14 days.
- 11Antiulcer – H₂ Blockers, Antacids & Cytoprotectives: H₂ blockers: Ranitidine, Famotidine — competitive antagonists of histamine H₂ receptors on parietal cells → ↓cAMP → ↓acid secretion (~70%). Less potent than PPIs. Antacids: neutralize secreted HCl. Al(OH)₃ (constipating), Mg(OH)₂ (laxative), CaCO₃ (milk-alkali syndrome). Often combined (Maalox = Al + Mg). Cytoprotectives: Sucralfate (forms protective barrier over ulcer base in acidic pH), Misoprostol (PGE₁ analog — ↑mucus, ↑HCO₃⁻, ↓acid; prevents NSAID-induced ulcers; abortifacient), Colloidal Bismuth Subcitrate (coats ulcer + kills H. pylori).
- 12Laxatives & Antidiarrheals: Laxatives: Bulk-forming (Ispaghula/Psyllium — absorbs water → ↑bulk → ↑peristalsis), Osmotic (Lactulose, PEG — retain water in lumen), Stimulant (Bisacodyl, Senna — stimulate myenteric plexus → ↑motility), Stool softeners (Docusate — surfactant), Lubricant (Liquid paraffin). Antidiarrheals: Loperamide (μ-opioid agonist in gut wall → ↓motility, ↓secretion; does NOT cross BBB → no CNS effects), Diphenoxylate (+ Atropine = Lomotil), ORS (Oral Rehydration Solution — MOST important intervention), Racecadotril (enkephalinase inhibitor → antisecretory).
- 13Appetite Modulators, Digestants & Carminatives: Appetite stimulants: Cyproheptadine (5-HT + H₁ antagonist), Megestrol acetate (progestational, cancer cachexia). Appetite suppressants (Anorexiants): Sibutramine (withdrawn — CV risk), Orlistat (pancreatic lipase inhibitor → ↓fat absorption), Lorcaserin (5-HT₂C agonist). Digestants: Pancreatin (pancreatic enzyme supplement — lipase, amylase, protease), Pepsin, Diastase. Carminatives: relieve flatulence — Simethicone (antifoaming agent — breaks gas bubbles), Peppermint oil.
- 14Emetics & Anti-Emetics: Emetics: Ipecac syrup (now rarely used), Apomorphine (D₂ agonist at CTZ). Anti-emetics: (1) 5-HT₃ antagonists: Ondansetron, Granisetron — most effective for chemotherapy-induced nausea. (2) D₂ antagonists: Metoclopramide (also prokinetic — ↑gastric emptying), Domperidone (does not cross BBB → no extrapyramidal effects), Prochlorperazine. (3) NK₁ antagonists: Aprepitant — for delayed chemotherapy-induced emesis. (4) Antihistamines: Dimenhydrinate, Meclizine — for motion sickness. (5) Anticholinergics: Scopolamine patch — motion sickness. (6) Cannabinoids: Dronabinol — chemotherapy-induced. (7) Corticosteroids: Dexamethasone — adjunct for chemotherapy-induced.
Learning Objectives
Exam Prep Questions
Q1. Why Are PPIs More Effective Than H₂ Blockers?
Proton pump inhibitors such as Omeprazole inhibit the gastric proton pump H+ K+ ATPase located in the parietal cells of the stomach. This enzyme represents the final common step in gastric acid secretion, regardless of the stimulus (histamine, acetylcholine, or gastrin). By irreversibly blocking this pump, PPIs suppress about 90–95% of gastric acid production, and acid secretion resumes only after new enzyme molecules are synthesized.
In contrast, H2 receptor antagonists such as Ranitidine block only the histamine-mediated pathway of acid secretion by inhibiting Histamine H2 receptor. They do not prevent acid secretion stimulated by gastrin or acetylcholine, and their inhibition is reversible. As a result, H₂ blockers suppress about 60–70% of acid secretion, making PPIs significantly more effective.
Q2. Why Should SABAs Not Be Used as Monotherapy for Asthma?
Short acting beta 2 agonists such as Salbutamol provide rapid bronchodilation by stimulating Beta 2 adrenergic receptor in airway smooth muscle. However, they only relieve symptoms and do not treat the underlying airway inflammation that characterizes asthma.
Frequent use of SABA alone may lead to worsening airway inflammation, increased airway hyperresponsiveness, development of tolerance to β₂ agonists, and a higher risk of severe or fatal asthma attacks. Modern asthma management guidelines recommend the use of Inhaled corticosteroids such as Fluticasone as controller therapy to suppress airway inflammation, with SABAs used only for rapid symptom relief.
Q3. What Is the Difference Between Loperamide and Diphenoxylate?
Loperamide and Diphenoxylate both act as μ-opioid receptor agonists in the intestinal wall to reduce gastrointestinal motility and control diarrhea.
However, loperamide does not significantly cross the blood–brain barrier because it is actively transported out of the central nervous system by P glycoprotein. Therefore, it produces minimal central nervous system effects and has very low abuse potential, allowing it to be sold over the counter.
Diphenoxylate, on the other hand, can cross the blood–brain barrier, which creates potential for CNS effects and abuse. For this reason, it is combined with Atropine in the formulation Lomotil. The atropine produces unpleasant anticholinergic side effects at high doses, discouraging misuse.
Q4. What Is Rhinitis Medicamentosa?
Rhinitis medicamentosa is a condition of rebound nasal congestion caused by prolonged use of topical nasal decongestants such as Oxymetazoline or Xylometazoline. These drugs initially relieve congestion by causing vasoconstriction of nasal blood vessels. However, continuous use for more than about 3–5 days leads to mucosal ischemia and reduced receptor responsiveness.
When the drug effect wears off, the nasal mucosa undergoes reactive vasodilation and swelling, resulting in worse congestion than before. Patients often respond by using the spray more frequently, creating a vicious cycle. Treatment involves discontinuing the decongestant and using intranasal corticosteroids such as Fluticasone to reduce inflammation and restore normal nasal function.