PART-B — Complete Answers

Q.5 — Classify NSAIDs; Discuss Mechanisms, Pharmacological Actions, Adverse Effects, Therapeutic Uses, and Contraindications of Aspirin (4+8 = 12)

Classification of NSAIDs

• Meloxicam, nimesulide, diclofenac (at therapeutic doses)

• Celecoxib, etoricoxib, parecoxib, rofecoxib (withdrawn)

Aspirin - Full Profile

1. Mechanism of Action

• Prostaglandins (PGs) - mediators of inflammation, pain, fever
• Thromboxane A2 (TXA2) - platelet aggregation promoter
• Prostacyclin (PGI2) - vasodilator and platelet aggregation inhibitor

2. Pharmacological (Three Major) Actions

• Inhibits COX → reduces PG synthesis at the site of inflammation
• Modulates aspects of inflammation mediated by prostaglandins
• Anti-inflammatory doses: 4-6 g/day (high doses)
• Does not arrest disease progression in arthritis

• PGE2 sensitizes peripheral nerve endings to bradykinin, histamine, and other pain mediators
• By decreasing PGE2 synthesis, pain sensation is reduced (peripheral mechanism)
• Central analgesic component via hypothalamic mechanisms
• Effective for mild-to-moderate pain (headache, myalgia, arthralgia)

• Fever results from PGE2 acting on the anterior hypothalamic thermoregulatory center, raising the set-point
• Aspirin inhibits PGE2 synthesis, resets the hypothalamic set-point to normal
• Promotes heat loss by peripheral vasodilation and sweating

• Irreversibly inhibits COX-1 in platelets → suppresses TXA2 → reduces platelet aggregation
• Used at low doses (75-150 mg/day) for cardiovascular prevention

3. Therapeutic Uses

4. Adverse Effects

• Gastrointestinal: Dyspepsia, nausea, gastric mucosal erosion, peptic ulceration, GI bleeding (due to loss of PGE2-mediated cytoprotection of gastric mucosa)
• Tinnitus and hearing loss: Dose-related; occurs at high anti-inflammatory doses (salicylism: tinnitus, dizziness, headache, sweating)
• Renal: Fluid retention, renal insufficiency, acute renal failure (especially in volume-depleted patients)
• Hypersensitivity: Aspirin-induced asthma/urticaria (up to 10% of asthmatics); related to shunting of arachidonic acid toward leukotriene pathway
• Platelet dysfunction: Prolonged bleeding time
• Reye's syndrome: Potentially fatal hepatic encephalopathy in children with viral illness (influenza, chickenpox) - aspirin must NOT be given to children
• Metabolic acidosis: Salicylate toxicity in overdose
• Hepatotoxicity: Rare; with prolonged high-dose use

5. Contraindications

• Children/teenagers with chickenpox or flu-like illness (Reye's syndrome risk)
• Active peptic ulcer disease or GI bleeding
• Aspirin-sensitive asthma or urticaria
• Bleeding disorders or concurrent anticoagulant therapy
• Severe hepatic or renal insufficiency
• Last trimester of pregnancy (premature closure of ductus arteriosus, inhibition of labor)
• Gout (low doses raise serum urate)
• Concurrent use with methotrexate (aspirin displaces it from protein binding, increasing toxicity)

Q.6 — Short Notes (4 × 3 = 12)

(a) Atropine

• Heart: Increases heart rate (tachycardia) by blocking M2 receptors - SA node increases firing rate
• Smooth muscle: Reduces tone in GI, urinary bladder, bronchi (bronchodilation)
• Exocrine glands: Inhibits salivation, lacrimation, sweating, reduces gastric acid and bronchial secretions
• Eye: Mydriasis (pupil dilation), cycloplegia (paralysis of accommodation), increased intraocular pressure
• CNS: At low doses, mild sedation; at high doses, restlessness, hallucinations

• Preoperative medication (reduce secretions)
• Bradycardia and heart block (emergency cardiac use)
• Organophosphate / cholinergic poisoning (primary antidote)
• Peptic ulcer disease (reduces acid secretion - now largely replaced by PPIs)
• Ophthalmology: mydriasis, cycloplegia for fundoscopy and refraction
• Antispasmodic (renal/biliary colic in combination)
• Motion sickness (with hyoscine/scopolamine)

• Closed-angle glaucoma (can precipitate acute attack by dilating pupil, blocking iris drainage)
• Prostatic hypertrophy (urinary retention)
• Paralytic ileus or pyloric stenosis
• Myasthenia gravis
• Tachycardia / thyrotoxicosis

(b) Calcium Channel Blockers (CCBs)

• Dihydropyridines (DHPs): Nifedipine, amlodipine, felodipine - primarily vascular smooth muscle
• Non-DHPs - Phenylalkylamines: Verapamil - primarily cardiac
• Non-DHPs - Benzothiazepines: Diltiazem - both cardiac and vascular

• Vascular smooth muscle relaxation → vasodilation → reduced peripheral resistance → reduced BP
• Reduced cardiac contractility (negative inotropy) - especially verapamil
• Slowed SA and AV node conduction (negative chronotropy and dromotropy) - verapamil and diltiazem

• Hypertension (all CCBs)
• Angina pectoris - stable and vasospastic (Prinzmetal's)
• Supraventricular tachyarrhythmias - SVT, atrial flutter/fibrillation (verapamil, diltiazem)
• Raynaud's disease / phenomenon (nifedipine)
• Hypertrophic cardiomyopathy (verapamil)
• Subarachnoid hemorrhage - nimodipine (cerebral vasospasm prevention)
• Migraine prophylaxis (verapamil)

• DHPs: Reflex tachycardia, flushing, headache, peripheral edema, gingival hyperplasia (nifedipine)
• Verapamil/diltiazem: Bradycardia, AV block, constipation (verapamil), cardiac depression

• Verapamil + diltiazem: Pre-existing bradycardia, AV block, sick sinus syndrome, heart failure
• Cardiogenic shock
• Verapamil is contraindicated with beta-blockers (risk of complete heart block)

(c) Chelating Agents

(d) Corticosteroids

1. Bind to intracellular glucocorticoid receptors (GCRs) → receptor-ligand complex enters nucleus
2. Upregulates anti-inflammatory genes (lipocortin/annexin-1) → inhibits phospholipase A2 → reduces arachidonic acid release → fewer prostaglandins, leukotrienes, and thromboxanes
3. Inhibits transcription factors NF-kB and AP-1 → suppresses pro-inflammatory cytokines (IL-1, IL-2, IL-6, TNF-alpha)
4. Reduces vascular permeability, leukocyte migration, and phagocytosis
5. Causes lymphocytopenia, eosinopenia

• Allergic disorders: Anaphylaxis, angioedema, urticaria, allergic rhinitis
• Respiratory: Asthma, COPD exacerbations, croup
• Autoimmune/rheumatic: Rheumatoid arthritis, SLE, vasculitis, polymyalgia rheumatica
• Inflammatory bowel disease: Crohn's disease, ulcerative colitis
• Dermatology: Eczema, psoriasis, dermatitis
• Endocrine: Addison's disease (replacement), congenital adrenal hyperplasia, thyroid storm
• Neurological: Raised intracranial pressure (dexamethasone), multiple sclerosis relapses
• Organ transplantation: Immunosuppression (with other agents)
• Malignancy: Lymphomas, leukemias (palliative)
• Septic shock (high-dose, though evidence is debated)

• Hyperglycemia/diabetes, weight gain, central obesity
• Osteoporosis, avascular necrosis of femoral head
• Hypertension, sodium/water retention
• Immunosuppression, increased infection risk
• Peptic ulceration (especially combined with NSAIDs)
• Cataracts, glaucoma
• Growth suppression in children
• Adrenal suppression (never stop suddenly - risk of Addisonian crisis)
• Psychiatric: Euphoria, psychosis, insomnia

Q.7(a) — Why Few Drugs Administered Orally Remain Therapeutically Ineffective? (3 × 2 = 6)

1. First-Pass Metabolism (Hepatic First-Pass Effect)

• Examples: Lignocaine/lidocaine (>90% first-pass, given IV), GTN/nitroglycerin (given sublingually or transdermally to bypass liver), morphine (significant first-pass, oral dose must be higher than IV), propranolol, verapamil - Katzung's Basic & Clinical Pharmacology, 16th Ed.

2. Poor Gastrointestinal Absorption

• Poor lipid solubility: Highly polar/ionized drugs cannot cross the lipid bilayer of intestinal epithelium (e.g., aminoglycosides - given IM/IV for systemic infections)
• Large molecular size: Macromolecules like heparin, insulin, and monoclonal antibodies cannot be absorbed through the GI mucosa
• Drug instability in GI tract: Drugs degraded by gastric acid (e.g., benzylpenicillin) or digestive enzymes (e.g., insulin, which is a polypeptide digested to amino acids in the gut)

3. P-Glycoprotein (P-gp) Efflux Pump

• P-gp in intestinal epithelial cells actively pumps absorbed drug back into the GI lumen, reducing net absorption (e.g., digoxin, some HIV antivirals, taxanes)

4. GI Mucosal Metabolism

• The GI mucosal cells themselves contain CYP450 enzymes (especially CYP3A4) that pre-systemically metabolize drugs before they even reach the portal vein, further reducing bioavailability

5. Altered GI Motility and Physiology

• Rapid transit (diarrhea) reduces contact time with absorptive surface
• Delayed gastric emptying (ileus, gastroparesis) alters rate and site of absorption
• Achlorhydria, surgical resection of bowel, food-drug interactions (e.g., tetracyclines chelated by milk/Ca²+), and drug-drug interactions all further reduce effective oral bioavailability

Summary Table