ANS Pharmacology - MBBS 2nd Year Reasoning Questions

Based on KD Tripathi's "Essentials of Medical Pharmacology"

SECTION 1 - CHOLINERGIC (PARASYMPATHOMIMETIC) DRUGS

• (a) M3 muscarinic receptors (on smooth muscle) and M2 (on heart for bradycardia).
• (b) Pilocarpine - direct-acting cholinomimetic alkaloid. It is a partial agonist at muscarinic receptors (both M2 and M3).
• (c) At therapeutic concentrations, pilocarpine's vasodilatory effect (M3 on vessels) is offset by reflex tachycardia and the drug does not accumulate enough systemically to cause hypotension when used as eye drops. However, systemic absorption from eye drops CAN cause cholinergic symptoms (hence salivation, sweating).

• (a) Organophosphate (OP) poisoning. OPs irreversibly inhibit acetylcholinesterase (AChE) by phosphorylating its serine residue at the esteratic site. This leads to accumulation of ACh at all cholinergic synapses.
• (b) ACh accumulates at:
  • Muscarinic synapses (postganglionic parasympathetic + sweat glands) → SLUDGE: Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis + miosis, bradycardia, bronchospasm.
  • Nicotinic synapses (NMJ + autonomic ganglia) → Muscle fasciculations, weakness, paralysis, hypertension (ganglionic stimulation).
  • CNS → Anxiety, convulsions, coma.
• (c) Treatment:
  • Atropine (high doses, IV) - blocks muscarinic effects (the life-threatening ones: bronchospasm, secretions, bradycardia). Endpoint: drying of secretions, NOT pupil size.
  • Pralidoxime (2-PAM) - reactivates phosphorylated AChE by nucleophilic attack, breaking the OP-enzyme bond. It must be given before "aging" occurs (irreversible conformational change of the OP-enzyme complex, typically within 24-48 hours). After aging, pralidoxime is useless.
  • Diazepam for convulsions.

• (a) Neostigmine inhibits AChE at the NMJ - ACh accumulates, prolonging and intensifying its action at nicotinic NMJ receptors. This improves neuromuscular transmission in MG where antibodies destroy nicotinic receptors.
• (b) Neostigmine is a quaternary ammonium compound - it does NOT cross the blood-brain barrier and does NOT penetrate the cornea well. Physostigmine is a tertiary amine that penetrates the eye and CNS.
• (c) Neostigmine also increases ACh at muscarinic junctions (heart M2 receptor) → bradycardia, increased secretions, cramps. Atropine (or glycopyrrolate) is co-administered to block muscarinic side effects without affecting the desired nicotinic action.

SECTION 2 - ADRENERGIC DRUGS

• (a) Epinephrine acts on ALL adrenergic receptors (α1, α2, β1, β2):
  • β2: Bronchodilation (reverses bronchospasm) + decreases mediator release from mast cells.
  • α1: Vasoconstriction → raises BP, reduces mucosal edema (angioedema).
  • β1: Positive inotrope + chronotrope → reverses cardiovascular collapse.
• (b) α1 vasoconstriction raises BP (needed in shock) while β2 bronchodilation opens airways (needed for breathing). These effects are on DIFFERENT organ systems - not opposing in context.
• (c) Low dose epinephrine: β2 > α1 effect on vasculature → peripheral vasodilation → reflex tachycardia + direct β1 tachycardia. High dose: α1 vasoconstriction dominates → BP rises sharply → reflex vagal bradycardia may occur (baroreceptor reflex).

• Low dose (1-3 mcg/kg/min): Stimulates D1 (dopaminergic) receptors → vasodilation of renal and splanchnic vessels → ↑ renal blood flow and GFR → "renal dose dopamine." (Note: clinical benefit of renal protection is now disputed)
• Medium dose (3-10 mcg/kg/min): β1 stimulation dominates → ↑ heart rate, ↑ contractility, ↑ cardiac output. Used in cardiogenic shock.
• High dose (>10 mcg/kg/min): α1 stimulation dominates → vasoconstriction → used in septic shock to raise peripheral resistance.

SECTION 3 - ADRENERGIC BLOCKERS (α AND β)

• (a) Prazosin is a selective α1-blocker. It blocks postsynaptic α1 receptors on arterioles and venules → vasodilation → ↓ peripheral resistance → ↓ BP. It does NOT block presynaptic α2 receptors.
• (b) First-dose syncope: the initial dose causes sudden vasodilation (especially venous) → postural hypotension → cerebral hypoperfusion → syncope. The reflex tachycardia is limited because NE feedback via presynaptic α2 (unopposed) is intact. Prevented by: starting with a low bedtime dose.
• (c) Phentolamine is a non-selective α-blocker (blocks BOTH α1 and α2). Blocking presynaptic α2 removes the feedback inhibition of NE release → excessive NE release → reflex tachycardia + palpitations. Prazosin's selectivity for α1 spares α2, so reflex tachycardia is minimal. Hence, prazosin is better tolerated long-term.

• (a) Propranolol is a non-selective β-blocker (β1 + β2). Bronchial smooth muscle tone is normally kept low by β2 receptor activation (by circulating adrenaline). Blocking β2 → bronchoconstriction → bronchospasm, especially dangerous in asthma/COPD.
• (b) Atenolol/Metoprolol/Bisoprolol are cardioselective β1-blockers. They preferentially block β1 (heart) and spare β2 (lungs). BUT: cardioselectivity is relative, not absolute - at higher doses, they lose selectivity and can still cause bronchospasm. Hence, beta-blockers are still relatively contraindicated in asthma.
• (c) Absolute contraindications to propranolol:
  1. Bronchial asthma / COPD
  2. Second or third degree AV block
  3. Prinzmetal's angina (vasospastic angina - β-blockade allows unopposed α-mediated coronary vasospasm)
  4. Pheochromocytoma (without prior α-blockade - causes hypertensive crisis)
  5. Acute decompensated heart failure

SECTION 4 - GANGLION & NEUROMUSCULAR JUNCTION

• (a) Succinylcholine is a depolarizing neuromuscular blocking agent (nicotinic NMJ agonist). It initially ACTIVATES the receptor → ion channel opens → depolarization → unsynchronized muscle contractions (fasciculations). Then the channel cannot repolarize (unlike ACh which is rapidly hydrolyzed, succinylcholine persists) → sustained depolarization → receptor desensitization → flaccid paralysis.
• (b) Phase I block (depolarizing block): Succinylcholine binds to nicotinic NMJ receptor, opens Na+ channel → membrane stays depolarized → end plate remains refractory to further stimulation → flaccid paralysis. Characteristics: train-of-four - no fade; tetanic stimulation - no fade; NOT reversed by neostigmine.
• (c) Phase II block (desensitization block): With prolonged or high dose succinylcholine - receptors undergo conformational change (desensitization) → behave like non-depolarizing block. Characteristics: fade on tetanic stimulation; neostigmine NOW reverses it. Seen after infusion or repeated doses.
• (d) Burn patients and those with denervation injuries/crush injury have up-regulation of extrajunctional nicotinic receptors throughout the muscle membrane. Succinylcholine causes massive K+ efflux from ALL these receptors → life-threatening hyperkalemia → cardiac arrest.

• (a) Trimethaphan blocks nicotinic receptors at autonomic ganglia (both sympathetic and parasympathetic). By blocking all ganglionic transmission, it abolishes ALL peripheral autonomic outflow.
• (b) Since BOTH sympathetic and parasympathetic ganglia are blocked simultaneously, every organ is affected: constipation and urinary retention (loss of parasympathetic), severe postural hypotension (loss of sympathetic vasoconstriction), tachycardia (loss of vagal tone predominates) or bradycardia depending on balance, mydriasis, dry mouth, impotence. They are pharmacologically dirty - no organ is spared.
• (c) Replaced by safer drugs: sodium nitroprusside for controlled hypotension, modern antihypertensives for BP control. The adverse effect profile makes them nearly obsolete except in hypertensive emergencies with aortic dissection.

BONUS - HIGH-YIELD COMPARISON QUESTIONS

• β2 → bronchodilation (physiologically opposes bronchoconstriction)
• α1 → vasoconstriction (opposes vasodilation, ↑BP)
• α1 → decreases vascular permeability (opposes edema/urticaria)
• β2 → inhibits further mediator release from mast cells

EXAM TIPS - KD Tripathi Focus Points for ANS