VSAQs - Pharmacology Answers

1. *** Mechanism of Action of a Miotic with Examples

• Direct-acting miotics (e.g., Pilocarpine, Carbachol): Stimulate muscarinic (M3) receptors on the sphincter pupillae → pupillary constriction. Also stimulate the ciliary muscle → increased aqueous drainage through the trabecular meshwork → lowers IOP.
• Indirect-acting miotics (e.g., Physostigmine, Echothiophate): Inhibit acetylcholinesterase → accumulation of ACh at muscarinic receptors → sustained stimulation of sphincter pupillae → miosis.

• Direct: Pilocarpine, Carbachol, Bethanechol
• Indirect (anticholinesterases): Physostigmine (reversible), Echothiophate (irreversible), Neostigmine

2. * 6 Ganglionic Blocking Agents

3. ***** Drugs Causing Mydriasis Without Cycloplegia & Mydriasis With Cycloplegia - Explain Difference

Mydriasis WITHOUT Cycloplegia:

• Sympathomimetics: Phenylephrine, Adrenaline, Cocaine, Hydroxyamphetamine
• Mechanism: Stimulate alpha-1 adrenoceptors on the dilator pupillae (radial muscle) → pupillary dilation. The ciliary muscle (which controls accommodation) has no adrenergic innervation, so accommodation is not affected - no cycloplegia.

Mydriasis WITH Cycloplegia:

• Anticholinergics (Antimuscarinics): Atropine, Homatropine, Cyclopentolate, Tropicamide, Scopolamine
• Mechanism: Block muscarinic (M3) receptors on BOTH:
  • Sphincter pupillae → loss of pupillary constriction → mydriasis
  • Ciliary muscle → paralysis of accommodation → cycloplegia (loss of near-vision)

Key Difference:

4. ***** Pharmacological Basis of Dale's Vasomotor Reversal & Dale's Vasomotor Re-reversal

Dale's Vasomotor Reversal:

• Normal response to Adrenaline (Epinephrine): IV adrenaline causes a rise in BP due to alpha-1 (vasoconstriction) + beta-1 (increased cardiac output) effects.
• After giving an alpha-blocker (e.g., Ergotamine, Phentolamine, Phenoxybenzamine), re-administration of adrenaline causes a fall in BP - this is the Vasomotor Reversal.
• Mechanism: Alpha-blockers selectively block alpha-1 mediated vasoconstriction. The beta-2 vasodilatory effect of adrenaline is now unopposed → net vasodilation → BP falls. This is also called "Epinephrine reversal" or Dale's phenomenon.

Dale's Vasomotor Re-reversal:

• After vasomotor reversal is established (alpha-blocked state), a beta-blocker is given.
• Now re-administration of adrenaline causes a rise in BP again (re-reversal).
• Mechanism: The beta-blocker blocks beta-2 vasodilation (which was causing the fall in BP). Only the alpha-mediated effects remain; however since alpha is already blocked, the pressor response is actually blunted. More precisely: the beta-2 vasodilatory component is abolished by beta-blockers, restoring the net pressor/neutral direction.

5. *** Rationale Behind Using Dopamine Over Adrenaline in Cardiogenic Shock

1. Increase cardiac output (inotropic support)
2. Maintain adequate perfusion of vital organs (especially kidneys)
3. Avoid excessive peripheral vasoconstriction (which increases afterload and worsens cardiac work)

• Low-to-moderate dose dopamine (2-10 mcg/kg/min) preferentially stimulates D1 receptors → renal and splanchnic vasodilation → maintains urine output and renal perfusion.
• At same doses, beta-1 stimulation increases cardiac output without excessive tachycardia.
• Adrenaline's potent alpha-1 vasoconstriction would increase afterload in an already failing heart, further decreasing cardiac output.
• Adrenaline also causes more pronounced tachycardia, increasing myocardial oxygen demand.

6. ***** Rationale Behind Giving Adrenaline Along with Lignocaine

1. Vasoconstriction (alpha-1 effect): Adrenaline constricts blood vessels at the injection site → reduces systemic absorption of lignocaine → prolongs the duration of local anaesthesia (from ~30-45 min to 60-90+ min).
2. Reduced toxicity: Slower absorption prevents high peak plasma concentrations of lignocaine → lowers the risk of CNS and cardiac toxicity (lignocaine toxicity causes seizures and arrhythmias).
3. Bloodless field: Vasoconstriction reduces bleeding at the surgical site, improving visibility.
4. Allows higher doses: Because absorption is slowed, the safe total dose of lignocaine can be increased (from 3 mg/kg without adrenaline to 7 mg/kg with adrenaline).

7. *** Nasal Decongestants - MoA, Therapeutic Uses & Adverse Effects

Mechanism of Action:

• Alpha-1/alpha-2 adrenoceptor agonists → vasoconstriction of nasal mucosal blood vessels → reduced nasal congestion and oedema.
• Examples: Xylometazoline, Oxymetazoline (topical); Pseudoephedrine (oral); Phenylephrine (topical/oral).

Therapeutic Uses:

• Allergic rhinitis
• Common cold (symptomatic relief)
• Sinusitis
• Before nasal endoscopy or surgery
• Eustachian tube dysfunction

Adverse Effects:

• Local: Rebound congestion (rhinitis medicamentosa) with prolonged use (>3-5 days); nasal dryness, burning, stinging
• Systemic (especially with oral forms): Hypertension, tachycardia, palpitations, anxiety, insomnia, urinary retention (in BPH patients)
• CNS: Headache, dizziness
• Contraindicated in uncontrolled hypertension, MAO inhibitor use, hyperthyroidism

8. *** Ephedrine - MoA, Therapeutic Uses & Adverse Effects

Mechanism of Action:

• Mixed-acting sympathomimetic (both direct and indirect)
• Direct: Stimulates alpha and beta adrenoceptors
• Indirect: Causes release of norepinephrine from adrenergic nerve terminals + inhibits re-uptake
• Effects: increased HR, BP, cardiac output; bronchodilation; CNS stimulation
• Tachyphylaxis develops rapidly with repeated doses (due to depletion of norepinephrine stores)

Therapeutic Uses:

• Hypotension during spinal anaesthesia (preferred due to ability to cross BBB and maintain cardiac output)
• Narcolepsy (historically)
• Nasal decongestant (topical)
• Mild asthma (bronchodilator - largely replaced by salbutamol)
• Myasthenia gravis (adjunct)
• Enuresis

Adverse Effects:

• Hypertension, tachycardia, arrhythmias
• Insomnia, anxiety, restlessness
• Urinary retention
• Tremors
• Tachyphylaxis
• Risk of stroke/MI at high doses

9. *** Phenylephrine - MoA, Therapeutic Uses & Adverse Effects

Mechanism of Action:

• Selective alpha-1 adrenoceptor agonist (minimal beta activity)
• Causes vasoconstriction (raises BP via increased peripheral resistance) without direct cardiac stimulation
• Bradycardia occurs reflexly (baroreceptor-mediated) when BP rises

Therapeutic Uses:

• Hypotension/shock (raises BP via vasoconstriction)
• Hypotension during spinal anaesthesia
• Nasal decongestant (topical/oral)
• Ophthalmology: Mydriasis (without cycloplegia) for fundal examination
• Paroxysmal supraventricular tachycardia (PSVT): Reflex vagal stimulation breaks the arrhythmia (rarely used now)
• Added to local anaesthetics (as vasoconstrictor)

Adverse Effects:

• Hypertension (reflex bradycardia)
• Headache
• Local: nasal dryness, rebound congestion
• Urinary retention (BPH)
• Tissue necrosis if IV extravasation occurs

10. ***** Rationale Behind Using Adrenaline in Anaphylactic Shock

11. *** Rationale for Using Phentolamine or Phenoxybenzamine in Pre-operative Preparation for Pheochromocytoma

Why Alpha-blockers First:

• Phenoxybenzamine (irreversible, non-selective alpha-blocker): Given 10-14 days pre-op. Blocks alpha-1 and alpha-2 receptors → prevents catecholamine-induced vasoconstriction and hypertensive crisis during tumour manipulation.
• Phentolamine (reversible, non-selective): Used IV for acute hypertensive crises during surgery.

Why Not Beta-blockers First:

• If beta-blockers are given BEFORE alpha-blockade, the beta-2 vasodilatory effect is blocked while alpha-1 vasoconstriction remains unopposed → paradoxical severe hypertension. Always alpha-block first, then add beta-blocker if needed (for tachycardia/arrhythmias).

Goals of Pre-op Preparation:

1. Control blood pressure (alpha-blockade)
2. Expand intravascular volume (dehydrated due to chronic vasoconstriction)
3. Prevent intraoperative hypertensive storms
4. Allow safe surgical removal

12. *** Drug Therapy for BPH (Benign Prostatic Hyperplasia)

1. Alpha-1 Adrenoceptor Blockers (Symptomatic relief, first-line):

• Tamsulosin (alpha-1A selective) - most commonly used
• Alfuzosin, Doxazosin, Terazosin (less selective)
• Mechanism: Block alpha-1A receptors on prostatic smooth muscle and bladder neck → relaxation → improved urine flow. Effect seen within days.

2. 5-Alpha Reductase Inhibitors (Reduce prostate size):

• Finasteride (5-ARI type 2), Dutasteride (5-ARI type 1+2)
• Mechanism: Block conversion of testosterone to dihydrotestosterone (DHT, the active androgen) → prostate shrinkage over 3-6 months. Best for large prostates (>40g).
• Adverse effect: Decreased libido, erectile dysfunction, ejaculatory dysfunction, gynaecomastia.

3. Combination Therapy:

• Alpha-blocker + 5-ARI (e.g., Tamsulosin + Dutasteride = COMBAT trial) - more effective than monotherapy for large glands/significant symptoms.

4. PDE-5 Inhibitors:

• Tadalafil - also approved for BPH (relaxes smooth muscle via NO/cGMP pathway).

5. Anticholinergics (for overactive bladder component):

• Tolterodine, Solifenacin - used cautiously.

13. * Treatment of Myasthenic Crisis

Immediate Management:

1. ICU admission + Mechanical ventilation if respiratory failure (FVC < 15-20 mL/kg, unable to protect airway)
2. Plasmapheresis (Plasma exchange): Removes circulating anti-AChR antibodies → rapid improvement within 3-5 sessions. Onset in 24-48 hours.
3. IV Immunoglobulin (IVIg): 2 g/kg over 2-5 days. Modulates immune response. Comparable efficacy to plasmapheresis, onset slightly slower.
4. Cholinesterase inhibitors: Pyridostigmine (oral or via NG tube) - symptomatic. Temporarily withheld or reduced during acute crisis to avoid cholinergic crisis (excess secretions complicate ventilation). Restart carefully after stabilisation.
5. Corticosteroids: Prednisolone for long-term immunosuppression (may initially worsen - "steroid dip").
6. Immunosuppressants (long-term): Azathioprine, Mycophenolate mofetil.
7. Identify and treat trigger: Infections (most common), medications (aminoglycosides, fluoroquinolones, beta-blockers, magnesium), stress, tapering of immunosuppression.
8. Thymectomy (if thymoma present or for generalised MG in appropriate patients - long-term benefit).

Note: Stars (* to *****) beside questions indicate frequency/importance in exams. All answers above follow standard pharmacology textbook knowledge (Goodman & Gilman, KD Tripathi, Rang & Dale).