MBBS Pharmacology Syllabus

Differentiate the two divisions of the autonomic nervous system by their primary neurotransmitters and dominant effects.

The sympathetic ('fight or flight') division releases noradrenaline at most target organs (acetylcholine at sweat glands/ganglia). The parasympathetic ('rest and digest') division releases acetylcholine. They generally exert opposing effects to maintain homeostasis.

Identify the neurotransmitter and receptor type at each location: autonomic ganglia, parasympathetic effector, sympathetic effector (most), and the skeletal neuromuscular junction.

Autonomic ganglia: ACh on nicotinic ($N_N$). Parasympathetic effector: ACh on muscarinic. Most sympathetic effectors: noradrenaline on adrenergic ($\alpha/\beta$). Neuromuscular junction: ACh on nicotinic ($N_M$).

Contrast the second-messenger pathways of the muscarinic receptor subtypes $M_1/M_3/M_5$ versus $M_2/M_4$.

$M_1, M_3, M_5$ couple to $G_q$, activating phospholipase C to raise $IP_3$ and $DAG$ (excitatory, smooth muscle/glandular). $M_2, M_4$ couple to $G_i$, inhibiting adenylyl cyclase and lowering cAMP (cardiac slowing).

Describe the mechanism and key clinical use of physostigmine versus neostigmine.

Both are reversible acetylcholinesterase inhibitors that increase synaptic ACh. Physostigmine is a tertiary amine that crosses the blood-brain barrier (used for anticholinergic/atropine toxicity). Neostigmine is a quaternary amine that does not enter the CNS (used for myasthenia gravis and reversal of non-depolarizing blockade).

What is the mechanism of organophosphate poisoning and its specific antidote?

Organophosphates irreversibly inhibit acetylcholinesterase, causing ACh accumulation and a cholinergic crisis (DUMBBELLS/SLUDGE). Treatment: atropine (blocks muscarinic effects) plus pralidoxime (reactivates cholinesterase before 'aging').

List the classic muscarinic (parasympathetic) effects summarized by the mnemonic DUMBBELS.

Diarrhea, Urination, Miosis, Bradycardia/Bronchospasm, Emesis, Lacrimation, Salivation/Sweating — the signs of muscarinic excess (cholinergic crisis).

Describe atropine's mechanism and its main clinical effects.

Atropine is a competitive muscarinic antagonist. Effects: tachycardia, mydriasis with cycloplegia, dry mouth, decreased secretions, bronchodilation, and reduced GI/bladder motility. Used for bradycardia, as an antisecretory agent, and in organophosphate poisoning.

Match adrenergic receptor subtypes $\alpha_1$, $\alpha_2$, $\beta_1$, $\beta_2$ to their principal effects.

$\alpha_1$: vasoconstriction, mydriasis, sphincter contraction. $\alpha_2$: presynaptic inhibition of NA release, decreased central sympathetic outflow. $\beta_1$: increased heart rate, contractility, and renin release. $\beta_2$: bronchodilation, vasodilation, uterine relaxation, glycogenolysis.

Compare the cardiovascular effects of adrenaline (epinephrine) at low versus high doses.

At low doses $\beta_2$ vasodilation predominates, lowering diastolic pressure and total peripheral resistance. At high doses $\alpha_1$ vasoconstriction dominates, raising systolic and diastolic pressure. $\beta_1$ effects raise heart rate and contractility throughout.

Explain the mechanism of action of beta-blockers and a key contraindication.

Beta-blockers competitively antagonize $\beta$-adrenergic receptors, reducing heart rate, contractility, AV conduction, and renin release, thereby lowering blood pressure and cardiac workload. Non-selective agents are contraindicated in asthma (risk of $\beta_2$-mediated bronchospasm).

How does prazosin lower blood pressure, and what notable adverse effect does it cause?

Prazosin is a selective $\alpha_1$-antagonist that causes arterial and venous dilation, reducing peripheral resistance. It can produce a 'first-dose' orthostatic hypotension/syncope.

Contrast the mechanisms of depolarizing and non-depolarizing neuromuscular blockers.

Depolarizing blockers (succinylcholine) are nicotinic agonists that persistently depolarize the motor end-plate, causing initial fasciculations then flaccid paralysis (Phase I, not reversed by anticholinesterases). Non-depolarizing blockers (e.g., vecuronium, rocuronium) are competitive $N_M$ antagonists causing flaccid paralysis reversible by anticholinesterases.

What is the mechanism of ganglionic blockers, and name a prototype.

Ganglionic blockers (e.g., hexamethonium, trimethaphan) competitively block nicotinic ($N_N$) receptors at autonomic ganglia, interrupting both sympathetic and parasympathetic transmission; net effect depends on the dominant autonomic tone at each organ.

List the major inhibitory and excitatory neurotransmitters of the CNS.

Principal inhibitory neurotransmitters: GABA and glycine. Principal excitatory neurotransmitter: glutamate (acting on NMDA, AMPA, kainate, and metabotropic receptors). Modulatory systems include dopamine, serotonin, noradrenaline, and acetylcholine.

Describe how benzodiazepines and barbiturates differently potentiate the $GABA_A$ receptor.

Both enhance $GABA_A$ chloride channel activity. Benzodiazepines increase the frequency of channel opening (require GABA present). Barbiturates increase the duration of channel opening and at high doses directly open the channel, accounting for their lower margin of safety.

What is the antidote for benzodiazepine overdose and its mechanism?

Flumazenil, a competitive antagonist at the benzodiazepine binding site of the $GABA_A$ receptor. Use cautiously, as it can precipitate seizures in chronically dependent patients.

Compare the sedative-hypnotic safety profiles of benzodiazepines versus barbiturates.

Benzodiazepines have a ceiling effect on CNS depression (rarely fatal alone) and a wide therapeutic index. Barbiturates lack a ceiling, directly opening Cl$^-$ channels, causing dose-dependent respiratory depression and a narrow therapeutic index, making overdose lethal.

Name three principal mechanisms by which antiepileptic drugs reduce neuronal excitability.

1) Blockade of voltage-gated sodium channels (phenytoin, carbamazepine, lamotrigine). 2) Enhancement of GABAergic inhibition (benzodiazepines, valproate, vigabatrin). 3) Blockade of T-type calcium channels (ethosuximide for absence seizures).

Which antiepileptic is first-line for absence seizures, and what is its mechanism?

Ethosuximide is first-line for absence (petit mal) seizures; it blocks T-type calcium channels in thalamic neurons. Valproate is an alternative, especially with coexisting generalized tonic-clonic seizures.

State two serious adverse effects of valproate and one important drug-interaction property.

Valproate can cause hepatotoxicity and neural tube defects (teratogenic, e.g., spina bifida). It is a broad enzyme inhibitor, raising levels of co-administered drugs such as lamotrigine and phenobarbital.

What is the dopamine hypothesis of schizophrenia and how do typical antipsychotics act on it?

The dopamine hypothesis attributes positive symptoms to excess dopaminergic activity in the mesolimbic pathway. Typical (first-generation) antipsychotics block $D_2$ receptors, relieving positive symptoms but causing extrapyramidal effects from nigrostriatal $D_2$ blockade.

Distinguish typical from atypical antipsychotics regarding receptor profile and side effects.

Typical antipsychotics are potent $D_2$ antagonists with high extrapyramidal symptom (EPS) and hyperprolactinemia risk. Atypicals block $D_2$ and $5\text{-}HT_{2A}$ receptors, causing fewer EPS but more metabolic side effects (weight gain, diabetes, dyslipidemia).

What is neuroleptic malignant syndrome and its key features?

A life-threatening idiosyncratic reaction to antipsychotics (dopamine blockade) marked by hyperthermia, severe muscle rigidity ('lead-pipe'), autonomic instability, altered mental status, and elevated creatine kinase. Treated by stopping the drug plus dantrolene and/or bromocriptine.

Compare the mechanisms of SSRIs, TCAs, and MAOIs as antidepressants.

SSRIs selectively block serotonin reuptake. TCAs block reuptake of both serotonin and noradrenaline (and block muscarinic, histaminergic, $\alpha_1$ receptors, causing more side effects). MAOIs inhibit monoamine oxidase, reducing breakdown of serotonin, noradrenaline, and dopamine.

Why must MAOIs be used with dietary caution, and what is serotonin syndrome?

MAOIs combined with tyramine-rich foods cause a hypertensive crisis (the 'cheese reaction'). Serotonin syndrome is excess serotonergic activity (e.g., SSRI + MAOI) causing the triad of altered mental status, autonomic hyperactivity, and neuromuscular abnormalities (clonus, hyperreflexia).

Describe the mechanism of action of NSAIDs and distinguish COX-1 from COX-2.

NSAIDs inhibit cyclooxygenase, reducing prostaglandin synthesis (analgesia, antipyresis, anti-inflammation). COX-1 is constitutive (gastric protection, platelet thromboxane, renal flow); COX-2 is inducible at inflammation sites. Selective COX-2 inhibitors spare the stomach but raise cardiovascular risk.

How does aspirin's effect on platelets differ from that of other NSAIDs?

Aspirin irreversibly acetylates COX-1, permanently inhibiting platelet thromboxane $A_2$ synthesis for the platelet's ~7-10 day lifespan. Other NSAIDs cause reversible, competitive COX inhibition lasting only while drug is present.

Explain the analgesic mechanism of opioids and three classic adverse effects.

Opioids agonize $\mu$ (and $\kappa$, $\delta$) receptors, $G_i$-coupled, reducing cAMP, decreasing neurotransmitter release and hyperpolarizing neurons to inhibit pain transmission. Classic adverse effects: respiratory depression, constipation, and miosis (with tolerance and dependence).

Why is buspirone preferred over benzodiazepines for chronic generalized anxiety, and what is its mechanism?

Buspirone is a $5\text{-}HT_{1A}$ partial agonist that relieves anxiety without sedation, dependence, or potentiation of alcohol. Its drawback is delayed onset (1-2 weeks), unlike the immediate but dependence-prone benzodiazepines.

Write the equation for mean arterial pressure (MAP) in terms of cardiac output and resistance, and in terms of systolic/diastolic pressures.

$$MAP = CO \times SVR \quad\text{and}\quad MAP \approx DBP + \frac{1}{3}(SBP - DBP)$$ where $CO$ is cardiac output, $SVR$ systemic vascular resistance, $SBP$ systolic and $DBP$ diastolic pressure (pulse pressure $= SBP - DBP$).

Name the five phases (0-4) of the ventricular cardiac action potential and the ion movement in each.

Phase 0: rapid depolarization (fast $\ce{Na+}$ influx). Phase 1: early repolarization ($\ce{K+}$ efflux, $\ce{Na+}$ channels close). Phase 2: plateau ($\ce{Ca^2+}$ influx balances $\ce{K+}$ efflux). Phase 3: repolarization ($\ce{K+}$ efflux). Phase 4: resting potential maintained by $\ce{Na+/K+}$-ATPase (spontaneous depolarization in pacemaker cells).