ANS Pharmacology – Nicotinic Receptors, Nicotine & Neuromuscular Blockers

What are the two main physiological subtypes of nicotinic acetylcholine receptors?

Neuronal-type (NN) located in autonomic ganglia, adrenal medulla and CNS; and muscle-type (NM) located at the skeletal neuromuscular junction.

All nicotinic receptors share what structural feature?

They are pentameric ligand-gated ion channels composed of five subunits that form a cation-selective pore.

Which ions mainly flow through open nicotinic receptors?

Na⁺ and Ca²⁺ enter (K⁺ exits muscle type) causing rapid depolarisation and excitation.

Which nicotinic receptor subtype mediates most of nicotine’s rewarding and addictive CNS effects?

The heteromeric α4β2 receptor subtype located in the mesolimbic dopaminergic pathway.

Name four principal locations of neuronal (NN) nicotinic receptors.

Autonomic ganglia, adrenal medulla, presynaptic sensory nerve terminals, various brain regions.

Where are muscle-type (NM) nicotinic receptors found?

On the motor end-plate of skeletal muscle fibres at the neuromuscular junction.

How does nicotine affect presynaptic terminals in the CNS?

It facilitates release of dopamine, acetylcholine and glutamate, enhancing alertness and reward.

List four common peripheral effects of nicotine due to ganglionic stimulation.

Tachycardia, increased blood pressure, nausea/vomiting, increased gut motility, sweating.

What inactive metabolite of nicotine is used to monitor smoking habits?

Cotinine (long half-life).

Which gene cluster is linked to nicotine dependence and lung cancer?

The CHRNA5/A3/B4 gene cluster encoding α5, α3 and β4 subunits.

What is the primary pharmacological action of Varenicline?

Partial agonist at α4β2 (and full agonist at α7) nicotinic receptors—reduces withdrawal and blocks smoking reward.

Which antidepressant is also used for smoking cessation and acts as a nicotinic antagonist?

Bupropion (also a noradrenaline/dopamine reuptake inhibitor).

Give two formulation examples of nicotine replacement therapy (NRT).

Transdermal patches (e.g., Nicorette CQ® 21 mg/24 h) and chewing gum (e.g., Nicabate® 4 mg).

What are the three pharmacological targets within the neuromuscular junction (NMJ) for drugs?

1) Nicotinic ACh receptor, 2) Presynaptic ACh release machinery, 3) Acetylcholinesterase.

Differentiate depolarising and non-depolarising neuromuscular blockers by mechanism.

Depolarising (e.g., suxamethonium) are nicotinic agonists causing persistent depolarisation; non-depolarising (e.g., rocuronium) are competitive antagonists preventing ACh binding.

Name three commonly used non-depolarising neuromuscular blockers.

Atracurium, Rocuronium, Vecuronium (others: Cisatracurium, Pancuronium, Mivacurium).

Which short-acting depolarising blocker is used to facilitate rapid tracheal intubation?

Suxamethonium (succinylcholine).

Why can suxamethonium cause prolonged paralysis in some individuals?

They are genetically deficient in plasma cholinesterase that normally hydrolyses the drug rapidly.

List two serious adverse effects of suxamethonium.

Hyperkalaemia-related arrhythmias (especially in burns/trauma) and malignant hyperthermia; others include postoperative myalgia & ↑intraocular pressure.

How are non-depolarising blockades typically reversed at the end of surgery?

By administering anticholinesterase agents (e.g., neostigmine) to raise ACh levels; or sugammadex for rocuronium/vecuronium.

What is sugammadex and how does it work?

A modified γ-cyclodextrin that encapsulates aminosteroid NMBs (rocuronium, vecuronium), reducing free drug available to bind NM receptors.

Why doesn’t sugammadex reverse mivacurium or atracurium blockade?

It selectively binds aminosteroid structures; benzylisoquinolinium agents lack this structure.

State two presynaptic toxins that inhibit ACh release at the NMJ.

Botulinum toxin type A and aminoglycoside antibiotics (e.g., gentamicin at high doses).

Describe the physiological sequence at the NMJ leading to muscle contraction.

Two ACh molecules bind NM receptor → Na⁺ influx depolarises end-plate → muscle action potential → contraction.

What is the ‘first-dose phenomenon’ associated with selective α₁ blockers like prazosin?

Marked orthostatic hypotension and syncope soon after the initial dose due to vasodilation.

Which nicotinic receptor subtype is targeted by drugs like varenicline and bupropion for smoking cessation?

α4β2 (heteromeric CNS type).

Explain why nicotine induces tolerance and physical dependence quickly.

Rapid receptor desensitisation and up-regulation, plus reinforcement via mesolimbic dopamine, drive compulsive use.

What peripheral autonomic effects result from NicotinicN receptor activation in adrenal medulla?

Release of adrenaline and noradrenaline, causing sympathetic responses such as hypertension and tachycardia.

Why should muscarinic agonists be avoided in asthma patients?

They cause bronchoconstriction and increased mucus via M3 receptor activation.

Which muscarinic antagonist is preferred for treating acute severe asthma via inhalation?

Ipratropium (short-acting antimuscarinic).

Name the enzyme that metabolises nicotine mainly in the liver.

Cytochrome P450 2A6 (CYP2A6).

What pharmacokinetic property of non-catecholamine adrenergic agonists like salbutamol allows oral activity?

Resistance to degradation by COMT and often by MAO.

Give an example of a ganglion-type (α3)₂(β4)₃ receptor antagonist used in smoking cessation.

Bupropion has antagonist activity at this receptor among other actions.

Which nicotinic receptor subtype is homopentameric and highly permeable to Ca²⁺?

The α7₅ receptor, implicated in cognition and neuroprotection.

State a pathophysiological consequence of chronic nicotine-induced α7 activation in peripheral tissues.

Pro-angiogenic effects that can accelerate progression of chronic kidney disease in smokers.

What is the principal clinical use of neostigmine besides myasthenia gravis?

Reversal of non-depolarising neuromuscular blockade during anaesthesia.

Which plasma enzyme rapidly hydrolyses suxamethonium?

Plasma (pseudo)cholinesterase, also called butyrylcholinesterase.

Why doesn’t neostigmine reverse suxamethonium paralysis?

Suxamethonium produces a depolarising block; increased ACh cannot repolarise or outcompete it.

What monitoring parameter can confirm recent nicotine exposure?

Blood or urine cotinine concentration.

List two central nervous system effects of therapeutic nicotine doses.

Increased alertness and decreased anxiety; also pleasurable reward sensations.

How does bupropion reduce nicotine cravings?

By inhibiting noradrenaline and dopamine reuptake and antagonising certain nicotinic receptors.

Which nicotinic receptor interface forms the ACh binding site in muscle-type receptors?

Between the α subunit and either ε, δ or γ subunits.

What is the clinical significance of the different durations of action among non-depolarising NMBs?

Allows selection of short, intermediate or long muscle relaxation according to surgical needs.

Name one short-acting non-depolarising blocker and one long-acting blocker.

Short: Mivacurium; Long: Pancuronium.

What adverse cardiovascular effect may occur with rapid IV nicotine exposure?

Transient hypertension and tachycardia due to sympathetic discharge.

State two common adverse effects of varenicline.

Nausea and insomnia (others: vivid dreams, headache).

Which receptor subtype mediates nicotine-induced increased gut motility?

NicotinicN receptors in autonomic ganglia activating parasympathetic tone.

Define ‘fasciculation’ in the context of suxameth