Session 10

Question 0

Compare and contrast the pathways of neurotransmitter synthesis, storage, release and termination at cholinergic and adrenergic synapses

Answer 0

Cholinergic - ACh synthesised by choline acetyltransferase from choline and acetyl CoA in cytoplasm of cholinergic terminals, transported into vesicles by an indirect active transport mechanism, in synoptic cleft cholinesterase rapidly degrades ACh to acetate and choline, choline transporter in synoptic cleft recaptures most choline
Adrenergic - NA is synthesised from tyrosine in nerve terminal by tyrosine hydroxylase, dopamine is transported into vesicles by dopamine-B-hydroxylase, vesicle has a H+-ATPase-generated-cytoplasm-vesicle-H+ gradient to move catecholamines against their concentration gradient, cytoplasmic NA is degraded by monoamine oxidase. Tyrosine –> dopa –> dopamine –> noradrenaline. Uptake 1 - high affinity, removes NA from synaptic cleft. Uptake 2 - low affinity, removes escaped NA from extracellular space.

Question 1

Understand the anatomical and pharmacological divisions of the autonomic nervous system (ANS)

Answer 1

ANS is comprised of two neurones - pre-ganglionic and post-ganglionic. One cell body is in the CNS and one is in the PNS. Neurones exert action via smooth muscle, viscera and secretory glands.
Sympathetic (thoraco-lumbar outflow) - cell bodies in 12 thoracic sections and first 2 lumbar sections, short cholinergic pre-ganglion, long noradrenergic post-ganglion, may synapse at same level as origin (paravertebral) or different level, two classes of adrenoceptors (a&B)
Parasympathetic (cranio-sacral outflow) - long cholinergic pre-ganglion, short cholinergic post-ganglion,

Question 2

Outline the regulation of noradrenaline and acetylcholine release

Answer 2

Ca2+ mediated exocytosis - triggered by depolarisation of nerve terminal, Ca2+ release, fusion of vesicles with pre-synaptic membrane

Question 3

List the major drug classes used to affect ANS function

Answer 3

Cholinergic nerve terminals:
Nicotinic cholinoceptor antagonist e.g. Tubocurarine - muscle paralysis during anaesthesia
Muscarinic cholinoceptor agonist e.g. Pilocarpine - treatment of glaucoma, suppression of atrial tachycardia
Muscarinic cholinoceptor antagonists e.g. Bromide - treat bronchoconstriction in asthmatics
Cholinesterase inhibitors e.g. Edrophonium - treat glaucoma, myasthenia gravis
Adrenergic nerve terminals:
a-methyl tyrosine - competitively inhibits tyrosine hydroxylase, blocks de novo synthesis of NA, used in pheochromocytoma
a-methyl dopa - converted to a-methyl dopamine, accumulates in vesicles, activates pre-synaptic a2, inhibits VOCC –> reduced Ca2+ mediated neurotransmitter release
CarbiDOPA - inhibits dopa carboxylase in PNS but not CNS, treatment of Parkinson’s
Adrenergic blocking drugs - concentrated in terminals by uptake 1, local anaesthetic action, severe side effects of postural hypotension
IASAs - transported into vesicle by uptake 1, displaced NA leaks into synaptic cleft
Uptake 1 inhibitors - tricyclic antidepressants, unwanted side effects of tachycardia, dysrhythmias
Adrenergic receptors:
B1 agonist e.g. Dobutamine - +ve ino/chronotrophic effects
B2 agonist e.g. Salbutamol - bronchodilation
A1 agonist e.g. Phenylephrine - nasal decongestant
A2 agonist e.g. Clonidine - anti-hypertensive
A1 antagonist e.g. Prazosin - treat hypertension
B antagonist e.g. Propranolol - treat hypertension, MI, angina