9. Drugs for the ANS

Question 1

Which neurones release acetylcholine and what receptors do they act on?

Answer 1

Acetylcholine is released by:

a) ALL PREGANGLIONIC neurones (act on nicotinic receptors)
b) ALL PARASYMPATHETIC postganglionic neurones (act on muscarinic receptors)
c) SOME sympathetic postganglionic neurones (act on muscarinic receptors) - SWEAT glands and PILOERECTOR muscles

Question 2

Which neurones release noradrenaline and adrenaline?

Answer 2

a) Most SYMPATHETIC postganglionic neurones release NORADRENALINE (acts on adrenoceptors)
b) CHROMAFFIN cells (adrenal medulla) are modified postganglionic neurones which release ADRENALINE into the circulation.

Question 3

What are NANC transmitters?

Answer 3

NANC transmitters are ‘Non Adrenergic, Non Cholinergic’ transmitters which are often co-released with acetylcholine or noradrenaline in a process called COTRANSMISSION.

NANC transmitters bind to their own receptors and perform different functions.

Examples include ATP, 5HT, NO etc.

Question 3

How is acetylcholine produced and packaged into vesicles?

Answer 3

1. CHOLINE ACETYLTRANSFERASE generates acetylcholine from acetyl CoA (from metabolism) and choline (from diet).
2. VACUOLAR ATPASE generates a proton gradient
3. VESICULAR ACETYLCHOLINE TRANSPORTER uses this to transport ACh into vesicles, coupled with H+ efflux.

Question 4

How is acetylcholine removed from the synaptic cleft?

Answer 4

1. ACETYLCHOLINESTERASE degrades acetylcholine in the synaptic cleft, into acetate and choline.
2. CHOLINE TRANSPORTER actively reuptakes choline.
3. Acetate diffuses away through extracellular medium

Question 5

Describe how neurotransmitter is released into the synaptic cleft.

Answer 5

1. VOCCs open in response to depolarisation due to action potential arriving at presynaptic knob.
2. Ca2+ influx into presynaptic knob.
3. Ca2+ binds to SYNAPTOTAGMIN on the vesicle.
4. Vesicle is brought to the plasma membrane where synaptotagmin binds to a SNARE COMPLEX to form a FUSION PORE.
5. Neurotransmitter is released.

Question 6

How do botulinum toxins affect acetylcholine release?

Answer 6

Botulinum toxins cleave specific proteins within the SNARE COMPLEX. Therefore a fusion pore cannot be produced, limiting acetylcholine release into the synaptic cleft.

Question 7

How is noradrenaline produced and packaged into vesicles?

Answer 7

1. TYROSINE HYDROXYLASE: tyrosine => dopa (rate limiting step)
2. DOPA DECARBOXYLASE: dopa => dopamine
3. VESICULAR MONOAMINE TRANSPORTER couples H+ efflux with the transport of DOPAMINE (or noradrenaline from reuptake) into vesicles. (vacuolar atpase generates the H+ gradient)
4. DOPAMINE Beta HYDROXYLASE: dopamine => noradrenaline
   (within vesicles)

Question 8

How is noradrenaline removed from the synaptic cleft?

Answer 8

UPTAKE 1: HIGH AFFINITY symport with 1Na+ and Cl- in presynaptic neurones. Noradrenaline is then either:

a) RECYCLED (some noradrenaline)
b) METABOLISED (most noradrenaline)

UPTAKE 2: LOW AFFINITY uptake by NON-NEURONAL cells

Question 9

What is the ultimate fate of noradrenaline reuptaken by the presynaptic neurone?

Answer 9

Some noradrenaline reuptaken, is recycled (i.e. repackaged into vesicles and released).

However, most noradrenaline is metabolised by
CATECHOL-O-METHYL TRANSFERASE and MONOAMINE OXIDASE

The end product for this is VANILLYL MANDELLIC ACID

Question 10

What can nicotinic cholinoceptor antagonists be used for?

Answer 10

Nicotinic cholinoceptor antagonists can be used to target:

a) ANS GANGLION (e.g. trimethaphan) - only used in hypertensive emergencies or to induce hypotension in surgery.
b) NMJ (e.g. tubocurarine) - induce muscle paralysis in anaesthesia

Question 11

What do drugs, which target muscarinic cholinoceptors, do?

Answer 11

Muscarinic cholinoceptor AGONISTS

• Pilocarpine treats glaucoma
• Bethanechol causes bladder emptying

Muscarinic cholinoceptor ANTAGONISTS

• Hyoscine used as anaesthetic premedication (reduce secretions, bradycardia and any bronchoconstriction)
• Oxybutynin treats overactive bladder
• Tropicamide used in opthalmoscopic examination (dilate pupils and paralyse accommodation)

Question 12

What do cholinesterase inhibitors do?

Answer 12

Cholinesterase inhibitors (e.g. physostigmine) increase cholinergic drive thus can be used to:

• treat GLAUCOMA
• reverse effects of non-depolarising neuromuscular blocking agents (which are used in anaesthesia)

Question 13

What does alpha methyl tyrosine do?

Answer 13

Alpha methyl tyrosine COMPETITIVELY INHIBITS tyrosine hydroxylase thus blocks noradrenaline synthesis (it is used to treat hypertension induced by pheochromocytoma)

Question 14

In what TWO ways does alpha methyl dopa act to reduce blood pressure?

Answer 14

1. COMPETITIVE INHIBITOR of dopa decarboxylase (reduces dopamine synthesis and thus reduces noradrenaline synthesis)
2. FALSE TRANSMITTER generated: dopa decarboxylase converts alpha methyl dopa into Alpha-METHYL NORADRENALINE. This agonises a2 receptors in the CNS to reduce sympathetic output.

Question 15

Why is Carbi-Dopa given in conjunction with L-Dopa, to Parkinson’s disease patients?

Answer 15

Parkinson’s Disease patients are deficient in dopamine in the basal ganglia (brain).

L-Dopa is used to produce dopamine and is thus given to Parkinson’s disease sufferers.

However to ensure that the production of dopamine increases in the CNS and not in the periphery, Carbi-Dopa is also used.

Carbi-Dopa inhibits DOPA DECARBOXYLASE thus reduces dopamine synthesis. However it only acts in the periphery because it cannot cross the blood-brain-barrier.

Therefore when given in conjunction, any increases in dopamine production are limited to the CNS.

Question 16

How can indirect acting sympathomimetic agents cause a spike in sympathetic output?

Answer 16

INDIRECT ACTING SYMPATHOMIMETIC AGENTS (e.g. amphetamine)

These are WEAK ADRENOCEPTOR AGONISTS however their main action is by:

1. UPTAKE 1 into presynaptic neurones
2. CONCENTRATION in vesicles
3. LEAKAGE of noradrenaline into cleft (not via Ca2+ mediated endocytosis)

Question 17

How do blockers of noradrenaline release (e.g. guanethidine) work?

Answer 17

BLOCKERS OF NORADRENALINE RELEASE (e.g. Guanethidine) act by:

1. Selectively CONCENTRATING in presynaptic terminal by UPTAKE 1
   (also partially blocking reuptake of noradrenaline)
2. DEPLETION of noradrenaline from vesicles

Question 18

Adrenoceptor agonists have high subtype specificity. What is each type used for clinically?

Answer 18

Adrenoceptor Agonists:

B1 SELECTIVE (e.g. Dobutamine) - circulatory shock (positive inotropy and chronotropy)

B2 SELECTIVE (e.g. Salbutamol) - asthma (reverse bronchoconstriction)

a1 SELECTIVE (e.g. Oxymetazoline) - nasal decongestion

a2 SELECTIVE (e.g. Clonidine) - antihypertensive (decreases SNS output by CNS action and on presynaptic receptors)

Question 19

Adrenoceptor antagonists exhibit some subtype specificity. What are each class of this drug used for?

Answer 19

Adrenoceptor Antagonists:

a1 SELECTIVE (e.g. Prazosin) - antihypertensive

a SELECTIVE (e.g. Phentolamine) - peripheral vascular disease (oppose vasoconstriction)

B SELECTIVE (e.g. Atenolol or Propranolol) - can treat MI, hypertension, angina, etc. (but can cause bronchoconstriction)

Question 20

Give FIVE types of drugs which can be used to treat glaucoma.

Answer 20

1. MUSCARINIC AGONIST (Pilocarpine) - acts on M3 to open up mesh work around canal of Schlemm to INCREASE DRAINAGE of aqueous humor.
2. Alpha ADRENERGIC AGONIST - decrease production of aqueous humor by ciliary bodies. (note: these act on feedback receptors)
3. Beta ADRENERGIC ANTAGONIST - decrease production of aqueous humor by ciliary bodies.
4. PROSTAGLANDIN ANALOGUES - increase uveoscleral outflow.
5. ACETYLCHOLINESTERASE INHIBITORS - increase cholinergic drive onto M3 receptors thus open up canal of Schlemm.