9. Drugs for the ANS Flashcards
Which neurones release acetylcholine and what receptors do they act on?
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
Which neurones release noradrenaline and adrenaline?
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.
What are NANC transmitters?
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.
How is acetylcholine produced and packaged into vesicles?
- CHOLINE ACETYLTRANSFERASE generates acetylcholine from acetyl CoA (from metabolism) and choline (from diet).
- VACUOLAR ATPASE generates a proton gradient
- VESICULAR ACETYLCHOLINE TRANSPORTER uses this to transport ACh into vesicles, coupled with H+ efflux.
How is acetylcholine removed from the synaptic cleft?
- ACETYLCHOLINESTERASE degrades acetylcholine in the synaptic cleft, into acetate and choline.
- CHOLINE TRANSPORTER actively reuptakes choline.
- Acetate diffuses away through extracellular medium
Describe how neurotransmitter is released into the synaptic cleft.
- VOCCs open in response to depolarisation due to action potential arriving at presynaptic knob.
- Ca2+ influx into presynaptic knob.
- Ca2+ binds to SYNAPTOTAGMIN on the vesicle.
- Vesicle is brought to the plasma membrane where synaptotagmin binds to a SNARE COMPLEX to form a FUSION PORE.
- Neurotransmitter is released.
How do botulinum toxins affect acetylcholine release?
Botulinum toxins cleave specific proteins within the SNARE COMPLEX. Therefore a fusion pore cannot be produced, limiting acetylcholine release into the synaptic cleft.
How is noradrenaline produced and packaged into vesicles?
- TYROSINE HYDROXYLASE: tyrosine => dopa (rate limiting step)
- DOPA DECARBOXYLASE: dopa => dopamine
- VESICULAR MONOAMINE TRANSPORTER couples H+ efflux with the transport of DOPAMINE (or noradrenaline from reuptake) into vesicles. (vacuolar atpase generates the H+ gradient)
- DOPAMINE Beta HYDROXYLASE: dopamine => noradrenaline
(within vesicles)
How is noradrenaline removed from the synaptic cleft?
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
What is the ultimate fate of noradrenaline reuptaken by the presynaptic neurone?
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
What can nicotinic cholinoceptor antagonists be used for?
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
What do drugs, which target muscarinic cholinoceptors, do?
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)
What do cholinesterase inhibitors do?
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)
What does alpha methyl tyrosine do?
Alpha methyl tyrosine COMPETITIVELY INHIBITS tyrosine hydroxylase thus blocks noradrenaline synthesis (it is used to treat hypertension induced by pheochromocytoma)
In what TWO ways does alpha methyl dopa act to reduce blood pressure?
- COMPETITIVE INHIBITOR of dopa decarboxylase (reduces dopamine synthesis and thus reduces noradrenaline synthesis)
- FALSE TRANSMITTER generated: dopa decarboxylase converts alpha methyl dopa into Alpha-METHYL NORADRENALINE. This agonises a2 receptors in the CNS to reduce sympathetic output.
Why is Carbi-Dopa given in conjunction with L-Dopa, to Parkinson’s disease patients?
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.
How can indirect acting sympathomimetic agents cause a spike in sympathetic output?
INDIRECT ACTING SYMPATHOMIMETIC AGENTS (e.g. amphetamine)
These are WEAK ADRENOCEPTOR AGONISTS however their main action is by:
- UPTAKE 1 into presynaptic neurones
- CONCENTRATION in vesicles
- LEAKAGE of noradrenaline into cleft (not via Ca2+ mediated endocytosis)
How do blockers of noradrenaline release (e.g. guanethidine) work?
BLOCKERS OF NORADRENALINE RELEASE (e.g. Guanethidine) act by:
- Selectively CONCENTRATING in presynaptic terminal by UPTAKE 1
(also partially blocking reuptake of noradrenaline) - DEPLETION of noradrenaline from vesicles
Adrenoceptor agonists have high subtype specificity. What is each type used for clinically?
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)
Adrenoceptor antagonists exhibit some subtype specificity. What are each class of this drug used for?
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)
Give FIVE types of drugs which can be used to treat glaucoma.
- MUSCARINIC AGONIST (Pilocarpine) - acts on M3 to open up mesh work around canal of Schlemm to INCREASE DRAINAGE of aqueous humor.
- Alpha ADRENERGIC AGONIST - decrease production of aqueous humor by ciliary bodies. (note: these act on feedback receptors)
- Beta ADRENERGIC ANTAGONIST - decrease production of aqueous humor by ciliary bodies.
- PROSTAGLANDIN ANALOGUES - increase uveoscleral outflow.
- ACETYLCHOLINESTERASE INHIBITORS - increase cholinergic drive onto M3 receptors thus open up canal of Schlemm.
