Autonomic + NMJ pharma Flashcards
Types of Cholinergic receptors
-Cholinergic receptors are either the ionotropic type with an intergral ion channel and these specific ones are selectively activated by nicotine so are called nicotinic receptors
OR
-They are of the muscarinic type which are selectively activated by muscarine and so are called muscarinic - they can be split into M1, M2, M3 based on what G-protein they are coupled to and therefore what 2nd messenger signals they produce.
Do ionotropic adrenergic receptors exist?
There are no ionotropic adrenergic receptors, intead they are all metabotropic and are split into alpha 1, alpha 2, alpha 3 and beta 1, beta 2, beta 3 and beta 4, based (partly) on what G-protein they are coupled to and what 2nd messengers get regulated.
Steps of Synaptic Transmission
- Synthesis and packaging of neurotransmitter (usually) in presynaptic terminals
- Na+ action potential invades terminal
- Activates voltage gated Ca2+-channels
- Triggers Ca2+-dependent exocytosis of pre-packaged vesicles of transmitter
- Transmitter diffuses across cleft and binds to ionotropic and/or metabotropic receptors to evoke postsynaptic response
- Presynaptic autoreceptors inhibit further transmitter release
- Transmitter is (usually) inactivated by uptake into glia or neurones
- Transmitter is metabolised within cells
NMJ - potential sites of action
- Inhibit choline transporter 9e.g. hemicholium)
- Block voltage-gated Ca2+ channels 9e.g. black widow spider venom)
- Block vesicle fusion (e.g. botulinium toxins)
- Use non-depolarising nicotinic receptor blockers (e.g. succinylcholine)
- Prolong the action potential (e.g. 3,4-aminopyridine)
- Block acetylcholinesterase (e.g. eserine)
NMJ - Clinical applications
Non-depolarising or depolarising blockers used for paralysis during: -surgical procedures -electroconvulsive therapy -controlling spasms in tetanus Botulinum toxin used for: -treating muscle spasm -cosmetic procedures Anti-cholisterases used for: -treating myasthenic syndromes -reversing action of non-depolarising blockers -countering botulium poisoning.
What is required to block NMJ trasnmission and paralyses patients during surgery or ECT?
- non-depolarising or depolarising blockers based mainly on the speed of action.
Where does ganglionic transmission occur?
At the connections between the preganglionic and the postganglionic autonomic fibres.
Includes both the sympathetic and parasympathetic systems.
ANS ganglionic transmission - potential sites of action
- Inhibit choline transporter (eg hemicholinium)
- Block voltage gated Ca2+ channels (eg black widow spider venom)
- Block vesicle fusion (eg botulinium toxins)
- Block ACh activated channel (eg hexamethoneum)
- Non-depolarising nicotinic receptor blockers (eg mecylamine)
- Depolarising nicotinic receptor blockers (eg suxamethoneum)
- Activate nicotinic receptors (e.g. nicotine, is more potent at ganglia than NMJ, N1>N2 receptors)
ANS ganglionic transmission - Clinical applications
- ALMOST NONE!
- Drugs modulate both sympathetic and parasympathetic ganglionic transmission, and probably NMJ transmission, producing complex actions with many side effects.
Connections between the postganglionic parasympathetic nerves and their targets.
They use ACh, but this time working on muscarinic receptors - the G-protein coupled ones.
ANS postganglionic parasympathetic transmission - potential sites of action
- Muscarinic receptor antagonists (e.g. atropine)
- Muscarinic receptor agonists (e.g. carbachol, pilocarpine)
ANS postganglionic parasympathetic transmission - Clinical applications
- Muscarinic agonists will mimic the effect of the parasympathetic system (ie slow heart rate, contract smooth muscle in airways and bladder, increase gut motility, bronchial secretions and salivation, constrict pupil)
- Muscarinic antagonists will block effects of the parasympathetic system (ie increase heart rate, relax smooth muscle in airways* and bladder, reduce gut motility, bronchial secretions and salivation, dilate pupil)
- Muscarininc agonists (eg pilocarpine) are also used in the treatment of glaucoma, ie high intra occular pressure
- Aqueous humour normally drains through the trabecular network into the canal of schlemm
- Muscarinic agonists contract the ciliary muscle supporting the lens and contracts the sphincter muscle of the pupil
- Depending who you read, one or both of these opens up the trabecular network and increase drainage of the aqueous humour
What is making the pupil smaller called?
Making the pupil smaller is called miosis, hence these drugs are called miotics, but it is nothing to do with meiois!
Cf mydriatics which dilate the pupil, and are useful in eye examinations
What is Glaucoma?
Raised intraoccular pressure
-muscarinic agonists (eg pilocarpine) contract the ciliary muscle supporting the lens and seem to open up the trabecular network through which the aqueous humour drains, and/or make the sphincter muscle of the iris contract which has the same effect.
How do you manipulate postganglionic sympathetic transmission?
-It is about how you can manipulate the release of noadrenaline and adrenaline presynaptically, and/or manipulate those adrenergic alpha and beta receptors postsynaptically.
