6. Cholinomimetics Flashcards by t k

what is acetylcholine (ACh) synthesised from and what catalyses the reaction?

acetyl CoA + choline

choline acetyltransferase (CAT)

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what does depolarisation of the presynaptic knob cause?

causes the opening of voltage sensitive calcium channels and the influx of calcium causes exocytosis of ACh

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what constitutes a muscarinic effect?

those that can be replicated by muscarine (selective muscarinic antagonist) and that correspond to parasympathetic stimulation

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give an example of a muscarinic antagonist

atropine

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what type of receptor do most motor neurones have and how many neurones are involved?

mostly cholinergic receptors

single neurone involved

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where can the muscarinic receptor subtypes be found?

*M1: salivary glands, stomach (HCl release), CNS (excitation)
*M2: heart (decreases HR)
*M3: salivary glands, bronchial/visceral smooth muscle, sweat glands, eye
M4,M5: CNS

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what similarities do all the muscarinic receptors share?

generally excitatory (except M2 on the heart which is inhibitory)
all type 2 receptors (G-protein coupled) -> M1, M3 and M5 involve Gq protein with IP3 and DAG, M2 and M4 involve Gi protein with cAMP

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what are nicotinic receptors and what 5 units make them up?

ligand gated ion channels

subunits: α β γ δ ε

subunit combination determines ligand binding properties of the receptor

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what are the 2 main types of nicotinic receptor and what subunits make them up?

in the muscle: 2α+ β + δ + ε

ganglion: 2α+ 3β

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what are the muscarinic effects on the eye?

ciliary muscle contracts: accommodation for near vision
sphincter pupillae contracts (circular muscle of iris): causes miosis (constriction), increases intraocular fluid drainage
lacrimation (tears)

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why is the stimulation of muscarinic receptors useful for glaucoma?

give patient a muscarinic agonist -> causes contraction of the iris -> opens up the angle and increases drainage of intraocular fluid through the canals of Schlemm

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what is the role of aq. humour?

to supply oxygen and nutrients to the lens and cornea

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what causes angle-closure glaucoma?

when the angle between the cornea and iris becomes narrowed, reducing the drainage of intraocular fluid via the canals of Schlemm

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what are the muscarinic effects on the heart?

M2 receptors found in the atria and in both nodes of the heart are inhibitory

reduced cAMP -> reduced Ca2+ entry -> decreased CO

reduced cAMP -> increased K+ efflux -> decreased HR

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what are the muscarinic effects on vasculature?

ACh acts on vascular endothelial cells to stimulate NO release via M3 AChR which induces vascular smooth muscle relaxation and results in decreased TPR

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what are the muscarinic effects on the CVS?

decreased heart rate
decreased CO die to decreased atrial contraction
vasodilation due to NO production
drop in BP

what are the muscarinic effects on non-vascular smooth muscle?

smooth muscle with parasympathetic innervation responds in the opposite way to vascular muscle (contracts):

lung: bronchoconstriction
gut: increases peristalsis
bladder: increased emptying

what are the muscarinic effects on exocrine glands?

salivation
increased bronchial secretions
increased GI secretions (inc. GI HCl)
increased sweating

summarise the muscarinic effects

decreased HR
decreased BP
increased sweating
difficulty breathing
bladder contraction
GI pain
increased salivation and tears

what are the directly acting cholinomimetic drugs that are typical muscarinic agonists?

choline esters (bethanechol)

- alkaloids (pilocarpine)

describe the muscarinic agonist bethanechol

minor modification of ACh
produces an M3 AChR selective agonist
resistant to degradation by acetylcholinesterase
orally active
limited access to brain
mainly used to assist bladder emptying and enhance gastric motility

describe the muscarinic agonist pilocarpine

non-selective muscarinic agonist
good lipid solubility
useful in ophthalmology as a local treatment for glaucoma -> constricts sphincter pupillae and opens up canal of Schlemm to increase IO fluid drainage

what are the side effects of bethanechol and pilocarpine?

impaired vision, nausea, sweating, hypotension, bradycardia, respiratory distress

what do indirectly acting cholinomimetic drugs do?

increase effect of normal parasympathetic nerve stimulation by inhibiting acetylcholinesterase to increase ACh in the synapse

give an example of a reversible and irreversible anticholinesterase

reversible - physostigmine irreversible - ecothiopate

what do cholinesterase enzymes do and what are the 2 types?

metabolise ACh into choline and acetate 1. acetycholinesterase (true) 2. butyrylcholinesterase (pseudocholinesterase)

describe acetylcholinesterase

- found in all cholinergic synapses (peripheral and central) - very rapid action - highly selective for ACh

describe butyrylcholinesterase

- found in plasma and most tissues but not cholinergic synapses - broad substrate specificity - shows variation in population - is principal reason for low plasma ACh - shows genetic variation

what are the effects of cholinesterase inhibitors at different doses?

``` LOW DOSE: - enhanced muscarinic activity MODERATE DOSE: - further enhancement - increased transmission at all autonomic ganglia HIGH DOSE (TOXIC): - depolarising block at autonomic ganglia and NMJ - overstimulation of nicotinic receptors ```

what do the reversible anticholinesterase drugs physostigmine and neostigmine do?

compete with ACh for active site on the cholinesterase enzyme donates a carbamyl group to the enzyme, blocking the active site and preventing ACh binding carbamyl group is removed by slow hydrolysis (mins) which increases the duration of ACh activity in the synapse

what is physostigmine used to treat and why?

- treats glaucoma (aids IO fluid drainage) - treats atropine poisoning atropine is a competitive muscarinic antagonist and is so surmountable, physostigmine increases the concentration of ACh in the synapse so that it can outcompete atropine

what do the irreversible anticholinesterase drugs such as ecothiopate do?

rapidly react with the enzyme active site, leaving a large blocking group which is stable and resistant to hydrolysis recovery may require the production of new enzymes (days/weeks)

what is ecothiopate used to treat and why?

used as eye drops in glaucoma treatment because it increases IO fluid drainage due to prolonged duration of action

what effects do anticholinesterase drugs have on the CNS?

non-polar anticholinesterases (e.g. physostigmine) can cross the BBB low doses: CNS excitation with possible convulsions high doses: unconsciousness, respiratory depression, death

what is used to treat alzheimer's disease?

donepezil and tacrine (anticholinesterases) ACh is important in learning and memory -> enhancement of central cholinergic transmission relieves AD symptoms and does not affect degeneration

what are non-clinical uses of anticholinesterases and what can exposure to these cause?

insecticides and nerve agents exposure can cause organophosphate poisoning: muscarinic activity -> CNS excitation -> depolarising NM block

what is the treatment for organophosphate poisoning?

- intravenous atropine which is a muscarinic antagonist on the effector organ - patient is put on a respirator because of respiratory destress - if found in the first few hours the patient can be given pralidoxime which unblocks the enzymes