Cholinomimetics Flashcards by Stephanie Dunn

what can muscarininc effects be replicated by? abolished by?

replicated by muscarine

- abolished by low doses of antagonist atropine

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what happens after atropine blockade of muscarinic receptors?

larger doses of ACh can induce similar effects similar to those caused by nicotine

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what are cholinomimetics?

ACh mimicking drugs

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what are the 5 receptor subtypes?

M1 - salivary glands, stomach, CNS
M2 - heart
M3 - salivary + sweat glands, bronchial/visceral SM, eye
M4,5 - CNS

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what are M1, M3, M5 (odd)?

PIP2 –> IP3 + DAG

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what are M2, M4 (even)?

cAMP

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what are nicotinic receptors?

faster ligand-gates ion channels

- 5 subunits (alpha, beta, gamma, delta, epsilon)

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what does the subunit combo determine?

ligand-binding properties of the receptor

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what are muscle and ganglion types made up of?

muscle: 2 alpha, beta, delta, epsilon
ganglion: 2 alpha, 3 beta

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what does the cholinergic innervation in the eye mediate

ciliary muscle contraction: near vision
sphincter pupillae contraction: miosis and drainage of intra-ocular fluid
lacrimation: tears

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describe normal drainage of aqueous humour. how is this different in glaucoma?

contraction of sphincter pupillae opens pathway for aqueous humour
allows drainage via Canals of Schlemm thus reducing IOP
glaucoma impeded

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what are the muscarinic effects on the heart?

M2 AChR are located mainly in atria and nodes
depressing effect on heart (Gi muscarinic receptors)
mediated by: reduction of cAMP, dec. Ca entry = dec. CO, inc. K efflux = dec. HR

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what are the muscarinic effects on the vasculature?

most blood vessels don’t have PNS innervation
ACh acts on vascular endothelial cells to stimulate NO release via M3 AChR
NO acts on vascular SM and relaxes it
dec. TPR

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what are the muscarinic effects on the CVS?

dec. HR, CO
vasodilation
= a drop in BP

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what are the muscarinic effects of Non-vascular SM?

SM with PNS innervation contracts (instead of relax)

lungs: bronchoconstriction
gut: inc. peristalsis (motility)
bladder: inc. bladder emptying

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what are the muscarinic effects on exocrine glands?

salivation
inc. bronchial and GI secretions
inc. sweating

what are the 2 directly acting cholinomimetic drugs?

agonists

bethanechol
pilocarpine

what is bethanechol? pharmacokinetics? uses?

choline ester
M3 AChR selective agonist
resistant to degradation
orally active
limited access to brain (half life around 4 hours)
used to aid bladder emptying and enhance GI motility

what are the side effects of bethanechol?

blurred vision
sweating
nausea
hypotension
resp distress
bradycardia

what is pilocarpine? pharmacokinetics? uses?

non selective muscarinic agonist with good lipid solubility
half life =3/4 hours
used to treat glaucoma

what are the side effects of pilocarpine?

blurred vision
sweating
GI pain
hypotension
resp distress

what do indirectly acting cholinomimetic drugs do?

inc. effect of normal PNS stimulation

- cholinesterase enzymes metabolise ACh to choline and acetate

what are the 2 types of enzymes?

acetylcholinesterase

- butyrylcholinesterase

where is acetylcholinesterase found?

found in synapses
rapid action
highly selective for ACh

where is butyrylcholinesterase found?

- found in plasma and most tissues - NOT in synapses - broad substrate specificity - principal reason for low plasma ACh - shows genetic variation

what are the effects of cholinesterase inhibitors at low, moderate and high doses?

low: enhanced muscarinic activity moderate: further enhancement, inc. transmission at ALL ANS ganglia High dose: toxic, depolarising block at ANS ganglia and NMJ

what are reversible anticholinesterases? MoA? examples?

- physostigmine, neostigmine, donepezil - donate a carbamyl group to enzyme active site, blcoking it - carbamyl group removed via slow hydrolysis

what is physostigmine? what is it used for?

- tertiary amine - acts at postganglionic PNS synpase - treat glaucoma (aids IOP reduction) - used to treat atropine poisoning

name some irreversible anticholinesterases. what is the MoA?

- Ecothiopate, dyflos, sarin - all organophosphate compounds - rapidly react to enzyme active site and leave a large blocking group

describe ecothiopate. what is it used for?

- potent inhibitor of acetylcholinesterases - slow reactivation of enzyme takes several days - used to treat glaucoma (eye drops) with prolonged duration of action

what are the side effects of ecothiopate?

- sweating - blurred vision - GI pain - bradycardia - hypotension - resp difficulty

non-polar anticholinesterases e.g. physostigmine can cross BBB. what do low doses and high doses cause?

- low: excitation with possibility of convulsions | - high: unconsciousness, resp depression, death

what drugs are used to treat Alzheimer's disease?

- donepezil - tacrine - potentiation of central cholinergic transmission relieves symptoms but doesn't affect degeneration

what is severe organophosphate poisoning caused by? how do you treat it?

accidental exposure to organophosphates used in insecticides/ nerve gas treatment: IV atropine, artificial resp, IV pralidoxime