Cholinomimetics

Question 1

what can muscarininc effects be replicated by? abolished by?

Answer 1

• replicated by muscarine

- abolished by low doses of antagonist atropine

Question 2

what happens after atropine blockade of muscarinic receptors?

Answer 2

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

Question 3

what are cholinomimetics?

Answer 3

ACh mimicking drugs

Question 4

what are the 5 receptor subtypes?

Answer 4

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

Question 5

what are M1, M3, M5 (odd)?

Answer 5

Gq

PIP2 –> IP3 + DAG

Question 6

what are M2, M4 (even)?

Answer 6

Gi

cAMP

Question 7

what are nicotinic receptors?

Answer 7

• faster ligand-gates ion channels

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

Question 8

what does the subunit combo determine?

Answer 8

ligand-binding properties of the receptor

Question 9

what are muscle and ganglion types made up of?

Answer 9

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

Question 10

what does the cholinergic innervation in the eye mediate

Answer 10

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

Question 11

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

Answer 11

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

Question 12

what are the muscarinic effects on the heart?

Answer 12

• 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

Question 13

what are the muscarinic effects on the vasculature?

Answer 13

• 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

Question 14

what are the muscarinic effects on the CVS?

Answer 14

dec. HR, CO
vasodilation
= a drop in BP

Question 15

what are the muscarinic effects of Non-vascular SM?

Answer 15

SM with PNS innervation contracts (instead of relax)

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

Question 16

what are the muscarinic effects on exocrine glands?

Answer 16

• salivation
• inc. bronchial and GI secretions
• inc. sweating

Question 17

what are the 2 directly acting cholinomimetic drugs?

Answer 17

agonists

• bethanechol
• pilocarpine

Question 18

what is bethanechol? pharmacokinetics? uses?

Answer 18

• 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

Question 19

what are the side effects of bethanechol?

Answer 19

• blurred vision
• sweating
• nausea
• hypotension
• resp distress
• bradycardia

Question 20

what is pilocarpine? pharmacokinetics? uses?

Answer 20

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

Question 21

what are the side effects of pilocarpine?

Answer 21

• blurred vision
• sweating
• GI pain
• hypotension
• resp distress

Question 22

what do indirectly acting cholinomimetic drugs do?

Answer 22

• inc. effect of normal PNS stimulation

- cholinesterase enzymes metabolise ACh to choline and acetate

Question 23

what are the 2 types of enzymes?

Answer 23

• acetylcholinesterase

- butyrylcholinesterase

Question 24

where is acetylcholinesterase found?

Answer 24

• found in synapses
• rapid action
• highly selective for ACh

Question 25

where is butyrylcholinesterase found?

Answer 25

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

Question 26

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

Answer 26

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

Question 27

what are reversible anticholinesterases? MoA? examples?

Answer 27

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

Question 28

what is physostigmine? what is it used for?

Answer 28

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

Question 29

name some irreversible anticholinesterases. what is the MoA?

Answer 29

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

Question 30

describe ecothiopate. what is it used for?

Answer 30

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

Question 31

what are the side effects of ecothiopate?

Answer 31

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

Question 32

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

Answer 32

• low: excitation with possibility of convulsions

- high: unconsciousness, resp depression, death

Question 33

what drugs are used to treat Alzheimer’s disease?

Answer 33

• donepezil
• tacrine
• potentiation of central cholinergic transmission relieves symptoms but doesn’t affect degeneration

Question 34

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

Answer 34

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