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LCRS Pharma > Cholinomimetics > Flashcards

Cholinomimetics Flashcards

1
Q

what produces muscarinic effects?

how are they stopped?

A

replicated by muscarine
stopped by low doses of antagonist atropine

after atropine blockade, larger doses of ACh has similar effect like nicotine

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2
Q

what are cholinomimetics?

A

ACh mimicking drugs acting almost exclusive on the PNS with the exception of the sweat glands that have sympathetic innervation

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3
Q

what are the main types of muscarinic receptors and where are they located?

A

M1- CNS, salivary glands, stomach
M2- heart
M3- salivary, sweat glands, bronchial/visceral smooth muscle, eye

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4
Q

which muscarinic receptors are stimulatory and inhibitory

A

M1, M3, (M5) are stimulatory

M2, (M4) are inhibitory

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5
Q

what G protein and secondary messengers are involved in the muscarinic receptors>?

A

M1 and M3 have Gq- [PIP2–> IP3 +DAG]

M2 have Gi- [cAMP]

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6
Q

nicotinic receptors

A

type 1 receptors with ion channel links

  • they are faster, ligand gated
  • located in muscle and ganglia
  • 5 subunits
  • ACh has weak effect on them
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7
Q

how many and which subunits make up the nicotinic receptors?

A

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

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8
Q

what do the subunits determine

A

the different combinations of the subunits determine the ligand binding properties of the receptor
ACh has a weak effect on the receptors so a lot is required

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9
Q

what are the muscarinic cholinergic target sites

A 
the eye
salivary glands 
lungs
bladder
vasculature 
gut 
heart
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10
Q

muscarinic effects on the eye(M3)

A

1) contraction of ciliary muscle for accommodation to near vision
2) contraction of sphincter pupillae- miosis and drainage of intraocular fluid (reduce intraocular pressure)
3) lacrimation- tears

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11
Q

role of the sphincter papillae in preventing glaucoma

A

opens pathway for aqueous humour (produced by ciliary body), allowing its draining through the Canals of Schlemm thus reducing IOP, preventing glaucoma

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12
Q

muscarinic effects on the heart (M2)

A

receptors are located mainly in the atria and the nodes
they have a depressing effect on the heart
mediated by cAMP

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13
Q

effect of the reduction of cAMP on the heart

A

decreased Ca2+ entry –>reduces CO

increased K+ efflux–> decreased HR

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14
Q

muscarinic effects on vasculature (M3)

A

does not have direct PNS innervation

ACh acts on endothelial to release NO via M3 AchR
NO acts on vascular smooth muscles and relaxes it

leads to decreased TPR

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15
Q

muscarinic effects on CVS (M2)

A

decreased HR and CO
vasodilation

drop in BP

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16
Q

muscarinic effects in non-vascular smooth muscle

A

smooth muscles with PNS innervation contract

lungs bronchoconstrict
gut- increased peristalsis
bladder- increased emptying

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17
Q

muscarinic effects on exocrine glands

A

salivation
increased bronchial and GI secretions
increased sweating

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18
Q

summary of muscarinic effects

A 
	Decreased HR and BP.
	Increased sweating, salivation and lacrimation. 
	Difficulty breathing.
	Bladder contraction.
	GI pain.
19
Q

directly acting cholinomimetic drugs categories

A

1) choline esters e.g bethanechol –> bladder emptying

2) alkaloids e.g. pilocarpine–>glaucoma

20
Q

bethanechol

A

M3 AchR selective agonist
not metabolised readily by ACh esterase
limited access to brain (3-4 hr HL)
orally active

21
Q

bethanechol use and side effects

A

use: bladder emptying, enhance gastric motility

side effects: blurred vision, sweating, nausea, hypotension, respiratory distress, bradycardia

22
Q

pilocarpine

A

non-selective agonist
lipid soluble therefore locally administered as eye drops
3-4 hr HL

23
Q

pilocarpine use and side effects

A

use: treatment of glaucoma

side effects: blurred vision, sweating, GI pain, hypotension, respiratory distress

24
Q

new drug

A

Cevimeline

M3 selective, more than bethanechol

25
Q

indirectly acting cholinomimetics

A

they target ACh degrading enzymes i.e. ACh esterase
increase normal PNS stimulation as ACh remains

e. g. ecothiopate (irreversible) used for glaucoma
e. g. physostigmine (reversible) used for atropine poisoning

26
Q

ACh degrading enzymes

A

1) acetylcholinestrase

2) butyrylcholinesterase

27
Q

acetylcholinesterase

A

true/specific enzyme found only in synapses
rapid action
highly selective for ACh

28
Q

butyrylcholinesterase

A

found in plasma and most tissues , not in synapses
broad substrate specificity
leads to the low conc of ACh in the plasma
shows genetic variation

29
Q

effects of cholinesterase inhibitors at different doses

A

low dose- enhanced muscarinic activity

moderate dose- further enhancement and increased transmission at all ANS ganglia

high dose- becomes toxic having a depolarising block effect on ANS ganglia and NMJ

30
Q

examples of reversible anticholinesterases

A

physostigmine
neostigmine
donepezil

31
Q

what is the MoA of reversible anticholinesterases?

A

donate carbamyl group to enzyme active site to block it (competitive)
carbamyl group is hydrolysed slowly (mins) therefore longer acting

32
Q

physostigmine

A

non selective mAChR agonist:

  • acts on postganglionic PNS synapse
  • non-polar so it crosses BBB readily
  • treat glaucoma
  • treat atropine poisoning
33
Q

examples of irreversible anticholinesterases

A

ecothiopate, dyflos, sarin

these are organosphate compounds

34
Q

irreversible anticholinesterases

A

rapidly react with enzyme active site leaving a large blocking group
stable and resistant to hydrolysis

35
Q

ecothiopate

A

potent inhibitor
slow reactive of the enzymes it binds to (several days)
treatment of glaucoma

side effects: sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty

36
Q

what drugs are used to treat Alzheimers

A

donepezil and tacrine

37
Q

low dose and high dose effects of physostigmine

A

low- excitations with possibility of convulsions

high- unconsciousness, respiratory depression, death

38
Q

organophosphate poisoning treatment

A

IV atropine, artificial respiration, IV pralidoxine (causes unbinding)

caused by nerve gas like sarin that caused a depolarising NMJ block

phosphorylated enzyme ages within a few hours so the patient needs to be kept alive till then

39
Q

what is the difference between acetylcholinesterase and butrylcholinesterases?

A

Acetylcholinesterase: Is found in all cholinergic synapses in the periphery

Butyrylcholinesterase is not associated with cholinergic synapses but is found in many tissues (e.g. liver, skin) and in plasma.

40
Q

Butyrylcholinesterase selectivity and effect on drug action

A

broader substrate specificity than AChE and hydrolyses other esters such as suxamethonium

shows genetic variance which influences the duration of action of the drugs it normally metabolises.

41
Q

what is the mechanisms by which ACh is broken down by acetylcholinesterase?

A

ACh binds to enzyme so enzymes becomes acetylated

the acetylated enzyme breaks down choline

leaves with acetate and free enzyme

42
Q

how do reversible anticholinesterases inhibit the enzyme?

A

carbamyl esters like physostigmine and neostigmine inactivate the enzyme by transferring their carbamyl group

the carbamylated enzyme is slowly reactivated by hydrolysis

43
Q

how do irreversible anticholinesterases inhibit the enzyme?

A

organophosphorus compounds like ecothiopate

labile group (fluoride or organic) can inactivate the enzyme by phosphorylation

the inactive enzyme is in a stable state and therefore reactivation can take weeks

its better off synthesising new enzymes

LCRS Pharma (32 decks)

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