Cholinomimetics Flashcards
what produces muscarinic effects?
how are they stopped?
replicated by muscarine
stopped by low doses of antagonist atropine
after atropine blockade, larger doses of ACh has similar effect like nicotine
what are cholinomimetics?
ACh mimicking drugs acting almost exclusive on the PNS with the exception of the sweat glands that have sympathetic innervation
what are the main types of muscarinic receptors and where are they located?
M1- CNS, salivary glands, stomach
M2- heart
M3- salivary, sweat glands, bronchial/visceral smooth muscle, eye
which muscarinic receptors are stimulatory and inhibitory
M1, M3, (M5) are stimulatory
M2, (M4) are inhibitory
what G protein and secondary messengers are involved in the muscarinic receptors>?
M1 and M3 have Gq- [PIP2–> IP3 +DAG]
M2 have Gi- [cAMP]
nicotinic receptors
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
how many and which subunits make up the nicotinic receptors?
alpha, beta, gamma, delta, epsilon
muscle type: 2 alpha, beta, delta, epsilon
ganglion type: 2 alpha, 3 beta
what do the subunits determine
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
what are the muscarinic cholinergic target sites
the eye salivary glands lungs bladder vasculature gut heart
muscarinic effects on the eye(M3)
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
role of the sphincter papillae in preventing glaucoma
opens pathway for aqueous humour (produced by ciliary body), allowing its draining through the Canals of Schlemm thus reducing IOP, preventing glaucoma
muscarinic effects on the heart (M2)
receptors are located mainly in the atria and the nodes
they have a depressing effect on the heart
mediated by cAMP
effect of the reduction of cAMP on the heart
decreased Ca2+ entry –>reduces CO
increased K+ efflux–> decreased HR
muscarinic effects on vasculature (M3)
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
muscarinic effects on CVS (M2)
decreased HR and CO
vasodilation
drop in BP
muscarinic effects in non-vascular smooth muscle
smooth muscles with PNS innervation contract
lungs bronchoconstrict
gut- increased peristalsis
bladder- increased emptying
muscarinic effects on exocrine glands
salivation
increased bronchial and GI secretions
increased sweating
summary of muscarinic effects
Decreased HR and BP. Increased sweating, salivation and lacrimation. Difficulty breathing. Bladder contraction. GI pain.
directly acting cholinomimetic drugs categories
1) choline esters e.g bethanechol –> bladder emptying
2) alkaloids e.g. pilocarpine–>glaucoma
bethanechol
M3 AchR selective agonist
not metabolised readily by ACh esterase
limited access to brain (3-4 hr HL)
orally active
bethanechol use and side effects
use: bladder emptying, enhance gastric motility
side effects: blurred vision, sweating, nausea, hypotension, respiratory distress, bradycardia
pilocarpine
non-selective agonist
lipid soluble therefore locally administered as eye drops
3-4 hr HL
pilocarpine use and side effects
use: treatment of glaucoma
side effects: blurred vision, sweating, GI pain, hypotension, respiratory distress
new drug
Cevimeline
M3 selective, more than bethanechol
indirectly acting cholinomimetics
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
ACh degrading enzymes
1) acetylcholinestrase
2) butyrylcholinesterase
acetylcholinesterase
true/specific enzyme found only in synapses
rapid action
highly selective for ACh
butyrylcholinesterase
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
effects of cholinesterase inhibitors at different doses
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
examples of reversible anticholinesterases
physostigmine
neostigmine
donepezil
what is the MoA of reversible anticholinesterases?
donate carbamyl group to enzyme active site to block it (competitive)
carbamyl group is hydrolysed slowly (mins) therefore longer acting
physostigmine
non selective mAChR agonist:
- acts on postganglionic PNS synapse
- non-polar so it crosses BBB readily
- treat glaucoma
- treat atropine poisoning
examples of irreversible anticholinesterases
ecothiopate, dyflos, sarin
these are organosphate compounds
irreversible anticholinesterases
rapidly react with enzyme active site leaving a large blocking group
stable and resistant to hydrolysis
ecothiopate
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
what drugs are used to treat Alzheimers
donepezil and tacrine
low dose and high dose effects of physostigmine
low- excitations with possibility of convulsions
high- unconsciousness, respiratory depression, death
organophosphate poisoning treatment
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
what is the difference between acetylcholinesterase and butrylcholinesterases?
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.
Butyrylcholinesterase selectivity and effect on drug action
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.
what is the mechanisms by which ACh is broken down by acetylcholinesterase?
ACh binds to enzyme so enzymes becomes acetylated
the acetylated enzyme breaks down choline
leaves with acetate and free enzyme
how do reversible anticholinesterases inhibit the enzyme?
carbamyl esters like physostigmine and neostigmine inactivate the enzyme by transferring their carbamyl group
the carbamylated enzyme is slowly reactivated by hydrolysis
how do irreversible anticholinesterases inhibit the enzyme?
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
