Cholinomimetics

Question 1

What is meant by Cholinomimetics?

Answer 1

Drugs that mimic the action of ACh-mainly with neurological effects

Question 2

How is ACh synthesised and degraded?

Answer 2

AcCOA+Choline with Choline acetyltransferase (CAT)
ACh stored in vesicles, released with Ca2+ enter the cell
ACh in synaptic cleft acts and is broken down immediatly by acetylcholineesterase (in the cleft)

Question 3

What are the muscarinic and nicotinic effects?

Answer 3

Muscarisic effects are those that can be replicated by muscarine-and can be abolished by low dose of atropine
Muscarisic actions correspond parasympathetic-except sweat glands
Nictoinic receptors need more ACh

Question 4

What are the main neurotransmitters used by ANS and where?

Answer 4

PNS-Ach pre, ACh post
SNS-Ach pre and NA post
Ach to adrenal-Na
Rare- ach post ganglionic

Question 5

Where are muscarinic ad nictonic receptors found

Answer 5

Muscarnic receptors are on effector organs of PSNS or some sweat glands
Nictonic receptors are on every “middle part” between pre/post

Question 6

What are the 3 main muscarinic receptors?

Answer 6

M1-Salivary glands, stomach, CNS
M2-heart (slow)
M3: Salivary glands, Bronchiole SM, Sweat glands, eyes
tend to be excitatory action (except M2 (reduce HR)
All are GCPR
M1,3 are IP3/DAG (Gq)
M2- inhbit of cAMP (Gi)
PSNS effects

Question 7

Describe the confirmation of nicotinic receptors

Answer 7

Ion channels–mainly Na+ (in). bit of K out
5 subunits alpha, beta, gamme, delta and epsilon
(any 5 makes a receptor-the combination determines what it binds to)
NMJ Muscle- 2a B delta epsi. ganglions-2a3b -> can be targeted
Effects of ACh on these are weak

Question 8

Describe the muscarinic effects in the Eye

Answer 8

M1
Contraction of cilliary muscle of the eye (accumulate near vision)
Contraction of sphincter pupillae (reduce pupils) and improve drainage of intraoccular fluid (contraction reveal pathway for drainage-canal of schlemm)-use to treat increase
Lacrimation (tears)

Question 9

Describe the muscarinic effects in the heart

Answer 9

M2-Mostly in Atrium and nodes
Reduce cAMP -> reduced Ca2+ entry with reduces contractility, etc CO down (iotropic)
-> increased K+ efflux -decrease Heart rate (bradychardia)
Drop BP
Effect on vasculature combine v low BP

Question 10

Describe the muscarinic effects in the vasculature

Answer 10

Vasculature does not have direct PSNS innervation
But do have muscarinic receptors (M3) -so can be activated by drugs
Stimulate the production of NO-decrease TPR. BP down
More relevant in clinical use of cholinomimetics
Combine with heart effects (drop BP)

Question 11

Describe the muscarinic effects in the Non-vascular smooth muscle

Answer 11

Lung, gut and bladder => causes constriction
Lung -bronchioconstriction
Gut-increased peristalsis
bladder-increase bladder emptying

Question 12

Describe the muscarinic effects in the exocrine glands

Answer 12

Increases :Salivation, bronchial secretion, GI secretions
increases sweating (SNS)

Question 13

What are the 2 main groups od Cholinomimetics?

Answer 13

Either directly acting (agonists) or indirect

Question 14

What are the 2 main groups of directly acting Cholinomimetics?

Answer 14

Choline esters (bethanechol (know that one)-selective to muscarinic) and Alkaloids (pilocarpine)

Question 15

Describe Pilocarpine, its effects and main use

Answer 15

Non selective (M1/2/3) MUSCARINIC agonist
good lipid soluble, t(1/2)= 3-4h
Used as local treatment of glaucoma to drain
Can cause hypotension, respiratory distress, all other effect of Ach

Question 16

Describe bethaecol, effects and main use

Answer 16

V close to ACh-
M3 AcH receptor agonist
Resistant to degradation, orally active and limited brain acess
T1/2=3-4h
Used to increase bladder emptying and enhance gastric motility
Cevimeline -new more M3 selective

Question 17

Describe indirectly acting cholinomimetics

Answer 17

Increase effect of PSNS by inhbiting AcetylCholineesterase
Either reversible (Physostigmine)
or irreversible (Ecothipate)

Question 18

What 2 forms of the cholinesterase enzyme are there?

Answer 18

2 types-acetylcholine esterase-true/specific

Butytrylcholineesterase (pseudo

Question 19

Where do you find Acetylcholinesterase?

Answer 19

Found in every cholinergic synapse-extremly fast and extremely selective
Hydrolysation by serine residue

Question 20

bWhere do you find burtyrylcholinesterase?

Answer 20

Found in plasma and tissue but not in cholinergic
Broad substrate selectivity
why low plasma ACh
can have genetic variation

Question 21

Describe the effects of doses of cholinesterase inhbitors

Answer 21

Low dose- enhances muscarinsic
Moderate dose-Further enhancement, increased transmission of ALL ganglia (nicotinic)
High dose-toxic-depolarisig block of ANS ganglia

Question 22

Describe reversible Anticholinesterase drugs

Answer 22

Competete with ACh in the enzyme
Donates Carbamyl group on the enzyme-blocks it
Removed by hydrolysis slowly-increases ACh lasting

Physostigmine-acts on post ganglionic PSNS syapse
t1/2 30min
used in treatment in glaucoma (for drainage)
Treats atropine poisoning by just allowing more Ach to overcome the block (because atropine is competitive)

Question 23

Describe irreversible Anticholinesterase drugs

Answer 23

Organophosphates
Compete with ACh and leave large blocking group (phosphorylation)-stable, resistant-can take very long time
used as poison or insecticids

Ecothiopate-only clinical used
Activation can take several days
CAn be used for glaucoma-with prolonged duration
systemic are the same as always

Question 24

What are the effects of the Anticholinesterase drugs on the CNS

Answer 24

Non polar can pass the blood barrier
low doses-excitatio
high doses-death

Question 25

What are the treatment of organophosphate poisioning?

Answer 25

Treatent-atropine, atrificial respiratio, prolidoxime (for pre-ganglionic as well-releases the block if given early enough)