Cholinomimetics Flashcards
What is meant by Cholinomimetics?
Drugs that mimic the action of ACh-mainly with neurological effects
How is ACh synthesised and degraded?
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)
What are the muscarinic and nicotinic effects?
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
What are the main neurotransmitters used by ANS and where?
PNS-Ach pre, ACh post
SNS-Ach pre and NA post
Ach to adrenal-Na
Rare- ach post ganglionic
Where are muscarinic ad nictonic receptors found
Muscarnic receptors are on effector organs of PSNS or some sweat glands
Nictonic receptors are on every “middle part” between pre/post
What are the 3 main muscarinic receptors?
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
Describe the confirmation of nicotinic receptors
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
Describe the muscarinic effects in the Eye
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)
Describe the muscarinic effects in the heart
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
Describe the muscarinic effects in the vasculature
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)
Describe the muscarinic effects in the Non-vascular smooth muscle
Lung, gut and bladder => causes constriction
Lung -bronchioconstriction
Gut-increased peristalsis
bladder-increase bladder emptying
Describe the muscarinic effects in the exocrine glands
Increases :Salivation, bronchial secretion, GI secretions increases sweating (SNS)
What are the 2 main groups od Cholinomimetics?
Either directly acting (agonists) or indirect
What are the 2 main groups of directly acting Cholinomimetics?
Choline esters (bethanechol (know that one)-selective to muscarinic) and Alkaloids (pilocarpine)
Describe Pilocarpine, its effects and main use
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
Describe bethaecol, effects and main use
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
Describe indirectly acting cholinomimetics
Increase effect of PSNS by inhbiting AcetylCholineesterase Either reversible (Physostigmine) or irreversible (Ecothipate)
What 2 forms of the cholinesterase enzyme are there?
2 types-acetylcholine esterase-true/specific
Butytrylcholineesterase (pseudo
Where do you find Acetylcholinesterase?
Found in every cholinergic synapse-extremly fast and extremely selective
Hydrolysation by serine residue
bWhere do you find burtyrylcholinesterase?
Found in plasma and tissue but not in cholinergic
Broad substrate selectivity
why low plasma ACh
can have genetic variation
Describe the effects of doses of cholinesterase inhbitors
Low dose- enhances muscarinsic
Moderate dose-Further enhancement, increased transmission of ALL ganglia (nicotinic)
High dose-toxic-depolarisig block of ANS ganglia
Describe reversible Anticholinesterase drugs
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)
Describe irreversible Anticholinesterase drugs
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
What are the effects of the Anticholinesterase drugs on the CNS
Non polar can pass the blood barrier
low doses-excitatio
high doses-death
What are the treatment of organophosphate poisioning?
Treatent-atropine, atrificial respiratio, prolidoxime (for pre-ganglionic as well-releases the block if given early enough)
