Cholniomimetics Flashcards
Give the 3 main muscarinic receptor subtypes and whether they are excitatory or inhibitory
M1 CNS - excitation Salivary Glands Stomach - stimulates release of HCl M2 Heart - decreases heart rate M3 Salivary Glands Bronchial/Visceral Smooth Muscle Sweat Glands Eye
What is the muscarinic effects on the vasculature
M3 receptors on endothelial cells are stimulated to release NO to cause vasodilation
Muscarinic effects on non-vascular smooth muscle
CONTRACTION:
Lungs - bronchoconstriction
Gut - increased peristalsis/motility
Bladder - increased bladder emptying
Describe the use of bethanechol
M3 Selective receptor agonist
Similar to ACh in structure but extra CH3 group makes it resistant to degradation
Used for help in gastric motility and bladder emptying
Half life of 3-4 hours
Orally active
Describe the use of pilocarpine
Non-selective muscarinic agonist Stimulates all muscarinic receptors Used in glaucoma Half life 3-4 hours Less effective in GI smooth muscle and heart
Give examples of reversible and irreversible anticholinesterases
Reversible: Phygostigmine, neostigtmine, donepezil
Irreversible: Ecothiopate, Dyflos, Sarin
What are the two cholinesterase enzymes?
Acetylcholinesterase; found in ALL cholinergic synapses, very rapid, highly selective for ACh
Butrylcholinesterase; not found in cholinergic synapses, found in plasma and most tissues. Broad substrate specificity (e.g. hydrolyses suxamethonium). Genetic variation influences duration of action. Low plasma ACH levels is due to it.
What are the effects of cholinesterase inhibitors at various doses?
LOW dose
Enhanced muscarinic activity
MODERATE dose
Further enhancement of muscarinic activity
Increased transmission at ALL autonomic ganglia (nAChRs)
This is because the anticholinesterase increases the acetylcholine concentration at ALL cholinergic synapses, muscarinic and nicotinic
HIGH dose
Depolarising block at autonomic ganglia and neuromuscular junction
The nicotinic receptors get overstimulated so they shut down
How do reversible anticholinesterases work?
They compete ACh for the active site on Acetylcholinesterase. They donate a carbamyl group to the active site so ACh cannot bind. This can only be broken by hydrolysis (minutes rather than ms). Increases duration of ACh in synapse.
Describe uses of Physostigmine
Used in treatment of glaucoma and atropine poisoning (surmountable reaction as it is competitive and it increases amount of ACh in synapse).
Acts on post-ganglionic parasympathetic synapse
half life of 30mins
Tertiary amine
Describe uses of Ecothiopate
Potent inhibitor of acetylcholinesterase
Slow reactivation of the enzyme takes several days
Used in treatment of glaucoma
How do irreversible anticholinesterases work?
They react with the active site and leave a large blocking group on acetylcholinesterase. It is stable and resistant to hydrolysis. Must make new enzymes to recover the cholinesterase active site (takes weeks)
What are the main side effects of parasympathetic discharge?
Increased sweating Blurred vision Nausea Gut pain Respiratory difficulty Bradycardia Low blood pressure
What is the significance of non-polar anti cholinesterase drugs?
They are able to cross the BBB (e.g. physostigmine). At low doses they lead to CNS excitation + possible convulsion but at high doses may lead to unconsciousness and death
What are the uses of Donepezil and Tacrine
Used in Alzhemier’s disease, ACh is important in learning and memory. They relieve symptoms (potentiates central cholinergic transmission) but do not stop degeneration.
