parasympathetic nervous system Flashcards
anticholinesterases: identify the explain the clinical uses and pharmacokinetic properties of anticholinesterase drugs
examples of reversible anticholinesterases
physostigmine, neostigmine, donepezil (Aricept - Alzheimer’s disease)
examples of irreversible anticholinesterases
ecothiopate (organophosphate), (dyflos, sarin - used as nerve gases)
what do cholinesterase enzymes do
metabolise ACh to choline and acetate
2 types of cholinesterase enzyme (differ in distribution, substrate specificity and function)
acetylcholinesterase (true/specific cholinesterase), butyrylcholinesterase (pseudocholinesterase)
where is acetylcholinesterase found
all cholinergic synapses (peripheral and central)
time frame of acetylcholinesterase hydrolysis
very rapid (>10000 reactions per second)
how are acetylcholinesterase highly selective for ACh
in active site of acetylcholinesterase, exposed OH on serine allows hydrolysis of acetate group on ACh
where is butyrylcholinesterase found
in plasma and most tissues but not cholinergic synapses
how does butyrylcholinesterase show broad substrate specificity, and its impact on plasma ACh
hydrolyses other esters e.g. suxamethonium, and causes low plasma ACh; shows genetic variation (so people respond differently to drugs like suxamethonium)
effect of low dose cholinesterase inhibitors
enhanced muscrinic activity
2 effects of moderate dose cholinesterase inhibitors
further enhancement of muscarinic activity, increased transmission at all ANS ganglia (nAChRs)
effect of high dose (toxic) cholineserase inhibitors
depolarising block at all ANS ganglia and NMJ (inactivating receptors and causing respiratory depression)
how do reversible anticholesterase drugs function
compete with ACh for active site on cholinesterase enzyme
how do reversible anticholesterase drugs (e.g. physostigmine) prevent ACh from binding
donate a carbamyl group to AChE enzyme, binding to serine and blocking active site
reversible anticholesterase drugs e.g. physostigmine: how is the donated carbamyl group removed, and impact
slow hydrolysis (mins rather than msecs), increases duration of ACh activity in synapse
where does physostigmine primarily act
at postganglionic PSNS synapse (half life of 30 mins)
what is physostigmine used to treat
glaucoma by aiding intraocular fluid drainage, treat atropine (competitive ACh antagonist) poisoning (esp. in children) by effectively raising ACh level
examples of irreversible anticholesterase drugs
organophosphate compounds such as ecothiopate, dyflos, parathion and sarin
how do irreversible anticholesterase drugs work
rapidly react with enzyme active site, leaving large blocking group which is stable and resistant to hydrolysis
how does the body overcome irreversible anticholesterase drugs
may require production of new enzymes, taking days or weeks
what irreversible anticholesterase drug is in clinical use
ecothiopate (potent inhibitor of AChE); others used as insecticides or nerve gases
what is ecothiopate used to treat
eye drops for glaucoma, acting to increase intraocular drainage with prolonged duration of action as slow reactivation of enzyme by hydrolysis takes several days
systemic side effects of ecothiopate
over stimulating muscarinic receptors so sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty
what can non-polar anticholinesterases like physostigmine do
cross the BBB so cause CNS effects
effects of low doses of non-polar anticholinesterases
excitation with possibility of convulsions
effects of high doses of non-polar anticholinesterases
unconsciousness, respiratory depression, death
