Pharmacology of cholergenic transmission Flashcards
what is acetylcholine?
neurotransmitter
- charged signalling molecule that is very soluble in water and is very flexible
why is Ach charged
due to acetyl end
what does Ach do
released from nerves at synapses and acts on postsynaptic target cells
what three systems is Ach a neurotransmitter in
somatic - NMJ
autonomic - ganglionic synapses and parasympathetic neuroeffector synapses
CNS
what distinguishes the two families of cholinergic receptors
nicotine
muscarine
describe nicotinic receptors
ionotropic (ligand gated ion channels - allows direct binding of Ach)
- main categories are autonomic ganglionic and muscle
- made up of 5 sub units with 2 alpha groups to which the Ach binds
describe muscarinic receptors
metabotropic (coupled to ion channels, transported and enzymes by G proteins 5 types (M1-5) 1,2,3 are important in peripheral tissues
what is similar and different between nicotinic and muscarinic receptors
pre synaptic mechanisms (synth, storage and release of ach) are similar but post synaptic are very different depending on the type of target cell
pre synaptic events in cholinergic neurotransmission
- ach synthesised from choline and acetyl coenzyme A by the action of choline acetyl transferase
- ach is stored in synaptic vesicles that are released by the process of exocytosis triggered by a rise in intracellular Ca conc within nerve terminal
which drugs act pre-synaptically to inhibit cholinergic neurotransmission
–must affect either storage synthesis or release
synth - hemicholiniums
storage - AH5183
release - botulinum toxin
where is botulinum toxin from
clostridium botulinum - found in uncooked foods and its ingestion gives rise to botulism
what is the lethal dose of botox in mice
10^-12 g
what do the toxin in botox do
- cause death due to paralysis of respiratory muscles
- toxin destroys key proteins involved in exocytosis
what is botox currently used to treat?
blepharospasm - involuntary tight closure of the eyelids
and in cosmetic medicine
what is botox being developed for use
hyperhidrosis - excessive sweating, bladder hyperactivity, migraine, spasticity associated with MS and cerebral palsy
post synaptic events in cholinergic transmission
-ach diffuses across synaptic cleft and activates either nicotinic or muscarinic receptors depending on synapse involved
ach broken down by acetylcholine esterase
what does AchE do
destroys ester bonds in Ach and choline part is taken back up into the nerve and recycled
clinical uses of drugs acting at nicotinic receptors
- no uses of nicotinic receptor agonists
- muscle relaxants
- ganglion blockers
how do drugs work as muscle relaxants
reversible competitive antagonists
- bind to receptor but do not open the associated channel
- prevent Ach activating the receptor
what are effects of drugs acting as ganglion blockers?
reduction in blood pressure
these drugs are mostly used experimentally
example of ganglion blocker and its use
trimetaphan - reduces bleeding during surgery
what do muscarinic receptor agonists do
mimic the effect of the parasympathetic NS
- act as parasympathoMIMETICS
what do muscarinic receptor antagonists do
block the effects of the parasympathetic NS
- act as parasympathoLYTICS
what are some parasympathetic agonist effects?
reduction of HR
stimulation of gut and bladder
contraction of bronchi
constrict pupils
clinical uses of muscarinic receptor agonists
pilocarpine - eye drops used in treatment of glaucoma
- also used to detect CF from a sweat test
bethanacol - used as stimulant laxative and to treat urinary retention
clinical uses of muscarinic receptor antagonists
atropine - bradychardia
tropicamide - dilate pupils
ipratropium - asthma COPD
what drugs can inhibit AchE
neostigmine
edrophonium
what is neostigmine used for
AchE inhibitor
to clinically reverse the effects of reversible, competitive antagonists muscle relaxants t skeletal NMJ
- can also be used in myasthenia gravis
what AchE inhibitors have been shown to benefit Alzheimer’s
donepezil
rivastigmine
