nicotinic pharmacology Flashcards
how do nicotinic receptors differ
receptors in autonomic ganglia are different than those in skeletal muscle because they are made up of different subunits
muscle receptors are blocked by tubocurarine
ganglion receptors blocked by hexamethonium (and by tubocuraraine at high concs)
what are steps of cholinergic transmission
choline is taken up into neurone, then Ach is synthesised in cytoplasm and packaged into vesicles before normal NT release mechanisms
how might cholinergic transmission be blocked by drugs
hemicholinium: prevents uptake of choline
yesamicol prevents packaging of Ach into vesicles
botulinum prevents release of Ach
what are acute effects of nicotine physiologically
CNS stimulant effect
increased parasympathetic and sympathetic activity
release of anti diuretic hormone (vasopressin)
smoking does not cause ganglion block but chewing tabacco may
what are physiological effects of ganglion blocking drugs
CV: mainly block sympathetic system at heart, dilation of arterioles and veins causing reduction in blood pressure and loss of CV reflexes
effects in GIT: due to parasympathetic block, inhibition of motility and secretion, leading to constipation
in genito-urinary system: due to both parasympathetic and sympathetic block; impotence
loss of accomodation in eye
name ganglion blocking drugs, are they used therapeutically?
hexamethonium, not used therapeutically
trimetaphan: occasionally used during surgery to produce hypotension
what are mechanisms for NMJ blocking drugs?
block combination of transmitter w receptor
or
production of postsynaptic response
what is a therapeutically used NMJ blocking drug and what is its use and what are other uses of NMJ blockers
suxamethonium: to cause muscle paralysis to help with intubation, has fast onset and short duration, rapidly hydrolysed by plasma cholinesterase so action is only 5 mins, if plasma cholinesterase is low activity can be prolonged up to several hours
reasons for low cholinesterase activity may be genetic, liver disease, malnutrition or anticholinesterase drugs
other uses: for abdominal surgery to reduce amount of anaesthesia needed
what are non depolarising NMJ blockers, how do they work and what are their effects
they are competitive blockers, work as regular competitive antagonists
usually have long residence in binding site
cause relaxation without preliminary excitation of muscles
relaxant effect is antagonised by anticholinesterases
myasthenia gravis patients more sensitive
tetanic fade is more pronounced
tubocuraraine is competitive blocker
what are depolarising blockers and how do they work and what are their effects
they are nAch receptor agonists, resistant to hydrolysis by cholinesterase
cause sustained depolarisation of endplate of muscle fibre
causes muscle fibre membrane to become inexcitable because sodium channels around endplate inactivate
only example in use is suxamethonium
what are features of depolarising block of the NMJ?
initial fasciculation (twitching) due to initial depolarisation
may cause hyperkalaemia
what is effect of botulinum toxin (botox)?
blocks cholinergic transmission by blocking release of Ach, does not affect post synaptic mechanisms
blocks at NMJ and ganglia
what are the 2 endogenous cholinesterases?
where are they found
acetylcholinesterase: a true cholinesterase, found at all cholinergic synapses and in red blood cells, is specific to Ach and similar esters
butyrylcholinesterase: a pseudo cholinesterase, found in plasma, liver and many other tissues, low specificity, can hydrolyse other esters, quicker than AchE
what is the catalytic site on cholinesterase
catalytic site on cholinesterase is also called the esteratic site, contains reactive serine OH group
ChE also has an anionic site which binds cationic quaternary ammonium group of Ach
how is Ach hydrolysed
Ach binds to 2 sites on cholinesterase
Ach then transfers acetyl group to serine OH of ChE
choline group dissociates and there is spontaneous hydrolysis of acetylated OH group
what is turnover rate of cholinesterase
10,000 molecules of Ach per second, Ach released at NMJ normally hydolysed in less than one ms
describe a short acting anticholinesterase
edrophonium:
quaternary ammonium group
no group complementary to esteratic site
competitive antagonists by binding to the anionic site via an ionic bond
what type of anti cholinesterases are there
short acting cholinesterase, medium or long acting reversible cholinesterase, long acting or irreversible cholinesterase
describe medium/ long reversible acting anti cholinesterases
e.g: eserine and neostigimine
bind to both sites and forms an ester bond with serine hydroxyl group of esteratic site
spontaneous hydrolysis is much slower when hydroxyl group is bound to neostigimine than when it is bound to an acetyl group and so enzyme molecule is inactive for several minutes
describe long acting/ irreversible anticholinesterases
e.g DFP and organophosphates
phosphorylate the serine OH
hydrolysis of phosphorylated enzyme is negligibly slow and recovery requires synthesis of new enzyme
what are physiological peripheral effects of anticholinesterases
parasympathetic effects: salivation, sweating, increased GIT motility causing vomiting and diarrhoea, bronchoconstrction, bradycardia, pupillary constriction and fall in intraocular pressure
NMJ:
repetitive firing at normal junctions,
restoration of transmission at junctions blocked by competitive blocking agents or in myasthenia gravis
alongside high doses of Ach, there is build up causing depolarising muscular block
what are central effects of anticholinesterases
mainly excitatory, leading to agitation and convulsions, followed by respiratory depression
what are therapeutic uses of anticholinesterases
treatment of glaucoma through eye drops of eserine or organophosphate
myasthenia gravis, use of quaternary compounds as they do not reach the brain
reversal of NMJ block following anaesthesia
alleviation of alzheimers symptoms
how might irreversible anticholinesterases by antagonised, and why is this used
cholinesterase reactivators: after being phosphorylated cholinesterase can be reactivated by oxime compounds
pralidoxime binds reversibly to anionic site, the oxime hydroxyl is at the right distance to react with phosphate group for substitution reaction
treatment of organophosphate poinsoning due to insecticides
