01 Cholinergic pharmacology Flashcards
1.01 MUSCARINICS - EYE
Pilocarpine, cevimeline - actions
muscarinic receptor agonists
parasympathomimetic actions: contract smooth muscle (e.g. gut, bladder, pupil); decrease rate and force of heart beat; increase secretions (e.g. salivary, sweat, gastric acid); inhibit neurotransmitter release
1.01 MUSCARINICS - EYE
Pilocarpine, cevimeline - MOA
action in glaucoma is due to interaction with M3 receptors which couple to Gq to increase cellular IP3 and DAG concentrations
constriction of pupil aids drainage of aqueous humour and lowers intraocular pressure
1.01 MUSCARINICS - EYE
Pilocarpine, cevimeline - abs/distrib/elim
for glaucoma, pilocarpine is given as eye drops and actions last for a day
a slow delivery system placed under the eyelid acts for several days
pilocarpine and cevimeline tablets are taken 3 times daily in patients with dry mouth
1.01 MUSCARINICS - EYE
Pilocarpine, cevimeline - clinical use
glaucoma (narrow and wide angle)
dry mouth due to poor salivary gland function (e.g. Sjogren’s syndrome)
1.01 MUSCARINICS - EYE
Pilocarpine, cevimeline - adverse effects
blurred vision (contraction of ciliary muscle)
topically applied formulations have limited systemic absorption and few adverse effects, whereas the oral formulations can increase gastrointestinal activity and sweating
1.02 ANTIMUSCARINICS - EYE
Atropine, tropicamide, cyclopentolate - actions
muscarinic receptor antagonists
relax smooth muscle of the iris and ciliary body (causing pupillary dilation and paralysis of accommodation)
1.02 ANTIMUSCARINICS - EYE
Atropine, tropicamide, cyclopentolate - MOA
competitive reversible antagonism at all muscarinic receptors
1.02 ANTIMUSCARINICS - EYE
Atropine, tropicamide, cyclopentolate - abs/distrib/elim
topical preparations vary in their duration of action: tropicamide is short-acting (~6h), cyclopentolate up to 24h, and atropine up to 1 week
1.02 ANTIMUSCARINICS - EYE
Atropine, tropicamide, cyclopentolate - clinical use
paralysis of accommodation and pupil dilation for examination of the fundus of the eye (tropicamide)
relief of ciliary spasm in patients with anterior uveitis (atropine, cyclopentolate)
1.02 ANTIMUSCARINICS - EYE
Atropine, tropicamide, cyclopentolate - adverse effects
blurred vision
sensitivity to light due to pupillary dilatation
raised intraocular pressure
1.03 ANTIMUSCARINICS - GASTROINTESTINAL
Hyoscine, dicycloverine, atropine, glycopyrronium - actions
muscarinic receptor antagonists
relax smooth muscle (causing inhibition of peristalsis and reduction of spasm in gastrointestinal tract, etc.)
inhibit secretions (salivary, bronchial, sweat, gastric acid, etc.)
CNS actions: antiemetic, amnesic
1.03 ANTIMUSCARINICS - GASTROINTESTINAL
Hyoscine, dicycloverine, atropine, glycopyrronium - MOA
competitive reversible antagonism at all muscarinic receptors
1.03 ANTIMUSCARINICS - GASTROINTESTINAL
Hyoscine, dicycloverine, atropine, glycopyrronium - abs/distrib/elim
given orally
hyoscine can be administered as transdermal patch for effects lasting 2-3 days
hyoscine butylbromide does not enter the CNS and has mainly gut effects
1.03 ANTIMUSCARINICS - GASTROINTESTINAL
Hyoscine, dicycloverine, atropine, glycopyrronium - clinical use
hyoscine is mainly used in: motion sickness; reduction of salivary and gut secretions as an adjunct for anaesthesia
hyoscine butylbromide and dicycloverine: irritable bowel syndrome and gut spasms
1.03 ANTIMUSCARINICS - GASTROINTESTINAL
Hyoscine, dicycloverine, atropine, glycopyrronium - adverse effects
constipation
dry mouth
urinary retention
blurred vision
raised intraocular pressure
drowsiness
1.04 ANTIMUSCARINICS - BLADDER
Oxybutynin, tolterodine, trospium, solifenacin - actions
muscarinic receptor antagonists
antispasmodic effect on smooth muscle of bladder
inhibits bladder contraction and increases bladder volume
1.04 ANTIMUSCARINICS - BLADDER
Oxybutynin, tolterodine, trospium, solifenacin - MOA
competitive inhibition of muscarinic receptors - some of these agents are thought to be more selective for bladder muscarinic receptors and the M3 receptor
1.04 ANTIMUSCARINICS - BLADDER
Oxybutynin, tolterodine, trospium, solifenacin - abs/distrib/elim
given orally
modified-release formulations are available for sustained effect
1.04 ANTIMUSCARINICS - BLADDER
Oxybutynin, tolterodine, trospium, solifenacin - clinical use
urinary incontinence or urgency due to idiopathic overactive bladder or neurogenic bladder
1.04 ANTIMUSCARINICS - BLADDER
Oxybutynin, tolterodine, trospium, solifenacin - adverse effects
dry eyes, dry mouth
abdominal discomfort
1.05 NEUROMUSCULAR BLOCKER
Depolarising agent: succinylcholine (suxamethonium) - actions
nicotinic receptor agonist/depolarising neuromuscular blocker
short-lasting paralysis of skeletal muscle
1.05 NEUROMUSCULAR BLOCKER
Depolarising agent: succinylcholine (suxamethonium) - MOA
action on nicotinic receptors produces a maintained depolarisation of the muscle membrane
this inactivates the Na+ channels
action potentials fail to spread along the muscle fibres, thus preventing muscle contraction in response to motor nerve activity
1.05 NEUROMUSCULAR BLOCKER
Depolarising agent: succinylcholine (suxamethonium) - abs/distrib/elim
given IV
hydrolysed by plasma cholinesterase within a few minutes (a small percentage of people have an enzyme with much lower activity and action is prolonged)
1.05 NEUROMUSCULAR BLOCKER
Depolarising agent: succinylcholine (suxamethonium) - clinical use
short-lasting paralysis to aid tracheal intubation and for short operative procedures
action is not reversed by anticholinesterases
1.05 NEUROMUSCULAR BLOCKER
Depolarising agent: succinylcholine (suxamethonium) - adverse effects
hyperkalaemia (with possible cardiac arrhythmia)
hypotension, bradycardia
muscle pain (resulting from spasm during the initial depolarisation)
raised intraocular pressure
malignant hyperthermia (rarely, when used with halothane)
1.06 NEUROMUSCULAR BLOCKER
Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - actions
non-depolarising neuromuscular blocker
paralysis of skeletal muscle
1.06 NEUROMUSCULAR BLOCKER
Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - MOA
reversible competitive antagonism at muscle-type nicotinic receptors
inhibits binding of ACh to the receptors at the muscle end-plate
end-plate potential fails to reach threshold for initiation and propagation of the action potential along the muscle fibre
action reversed by anticholinesterases (e.g. neostigmine) or by sugammadex (for vecuronium and rocuronium)
1.06 NEUROMUSCULAR BLOCKER
Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - abs/distrib/elim
given IV
rocuronium and mivacurium have faster onset (1-2min) and shorter duration of action (15min) compared to pancuronium (onset 2-3min, duration 1-2h)
1.06 NEUROMUSCULAR BLOCKER
Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - clinical use
in general, anaesthesia and intensive care - aids tracheal intubation and mechanical ventilation, provides muscle relaxation for general surgery
1.06 NEUROMUSCULAR BLOCKER
Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - adverse effects
tachycardia (muscarinic antagonist action)
1.06 NEUROMUSCULAR BLOCKER
Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - special points
hypotension
skin flushing
bronchoconstriction due to histamine release
1.07 PERIPHERAL ANTICHOLINESTERASES
Neostigmine, pyridostigmine, physostigmine - actions
peripheral cholinesterase inhibitors
parasympathomimetic: increased peristalsis; increased secretions; bradycardia; bronchoconstriction; decreased intraocular pressure
at the neuromuscular junction: fasciculation and increased twitch tension
CNS: agitation and dreaming
1.07 PERIPHERAL ANTICHOLINESTERASES
Neostigmine, pyridostigmine, physostigmine - MOA
reversible inhibition of acetylcholinesterase reduces breakdown of ACh at cholinergic nerve endings, so potentiating transmitter action
binds to both esteratic and anionic sites in the enzyme
the esterase is carbamylated
1.07 PERIPHERAL ANTICHOLINESTERASES
Neostigmine, pyridostigmine, physostigmine - abs/distrib/elim
given IV (to reverse neuromuscular block), by mouth (for myasthenia gravis)
mostly ionised, so low oral bioavailability and poor penetration of the blood-brain barrier
duration of action 2-4h
1.07 PERIPHERAL ANTICHOLINESTERASES
Neostigmine, pyridostigmine, physostigmine - clinical use
neostigmine and pyridostigmine for myasthenia gravis
IV neostigmine for reversal of non-depolarising neuromuscular block
cholinesterase inhibitors in Alzheimer’s dementia
1.07 PERIPHERAL ANTICHOLINESTERASES
Neostigmine, pyridostigmine, physostigmine - adverse effects
nausea, vomiting, diarrhoea, hypersalivation, bronchoconstriction
unwanted parasympathomimetic actions can be reduced by atropine
1.08 NICOTINIC PARTIAL AGONISTS
Varenicline - actions
partial agonist activity at nicotinic receptors to alleviate smoking craving and withdrawal
reduces the rewarding and reinforcing pattern of smoking by blocking nicotine
1.08 NICOTINIC PARTIAL AGONISTS
Varenicline - MOA
binds to α4β2 neuronal nicotinic acetylcholine receptors, but with lower degree of activity than nicotine
also exerts antagonistic effect by preventing nicotine from fully activating the α4β2 receptor
1.08 NICOTINIC PARTIAL AGONISTS
Varenicline - abs/distrib/elim
given orally, with high bioavailability
steady-state reached within 4 days
1.08 NICOTINIC PARTIAL AGONISTS
Varenicline - clinical use
smoking cessation in adults
1.08 NICOTINIC PARTIAL AGONISTS
Varenicline - adverse effects
nausea, poor appetite, nightmares
