01 Cholinergic pharmacology

Question 1

1.01 MUSCARINICS - EYE

Pilocarpine, cevimeline - actions

Answer 1

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

Question 2

1.01 MUSCARINICS - EYE

Pilocarpine, cevimeline - MOA

Answer 2

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

Question 3

1.01 MUSCARINICS - EYE

Pilocarpine, cevimeline - abs/distrib/elim

Answer 3

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

Question 4

1.01 MUSCARINICS - EYE

Pilocarpine, cevimeline - clinical use

Answer 4

glaucoma (narrow and wide angle)
dry mouth due to poor salivary gland function (e.g. Sjogren’s syndrome)

Question 5

1.01 MUSCARINICS - EYE

Pilocarpine, cevimeline - adverse effects

Answer 5

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

Question 6

1.02 ANTIMUSCARINICS - EYE

Atropine, tropicamide, cyclopentolate - actions

Answer 6

muscarinic receptor antagonists
relax smooth muscle of the iris and ciliary body (causing pupillary dilation and paralysis of accommodation)

Question 7

1.02 ANTIMUSCARINICS - EYE

Atropine, tropicamide, cyclopentolate - MOA

Answer 7

competitive reversible antagonism at all muscarinic receptors

Question 8

1.02 ANTIMUSCARINICS - EYE

Atropine, tropicamide, cyclopentolate - abs/distrib/elim

Answer 8

topical preparations vary in their duration of action: tropicamide is short-acting (~6h), cyclopentolate up to 24h, and atropine up to 1 week

Question 9

1.02 ANTIMUSCARINICS - EYE

Atropine, tropicamide, cyclopentolate - clinical use

Answer 9

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)

Question 10

1.02 ANTIMUSCARINICS - EYE

Atropine, tropicamide, cyclopentolate - adverse effects

Answer 10

blurred vision
sensitivity to light due to pupillary dilatation
raised intraocular pressure

Question 11

1.03 ANTIMUSCARINICS - GASTROINTESTINAL

Hyoscine, dicycloverine, atropine, glycopyrronium - actions

Answer 11

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

Question 12

1.03 ANTIMUSCARINICS - GASTROINTESTINAL

Hyoscine, dicycloverine, atropine, glycopyrronium - MOA

Answer 12

competitive reversible antagonism at all muscarinic receptors

Question 13

1.03 ANTIMUSCARINICS - GASTROINTESTINAL

Hyoscine, dicycloverine, atropine, glycopyrronium - abs/distrib/elim

Answer 13

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

Question 14

1.03 ANTIMUSCARINICS - GASTROINTESTINAL

Hyoscine, dicycloverine, atropine, glycopyrronium - clinical use

Answer 14

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

Question 15

1.03 ANTIMUSCARINICS - GASTROINTESTINAL

Hyoscine, dicycloverine, atropine, glycopyrronium - adverse effects

Answer 15

constipation
dry mouth
urinary retention
blurred vision
raised intraocular pressure
drowsiness

Question 16

1.04 ANTIMUSCARINICS - BLADDER

Oxybutynin, tolterodine, trospium, solifenacin - actions

Answer 16

muscarinic receptor antagonists
antispasmodic effect on smooth muscle of bladder
inhibits bladder contraction and increases bladder volume

Question 17

1.04 ANTIMUSCARINICS - BLADDER

Oxybutynin, tolterodine, trospium, solifenacin - MOA

Answer 17

competitive inhibition of muscarinic receptors - some of these agents are thought to be more selective for bladder muscarinic receptors and the M3 receptor

Question 18

1.04 ANTIMUSCARINICS - BLADDER

Oxybutynin, tolterodine, trospium, solifenacin - abs/distrib/elim

Answer 18

given orally
modified-release formulations are available for sustained effect

Question 19

1.04 ANTIMUSCARINICS - BLADDER

Oxybutynin, tolterodine, trospium, solifenacin - clinical use

Answer 19

urinary incontinence or urgency due to idiopathic overactive bladder or neurogenic bladder

Question 20

1.04 ANTIMUSCARINICS - BLADDER

Oxybutynin, tolterodine, trospium, solifenacin - adverse effects

Answer 20

dry eyes, dry mouth
abdominal discomfort

Question 21

1.05 NEUROMUSCULAR BLOCKER

Depolarising agent: succinylcholine (suxamethonium) - actions

Answer 21

nicotinic receptor agonist/depolarising neuromuscular blocker
short-lasting paralysis of skeletal muscle

Question 22

1.05 NEUROMUSCULAR BLOCKER

Depolarising agent: succinylcholine (suxamethonium) - MOA

Answer 22

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

Question 23

1.05 NEUROMUSCULAR BLOCKER

Depolarising agent: succinylcholine (suxamethonium) - abs/distrib/elim

Answer 23

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)

Question 24

1.05 NEUROMUSCULAR BLOCKER

Depolarising agent: succinylcholine (suxamethonium) - clinical use

Answer 24

short-lasting paralysis to aid tracheal intubation and for short operative procedures
action is not reversed by anticholinesterases

Question 25

1.05 NEUROMUSCULAR BLOCKER Depolarising agent: succinylcholine (suxamethonium) - adverse effects

Answer 25

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)

Question 26

1.06 NEUROMUSCULAR BLOCKER Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - actions

Answer 26

non-depolarising neuromuscular blocker paralysis of skeletal muscle

Question 27

1.06 NEUROMUSCULAR BLOCKER Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - MOA

Answer 27

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)

Question 28

1.06 NEUROMUSCULAR BLOCKER Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - abs/distrib/elim

Answer 28

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)

Question 29

1.06 NEUROMUSCULAR BLOCKER Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - clinical use

Answer 29

in general, anaesthesia and intensive care - aids tracheal intubation and mechanical ventilation, provides muscle relaxation for general surgery

Question 30

1.06 NEUROMUSCULAR BLOCKER Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - adverse effects

Answer 30

tachycardia (muscarinic antagonist action)

Question 31

1.06 NEUROMUSCULAR BLOCKER Nicotinic antagonist: pancuronium, vecuronium, rocuronium, mivacurium, etc. - special points

Answer 31

hypotension, skin flushing bronchoconstriction due to histamine release

Question 32

1.07 PERIPHERAL ANTICHOLINESTERASES Neostigmine, pyridostigmine, physostigmine - actions

Answer 32

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

Question 33

1.07 PERIPHERAL ANTICHOLINESTERASES Neostigmine, pyridostigmine, physostigmine - MOA

Answer 33

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

Question 34

1.07 PERIPHERAL ANTICHOLINESTERASES Neostigmine, pyridostigmine, physostigmine - abs/distrib/elim

Answer 34

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

Question 35

1.07 PERIPHERAL ANTICHOLINESTERASES Neostigmine, pyridostigmine, physostigmine - clinical use

Answer 35

neostigmine and pyridostigmine for myasthenia gravis IV neostigmine for reversal of non-depolarising neuromuscular block cholinesterase inhibitors in Alzheimer’s dementia

Question 36

1.07 PERIPHERAL ANTICHOLINESTERASES Neostigmine, pyridostigmine, physostigmine - adverse effects

Answer 36

nausea, vomiting, diarrhoea, hypersalivation, bronchoconstriction unwanted parasympathomimetic actions can be reduced by atropine

Question 37

1.08 NICOTINIC PARTIAL AGONISTS Varenicline - actions

Answer 37

partial agonist activity at nicotinic receptors to alleviate smoking craving and withdrawal reduces the rewarding and reinforcing pattern of smoking by blocking nicotine

Question 38

1.08 NICOTINIC PARTIAL AGONISTS Varenicline - MOA

Answer 38

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

Question 39

1.08 NICOTINIC PARTIAL AGONISTS Varenicline - abs/distrib/elim

Answer 39

given orally, with high bioavailability steady-state reached within 4 days

Question 40

1.08 NICOTINIC PARTIAL AGONISTS Varenicline - clinical use

Answer 40

smoking cessation in adults

Question 41

1.08 NICOTINIC PARTIAL AGONISTS Varenicline - adverse effects

Answer 41

nausea, poor appetite, nightmares