Cholinergic pharma

Pilocarpine

A muscarinic agonist

Pilocarpine actions

Parasympathetic:

-Contracts smooth muscle

-Decreases heart rate and force of contraction

-Promotes glandular secretion

-Inhibits neurotransmitter release

Pilocarpine mode of action

-Interacts with M3 receptors that couple with Gq so increase concentration of DAG and IP3

-Constricts pupils to aid drainage of aqueous humour and lower intraocular pressure

Pilocarpine administer

For glaucoma given via eye drops and action lasts for days.

Pilocarpine clinical use

-Glaucoma

-Bethanechol to stimulate bladder emptying/ improve gut motility.

Pilocarpine adverse effects

-Blurred vision

-Few unwanted effects due to limited systemic absorption

-Bethanechol may cause bronchoconstriction

Atropine

Muscarinic antagonist

Atropine action

Inhibits parasympathetic response

-Inhibits secretions

-Tachycardia

-Relaxes smooth muscle

-Antiemetic

Atropine mode of action

Competitive reversible antagonism at ALL muscarinic receptors

Atropine administer

Given orally

Half-life 3 hrs

Atropine clinical use

Tropicamide: paralysis accommodation and pupil dilation for eye exam

Oxybutinin: incontinence

Dicycloverine: irritable bowel syndrome

Antidote for anticholinesterase poisoning

Treats cardiac slowing

Atropine adverse effects

Constipation

Hyperthermia

Dry mouth

Urinary retention

Blurred vision

Raised intraocular pressure

CNS excitement

Scopolamine (hyoscine)

Muscarinic antagonist

Scopolamine (hyoscine) Actions

-Inhibits secretions

-Tachycardia

-Relaxes smooth muscle

-Antiemetic

-Amnesic

Scopolamine Mode of action

Competitive reversible antagonism at all muscarinic receptors

Scopolamine administer

Oral admin

Half life: 4hrs

Also administered as transdermal patch for effects lasting 2-3 days

Scopolamine clinical use

MAIN USE: IN MOTION SICKNESS

-Anaesthesia

-Urinary incontinence

Scopolamine adverse effects

-Constipation

-Dry mouth

-Urinary retention

-Blurred vision

-Raised intraocular pressure

-Drowsiness

Succinylcholine (suxamethonium)

Nicotinic agonist

Succinylcholine actions

Short-lasting skeletal muscle paralysis

Succinylcholine mode of action

-Acts on nicotinic receptors

-Creates a maintained depolarisation of sarcolemma

-Inactivates sodium channels + propagates AP through muscle

It mimics the action of acetylcholine, causing an initial depolarization of the muscle fiber, which leads to muscle twitching (fasciculations) followed by muscle paralysis

Succinylcholine administer

Intravenous injection which is hydrolysed by plasma cholinesterase within a few minutes.

Succinylcholine clinical use

Short-lasting paralysis to aid tracheal intubation and for short operative procedures.

Anticholinesterase doesn’t reverse action!

Succinylcholine adverse effects

-Hyperkalaemia

-Hyoptension

-Bradycardia

-Muscle pain from spasm

-Raised intraocular pressure

-Malignant hyperthermia

Pancuronium

Nicotinic antagonist

Pancuronium actions

Skeletal muscle paralysis

Pancuronium Mode of action

-Reversible competitive antagonism of nicotinic receptors Oral

-Inhibits action of Ach

-Failure of EPP to reach threshold

-Action reversed by anticholinesterase

Pancuronium Administer

-Intravenous injection

-Half life 2-3hrs

-Substantial renal excretion

Pancuronium Clinical use

-General anaesthesia: aids tracheal intubation + relaxes muscle + aids mechanical ventilation

Pancuronium Adverse effects

Tachycardia- muscarinic antagonistic action

Pancuronium Special points

Tubocurarine-NMJ blocker:

-bronchoconstriction- histamine release

Atracurium

Nicotinic antagonist

Atracurium Action

Skeletal muscle paralysis

Atracurium MOA

Reversible competitive antagonism

Failure of EPP to reach threshold

Action reversed by anticholinesterases

Atracurium Administer

Intravenous injection

Half life 30 mins

Eliminated by spontaneous chemical reactions in plasma- so duration of action is independent of renal function.

Atracurium Clinical use

General anaesthesia:

-aids tracheal intubation

-muscle relaxation

-aids mechanical ventilation

Cisatracurium is one of 10 isomers and is the main clinical use

Atracurium Adverse effects

Minor effects attributed to histamine release.

Neostigmine

Acetylcholinesterase reversible inhibitor

Neostigmine action

Parasympathetic:

-increased peristalsis

-increased secretions

-bradycardia

-bronchoconstriction

-decreased intraocular pressures

Neostigmine MOA

Potentiates transmitter action

Binds to both esteratic and anionic sites in enzyme

Esterase is carbamylated

Neostigmine Distribution

Given i.v. (to reverse neuromuscular block), by mouth (for myasthenia gravis). Mostly ionised, so low oral bioavailability and poor penetration of the blood–brain-barrier. Half-life 1h.

Neostigmine Clinical use

Myasthenia gravis.

Reversal of non-depolarising neuromuscular block.

Post-operative urinary retention.

Pyridostigmine – myasthenia gravis. Physostigmine – glaucoma.

Neostigmine Adverse effects

May exacerbate asthma.

Unwanted parasympathomimetic actions can be reduced by atropine.

Edrophonium

Reversible inhibition of acetylcholinesterase

Edrophonium Action

At the neuromuscular junction – fasciculation and increased twitch tension.

Parasympathomimetic–increased peristalsis, increased secretions, bradycardia, bronchoconstriction.

Edrophonium MOA

So potentiating neurotransmission.

Edrophonium binds only to the anionic site in the esterase. The binding is mainly electrostatic and reverses readily.

Edrophonium Administer

Given i.v. or i.m. Short duration of action (10min).

Edrophonium Clinical use

Diagnosis of myasthenia gravis. To confirm that a proper dose of neostigmine or pyridostigmine is being used in the treatment of myasthenia gravis. Action too short for therapeutiic use.

Edrophonium Adverse effects

May exacerbate asthma.

Unwanted parasympathomimetic actions can be reduced by atropine

Echothiophate

Irreversible inhibition of acetylcholinesterase

Echothiophate actions

Parasympathomimetic – increased peristalsis, increased secretions, bradycardia, bronchoconstriction,decreased intraocular pressure.

At the neuromuscular junction – fasciculation and increased twitch tension.

With nerve gases (e.g. sarin) persistent potentiation of ACh action leads to paralysis and death.

Echothiophate MOA

Binds to enzyme’s esteratic site causing irreversible phosphorylation. (Pralidoxime, a cholinesterase reactivator, can reverse the phosphorylation.)

Echothiophate administer

Most are readily absorbed through the skin, gut and lungs. (Protective clothing needed to avoid absorption of insecticides and nerve gases.) Long-acting.

Echothiophate Clinical use

Glaucoma

Echothiophate Adverse effects

May exacerbate asthma. Unwanted parasympathomimetic actions can be reduced by atropine