1.01 Pilocarpine Cholinergic pharmacologymedicaltextbooksrevealed.s3.amazonaws.com/files/16679-53.pdf · 1.01 Pilocarpine Cholinergic pharmacology ... cholinergic transmission with

Cholinergic pharmacologyPilocarpine1.01

AcetylCoA

CoA

Exocytosis choline + acetate

Cholinecarrier

ACh

ACh

ACh

Nicotinic receptors in: neuromuscular junction autonomic ganglia adrenal medulla CNS neurones

AChCAT

Acetylcholinesterase

+ +

Acts on, causes,gives rise toMovement

Muscarinic receptors in: smooth muscle cardiac muscle glands CNS neurones

Simple figure of cholinergic transmission with potential sites of drug action

A muscarinic receptor agonist (Similar drug: bethanechol) Pilocarpine

Actions Parasympathomimetic actions: contracts smooth muscle (e.g. gut, bladder, pupil); decreases rate andforce of heart beat; glandular secretion (e.g. salivary, sweat, gastric acid); inhibits neurotransmitterrelease.

Action in glaucoma is due to interaction with M3 receptors which couple to Gq to increase cellular IP3and DAG concentrations. Constriction of pupil aids drainage of aqueous humour and lowersintraocular pressure.

MOA

Glaucoma (narrow and wide angle). Bethanechol to stimulate bladder emptying or to improve gutmotility.

Clinical use

Blurred vision (contraction of ciliary muscle). Otherwise few unwanted effects because of verylimited systemic absorption of topically applied drug. Bethanechol may producebronchoconstriction.

Adverse effects

R&D Ch 10, pp150–153: D&H Ch10, pp28–31

For glaucoma pilocarpine is given as eye drops and actions last for a day. A slow delivery systemplaced under the eyelid acts for several days.

Abs/Distrb/Elim

Cholinergic pharmacologyAtropine1.02

Pilocarpine+

AcetylCoA

CoA


Cholinecarrier

ACh

ACh

ACh



AChCAT


+ +



Muscarinic receptor antagonist (Similar drugs: dicycloverine, oxybutinin, tropicamide) Atropine

Actions

R&D Ch 10, pp153–154: D&H Ch10, pp28–31

MOA Competitive reversible antagonism at all muscarinic receptors.

Abs/Distrb/Elim Given orally. Half-life 3h.

Clinical use Paralysis of accommodation and pupil dilation for eye examination (tropicamide). Urinaryincontinence (oxybutinin). Irritable bowel syndrome (dicycloverine). Antidote for anticholinesterasepoisoning. Treatment of cardiac slowing.

Adverse effects Constipation, hyperthermia (reduced sweating), dry mouth, urinary retention, blurred vision, raisedintraocular pressure, CNS excitement (delerium, hallucinations).

Inhibits secretions (salivary, bronchial, sweat, gastric acid, etc.). Tachycardia. Relaxes smooth muscle(causing inhibition of peristalsis, pupillary dilation, paralysis of accommodation, etc.).Antiemetic (CNS effect).

Cholinergic pharmacologyScopolamine (hyoscine)

1.03

AcetylCoA

CoA


Cholinecarrier

ACh

ACh

ACh


AChCAT


+ +




Pilocarpine+

Atropine–

Muscarinic receptor antagonist (Similar drug: atropine) Scopolamine

R&D Ch 10, p160, Table 10.7: D&H Ch10, pp28–31

MOA Competitive reversible antagonism at all muscarinic receptors.

Actions Inhibits secretions (salivary, bronchial, sweat, gastric acid etc.). Tachycardia. Relaxes smooth muscle(causing inhibition of peristalsis, pupillary dilation, paralysis of accommodation etc.). CNS actions:antiemetic, amnesic.

Abs/Distrb/Elim Oral admin. T0.5 4h. Also administered as transdermal patch for effects lasting 2–3 days.

Clinical use Main use is in motion sickness. Adjunct for anaesthesia (amnesia, inhibition of secretions and ofbronchoconstriction, reduction of post-operative vomiting). Urinary incontinence.

Adverse effects Constipation, dry mouth, urinary retention, blurred vision, raised intraocular pressure, drowsiness.

Cholinergic pharmacologySuccinylcholine (suxamethonium)

1.04

AcetylCoA

CoA


Cholinecarrier

ACh

ACh

ACh



AChCAT


+ +



Pilocarpine+

Atropine, scopolamine–

Nicotinic receptor agonist / depolarizing neuromuscular blocker Succinylcholine


Actions Short-lasting paralysis of skeletal muscle.

MOA Action on nicotinic receptors produces a maintained depolarization of the muscle membrane. Thisinactivates the Na+ channels, which propagate the action potential throughout the muscle. Actionpotentials fail to spread along the muscle fibres preventing muscle contraction in response to motornerve activity.

Abs/Distrb/Elim Given i.v. Hydrolysed by plasma cholinesterase within a few minutes. (A small percentage of peoplehave an enzyme with much lower activity and action is prolonged.)

Clinical use Short-lasting paralysis to aid tracheal intubation and for short operative procedures. Action is notreversed by anticholinesterases.

Adverse effects Hyperkalaemia (with possible cardiac arrhythmia). Hypotension. Bradycardia. Muscle pain (resultingfrom spasm during the initial depolarisation). Raised intraocular pressure. Malignant hyperthermia(rarely, when used with halothane).

Cholinergic pharmacologyPancuronium1.05

AcetylCoA

CoA


Cholinecarrier

ACh

ACh

ACh



AChCAT


+ +



Atropine, scopolamine

–

Pilocarpine++ Succinylcholine

Nicotinic receptor antagonist / non-depolarizing neuromuscular blocker (Similar drugs: vecuronium, rocuronium)

Pancuronium


Actions Paralysis of skeletal muscle.

MOA Reversible competitive antagonism at muscle-type nicotinic receptors. Inhibits binding of ACh to thereceptors at the muscle end-plate. End-plate potential fails to reach threshold for initiation andpropagation of the action potential along the muscle fibre. Action reversed by anticholinesterases(e.g. neostigmine 1.07).

Abs/Distrb/Elim Given i.v. Half-life 2–3h. Substantial renal excretion (duration increased in renal failure).

Clinical use In general anaesthesia – aids tracheal intubation, provides muscle relaxation for general surgery andaids mechanical ventilation.

Adverse effects Tachycardia (muscarinic antagonist action).

Special points Tubocurarine is the archetypal non-depolarizing neuromuscular blocker, but it has more side effects,such as bronchoconstriction due to histamine release, and is now rarely used.

Cholinergic pharmacologyAtracurium1.06


–Pancuronium

AcetylCoA

CoA


Cholinecarrier

ACh

ACh

ACh



AChCAT


+ +



Pilocarpine++

–

Succinylcholine

Nicotinic receptor antagonist / non-depolarizing neuromuscular blocker (Similar drug: cisatracurium) Atracurium


Actions Paralysis of skeletal muscle.

MOA Reversible competitive antagonism at muscle-type nicotinic receptors. Inhibits binding of ACh to thereceptors at the muscle end-plate. End-plate potential fails to reach threshold for initiation andpropagation of the action potential along the muscle fibre. Action reversed by anticholinesterases(e.g. neostigmine 1.07).

Abs/Distrb/Elim Given i.v. Half-life 30min. Eliminated mainly by a spontaneous chemical reaction (Hofmannelimination) in the plasma which makes duration of action relatively independent of renal function.

Clinical use In general anaesthesia – aids tracheal intubation, provides muscle relaxation for general surgery andaids mechanical ventilation. Cisatracurium is one of the 10 isomers of atracurium and is replacing itin clinical use.

Adverse effects Minor effects attributed to histamine release.

Cholinergic pharmacologyNeostigmine1.07


–Pancuronium,atracurium

AcetylCoA

CoA


Cholinecarrier

ACh

ACh

ACh



AChCAT


+ +



Pilocarpine++

–

Succinylcholine

Anticholinesterase (Similar drugs: pyridostigmine, physostigmine) Neostigmine

R&D Ch 10, pp162–166, Table 10.8: D&H Ch10, pp28–31

Actions Parasympathomimetic: increased peristalsis; increased secretions; bradycardia; bronchoconstriction;decreased intraocular pressure. At the neuromuscular junction – fasciculation and increased twitchtension. CNS – agitation and dreaming.

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. Theesterase is carbamylated.

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

Clinical use Myasthenia gravis. Reversal of non-depolarising neuromuscular block. Post-operative urinaryretention. Pyridostigmine – myasthenia gravis. Physostigmine – glaucoma.

Adverse effects May exacerbate asthma. Unwanted parasympathomimetic actions can be reduced by atropine (1.02).

Cholinergic pharmacologyEdrophonium1.08

Atropine, scopolamine–Pancuronium,

atracurium

AcetylCoA

CoA


Cholinecarrier

ACh

ACh

ACh



AChCAT


+ +



Pilocarpine++

–

Succinylcholine

–

Neostigmine

Anticholinesterase (Similar drugs: neostigmine, physostigmine) Edrophonium


Actions At the neuromuscular junction – fasciculation and increased twitch tension. Parasympathomimetic –increased peristalsis, increased secretions, bradycardia, bronchoconstriction.

MOA Reversible inhibition of acetylcholinesterase reduces the breakdown of ACh at cholinergic nerve-endings, so potentiating neurotransmission. Edrophonium binds only to the anionic site in theesterase. The binding is mainly electrostatic and reverses readily.

Abs/Distrb/Elim Given i.v. or i.m. Short duration of action (10min).

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


Cholinergic pharmacologyEchothiophate1.09



AcetylCoA

CoA


Cholinecarrier

ACh

ACh

ACh



AChCAT


+ +



Pilocarpine++

–

Succinylcholine

–Neostigmine, edrophonium

Irreversible (organophosphate) anticholinesterase (Similar drugs: dyfl os, sarin) Echothiophate


Actions Parasympathomimetic – increased peristalsis, increased secretions, bradycardia, bronchoconstriction,decreased intraocular pressure. At the neuromuscular junction – fasciculation and increased twitchtension. With nerve gases (e.g. sarin) persistent potentiation of ACh action leads to paralysis and death.

MOA Irreversible inhibition of acetylcholinesterase potentiates actions of released ACh at cholinergicnerve-endings. Binds to enzyme’s esteratic site causing irreversible phosphorylation. (Pralidoxime, a cholinesterase reactivator, can reverse the phosphorylation.)

Abs/Distrb/Elim Most are readily absorbed through the skin, gut and lungs. (Protective clothing needed to avoidabsorption of insecticides and nerve gases.) Long-acting.

Clinical use Glaucoma.


Cholinergic pharmacologySummary1.10



AcetylCoA

CoA


Cholinecarrier

ACh

ACh

ACh



AChCAT


+ +



Pilocarpine++

–

Succinylcholine

–

Neostigmine, edrophonium,echothiophate

Notes

Notes

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1.01 Pilocarpine Cholinergic pharmacologymedicaltextbooksrevealed.s3.amazonaws.com/files/16679-53.pdf · 1.01 Pilocarpine Cholinergic pharmacology ... cholinergic transmission with