Pharmcol201 2005: Lecture 17

PHARMCOL201 2005: Lecture 17

Lecture 17 Drugs That Enhance Cholinergic Transmission Rang, Dale and Ritter (5th Edition), Chapter 10

Drugs That Enhance cholinergic Transmission • Increase release –aminopyridines which block K+ channels can increase release of Ach – not selective • Prevent breakdown – anticholinesterases – inhibit metabolism by acetylcholinesterase (AchE)

Cholinesterase - Structure • The active site of the enzyme comprises an anionic site and an esteric site. • The esteric site contains a histidine imadazole ring and a serine -OH group. The acetyl group from Ach is transferred to the serine-OH group, leaving an acetylated enzyme molecule and a molecule of free choline. • Acetate is then released. The anionic site is thought to help in aligning the two molecules. • Rapid turnover – 10,000 molecules/second per active site.

Learning Objectives • Describe the means by which drugs can enhance cholinergic transmission • Describe (with examples) the mechanism of action of the three classes of anticholinesterase • Describe the clinical uses and adverse effects of anti-cholinesterases

Cholinesterases • Two types of cholinesterase in the body – AchE and butyrylcholinesterase (BchE). • AchE – basement membrane of synaptic cleft at cholinergic synapse, and cholinergic nerve terminals – specific for Ach. • BchE – widespread distribution, broader substrate specificity, keeps Ach levels in the plasma negligible, and metabolises some Ach like drugs (suxamethonium).

Drugs That Inhibit Cholinesterase • Short Acting – alcohols bearing a quaternary ammonium group – form a readily reversible ionic bond with anionic group of enzyme e.g. edrophonium. • Used as a diagnostic tool for myasthenia gravis – improvement of muscle strength by AChE is characteristic of this disease.

PHARMCOL201 2005: Lecture 17

Medium Duration AChE • Carbamic acid esters of alcohol bearing quaternary or tertiary amine groups (carbamates) • Hydrolysis produces are carbamylated enzyme (not acetylated) which is quite resistant to hydrolysis – so enzyme is inhibited for longer, e.g. neostigmine, pyridostigmine

Irreversible Anti-cholinesterases • Organic derivatives of phosphoric acid (organophosphates) e.g. isoflurophate • Initial binding and hydrolysis results in a phosphate covalently bound to active site of enzyme – this is very stable and may take days to reverse • Some form non-hydrolysable bonds and require resynthesis of the enzyme - may take weeks • Most have high lipid solubility

Neostigmine

Irreversible Anti-Cholinesterase Parathion – a long duration anti-cholinesterase Used as an insecticide but commonly causes toxicity in humans

Autonomic Effects • What effects would increased Ach at post synpatic parasympathetic ganglia cause? • Why do the autonomic ganglia first become activated and then inactivated?

Effects of Anti-Cholinesterase Drugs • At parasympathetic post ganglionic synapses • At autonomic ganglia • At neuromuscular junction • In CNS

Effects on NMJ • Greater muscle tension. • In myasthenia gravis transmission fails because there are too few Ach receptors, AchEs improve this because they give the Ach a better chance of reaching the receptors. • In large doses cause twitching, and may cause paralysis.

PHARMCOL201 2005: Lecture 17

Effects of CNS • Those that cross the bbb. • Initial excitation including convulsions • Depression, unconsciousness, respiratory failure. • Organophosphates can also cause demyelination leading to sensory loss.

Clinical Uses • Myasthenia gravis: – Incidence 1:2000 – Autoimmune disease – decrease Nicotinic receptors on functional end plates – Weakness of head, neck extremities

• Edrophonium – diagnostic test, and dose tailoring • Neostigmine, pyridostigmine – longer term treatment – both relatively short acting (2-6 hours) so require frequent dosing. • What side effects might this treatment produce?

Clinical Uses

Organophosphate Poisoning

• In anaesthesia reverse the action of nondepolarising neuromuscular blocking drugs – neostigmine IV • In the treatment of glaucoma: ecthiopate as eye drops.

• If treated within a few hours Pralidoxime may reactivate enzyme. • Has an oxime group that can attract the phosphate group from the esteratic site of the enzyme. • After a few hours the phosphorylated enzyme “ages” and is no longer susceptible to reactivation. • Pralidoxime does not enter the brain.