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Lecture 17 Drugs That Enhance Cholinergic Transmission
Rang, Dale and Ritter (5th Edition), Chapter 10
• 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
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)
• 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).
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.
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
• 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
Parathion – a long duration anti-cholinesterase Used as an insecticide but commonly causes toxicity in humans
Effects of Anti-Cholinesterase Drugs
• At parasympathetic post ganglionic synapses • At autonomic ganglia • At neuromuscular junction • In CNS
• What effects would increased Ach at post synpatic parasympathetic ganglia cause? • Why do the autonomic ganglia first become activated and then inactivated?
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.
• 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?
• 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.