PHARMCOL201 2005: Lecture 17
Lecture 17
Drugs That EnhanceCholinergic Transmission
Rang, Dale and Ritter (5
th
Edition),Chapter 10
Learning Objectives
•Describe the means by which drugs canenhance cholinergic transmission•Describe (with examples) the mechanism of action of the three classes of anti-cholinesterase•Describe the clinical uses and adverseeffects of anti-cholinesterases
Drugs That Enhance cholinergicTransmission
•Increase release –aminopyridineswhichblock K+ channels can increase release of Ach –not selective•Prevent breakdown –anticholinesterases–inhibit metabolism by acetylcholinesterase(AchE)
Cholinesterases
•Two types of cholinesterase in the body –AchEand butyrylcholinesterase(BchE).•AchE–basement membrane of synaptic cleft atcholinergic synapse, and cholinergic nerveterminals –specific for Ach.•BchE–widespread distribution, broader substratespecificity, keeps Ach levels in the plasmanegligible, and metabolisessome Ach like drugs(suxamethonium).
Cholinesterase -Structure
•The active site of the enzyme comprises ananionic site and an estericsite.•The estericsite contains a histidineimadazoleringand a serine -OH group. The acetyl group fromAch is transferred to the serine-OH group, leavingan acetylated enzyme molecule and a molecule of free choline.•Acetate is then released. The anionic site isthought to help in aligning the two molecules.•Rapid turnover –10,000 molecules/second peractive site.
Drugs That Inhibit Cholinesterase
•Short Acting –alcohols bearing aquaternary ammonium group –form areadily reversible ionic bond with anionicgroup of enzyme e.g.
edrophonium.
•Used as a diagnostic tool for myastheniagravis –improvement of muscle strengthby AChEis characteristic of this disease.
PHARMCOL201 2005: Lecture 17
Medium Duration AChE
•Carbamicacid esters of alcohol bearing quaternaryor tertiary amine groups (carbamates)•Hydrolysis produces are carbamylatedenzyme(not acetylated) which is quite resistant tohydrolysis –so enzyme is inhibited for longer, e.g.neostigmine, pyridostigmine
Neostigmine
Irreversible Anti-cholinesterases
•Organic derivatives of phosphoric acid(organophosphates) e.g. isoflurophate•Initial binding and hydrolysis results in aphosphate covalently bound to active site of enzyme –this is very stable and may take days toreverse•Some form non-hydrolysable bonds and requireresynthesisof the enzyme -may take weeks•Most have high lipid solubility
Irreversible Anti-Cholinesterase
Parathion –a long duration anti-cholinesteraseUsed as an insecticide but commonly causestoxicity in humans
Effects of Anti-CholinesteraseDrugs
•At parasympathetic post ganglionicsynapses•At autonomic ganglia•At neuromuscular junction•In CNS
Autonomic Effects
•What effects would increased Ach at postsynpaticparasympathetic ganglia cause?•Why do the autonomic ganglia first becomeactivated and then inactivated?
Effects on NMJ
•Greater muscle tension.•In myasthenia gravis transmission failsbecause there are too few Ach receptors,AchEsimprove this because they give theAch a better chance of reaching thereceptors.•In large doses cause twitching, and maycause paralysis.
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