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Pharmcol201 2005: Lecture 17

Pharmcol201 2005: Lecture 17

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Published by: Samer Farhan on Oct 15, 2009
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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 transmissionDescribe (with examples) the mechanism of action of the three classes of anti-cholinesteraseDescribe the clinical uses and adverseeffects of anti-cholinesterases
Drugs That Enhance cholinergicTransmission
Increase release –aminopyridineswhichblock K+ channels can increase release of Ach –not selectivePrevent breakdown anticholinesterasesinhibit metabolism by acetylcholinesterase(AchE)
Cholinesterases
Two types of cholinesterase in the body AchEand butyrylcholinesterase(BchE).AchEbasement membrane of synaptic cleft atcholinergic synapse, and cholinergic nerveterminals specific for Ach.BchEwidespread 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. isoflurophateInitial binding and hydrolysis results in aphosphate covalently bound to active site of enzyme –this is very stable and may take days toreverseSome form non-hydrolysable bonds and requireresynthesisof the enzyme -may take weeksMost 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 ganglionicsynapsesAt autonomic gangliaAt neuromuscular junctionIn 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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