CHOLINESTERASE ENZYMES

 Acetylcholinesterase (AchE) (true cholinesterase)  Butyrylcholinesterase (BchE) (Pseudocholinesterase) Basic Structure (Enzymatic active site)
OH

Anioinic site

Esteratic site

+ (CH3)3 N

OCH2 CH2 O C O O CH3

ENZYMATIC HYDROLYSIS OF ACETYLCHOLINE

 Binding of Ach to enzyme
CH3

+ (CH3)3 N

CH2

CH2 OH

C O

)3 N + Choline
3

(CH

CH

2

CH

2

OH

O C O O C OH OH CH3 CH3

 Ach hydrolysis  Acetylation of enzyme  Dissociation of choline  Hydrolysis (fast) and enzyme regeneration

ANTI-CHOLINESTERASES
Bind to and Inhibit ACHEs .to prevent hydrolysis of ACh

Pharmacological effects due to .accumulated ACh

Indirect agonists at both muscarinic and nicotinic receptors

CLASSIFICATION OF ANTI-CHOLINESTERASES
 Short-acting (eg. Edrophonium)  Medium-acting (eg. Physostigmine, neostigmine and pyridostigmine)  Long-acting or irreversible (eg. Organophosphates)

EDROPHONIUM – ENZYME INTERACTION

Edrophonium
C2 H5 C2 H5 + N CH3 OH OH

NEOSTIGMINE – ENZYME INTERACTION
O + (CH3)3 N O C OH NH2

Neostigmine

O + (CH3)3 N OH C O NH2

Carbamylation of enzyme Reactivation by Hydrolysis (slow)

ORGANOPHOSPHATE – ENZYME INTERACTION
O F P O O CH3CHCH3 O H3C H3C CH O P O O CH3 CH CH3 CH3 CH CH3

Dyflos

Negligible spontaneous hydrolysis

EFFECTS OF ANTICHOLINESTERASES
(Effect of increased Acetylcholine at synapses) Peripheral  Enhanced Neuromuscular transmission  Increased GIT motility/bladder contraction

 Bradycardia  Pupillary constriction  Bronchoconstriction

EFFECTS OF ANTICHOLINESTERASES
(Effect of increased Acetylcholine at synapses) Central
• General CNS stimulation) )agitation and convulsion followed by • Respiratory depression) )cause of death

USES OF ANTICHOLINESTERASES
Clinical:  Treatment of gluacoma (Physostigmine, organophosphate, eg, ecothiophate)  Diagnosis and treatment of myasthenia gravis (also to distinguish cholinergic crisis) (edrophonium, neostigmine)  Reversal of competitive neuromuscular block (neostigmine, edrophonium)

USES OF ANTICHOLINESTERASES
Clinical (cont’d):  Treatment of atropine poisoning (physostigmine)  Treatment of paralytic ileus and bladder atony (neostigmine)  Treatment of Alzheimer’s disease (tacrine, physostigmine)

USES OF ANTICHOLINESTERASES
Others:  As insecticides (parathion, malathion)  As nerve gas (sarin, soman)

TOXICITY OF ANTICHOLINESTERASES (common with organophosphates) Acute:      Vomiting, colic and diarrhoea Constricted pupils unresponsive to light Sweating and salivation Bronchoconstriction Bradycardia

 Agitation, convulsion and respiratory depression (especially physostigmine and organophosphates)

TOXICITY OF ANTICHOLINESTERASES
(common with organophosphates) Chronic  Demyelination (sensory loss and paralysis)

CHOLINESTERASE REACTIVATORS ♣ Oxime compounds )pralidoxime, obidoxime( ♣ Induce reactivation of enzymes inactivated by phosphorylation ♣ Used early to treat organophosphate .)poisoning )with atropine

REACTIVATION OF PHOSPHORYLSTED ENZYME BY PRALIDOXIME O
CH3 N CH NOH

+

P O

OC3H7 OC3H7

Pralidoxime
N CH3 +

Phosphorylated enzyme
O CH N O P OC3H7 OC3H7 OH

O N CH NO P OC3H7 OC3H7

+

OH

Regenerated enzyme

LEARNING OBJECTIVES
• Classify anti-ChEs • Describe the clinical uses of anti-ChEs • Understand the basis for the similarity and differences in the clinical uses between anti-ChEs and direct .muscarinic agonists • Understand the pharmacodynamic and pharmacokinetic requirements for the use of anti-ChEs in the treatment .of atropine poisoning • List the signs and symptoms of organophosphate .poisoning and describe its treatment

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