ANTICHOLINESTERASES (antiChEs) OR CHOLINESTERASE INHIBITORS ARE DRUGS WHICH INHIBIT THE ENZYME

CHOLINESTERASE antiChEs ARE EITHER ESTERS OF CARBAMIC ACID (CARBAMATES) OR DERIVATIVES OF PHOSPHORIC ACID (ORGANOPHOSPHATES). THEY MAY BE 1.REVERSIBLE or 2.IRREVERSIBLE

 REVERSIBLE

1.CARBAMATES PHYSOSTIGMINE NEOSTIGMINE PYRIDOSTIGMINE RIVASTIGMINE etc IRREVERSIBLE 1.ORGANOPHOSPHATES MALATHION PARATHION SUMITHION ECHOTHIOPHATE etc

2.CARBAMATE INSECTICIDES CARBARYL PROPOXURE ALDICARB

CH3 CH3 N

CH3

O O
+ (CH ) (CH3 ) 2 N 3 3

O N

O
Physostigmine

Neostigmine

CH3 CH3

CH3

C2 H5
H5 C2

HO

N+
CH3
Edrophonium

O P

O S
(CH2 ) 2

H5 C2

N+ (CH3 )3

Echothiophate
CH3 O

CH3 CH CH3 CH3

Sarin (GB)

O P

O F

S P
S
Malathione

COOC2 H5

CH
COOC2 H5

CH3 O

1.NORMAL BINDING OF ACh WITH AChE ENZYME

ACETYLCHOLINE ANIONIC SITE AChE enzyme ESTERATIC SITE

BINDING REVERSIBLE IN MILLISECONDS

2.REVERSIBLE ANTICHOLINESTERASES EXEPT EDROPHONIUM BINDS TO BOTH ANIONIC AND ESTERIC SITES

REVERSIBLE ANTIChE ANIONIC SITE AChE enzyme ESTERATIC SITE

BINDING IS REVERSIBLE IN HOURS

IRREVERSIBLE ANTICHOLINESTERASE ORGANO PHOSPHATES BINDS TO THE ESTERATIC SITE ONLY BUT THE ENZYME IS PHOSPHORYLATED BY COVALENT BONDS AND THE BINDING IS STABLE

ORGANO PHOSPHORUS COMPOUNDS

ANIONIC SITE AChE enzyme

BINDING ONLY TO THE ESTERATIC SITE

BINDING IS STABLE DUE TO PHOSPHORYLATION AND IS REVERSIBLE EITHER IN DAYS OR NOT AT ALL

1.THE ACTIONS ARE SIMILAR TO THAT OF CHOLINERGIC STIMULATION AS THEY CAUSE ACCUMULATION OF Ach
2.ANTIChEs STIMULATE BOTH SYMPATHETIC AND PARASYMPATHETIC GANGLIA 3.ON CVS PARASYMPATHETIC EFFECTS PREDOMINATE LEADING TO 1.BRADYCARDIA 2.HYPOTENSION 3.CARDIAC OUTPUT FALLS etc 4.IN HIGHER DOSES BP INCREASES DUE TO STIMULATION OF THE SYMPATHETIC GANGLIA

 GASTROINTESTINAL TRACT

1.TONE AND PERISTALSIS ENHANCED 2.SPHINCTERS ARE RELAXED 3.RESULTING IN RAPID FORWARD PROPULTION OF INTESTINAL CONTENTS 2.RESPIRATORY TRACT ENHANCED BRONCHIAL SECREATIONS AND BRONCHOSPASM RESULT IN SEVERE DYSPNOEA 3.EYE 1.CONSTRICTION OF PUPIL (M3 RECEPTOR) 2.DRAINAGE OF AQUEOUS HUMOR IS FECILITATED AND INTRA OCCULAR PRESSURE FALLS 3.CILIARY MUSCLES CONTRACTS- SPASM OF ACCOMMODATION

PHYSOSTIGMINE
PHYSOSTIGMINE IS AN ALKALOID OBTAINED

FROM THE PLANT Physostigma venenosum . IT IS A LIPID SOLUBLE,TERTIARY AMMONIUM COMPOUND HENCE HAS BETTER PENETRATION IN TO TISSUES AND ALSO CROSSES THE BBB. IT IS AVAILABLE FOR IV INJECTION, 0.1-1% EYE DROPS AND IN COMBINATION WITH PILOCARPINE NITRATE 2%. IT IS WELL ABSORBED,REACH CNS AND HAVE BOTH CENTRAL AND PERIPHERAL EFFECT USES 1.PHYSOSTIGMINE IS USED IN GLAUCOMA-USED AS EYEDROPS

 LONG TERM USE CAN CAUSE

1.BROWACHE 2.RETINAL DETACHMENT 3. CATARACT

2.PHYSOSTIGMINE IS USED IN ATROPINE AND TRICYCLIC ANTIDEPRESSANT POISONING

 NEOSTIGMINE IS A SYNTHETIC QUATERNARY

AMMONIUM COMPOUND POORLY ABSORBED FROM GUT IT DOES NOT CROSS THE BBB SO HAVE MOSTLY PERIPHERAL EFFECTS NEOSTIGMINE ENHANCES THE SKELETAL MUSCLE STRENGTH AND FORCE OF CONTREACTION IN MYASTHENIA GRAVIS USED IN 1.MYASTHENIA GRAVIS,
2. POST OPERATIVE PARALYTIC ILEUS etc

 1. AS A MIOTIC

PHYSOSTIGMIN CAUSES MIOSIS, SPASM OF ACCOMODATION AND A DECREASE IN IOP. IT IS USED IN a. GLAUCOMAPHYSOSTIGMINE(0.1%) CAN BE USED WITH PILOCARPINE FOR BETTER EFFECT b. ALTERNATELY WITH A MYDRIAC TO BREAK THE ADHESIONS BETWEEN THE IRIS AND THE LENS c. TO REVERSE THE EFFECT OF MYDRIATICS AS THEY CAUSE BLURRING OF VISION AND PHOTOPHOBIA

 2.PHYSOSTIGMINE IS USED IN ATROPINE AND TRICYCLIC ANTIDEPRESSANT POISONING

3.NEOSTIGMINE IS USED IN MYASTHENIA GRAVIS,POST OPERATIVE PARALYTIC ILEUS

4.PYRIDOSTIGMINE AND AMBENONIUM ARE

SIMILAR TO NEOSTIGMINE BUT LONGER ACTING 5.EDROPHONIUM USED IN DIAGNOSIS OF MYASTHENIA GRAVIS AND IV IN SNAKE BITE 6.RIVASTIGMINE USED IN MILD TO MODERATE ALZHEIMERS DISEASE.

 7)MYASTHENIA GRAVIS IS A CHRONIC AUTOIMMUNE DISEASE ANTIBODIES TO NICOTINIC RECEPTORS ARE

FORMED AND THEY ACT AS FOLLOWS 1.BIND TO THE RECEPTOR AND INHIBIT THE ACTION OF ACETYLCHOLINE 2.CAUSE CROSSLINKING OF NICOTINIC RECEPTORS AND STIMULATE THEIR DEGRADATION THERBY RESULTING IN A DECREASE IN THE NUMBER OF THESE RECEPTORS AT THE NMJ 3.DAMAGE THE POST SYNAPITIC MEMBRANE

Treatment
ANTIChEs ENHANCES Ach LEVEL AT NMJ

IMPROVES MUSCLE POWER

ONLY SYMPTOMATIC TREATMENT THE ADVERSE EFFECTS ARE DUE TO CUNCURRENT

MUSCARINIC STIMULATION SALIVATION MIOSIS ABDOMINAL CRAMPS DIARRHOEA THESE MAY BE BLOCKED BY ATROPINE

 NEOSTIGMINE (15mg 6 hrly)

/pyridostigmine/ambenonium or a combination of these. EDROPHONIUM USED IV FOR DIAGNOSIS OTHER DRUGS 1.GLUCOCORTICOIDS-inhibit the production of antibodies 2.IMMUNOSUPPRESSANTS-azathioprine ,cyclosporine

 8) POISONING DUE TO ANTICHOLINERGIC

DRUGS 9)COBRA BITE-EDROPHONIUM IV PREVENTS RESPIRATORY PARALYSIS 10)ALZHEIMERS DISEASERIVASTIGMINE,DONEPEZIL AND GALANTAMINE 11) CURARE POISONING-NEOSTIGMINE
PYRIDOSTIGMINE CAN BE USED

 CURARE

Common Names: Curare, Grieswurzel, Pareira Brava, Pareira, Vigne Sauvage Genus: Chondrodendron Species: tomentosum Parts Used: Leaf, Root
Curare grows in the canopy of the South

American rainforest. It has large alternate, heart-shaped leaves Leaves and roots used as poison

 ALL ORGANOPHOSPHATES EXEPT

ECHOTHIOPHATE ARE HIGHLY LIPID SOLUBLE AND HENCE ARE ABSORBED FROM ALL ROUTESINCLUDING INTACT SKIN ECHOTHIOPHATE EYDROPS ARE SOMETIMES USEDIN GLAUCOMA ORGANOPHOSPHORUS POISONING

 ORGANOPHOSPHATES ARE USED AS

AGRICULTURAL AND DOMESTIC INSECTICIDES POISONING BY THEM IS QUITE COMMON POISONING MAY BE OCCUPATIONAL ACCIDENTAL SUICIDAL

EPIDEMIOLOGY OF TOXIC EXPOSURE

Medical Products 22.4% Household Products 21.7% Occupational Products 6.3% Others 8.0% Pesticide 41.6%

SYMPTOMS
MAINLY MUSCURANIC,NICOTINIC,AND CNS

MANIFESTATIONS MUSCURANIC (SLUDGE) S-SALIVATION L-LACHRYMATION U-URINATION D-DEFAECATION G-GASTRO INTESTINAL E-EMESIS

 G.I TRACT
VOMITING DIARRHOEA

CRAMPS
CVS BRADYCARDIA

HYPOTENSION
PUPILS MIOSIS

INCREASED SWEATING

 NICOTINIC MANIFESTATIONS
MUSCULAR WEAKNESS MUSCLE PARALYSES CNS MANIFESTATIONS RESTLESSNESS HEADACHE TREMORS CONVULSIONS COMA etc

DIAGNOSIS
DEPENDS UPON SIGNS AND SYMPTOMS
CONFIRMED BY 2 mg OF ATROPINE IN CASE OF

POISONING SYMPTOMS ARE RELIEV ED WITHOUT ATROPINISING RED CELLS AND PLASMA CHOLINESTERASE LEVELS OF LESS THAN 50 %

TREATMENT
1.IF THE POISONING IS THROUGH SKIN REMOVE CLOTHING AND WASH SKIN WITH SOAP AND WATER 2.IF INGESTED STOMACH SHOULD BE WASHED WITH 1:5000 POTASSIUM PERMANGANATE SOLUTION 3.PATIENT SHOULD BE PUT IN PRONE POSITION TO AVOID ASPIRATION OF SECREATIONS 4.MAINTAIN BP AND PATENT AIRWAY

 DRUG OF CHOICE IS ATROPINE

IV 2mg EVERY 10 MINUTES TILL PUPIL DILATES MAXIMUM DOSE CAN BE ANYTHING FROM 50 TO

100 mg

 CHOLINESTERASE REACTIVATORS-

PRALIDOXIME,OBIDOXIME,DIACETYLMONOXIME

THESE COMBINE WITH THE COMPLEX AND

RELEASE THE FREE AChE ENZYME NOT USEFUL IN CARBAMATE POISONING

 THE ADULT DOSE IS 1 TO 2 gm IV EITHER AS 5%

SOLUTION GIVEN OVER 5 MINUTES REPEATED AFTER 6 HOURS INTERVAL FOR 24 TO 48 HOURS MAXIMUM DOSE 12 gm IN 24 HOURS CHRONIC ORGANOPHOSPHATE TOXICITY SOME OP COMPOUNDS CAN PRODUCE NEUROTOXICITY SEVERAL DAYS AFTER EXPOSURE TO THE COMPOUND THE SYMPTOMS INCLUDE WEAKNESS,FATIQUE, ATAXIA,SENSORY DISTURBANCE,MUSCLE TWICHING etc