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LECTURE 4
INTRODUCTION
Irreversible type of indirect cholinomimetics are phosphate esters which are very stable to hydrolysis.
Cholinomimetics
DirectIndirect
ReversibleIrreversible
2- Irreversible AChEIs
Mechanism of action:
-They inhibit AChE by the same mechanism as the carbamate inhibitors except that they leave the enzyme esterified as phosphate esters.
-The rate of hydrolytic regeneration of the phosphorylated enzyme is much slower than that of the carbamylated enzyme (in hours).
Indirect Cholinomimetics
Inactive
Inactive
Inactive
2- Irreversible AChEIs
Why referred to as irreversible inhibitors?1 -because the duration of action is very long >>> death occurs
before regeneration takes place.
2 -because the phosphorylated ACHE can undergo a process known as aging.
2- Irreversible AChEIs
2- Irreversible AChEIs
Applications
1- Medical (Isofluorophate)2- Insecticides (Parathion)3- Warfare agents (Sarin)
2- Irreversible AChEIs
Aging is the result of cleavage of one or more of the phosphoester bonds while the AChE is phosphorylated.
Phosphorus atom become much less electrophilic >>> will not undergo hydrolytic regeneration to give the active form of AChE.
Only those phosphorus-derived AChEIs that possess at least one phosphoester group undergo this aging
process .
Isofluorophate-It is an irreversible AChEI & a powerful miotic
agent which can effectively reduce eye pressure.
Uses: Chronic glaucoma(topical).
Parathion
-It contains Sulfur atom bonded to the Phosphorous atom. -It is a very weak AChEI
-Parathion is rapidly bioactivated by microsomal oxidation in insects (but not in human)to afford the corresponding oxo dv. which is a
powerful AChEI :
NO2OPO
O
S
Parathion
NO2OPO
O
O
Paraoxon
Isofluorophate
Disadvantage : Its vapor is highly toxic (nerve gas)and it is recommended that only solutions in arachis oil can be used therapeutically.
SARIN
-It is a colorless, odorless heavy lipophilic liquid- It is an illegal chemical warfare
-After phosphorylation, only one aging reaction takes place, and then the enzyme becomes completely refractory to regeneration.
SARIN
- It is lethal even at very low conc.
- People who absorb a non-lethal dose, but do not receive immediate medical treatment, may suffer of permanent neurological damage
SARIN
• Symptoms of sarin exposure could be summarized in what is known as
SLUDGEM syndrome:• Which is a summary of the
pathological effects indicative of massive discharge of peripheral nervous system.
SARIN
SLUDGEM (cont.)
1-Salivation: stimulation of salivary gland
2-Lacrimation: stimulation of lacrimal gland
3-Urination: relaxation of int. sphincter of urethra
4-Defecation: relaxation of int. anal sphincter
5-GIT upset: diarrhea
6-Emesis: vomiting
7-Miosis: stimulation of pup. constrictor muscles
or 8-Muscle spasm: Stimulation of skeletal muscle
Antidote for irreversible AChEIs
The problem required the design of reagents capable of:
1 -efficiently catalyzing phosphate ester hydrolysis (strong nucleophile)and regenerating active AChE.
2 -being safe enough for use as therapeutic agents.
PRALIDOXIME
-Pralidoxime (PAM) is an oxime derivative
2-pyridinealdoxime chloride
-It is a strong nucleophile and safe at the same time.
CHEMICAL SYNTHESIS
• PAM is synthesized by reacting picolinaldehyde (2-formyl pyridine) with hydroxylamine, giving pyridine-2-aldoxime, which is further reacted with an alkyl halide, giving the desired pralidoxime:
MODE OF ACTION
1-In organophosphate poisoning, an organophosphate binds to just one end of the acetylcholinesterase enzyme [ the anionic site ], blocking its activity. Pralidoxime is able to attach to the other half [ the unblocked, esteric site ] of the acetylcholinesterase enzyme.
MODE OF ACTION
2-It then binds to the organophosphate, the organophosphate changes conformation, and loses its binding to the acetylcholinesterase enzyme.
MODE OF ACTION
3-The conjoined poison / antidote then unbinds from the site, and thus regenerates the enzyme, which is now able to function again.
LIMITATIONS
1 -It must be given within a short period of time, after enzyme phosphorylation.. Why?
1- because of the aging process .
2 -It is only effective in organophosphate toxicity• 2- (i.e. it does not have an effect if the AChE is
carbamylated )
LIMITATIONS
3- It can not cross the blood-brain barrier to regenerate phosphorylated AChE in the brain,
3- this is why atropine, is concomitantly administered with pralidoxime during the treatment of organophosphate poisoning
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