Cholinesterase inhibitors The actions of acetylcholine released from
Cholinesterase inhibitors
The actions of acetylcholine released from autonomic and somatic motor nerves are terminated by enzymatic destruction of the molecule. Hydrolysis is accomplished by the action of acetylcholinesterase, which is present in high concentrations in cholinergic synapses.
The indirect acting cholinomimetics have their primary effect at the active site of this enzyme, although some also have direct actions at nicotinic receptors. n The chief differences between members of the group are chemical and pharmacokinetic—their pharmacodynamic properties are almost identical. n
CLASSIFICATION n n Reversible inhibitors which produce reversible inhibition of cholinesterase as physiostigmine, neostigmine, edrophonium, …. etc Irreversible inhibitors which induce practically irreversible inhibition of cholinesterase as organophosphorus compounds.
Pharmacokinetics n n Absorption of the quaternary is predictably poor, (insoluble in lipids). Distribution into the CNS is negligible
n Physostigmine, in contrast, is well absorbed from all sites and can be used topically in the eye. n It is distributed into the CNS and is more toxic than the quaternary compounds. n However, the duration of their effect is determined chiefly by the stability of the inhibitor-enzyme complex (Mechanism of Action), not by metabolism or excretion.
n The organophosphate cholinesterase inhibitors (except for echothiophate) are well absorbed thereby making them dangerous to humans and highly effective as insecticides. n Echothiophate is highly polar and more stable than most other organophosphates. It can be made up in aqueous solution for ophthalmic use and retains its activity for weeks.
n n n The thiophosphate insecticides (parathion, malathion, and related compounds) are quite lipid soluble and are rapidly absorbed by all routes. They must be activated in the body a process that occurs rapidly in both insects and vertebrates. Malathion and certain other organophosphate insecticides are also rapidly metabolized by other pathways to inactive products in birds and mammals but not in insects.
n Parathion is not detoxified effectively in vertebrates; thus, it is considerably more dangerous than malathion to humans and livestock and is not available for general public use. n All of the organophosphates except echothiophate are distributed to all parts of the body, including the CNS. Poisoning with these agents therefore includes an important component of CNS toxicity.
Mechanism of Action n n Acetylcholinesterase is the primary target of these drugs, butyrylcholinesterase is also inhibited. Acetylcholinesterase is an extremely active enzyme.
n n n In the initial step, acetylcholine binds to the enzyme's active site and is hydrolyzed, yielding free choline and the acetylated enzyme. In the second step, the covalent acetylenzyme bond is split, with the addition of water (hydration). The entire process takes place in approximately 150 microseconds.
n All of the cholinesterase inhibitors →↑Ach concentration at cholinoceptors. n Edrophonium reversibly bind with the anionic site by hydrogen bonds. n The enzyme-inhibitor complex does not involve a covalent bond and is correspondingly short-lived (on the order of 2 – 10 minutes)
n Neostigmine and physostigmine undergo a two-step hydrolysis sequence analogous to that described for acetylcholine. n However, the covalent bond of the enzyme is considerably more resistant to the second (hydration) process, and this step is correspondingly prolonged (on the order of 30 minutes to 6 hours).
n Organophosphates undergo initial binding and hydrolysis by the enzyme, resulting in a phosphorylated active site. n The covalent phosphorus-enzyme bond is extremely stable and hydrolyzes in water at a very slow rate (hundreds of hours).
n n After the initial binding-hydrolysis step, the phosphorylated enzyme complex may undergo a process called aging. This process apparently involves the breaking of one of the oxygen-phosphorus bonds of the inhibitor and further strengthens the phosphorusenzyme bond.
n n The rate of aging varies with the particular organophosphate compound. Once aging has occurred, the enzymeinhibitor complex is even more stable and is more difficult to split, even with oxime regenerator compounds.
Organ System Effects CVS: n Negative chronotropic, dromotropic, and inotropic effects are produced, and cardiac output falls. n The effects on Eye, Respiratory Tract, Gastrointestinal Tract, Urinary Tract are similar to the effects of the direct acting cholinomimetics.
Therapeutic uses n 1) paralytic ileus and atony of the bladder without obstruction, n 2)glaucoma n 3)certain atrial arrhythmias. n 4) Cholinesterase inhibitors are occasionally used in the treatment of atropine overdosage.
n n 5)Alzheimer's disease: use newer cholinesterase inhibitors as tacrine, donepezil and rivastigmine. 6)Antidote to competitive neuromuscular blockers to hasten recovery from respiratory paralysis, neostigmine combined with atropine may be used
Myasthenia gravis is a disease affecting skeletal muscle neuromuscular junctions. An autoimmune process causes production of antibodies that decrease the number of functional nicotinic receptors on the postjunctional end plates. The patient is unable to maintain voluntary muscular contraction
Severe disease may affect all the muscles, including those necessary for respiration. The disease resembles the neuromuscular paralysis produced by d tubocurarine and similar nondepolarizing neuromuscular blocking drugs n n Edrophonium is sometimes used as a diagnostic test for myasthenia.
n If the patient has myasthenia gravis, an improvement in muscle strength that lasts about 5 minutes will usually be observed. n Edrophonium is also used to assess cholinergic crisis small doses of edrophonium will produce no relief or even worsen weakness if the patient is cholinergic crisis
Side effects and toxicity n n Salivation, sweating, lacrimation, diarrhea, sense of constriction in the chest, abdominal cramps, bradycardia and hypotension (muscarinic action). Cholinergic crisis due to excessive depolarization at the motor end plate treated by large doses of atropine and artificial respiration.
Organophosphorus poisoning n n n Accidental Homicidal Suicidal
n n n Acute intoxication include both muscarinic and nicotinic responses: ↑ activity of smooth muscles and secretory glands (nausea, vomiting, diarrhea salivation, sweating, lacrimation, ↑ bronchial secretion and bronchospasm) muscular weakness and fasiculations CNS: initial stimulation followed by depression
Treatment n 1) Atropine immediately in large doses IV or IM until muscarinic symptoms disappear as evidenced by pupillary dilatation.
n n n 2) Cholinesterase reactivators (oximes) are drugs which combine with phosphorylated esteratic sites forming soluble complex This results in setting free the esteratic site and reactivation of the enzyme. Oximes are effective only when administered within short time after poisoning before aging of the complex
n Pralidoxime only one available for clinical use, injected IV and can be repeated.
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