VPT 321: Veterinary Neuropharmacology (2+1) copy 1

REVERSIBLE ANTI CHOLINE ESTERASE AGENTS

• These drugs form reversible complex with AChE , leading to temporary inhibition of enzyme. Depending on chemical structure these drugs are sub grouped in to:
  • Quaterinary ammonium compounds. Eg. Neostigmine, Pyridostigmine, Edorphonium
  • Tertiary amine alkaloids. Eg. Physostigmine
  • Acridine derivatives. Eg. Tacrine
  • Carbamates. Eg. Carbaryl, Carbofuran, Aldocarb

Mechanism of Action

• Reversible choline esterase transiently inhibits the AChE and hence delay the hydrolysis of AChE.
• AChE possesses two active sites: an anionic (negatively charged) binding sites and esteratic sites.
• The anionic site electrostatically binds with cationic nitrogen of Ach and the esteratic site binds to the carboxyl position of ACh, forming the enzyme substrate complex.
• This complex then leaves the acetylated enzyme after the release of  choline.
• The enzyme is then regenerated with in microseconds by forming acetic acid (after reaction with water), freezing the esteratic sites.
• The reversible choline esterase inhibitors like physostigmine, neostigmine etc., bind with AChE like ACh, but are hydrolysed at very slow rates and rate of regeneration of enzyme is 10-6 times slower than acetyl choline because of carbamylated enzyme.

Edrophonium

• A short acting reversible choline esterase inhibitor differs from other drugs in this group. Edrophonium primarily binds with the anionic site of AChE and reactivation of Edrophonium inhibited enzyme doesn’t involve its hydrolysis.
• Accordingly the duration of edrophonium is very shortened it is less potent.

Neostigmine

• It is a synthetic quaternary ammonium compound with rigid onset of action
• The pharmacological properties of neostigmine resemble those of acetyl choline. Neostigmine in addition to inhibiting AchE , can also directly stimulates the nicotinic receptors.
• The action on nicotinic receptors is stronger than on the muscarinic receptors, and hence its skeletal muscle effects are more predominant. Thus Neostigmine has powerful anticurare effect.
• Neostigmine is not absorbed when given orally and is not able to penetrate the BBB.
• It is metabolized in the liver and also hydrolyzed plasma choline esterase and excreted in urine.
• Neostigmine is contraindicated in late pregnancy, intestinal and urinary obstruction, bronchial asthma, epilepsy, peptic ulcer ad arrhythmias.

Clinical uses

• Neostigmine is clinically used to reverse effects of non depolarising skeletal muscle relaxants , treat ruminal and urinary atony, and in the symptomatic treatment myasthenia gravis.

Pyridostigmine

• It is similar to neostigmine, but has slower onset of action, than neostigmine.

Edrophonium

•  Primarly used in the diagnosis of myasthenia gravis.

Ambenonium

• It is slightly more potent and longer acting than neostigmine.

Physostigmine (Eserine)

• Physostigmine is a tertiary amine alkaloid obtained from the dried ripe seeds of plant Physostigma venenosum. Unlike quarternary ammonium compounds, physostigmine is well absorbed orally and crosses blood brain barrier. It is also absorbed from conjunctiva when applied in the eye.
• It used as a miotic agent and to treat glaucoma. It is also used in ruminal atony and in treatment of atropine poisoning. Physostigmine effectively antagonizes the effects of atropine both centrally and peripherally.

Tacrine

• Tacrine is a lipophilic acridine compound and is able to cross blood brain barrier easily.
• As it increase brain ACh levels, it is used in the symptomatic treatment of Alzemier’s disease in humans.

Carbamates

• These are used as insecticides in agriculture and in control of ectoparasites in animals. These compounds are non polar, highly soluble and hence, easily absorbed from the site of exposure.
• These are potent poisons, but their poisoning is of shorter duration than that of organophosphorus insecticides.