Anticholinesterase drugs

Anticholinesterase drugs

Anticholinesterase drugs inhibit cholinesterase enzyme and protect acetylcholine from hydrolysis, thereby increasing the concentration of ACh at cholinergic sites.

Anticholinesterase drugs are classified in two categories-

  1. Reversible anticholinesterases Physostigmine (eserine), Neostigmine, pyridostigmine, ambenonium, edrophonium, demecarium, carbamates  and tacrine
  2. Irreversible anticholinesterases Organophosphorus compounds / OPC like dichlorvos, parathion, malathion, diazenon, carbaryl, echothiophate,  and nerve gases used in chemical warfare like tabun, sarin and soman.

1. Reversible anticholinesterase (RAC)

  • 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

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. Edrophonium primarily used in the diagnosis of myasthenia gravis.

Neostigmine

Neostigmine 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, urinary and intestinal obstruction, bronchial asthma, epilepsy, peptic ulcer ad arrhythmias.

Clinical use of Neostigmine

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

Pyridostigmine

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

Ambenonium

Ambenonium 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. Physostigmine is also used in ruminal atony and in treatment of atropine poisoning (Drug of choice in case 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

Carbamates 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.

2. Irreversible anticholinesterase (IAC)

Irreversible anticholinesterase (IAC) compounds are covalently bind to AChE and cause its inhibition irreversibly. Unlike carbamate and other reversible cholinesterase inhibitors, these do not posses cation group and thus react only with the esteratic site of ChE enzyme.

The enzyme-substrate complex thus formed is highly stable and does not undergo spontaneous hydrolysis. Eg: Organophosphorus compounds.

Mechanism of action of organophosphorus compounds

  • The four stages of anticholinesterase action produced by these compounds are:
  • Inhibition (phosphorylation), reactivation, aging and regeneration/recovery
    1. Phosphorylation: Organophosphorus compounds react only at the esteratic site of cholinesterase to form a phosphorylated enzyme.
    2. Reactivation: Following alkylphosphorylation, spontaneous reactivation can occur. But the rate is dependent on the nature of the alkyl group.
    3. Aging
      • Aging is the loss of one alkyl group, which generally occurs more rapidly than spontaneous hydrolysis.
      • Aging makes the product more resistant to regeneration by oximes.
      • Pralidoxime is a compound that is used to reactivate the enzyme cholinesterase from organophosphorus compounds. This agent combines with the cation binding site which orients the oxime group of this agent to react with the elecrophillic phosphorus atom.
      • The oxime-phosphonate is split off, leaving the regenerated enzyme.
    4. Regeneration: If the enzyme is not reactivated, new acetylcholinesterase must be synthesized. This takes weeks or months. However, recovery can occur more rapidly since only a small fraction of acetylcholinesterase is needed to be resynthesized.

Organophosphorus compounds (Phosphorylating agents)

Organophosphorus compounds produce essentially irreversible inhibition of cholinesterase and new enzyme must be synthesized for recovery to occur. They are not important clinically for their therapeutic uses as they are for toxicity and poisoning.

The organophosphorus compounds are highly lipid soluble (exception is echothiophate) and they have high vapour pressures (volatile). These characters make them extremely dangerous. Metabolism may activate (eg. Parathion to paraoxon) and deactivation is by hydrolysis in the liver. They are eliminated almost entirely as hydrolysis products in urine.

Read more about “OPC Poisonings

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