Anti-cholinesterases

Cholinesterase are enzymes which mainly metabolites acetylcholine known as true cholinesterase or acetyl cholinesterase. But other esterase are also present in various tissues mainly in blood plasma, which not only metabolized acetylcholine but also other ester of choline. They are called pseudocholinesterase or non-specific cholinesterase.

Anticholinesterases are the agents which inhibit the enzyme pseudo or true cholinesterase and increase the concentration of acetylcholine. The anticholinesterases or cholinesterase inhibitor are of two type, Reversible Anticholinesterase and irreversible Anticholinesterase.

 

Mechanism of Action:

Acetylcholine is postulated to be inactivated by combination with two sites on the enzyme cholinesteraseanionic site bearing a negative charge which attracts the quaternary nitrogen atom (N+) of acetylcholine and an esteratic site which attract the carboxylic acid group (COOH) of the acetylcholine molecules.

Similar site have also been faced for the acetylcholine receptors on the organs having cholinergic innervation. As a result of the union of acetylcholine with cholinesterase, the esteratic site of the enzyme is acetylated and this results is splitting of choline. The acetyl group in combinations with the esteratic site is however immediately remove as a result of combination with water forming acetic acid. This sets the esteratic site of the enzyme free for further inactivation of acetylcholine. The reversible anticholinesterases bear a structural similarity to acetylcholine. They are therefore capable of combining with the anionic and esteratic sites of cholinesterase as well as with acetylcholine receptors. It produces temporary inhibition of enzymes.

The irreversible anticholinesterases (organophosphate compound) combined only with esteratic site of cholinesterase and consequently the esteratic site is phosphorylated. The hydrolysis of the phosphorylated site, however is slow and in certain cases does not occur at all. These produces and almost irreversible inhibition of cholinesterase.

 

 

Physostigmine

This is an alkaloid obtained from the dried ripe seed of a Physostigmavenenosum.

Pharmacological action: Topical instillation of the drug into the eye produces miosis, spasm of accommodation & a fall in intraoculartension. It can cross the blood brain barrier & exerts central cholinergic actions.

It is rapidly absorbed from G.I tract & parenteral sites. Applied to the eye, it penetrates cornea freely, it crosses blood brain barrier & is disposed after hydrolysis by cholinesterase.

Dose:  0.5 – 1 mg (oral/parenteral).

            0.1 – 10% Eye drops.

Uses:

It is used for the treatment of glaucoma.

To counteract the effect of mydriatics after refraction testing.

To prevent formation of adhesions between iris and lens or iris and cornea.

It is used for the treatment of anticholinergic drug (atropine) poisoning.

It is also used for the treatment of poisoning with phenothiazines and tricyclic antidepressants.

Adverse Reaction: (Reversible Anticholinesterase) epigastric distress, salivation, sweating, lacrimation, paraesthesia  (Burning of Skin), sense of constriction in chest, nausea, abdominal cramps and diarrhoea. Hypotension and tumors have been occasionally reported. On over dose it produces skeletal muscle paralysis, convulsions, coma and death.

Brand name: ESERINE.

 

 

NEOSTIGMINE

Neostigmine is a synthetic, quaternary ammonium compound that inhibits both true & pseudocholinesterases.

Pharmacological action:

In addition to its anticholinesterase activity, neostigmine also directly stimulates certain organs receiving cholinergic innervation. The important actions are –

Gastrointestinal tract: Neostigmine increases the tone & motility of the gut, enhances the production of gastric juice promotes the propulsion of intestinal contents.

Skeletal muscles: Neostigmine produces a striking increase in the power of skeletal muscles in patients with myasthenia gravis.

Cardiovascular system: The drug usually reduces the heart rate & tends to lower blood pressure by peripheral vasodilation & bradycardia.

Eye: Local instillation of the drug into the eye produces miosis, spasm of accommodation & reduction in intraocular tension.

Autonomic ganglia: In low concentration neostigmine stimulates the autonomic ganglia. While in large doses, it blocks them. It cannot cross the blood brain barrier.

Miscellaneous: It increases the various secretions. It also produces bronchoconstriction.

Neostigmine is not absorbed satisfactorily on oral administration. It is therefore, usually administered by Subcutaneous or I.M.

Contra Indication: Hypersensitivity, mechanical urinary& intestinal obstruction.

Dose: Neostigmine bromide tablet 15 – 30mg/day.

 

 

Therapeutic uses of reversible Anticholinesterase –

Glaucoma: It is a disease of eye where intraocular pressure is increased if untreated can cause irreversible damage. In acute congestive (narrow angle) glaucoma, the iris probably block the entrance to trabecular space at canal of schlemm. This blockade by iris results increase intraocular tension producing severe pain, nausea & often loss of vision due to optic atrophy. The Anticholinesterase removes the iris blockade & facilitates the drainage of the intraocular fluid. So, reduce the intraocular pressure.

 

Drugs used in glaucoma:

1. Those which increase the outflow of aqueous humor

A. Cholinergic agonist (miotics)– Pilocarpine eye drops 0.25 – 4.00%

B. Cholinesterase inhibitors (miotics)

a. Physostigmine – 0.25% ointment

b. Demecarium – 0.125 – 0.25% eye drops

c. Echothiophate – 0.03 – 0.25% eye drops

2. Prostaglandin analogues– Latanoprost – 0.005% eye drops

3. Those which decrease the production of aqueous humor by the ciliary body

A. Non-selective β-adrenergic blocking agents– Timolol 0.25 – 0.5% eye drops.

B. Selective β-adrenergic blocking agents – Betaxolol 0.5% eye drop

C. Non-selective adrenergic agonists– Adrenaline hydrochloride 0.1 – 2% eye drops

D. Selective α2-adrenergic agonists Apraclonidine 0.5 – 1% drops, Brimonidine 0.2% eye drops.

E. Carbonic anhydrase inhibitors

Systemic – Acetazolamide tab 250mg QID, Methazolamide 25mg BID

Topical – Brinzolamide 1% eye suspension, Dorzolamide 2% eye drops

 

Myasthenia Gravis:

Myasthenia gravis is a disease characterized by easy fatigability & progressive weakness & with intermittent periods of exacerbation. Pregnancy usually leads to an improvement or even temporary remissio of this condition.

Myasthenia gravis is an autoimmune disease caused by a deficiency of the post synaptic neuromuscular acetyl choline receptor complex. Thus the receptor in myasthenic muscles are degraded & cleared much faster than normally. The number of available acetylcholine receptors in the involved muscles are reduced.

Another myasthenic syndrome of autoimmune nature occurs in association with small cell carcinoma of the lung. The autoantibodies are directed to the calcium channel in the nerve terminals, with resultant diminution in the release of acetylcholine from the nerve terminals. Myasthenia can also be induced by penicillamine during the treatment of rheumatoid arthritis &wilson’s disease.

The diagnosis of myasthenia gravis depends upon typical clinical picture. Administration of 1 – 1.5mg of neostigmine I.M produces marked improvement in muscles power of myasthenic individuals, which lost for a period of 3 – 4 hours.

 

Treatment:

Treatment usually started with neostigmine 15mg orally 6 hourly, dose & frequency is then adjusted according to response. Pyridostigmine & ambenonium are alternatives which need less frequent dosing. It intolerable muscarinic side effects are produced, atropine can be used to block them.

For suppression of autoimmune action glucocorticoids like prednisolone has been used in the dose of 25 – 100mg once daily.

Other immunosuppressants have also been used with benefit in advance cases. Both azathioprine& cyclosporine also inhibit nicotinic receptor – antibody synthesis by affecting T – cells.

Thymectomy (excision of thymus) – Produces gradual improvement in majority of cases. Even complete remission can be achieved. Thymus has been found to contain modified muscle cells with NR on their surface which may be the source of the antigen for production of Anti – NR antibodies in myasthenic patients.

 

Gastrointestinal and Urinary tract:

Neostigmine is employed parenterally in the dose of 0.5 – 1mg in the treatment of postoperative paralytic ileus & urinary retention. Neostigmine is used in the treatment of achalasia (failure to relax of smooth muscles)& in patients with marked dilatation of the oesophagus because of its stimulant action on the lower end of the oesophagus.

 

Postoperative Decurarization:

Neostigmine 0.5 – 2.0mg I.V preceded by atropine to block muscarinic effects,

rapidly reverses muscle paralysis induced by competitive neuromuscular blockers.

 

Cobra Bite:

Cobra venam has a curare like neurotoxin. Neostigmine with atropine prevent

Respiratory paralysis.

 

Belladonna Poisoning:

Physostigmine 0.5 – 2.0mg I.V repeated as required is specific antidote for poisoning

With belladonna or other anticholinergic. It penetrates blood brain barrier & antagonizes both central & peripheral actions.

 

Other Drug Overdoses:

Tricyclic antidepressants, phenothiazines & many antihistamines have additional

anticholinergics property. Over dose symptoms & coma produced by this drug is antagonized by physostigmine.

 

Alzheimer’s Disease:

This is characterized by progressive dementia (loss of memory or intellectual abilities), it is a neurodegenerative disorder primarily affecting cholinergic neurons in the brain. The relatively cerebroselective anti cholinesterasetacrine has been used.

 

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