ANTICHOLINESTERASES

KANAV BHANOTROLL NO. 5

CONTENTS• GENERAL- Anticholinesterases• MECHANISM OF ACTION• THERAPEUTIC USES• ADVERSE DRUG REACTIONS• ORGANOPHOSPHOROUS

POISONING(TREATMENT)

ANTICHOLINESTERASES

The Indirectly-acting CHOLINERGIC DRUGS are also known as ANTICHOLINESTERASES.

Anticholinesterases are drugs that increase the level of acetylcholine after it is released from cholinergic nerve endings by inhibiting both acetylcholinesterase and butyrylcholinesterase.

They increase the level of Acetylcholine. They act where Ach is physiologically released.

MECHANISM OF ACTION

They act by increasing the concentration of Ach at cholinoceptors by inhibiting AchE. Thus they prevent the degradation of Ach into choline and acetate.

The anti-ChEs react with the enzyme essentially in the same way as ACh.

The carbamates and phosphates respectively carbamylate and phosphorylate the esteratic site of the enzyme.

CONTD.The acetylated enzyme reacts with water extremely rapidly and the esteratic site is freed in a fraction of a millisecond, whereas THE CARBAMYLATED ENZYME (REVERSIBLE INHIBITORS) REACTS SLOWLY AND THE PHOSPHORYLATED ENZYME (IRREVERSIBLE INHIBITORS) REACTS EXTREMELY SLOWLY.

It is noteworthy that edrophonium and tacrine attach only to the anionic site and do not form covalent bonds with the enzyme(REVERSIBLE INHIBITION), while organophosphates attach only to the esteratic site forming covalent bonds (IREVERSIBLE INHIBITION).

THERAPEUTIC USESI. EYES1. Glaucoma Acute congestive glaucoma: Pilocarpine is the preferred cholinergic drug (pilocarpine eye drops 0.5-4% every 4-6 hourly), the main action is that they improve the aqueous outflow. Physostigmine (0.1%) is used to supplement action of pilocarpine in closed angle glaucoma.

2. Pilocarpine or Physostigmine is used alternate with a mydriatic in iritis, uveitis or corneal ulcer.

II. ALZHEIMER’S DISEASE Treatment: Cholinergic replacement using cholinesterase inhibitors such as: Donepezil 5-10 mg/day (drug of choice) Rivastigmine 1.5 mg BID (max: 12 mg/day)

III. POST-OPERATIVE AND NEUROGENIC ILEUS AND URINARY RETENTION Neostigmine: 0.5-2mg SC

IV. MYAESTHENIA GRAVIS

DIAGNOSIS- Edrophonium is used for Tensilon test .

TREATMENT-Anti-cholinesterase agent (increase Ach) 1.Pyridostigmine 60-120 mg 3-4 times/day orally [less frequent dosing compared to Neostigmine] 2. or Pyridostigmine 2 mg IM 3. Or Neostigmine 15 mg q 6hourly

V. POST-OPERATIVE DECURARIZATION Neostigmine: 0.5-2mg IV Or Edrophonium

VI. COBRA BITE (release a ‘curare-like neuro-toxin’ )Treatment: Neostigmine/pyridostigmine

VII. BELLADONNA POISONING (Atropine poisoning) Physostigmine 0.5-2mg is used by IV route.

ADVERSE DRUG REACTIONS1. Nausea, Increased Salivation,

Increased Sweating 2. Flushing, Bradycardia 3. Bronchospasm 4. Abdominal Pain, Diarrhoea 5. Increased Urination 6. At High Dose: Convulsions ; Skl. Muscle

weakness7. ADR On Eyes When Used As Eye Drops:

Miosis, Decrease Vision In Dim-light, Impaired Accommodation.

ORGANOPHOSPHOROUS POISONING (TREATMENT)

1. Termination of further exposure to the poison— fresh air, wash the skin and mucous membranes with soap and water, gastric lavage according to need.

2. Maintain patent airway, positive pressure respiration if it is failing.

3. Supportive measures—maintain BP, hydration, control of convulsions with judicious use of diazepam.

4. Specific antidotes— (a)Atropine (b)Cholinesterase reactivators

(A) ATROPINE It is highly effective in counteracting the muscarinic symptoms, but higher doses are required to antagonize the central effects.

It does not reverse peripheral muscular paralysis which is a nicotinic action.

All cases of anti-ChE (carbamate or organophosphate) poisoning must be promptly given ATROPINE 2 mg I.V. REPEATED EVERY 10 MIN till dryness of mouth or other signs of atropinization appear

Continued treatment with maintenance doses may be required for 1–2 weeks.

(B) CHOLINESTERASE REACTIVATORS Oximes are used to restore neuromuscular transmission only in case of organophosphate anti-ChE poisoning.

The phosphorylated ChE reacts very slowly or not at all with water. However, if more reactive OH groups in the form of oximes are provided, reactivation occurs more than a million times faster.

Pralidoxime 1-2 mg (30mg/kg), IV as 15-30 min infusion [max 12g]

Oximes improve action at nicotinic sites. It should be administered within 48 hours of organophosphorus poisoning; otherwise when ageing occurs; the phosphorylated enzyme becomes resistant to hydrolysis (following loss of an alkyl group).