Uses of Anticholinesterases

USES

1. As miotic

In glaucoma: Miotics increase the tone of ciliary muscle (attached to scleral spur) and sphincter pupillae which pull on and somehow improve alignment of the trabeculae so that outflow facility is increased → i.o.t. falls in open angle glaucoma.

Pilocarpine is the preferred miotic. The action is rapid and short lasting (4–6 hr); 6–8 hourly instillation is required and even then i.o.t. may fluctuate inbetween. Diminution of vision, especially in dim light (due to constricted pupil), spasm of accommodation and brow pain are frequent side effects. Systemic effects—nausea, diarrhoea, sweating and bronchospasm may occur with higher concentration eye drops.

Physostigmine (0.1%) is used only to supplement pilocarpine. Miotics are now 3rd choice drugs, used only as add on therapy in advanced cases. However, they are effective in aphakic glaucoma. Pilocarpine (along with other drugs) is used in angle closure glaucoma as well.

To reverse the effect of mydriatics after refraction testing.

To prevent formation of adhesions between iris and lens or iris and cornea, and even to break those which have formed due to iritis, corneal ulcer, etc.—a miotic is alternated with a mydriatic.

2. Myasthenia gravis

Myasthenia gravis is an autoimmune disorder affecting about 1 in 10,000 population, due to development of antibodies directed to nicotinic receptors (NR) at the muscle endplate → reduction in number of free N_M cholinoceptors to 1/3 of normal or less (Fig. 7.3) and structural damage to the neuromuscular junction → weakness and easy fatigability on repeated activity, with recovery after rest. Neostigmine and its congeners improve muscle contraction by allowing ACh released from prejunctional endings to accumulate and act on receptors over a larger area, and by directly depolarizing the endplate.

Treatment is usually started with neostigmine 15 mg orally 6 hourly; dose and frequency is then adjusted according to response. However, the dosage requirement may fluctuate from time to time and there are often unpredictable periods of remission and exacerbation. Pyridostigmine is an alternative which needs less frequent dosing. If intolerable muscarinic side effects are produced, atropine can be added to block them. These drugs have no effect on the basic disorder which often progresses; ultimately it may not be possible to restore muscle strength adequately with antiChEs alone.

Corticosteroids afford considerable improvement in such cases by their immunosuppressant action. They inhibit production of NR antibodies and may increase synthesis of NRs. However, their long term use has problems of its own. Prednisolone 30–60 mg/day induces remission in about 80% of the advanced cases; 10 mg daily or on alternate days can be used for maintenance therapy. Other immunosuppressants have also been used with benefit in advanced cases. Both azathioprine and cyclosporine also inhibit NR-antibody synthesis by affecting Tcells, but response to the former is slow in onset (takes upto 1 year), while that to the latter is relatively quick (in 1–2 months). Removal of antibodies by plasmapheresis (plasma exchange) is another therapeutic approach. Dramatic but short lived improvement can often be achieved by it in myasthenic crisis.

Myasthenic crisis is characterized by acute weakness of respiratory muscles. It is managed by tracheal intubation and mechanical ventilation. Generally, i.v. methylprednisolone pulse therapy is given while antiChEs are withheld for 2–3 days followed by their gradual reintroduction. Most patients can be weaned off the ventilator in 1–3 weeks. Plasmapheresis hastens recovery.

Thymectomy produces gradual improvement in majority of cases. Even complete remission has been obtained. Thymus may contain modified muscle cells with NRs on their surface, which may be the source of the antigen for production of antiNR antibodies in myasthenic patients.

Overtreatment with antiChEs also produces weakness by causing persistent depolarization of muscle endplate: this is called cholinergic weakness. Late cases with high antiChE dose requirements often alternately experience myasthenic and cholinergic weakness and these may assume crisis proportions. two types of weakness require opposite treatments. They can be differentiated by edrophonium test—

Diagnostic tests for myasthenia gravis

Ameliorative test: Edrophonium 2–10 mg injected slowly i.v. improves muscle strength only in myasthenia gravis and not in other muscular dystrophies.

Provocative test: Myasthenics are highly sensitive to dtubocurarine; 0.5 mg i.v. causes marked weakness in them but is ineffective in nonmyasthenics. This test is hazardous: facilities for positive pressure respiration must be at hand before performing it.

Demonstration of anti-NR antibodies in plasma or muscle biopsy specimen is a more reliable test.

Postoperative Paralytic Ileus/Urinary Retention This can be relieved by 0.5–1 mg s.c. neostigmine, provided no organic obstruction is present.

Postoperative Decurarization Neostigmine 0.5–2.0 mg i.v., preceded by atropine to block muscarinic effects, rapidly reverses muscle paralysis induced by competitive neuromuscular blockers.

Cobra Bite Cobra venom has a curare like neurotoxin. Though specific antivenom serum is the primary treatment, neostigmine + atropine prevent respiratory paralysis.

Belladonna Poisoning  Physostigmine 0.5–2 mg i.v.

repeated as required is the specific antidote for poisoning with belladonna or other anticholinergics. It penetrates bloodbrain barrier and antagonizes both central and peripheral actions. However, physostigmine often itself induces hypotension and arrhythmias; is employed only as a last resort. Neostigmine does not block the central effect, but is less risky.

Other Drug Overdosages Tricyclic antidepressants, phenothiazines and many antihistaminics have additional anticholinergic property. Overdose symptoms and coma produced by these drugs are partly antagonized by physostigmine. It also appears to have a modest nonspecific arousal effect in CNS depression produced by diazepam or general anaesthetics, but is rarely used.

Alzheimer’s  Disease  Characterized  by progressive dementia, is a neurodegenerative disorder, primarily affecting cholinergic neurones in the brain. Various measures to augment cholinergic transmission in the brain have been tried. The relatively cerebroselective antiChEs tacrine, rivastigmine, donepezil and galantamine have been approved for clinical use.