Neostigmine

Structure

Quaternary ammonium compound.

Mode of action

Neostigmine has dual action:

1. Directly by binding neuromuscular ‘N’ receptors
2. Indirectly by inhibiting cholinesterases

Pharmacokinetics

CNS effects are not seen. It is an indirectly acting choline esterase having dual mechanism of action. It acts directly on nicotinic receptors, proving to be effective in management of Myasthenia Gravis. Skeletal muscle effects are same as those of directly acting drugs, producing state of depolarization and enhancing the strength of skeletal muscles.

If given orally, it is soluble but leads to toxicity, thus given I/M or subcutaneously.

Mechanism of action:

Carbamate compound

Duration of action is 2 to 8 hours.

Pharmacological Actions

Pharmacological actions are seen on:-

A) skeletal muscles

B) eye

C) G.I.T.

D) urinary bladder

E) exocrine glands

Effects are same as those of parasympatholytic drugs.

F) C.V.S.-depressant effect, negative ionotropic, chronotropic and dromotropic decreasing heart rate and bradycardia. The contractility of ventricles and atria is decreased. Thus depressant effects are more pronounced.

Effects on blood vessels are minimum or none. There is little decrease or no change in blood pressure.

Neostigmine only acts on those pathways which are cholinergic in nature.

G) CNS- excitatory effects. It is a tertiary compound and does not cross blood brain barrier.

Therapeutic uses

1.  relief of abdominal distension / paralytic ileus (only if mechanical obstruction is not present)

2. relief of urinary retention.

Orally given in 15 mg dose, subcutaneously 0.5-1 mg

3. Treatment of myasthenia gravis

Myasthenia gravis is an autoimmune disease in which functional nicotinic receptors are destroyed due to production of antibodies in skeletal muscle NMJ leading to decreased nicotinic receptors for normal actions. This produces muscular weakness, diplopia, ptosis, difficulty in swallowing, speech and respiration.

a. Drugs which are used include:

• Neostigmine
• Pyridostigmine
• Ambenonium
• Corticosteroids, immunosuppressants (e.g. Azathioprine, cyclosporine)

Other options include:

• Plasmapheresis / plasma exchange
• Thymectomy

Only those drugs are used which have short duration of action because fluctuations occur and dose needs to be monitored according to the response of patients. Dose needs to be titrated.

Neostigmine is effective because it has dual mechanism of action:

1. More neurotransmitter to act on lesser receptors
2. Direct effects on nicotinic receptors

Drugs Contraindicated in Myasthenia gravis

1. Neuromuscular blocking drugs
2. aminoglycoside  antibiotics,
3. ether
4. phenothiazines
5. Phenytoin

4. post operational anti-curare use

5. reversal of neuromuscular blocking effect.

6. treatment of glaucoma (3% eye drops)

Myasthenic Crisis	Cholinergic Crisis
Under dosage of anticholinesterases	Over dosage of anticholinesterases
No depolarization	Excessive depolarization, thus no impulse can be generated
Flaccidity	Rigidity
Decreased GIT motility	Increased GIT motility
Edrophonium relieves the condition	Edrophonium aggravates the condition

Tensilon Test (trade name of Edrophonium)

This test is used for diagnosis of myasthenia gravis. Edrophonium has a very short duration of action (2-10 minutes). It is rapidly eliminated. Baseline muscle strength is measured then waited for 45 seconds. If no effect is produced, 3 mg is injected IV initially followed by 5 mg after 45 seconds.

If muscle strength is increased, it is indicative of myasthenia gravis.

When drug therapy is started, dose regulation is important otherwise adverse effects might occur.

If 2 mg edrophonium is injected IV and no improvement of muscle strength occurs, or if it worsens, it is indicative of excessive drug therapy. If improvement occurs, then less dose is being administered.

Physostigmine is not recommended in myasthenia gravis because it crosses blood brain barrier and has longer duration of action.

If during course of therapy excessive muscarinic effects occur, anticholinergic agents like atropine may be used (1-2 mg IV). Dose is slightly increased after assessing effects. Reversal of meiosis occurs (anti-muscarinic) if dryness of mouth occurs dose of atropine is halted.

In severe cholinesterase intoxication given on daily basis, 1 mg daily for 1 month.

Neostigmine is also used for skeletal muscle relaxation during surgery

Treatment of Glaucoma

Not first line drug, no longer used, same is true for physostigmine.

Adverse Effects

1. nausea
2. vomiting
3. diarrhea
4. hypotension
5. bradycardia

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Anticholinesterases

Physostigmine

Pyridostigmine, Edrophonium and Echothiophate

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