Anticholinesterase agents

·         Types of cholinesterases.

·         Classes of agents.

·         Pharmacological actions.

·         Anticholinesterase poisoning.

·         Pharmacokinetics.

·         Therapeutic uses.

Types of Cholinesterases

1.       Acetylcholinesterase (AChE):

a.    Also called true/specific cholinesterase.

b.    It is located mainly in cholinergic synapses (CNS, ganglia, neuromuscular junction) and in red blood cells.

c.       Specific for acetylcholine and closely related esters, e.g. methacholine whereas most other esters are not good substrates.

2.       Butyrylcholinesterase (BuChE):

a.    Also called pseudocholinesterase.

b.    It is located mainly in the plasma and liver and also in the skin and gastrointestinal smooth muscle.

c.    It has a wider substrate specificity than AChE and hydrolyzes many non-choline esters.

d.       Important for the inactivation of such drugs.

Classes of anticholinesterase agents

1.       Active-site inhibitors:

a.       Short-acting: edrophonium.

b.       Binds selectively to cholinesterase by hydrogen bonding.

c.       Duration of action is brief due to rapidly reversible binding to AChE and to rapid renal elimination.

2.       Carbamylating agents:

a.       Intermediate acting: neostigmine (quarternary amine), physostigmine (tertiary amine).

b.    They posses a carbamyl ester linkage that also undergoes hydrolysis by AChE but at a much slower rate than acetylcholine.

c.       Regeneration of inactivated AChE takes 3 – 4h.

3.       Irreversible compounds:

a.    Very long-acting: organophosphates, DFP, parathion, malathion.

b.    The phosphorylated enzyme is very stable.

c.    The return of AChE activity depends on synthesis of new enzyme.

Pharmacological actions

1.    The anticholinesterases produce their effects by preventing the hydrolysis of ACh at all cholinergic synapses.

2.       Consequently, large quantities of endogenous ACh accumulate and exert highly enhanced ACh actions at such sites.

3.       Autonomic effects are due to the accumulation of ACh acting at post-junctional muscarinic receptors and the ganglia.

4.       Effects of Neuromuscular junction:

a.       Accumulation of ACh at the NMJ can lead to repetitive firing in the muscle fibre with increased muscle tension.

b.       Large doses produce muscle twitching and fasciculations.

c.       Ultimately, depolarization block is induced and muscle paralysis then occurs.

5.    CNS effects:

a.    The more lipid soluble physostigmine and the organophosphates distribute readily into the CNS.

b.    They cause initial excitation with possible convulsions followed by depression, loss of consciousness and respiratory failure which is usually the primary cause of death.

Anticholinesterase poisoning

1.    Early symptoms are dependent upon the route of entry of the compound and are mainly due to localized effects produced.

2.       Localized effects:

a.       Inhalation of vapors or aerosols: ocular effects (marked miosis, ocular pain, conjunctival congestion, disturbed vision); rhinorrhoea, tightness of chest and wheezing.

b.       Percutaneous absorption of liquid: localized sweating and muscular fasciculations in the immediate vicinity.

c.    Oral ingestion: anorexia, nausea, vomiting, abdominal cramps and diarrhoea.

3.       Generalized effects:

a.       Muscarinic effects: excessive salivation, involuntary defaecation and urination, sweating, lacrimation, bradycardia and hypotension.

b.       Nicotinic effects: muscle twitchings and fasciculations leading to severe muscle weakness and paralysis.

4.    CNS effects:

a.    Act on muscarinic receptors mainly in the cortical and subcortial region.

b.       Symptoms: confusion, ataxia, slurred speech, loss of reflexes, Cheyne-stokes respiration, generalized convulsions, coma and central respiratory/vasomotor depression.

5.       Death:

a.    Can occur within 5 minutes or up to 24 hours after exposure depending on the dose, route and agent involved.

b.       Primarily due to respiratory failure resulting from muscarinic (laryngospasm & bronchoconstriction), nicotinic (paralysis of diaphragm & intercostal muscles) and CNS effects (CNS respiratory depression).

6.       Management of Poisoning:

a.       Removal of contaminated clothing and skin washed.

b.       Gastric lavage to remove any ingested substance.

c.       Atropine is used to antagonize the autonomic and CNS effects.

d.       Pralidoxime, a cholinesterase reactivator, is used to antagonize peripheral neuromuscular effects.

e.       Diazepam: convulsions.

f.       Mechanical ventilation: to assist respiratory muscles.

7.       Antidote to Poisoning:

a.       Pretreatment with oral pyridostigmine may be used to prevent or reduce the severity of poisoning.

b.       Pyridostigmine occupies the active site of the cholinesterase molecule and blocks the action of the nerve agents.

c.    In the recommended doses, pyridostigmine is non-toxic and greatly enhances the effectiveness of atropine and pralidoxime.

Pharmacokinetics

1.       Carbamates:

a.    The quarternary carbamates are poorly absorbed from the conjunctiva, skin and lungs and distribution into the CNS is negligible.

b.       Physostigmine is well absorbed from all sites and distribute readily into the CNS.

2.       Organophosphates:

a.    The organophosphates, except for ecothiophate, are well absorbed from all sites and distribute readily into the CNS.

b.    They are less stable than the carbamates when dissolved in water and thus have a limited half-life in the environment.

c.       Ecothiophate, being highly soluble, is relatively stable and retains its activity for weeks when made up in aqueous solution for ophthalmic use.

Therapeutic uses

Use of some anticholinesterases

1.       Physostigmine:

a.    An alkaloid which acts for a few hours.

b.    Used synergistically with pilocarpine to reduce intraocular pressure.

c.       Shown some efficacy in improving cognitive function in Alzheimer type dementia.

2.       Neostigmine:

a.    Half-life: 2h.

b.    A synthetic reversible anticholinesterase with more prominent actions on the NMJ and GI tract.

c.    Used in myasthenia gravis, to stimulate the bowels and bladder after surgery, and as an antidote to competitive neuromuscular blocking agents.

d.       Effective orally and by injection.

e.       Often combined with atropine to reduce unwanted muscarinic effects.

3.       Edrophonium:

a.       Action is brief.

b.       Autonomic effects are minimal except at high doses.

c.    Used to diagnose myasthenia gravis and to differentiate a myasthenic crisis from a cholinergic crisis.

d.       Myasthenic weakness is substantially improved by edrophonium whereas cholinergic weakness is aggravated.