• Anticholinesterases are indirect-acting cholinergic agonists that function by inhibiting cholinesterase, the enzyme that destroys endogenous acetylcholine secreted by cholinergic neurons. Consequently, the synaptic half-life of acetylcholine is extended, boosting its physiological effect. This enhancement of cholinergic stimulation is non-specific, acts on both nicotinic and muscarinic receptors, and can occur at any location of cholinergic activity including the CNS, autonomic ganglia, and neuromuscular junction. Consequently, these drugs have wide-ranging effects that depend on their particular pharmacological properties, including half-life, lipid solubility, and reversibility of action.
Mechanism of Action
  • The therapeutically used anticholinesterases are all reversible antagonists of cholinesterase and have variable half-lives. Irreversible antagonists exist and have extremely long durations of actions, requiring synthesis of new cholinesterase for reversal. These irreversible antagonists are largely used as agricultural pesticides and include the infamous "organophosphates"
Pharmacological Effects
  • Overview
    • As mentioned, anticholinesterases result in non-specific activation of both nicotinic and muscarinic cholinergic receptors at potentially all of their physiological sites of action. As a result they can directly activate end-organ muscarinic receptor activity, potentiate both parasympathetic and sympathetic outflow by stimulating autonomic ganglia, activate muscular contraction at the neuromuscular junction, and potentiate cholinergic pathways in the CNS. The particular pharmacological effect of any drug depends on its lipid solubility which dictates to which areas it ultimately gains access. We present a generalized picture below and then discuss the therapeutic uses of particular compounds in the next section.
  • Ocular Effects
    • Results in contraction of the pupilary sphincter muscle, yielding miosis. Contraction of the ciliary muscle results in blockage of accomodation and thus prevents near vision.
  • GI Effects
  • Skeletal Muscle Effects
    • Sustained presence of acetylcholine at the neuromuscular junction yields chronic depolarization of the muscle and ultimately reduced motor activity. While these effects are negligible at therapeutic doses of reversible antagonists, muscular paralysis can occur at toxic doses, especially of irreversible antagonists like organophosphates.
  • Glandular Effects
    • At therapeutic doses, secretions from all glands which can produce enhanced lacrimation, salivation, and diaphoresis.
  • Cardiovascular Effects
    • The cardiovascular effects of anticholinesterases include both stimulation of parasympathetic tone by activation of muscaranic receptors as well as stimulation of sympathetic tone via ganglionic effects.