Anticholinesterases: peripheral effects, pharmacokinetics and individual agents
THE CONTEXT
Anticholinesterases stimulate smooth muscles and glands, while individual drugs differ in absorption, tissue penetration, duration and clinical use.
Smooth muscle, glandular and ocular effects
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Effects include increased gastrointestinal motility and secretion, bronchoconstriction and increased airway secretion.
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Bladder voiding results from detrusor contraction with relaxation of the trigone and sphincter.
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Ocular effects include miosis, ciliary muscle contraction and lowering of intraocular tension in glaucoma.
Pharmacokinetic differences
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Physostigmine is rapidly absorbed from the gastrointestinal tract and parenteral sites, penetrates the cornea freely, crosses the blood-brain barrier and is disposed of after hydrolysis by cholinesterase.
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Neostigmine and its congeners are poorly absorbed orally; oral doses are 20–30 times higher than parenteral doses. They do not effectively penetrate the cornea or cross the blood-brain barrier.
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Neostigmine and its congeners are partly hydrolysed and partly excreted unchanged in urine.
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Organophosphates are absorbed from all sites, including intact skin and lungs. They undergo hydrolysis and oxidation, with little excreted unchanged.
Individual compounds
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Physostigmine eye drops are usually freshly prepared by ophthalmology departments.
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Pyridostigmine resembles neostigmine but is less potent dose for dose and longer acting, allowing less frequent dosing in myasthenia gravis.
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Edrophonium resembles neostigmine in action but lasts only 10–30 minutes and is suitable only as a diagnostic agent for myasthenia gravis.
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Tacrine is a lipophilic acridine compound that interacts with cholinesterase analogously to edrophonium. It crosses the blood-brain barrier and has a longer duration of action.
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Tacrine increases brain acetylcholine and produced some symptomatic improvement in Alzheimer's disease, but fell into disuse because of hepatotoxicity.
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Rivastigmine is a lipophilic, relatively cerebroselective cholinesterase inhibitor introduced for Alzheimer's disease.