Chronic exposure to certain organophosphate compounds, including some organophosphate cholinesterase inhibitors, causes delayed neuropathy associated with demyelination of axons. Triorthocresyl phosphate, an additive in lubricating oils, is the prototype agent of this class. The effects are not caused by cholinesterase inhibition but rather by inhibition of neuropathy target esterase (NTE) whose symptoms (weakness of upper and lower extremities, unsteady gait) appear 1–2 weeks after exposure. Another nerve toxicity called intermediate syndrome occurs 1–4 days after exposure to organophosphate insecticides. This syndrome is also characterized by muscle weakness; its origin is not known but it appears to be related to cholinesterase inhibition.
Activates M1, M2, and M3 receptors in all peripheral secretion, smooth muscle contraction (except vascular smooth muscle relaxes), and changes in heart rate Postoperative and neurogenic ileus and urinary retention
Oral and parenteral, duration ~30 min • does not enter central nervous system (CNS) • Toxicity:
Excessive parasympathomimetic effects, especially bronchospasm in asthmatics • Interactions: Additive with other parasympathomimetics • Carbachol: Nonselective muscarinic and nicotinic agonist; otherwise similar to bethanechol; used topically almost exclusively for glaucoma
DIRECT-ACTING MUSCARINIC ALKALOIDS OR SYNTHETICS •PilocarpineLike bethanechol, partial agonist Like bethanechol Glaucoma; Sjögren’s syndrome Orallozengeandtopical•Toxicity & interactions: Like bethanechol •Cevimeline: Synthetic M3-selective; similar to pilocarpine DIRECT-ACTING NICOTINIC AGONISTS •NicotineAgonist at both NN and NM receptors cessation • nonmedical Oral gum, patch for smoking cessation • Toxicity:
Acutely increased gastrointestinal (GI) activity, • Varenicline: Selective partial agonist at α4β2 nicotinic receptors; used exclusively for smoking cessation •NeostigmineForms covalent bond with AChE, but hydrolyzed and released Like edrophonium, but longer-acting Myasthenia gravis •postoperativeandneurogenic ileus and urinary retention Oral and parenteral; quaternary amine, does not enterCNS.Duration2–4h•Toxicity & interactions: Like edrophonium
Pyridostigmine: Like neostigmine, but longer-acting (4–6 h); used in myasthenia
Physostigmine: Like neostigmine, but natural alkaloid tertiary amine; enters CNS
Like neostigmine, but
Like neostigmine, but
Topical only • Toxicity: Brow ache, uveitis, blurred
Malathion: Insecticide, relatively safe for mammals and birds because metabolized by other enzymes to inactive products; some medical use as ectoparasiticide
Parathion, others: Insecticide, dangerous for all animals; toxicity important because of agricultural use and exposure of farm workers (see text)
Sarin, others: “Nerve gas,” used exclusively in warfare and terrorism
Bethanechol Generic, Urecholine
Ophthalmic (topical) Isopto Carbachol, Carboptic
Ophthalmic (intraocular) Miostat, Carbastat
Cevimeline Generic, Evoxac
Transdermal Generic, Nicoderm CQ, Nicotrol
Inhalation Nicotrol Inhaler, Nicotrol NS
Gum Generic, Commit, Nicorette
Ophthalmic (drops)1, 2, 4, 6 Generic, Isopto Carpine
Ophthalmic sustained-release Ocusert Pilo-20, Ocusert Pilo-40 inserts