Physostigmine
Physostigmine, an alkaloid. Carbamate reversible acetylcholinesterase inhibitor from the Calabar bean. A tertiary amine, so unlike the… Transdermal half-life 0.5 h.
Carbamate reversible acetylcholinesterase inhibitor from the Calabar bean. A tertiary amine, so unlike the quaternary neostigmine it crosses the blood-brain barrier and raises central as well as peripheral acetylcholine — which is what made it the reference cholinergic challenge agent in human memory pharmacology and the antidote for central antimuscarinic delirium. Peripheral muscarinic excess gives the dose-limiting effects: bradycardia, bronchial secretion and GI cramping.
PubChem CID 5983 (C15H21N3O2). PK: Walter 1995 (PMID:7756100), six healthy male volunteers, three-way crossover of a transdermal system (PTS), an oral solution and an i.v. infusion. Verbatim: "A mean absolute bioavailability of 36% was determined for the transdermal system and 3% for the oral solution"; "A single application of the patch over 24 h produced detectable plasma drug concentrations after a mean lag-time of 4 h"; "the drug was absorbed continuously from the PTS and putative therapeutic plasma concentrations were measured over approximately 18 h"; "After removing the PTS, the mean apparent half-life of elimination was 4.9 h, compared with 0.5 h for the i.v. infusion"; "The mean amount of physostigmine released from the transdermal system after 24 h was 5.7 mg". MODELLING NOTE — the 4.9 h is deliberately NOT stored as the transdermal half-life. The paper itself attributes it to absorption, not disposition ("This indicates continued drug absorption from a skin depot"), so storing it would model a flip-flop artefact as elimination AND then double-count it against the zero-order input. Instead TD carries the real disposition half-life (0.5 h, the i.v. value) with the patch represented as what it is: a 4 h lag then an 18 h constant-rate input at F 0.36, which is the schema's zo_dur_hr path. PO IS NOT AUTHORED despite its bioavailability being stated verbatim in the source — at F 0.03 an oral dose is almost entirely destroyed pre-systemically, oral physostigmine is not a marketed form, and offering a PO route would invite a log that renders a near-flat curve as though it were a therapy. IV dose range is the conventional antidote range and is NOT from the cited abstract, which reports an infusion without stating its dose; the TD dose is the verbatim 24 h released amount. No volume is published in the abstract for any route — all three default, and the record is counted by pk.defaulted-volume.
Pharmacokinetics
- IV — t½ 30 min · F 100%
- Transdermal — t½ 30 min · F 36%
Sources: PMID:7756100, PMID:8128833