Pirenzepine

Obsolete as an ulcer drug and important anyway. The entire M1 to M5 vocabulary starts with this molecule, and its second life in myopia control and peripheral neuropathy is a useful reminder that a drug displaced by a better one is not the same as a drug that failed.

The adverse effects are the ones any antimuscarinic produces at the dose required to do its job: dry mouth and blurred vision were the common complaints across the ulcer trials, and both are dose related ^[10]. Because pirenzepine penetrates the brain poorly, the central anticholinergic burden that makes agents such as scopolamine or oxybutynin a cognitive concern is much smaller here, although that is an argument from pharmacokinetics and not from a trial designed to measure cognition ^[6].

In the paediatric myopia trials of 2% ophthalmic gel, about 11% of treated children stopped for adverse effects, mostly local, and antimuscarinic eye drops as a class raise the rate of accommodation difficulty and conjunctival follicles against placebo ^[8][6]. The mechanism-based cautions are the ones that follow from blocking M3: relaxing the ciliary muscle and iris sphincter can precipitate angle closure in a predisposed eye, and blocking M3 on the detrusor can worsen urinary retention in bladder outflow obstruction.

Pirenzepine was developed by Boehringer Ingelheim in the 1970s and marketed as Gastrozepin. It was the first antimuscarinic that could suppress gastric acid without the full anticholinergic penalty, and for a few years it was a genuine competitor to cimetidine, with duodenal ulcer healing rates that were not statistically different in head to head trials ^[3]. It never became a United States product, and H2 blockers followed by proton pump inhibitors displaced it almost everywhere else. Its scientific legacy long outlived the commercial one, since the 1980 Nature paper on its heterogeneous binding is the origin of muscarinic subtype classification. Two later programmes revived the molecule: a 2% ophthalmic gel for slowing childhood myopia, and a topical formulation, WST-057, taken into phase 2 trials for diabetic, HIV-associated and chemotherapy-induced peripheral neuropathy.

Among pharmacologists pirenzepine is a reference compound rather than a therapy; tritiated pirenzepine is still a standard radioligand for labelling M1 sites, and a large slice of the 1980s muscarinic literature is organised around whether a given response was pirenzepine sensitive. Among clinicians it is a historical drug, remembered mostly as what came before proton pump inhibitors. The myopia and neuropathy work has given it a small modern following in ophthalmology and neurology, where the interest is in the antagonism itself rather than in gastric acid.