Phenothiazine effect on gastrointestinal tract function

Clinical evidence indicates that phenothiazines, specifically chlorpromazine (CPZ), used extensively in the treatment of patients with mental and/or neurologic disorders produce an ileus characterized by pseudoobstruction with an extended barium transit time of eight to ten days. Postoperatively, these patients have a protracted ileus, lasting from ten to fourteen days. In our present study we investigated the mechanism of action by which phenothiazines block gastrointestinal tract function as well as the possible reversal of this effect by pharmacologic agents. Guinea pigs were injected intraperitoneally with CPZ at a dose of 30 mg/kg/day for five to seventeen days. This caused deleterious effects in the gastrointestinal tract, such as cessation of peristalsis of small intestine and colon, and marked distension of the cecum. In vitro pharmacologic studies were performed on the electrically stimulated longitudinal muscle-myenteric plexus of the guinea pigs. We found that phenothiazines interfered with the neuromuscular mechanism of the intestine, as exemplified by a lack of response to electrical current stimulation. The effect was protracted, lasting at least 24 hours. These effects were reversed by the administration of the anticholinesterase, physostigmine (PGM), provided the block was less than 80 per cent. The paralytic ileus produced was similar to that found in man.