Side effects of the phenothiazines are frequent and often serious. All of them may cause a cholestatic type of jaundice, agranulocytosis, seizures, orthostatic hypotension, skin sensitivity reactions, mental depression, and, most importantly, immediate or delayed extrapyramidal motor disorders. The neuroleptic malignant syndrome is the most extreme complication and is discussed separately further on and in Chap. 49. The following types of extrapyramidal symptoms, also discussed in Chap. 4, have been noted in association with all of the phenothiazines as well as the butyrophenones, and to a lesser extent with metoclopramide and pimozide, which block dopaminergic receptors. These are summarized in Table 49-1.
1. A parkinsonian syndrome is the most common complication—masked facies, slight symmetric tremor, reduced blinking, generalized rigidity, shuffling gait, and slowness of movement. These symptoms may appear after several days of drug therapy but more often after several weeks. Suppression of dopamine in the striatum (similar to the effect of loss of dopaminergic nigral cells that project to the striatum) is presumably the basis of the parkinsonian signs.
2. Acute dyskinetic and dystonic reactions, taking the form of involuntary movements of lower facial muscles (mainly around the mouth) and protrusion of the tongue (buccolingual or oral-masticatory syndrome), dysphagia, torticollis and retrocollis, oculogyric crises, and tonic spasms of a limb. These complications usually occur early in the course of administration of the drug, sometimes after the initial dose, in which case they recede dramatically upon immediate discontinuation of the drug and the intravenous administration of diphenhydramine hydrochloride or benztropine.
3. Akathisia, which is an inner restlessness reflected by a persistent shifting of the body and feet and an inability to sit still, such that the patient paces the floor or jiggles the legs constantly (see Chap. 4). Of all the phenothiazines, molindone has a tendency to cause akathisia. This disorder often responds to oral propranolol.
4. Tardive dyskinesias are a group of late and persistent complications of neuroleptic therapy, which may continue after removal of the offending drug, that comprises lingual-facial-buccal-cervical dyskinesias, choreoathetotic and dystonic movements of the trunk and limbs, diffuse myoclonus (rare), perioral tremor (“rabbit” syndrome), and dysarthria or anarthria. Snyder postulated that the movements are because of hypersensitivity of dopamine receptors in the basal ganglia, secondary to prolonged blockade of the receptors by antipsychotic medication. Baldessarini estimates that as many as 40 percent of patients receiving long-term antipsychotic medication develop tardive dyskinesia of some degree. The effect is likely a result of subcellular pathophysiologic alterations in the basal ganglia. Treatment is discussed later.
5. The neuroleptic malignant syndrome is discussed separately later because of its gravity and requirement for specific treatment.