CHAPTER 5 Fluphenazine Toxicosis
Fluphenazine is a neuroleptic antipsychotic drug used in humans. Esterification at a free hydroxyl group with a long-chain fatty acid results in slowly absorbed, long-acting, highly lipophilic formulations such as fluphenazine decanoate. The pharmacokinetics of fluphenazine in horses has not been reported, to my knowledge, but in humans the half-life has been reported as 7 to 14 days, although the overall clearance and normalization of hyperprolactinemia following repeated dosing can require 6 to 8 months.
Fluphenazine has a greater affinity for D2-dopamine receptors than does dopamine itself, and it acts as an antagonist, blocking the receptor from binding dopamine. Fluphenazine blocks both postsynaptic D2 receptors and presynaptic D2 autoreceptors, resulting in decreased dopamine activity and synthesis. Dopaminergic neurons from the limbic system project into the forebrain, where they have a suppressive effect by activating receptor-activated K+ channels and suppressing voltage-activated Ca2+ channels. Members of this drug class, especially older agents, may have a prominent sedative effect early in treatment that can lead to a drowsy appearance and slow response to external stimuli. However, clinical human subjects tend to be easily aroused and retain intact cognition. Ataxia and incoordination do not tend to occur at normal therapeutic doses. Aggressive and impulsive behavior diminishes with doses in the therapeutic range. In humans, these drugs reduce initiative and interest in the environment as well as manifestations of emotion. In laboratory animals, conditioned avoidance behavior is diminished, whereas unconditioned escape or avoidance behaviors are not. The animal appears to be indifferent to most stimuli, although the animal will actively respond to noxious or painful stimuli. Learned tasks can still be performed with sufficient stimulation and motivation.
The most serious adverse effects associated with fluphenazine administration involve the extrapyramidal motor system, in which dopamine antagonism may induce acute dystonia, akathisia, parkinsonism, tardive dyskinesia, and neuroleptic malignant syndrome. Horses seem to be more sensitive to fluphenazine decanoate on a milligram per kilogram basis and generally require a smaller dose per body weight than do humans to achieve the desired effect. Whether this reflects a greater sensitivity to the drug, as has been proposed, or a more rapid rate of mobilization of the depot form remains speculative because no controlled pharmacokinetic studies in horses have been reported. Serum concentrations in horses with these signs, however, are similar to those found in humans with similar signs, suggesting that more rapid mobilization of the depot form may be responsible. The serum concentration, which causes unwanted side effects in humans, varies widely, presumably because of wide variations in patient sensitivity to the action of the drug. In general, the higher the dose and resultant serum concentration, the greater the risk of adverse effects, with toxic plasma concentrations in humans generally in the range of 2 to 3 ng/mL. In the few reported cases in horses where fluphenazine serum concentrations were monitored, clinical signs of toxicosis subsided as serum fluphenazine concentrations fell below those associated with the symptoms in humans. There is some individual variation, as one reported case of toxicosis in a horse occurred at a fluphenazine concentration well below that which would normally be considered dangerous in humans. Similar variation has also been seen in humans.