Adverse Side Effects in Horses Following the Administration of Fluphenazine Decanoate

Adverse behavioral side effects may occur in some horses after the intramuscular administration of fluphenazine decanoate. In severe cases, these side effects are difficult to manage and may be life-threatening to the horse, stable personnel, and treating veterinarians. The drug is not approved for use in the horse, and testing for fluphenazine is now conducted by various regulatory organizations involved in racing and equestrian competitions. Authors’ addresses: Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON Canada N1G 2W1 (Baird); and Equine Drug Testing and Research Program, New York Drug Testing and Research Program Morrisville State College, 777 Warren Road, Ithaca, NY 14850 (Maylin); e-mail: jbaird@ovc. uoguelph.ca. *Corresponding author. © 2011 AAEP.

1. Introduction

Fluphenazine is a trifluoromethyl phenothiazine derivative (Fig. 1). The systematic International Union of Pure and Applied Chemistry (IUPAC) name of fluphenazine is 2-[4-[3-[2-(trifluoromethyl) phenothiazin-10-yl]propyl]-piperazin-1-yl]ethanol and it has the following structural formula.

2. Clinical Pharmacology

Fluphenazine is a highly potent antipsychotic drug that has been used in human medicine in the maintenance treatment of schizophrenia and other forms of psychotic illness since the 1960s.^1–3  Long-acting intramuscular depot formulations of fluphenazine, such as fluphenazine decanoate and fluphenazine enanthate, were developed for use in human patients, who cannot be relied on to take oral antipsychotic drugs.^1,2,4  The fluphenazine decanoate ester markedly prolongs the duration of action. Fluphenazine decanoate is formulated as a sesame oilbased intramuscular (IM) depot injection and is more commonly used clinically than fluphenazine enanthate. In humans, the most common dosage of fluphenazine decanoate is 25 mg (range, 12.5 to 50 mg), with patients injected once every 2 weeks (range, 1 to 4 weeks).^1,5,6  After the IM injection of fluphenazine decanoate, the drug gradually diffuses from the oily vehicle into the surrounding lymph nodes and tissues. Once the drug enters the tissue, it is rapidly hydrolyzed by ubiquitous esterases, and the parent compound (fluphenazine) is released. The hydrolysis of fluphenazine decanoate has been shown to be slow at the IM injection sites, probably because the oil protects the ester from exposure to esterases. Hydrolysis of fluphenazine decanoate has also been shown to occur in a variety of tissues including the lymphatic system and blood.¹ Anti-psychotic drugs are highly lipophilic, highly membrane-bound or protein-bound, and accumulate in the brain, lung, and other tissues with a high blood supply. It is virtually impossible (and usually not necessary) to remove antipsychotic agents by dialysis.⁵ Studies in laboratory rats showed that fluphenazine is 10-fold to 27-fold higher in brain regions than is plasma.⁷ Fluphenazine may also enter the fetal circulation and breast milk.⁵

After a single injection of fluphenazine decanoate in humans, an early high peak of the drug occurs during the first day and then declines, with a half-life ranging from 6.8 to 9.6 days. After multiple injections of fluphenazine decanoate, however, the mean apparent half-life increases to 14.3 days.⁸ The individual response to treatment with antipsychotics is highly variable in humans.^6,9 Patients must be monitored closely to find a dose that is both safe and effective.⁶ Humans treated with 25 mg fluphenazine decanoate require 3 months to reach a steady-state plasma level.⁶ Substantial evidence exists that there is also a sex difference in antipsychotic dosing, in that women require lower doses given at longer intervals.¹⁰

Antipsychotic agents are also referred to as neuroleptics and are categorized as either typical (also known as first generation) or atypical (also known as second generation).¹¹ Fluphenazine is classified as a typical antipsychotic, which refers to the fact that when used in clinically effective dosages, they typically induce extrapyramidal side effects (EPS) and symptoms.¹² Typical antipsychotics have also been referred to as classic,⁹ traditional,^13,14 or conventional antipsychotics.^12,15 The typical antipsychotics are associated with adverse side effects in humans that can affect every system of the body.¹⁶ 
 

3. Mode of Action

The primary site of action for all antipsychotics is the dopamine D₂ receptor.¹⁷ Dopamine transmission has been found to play an important role in four major pathways: nigrostriatal, mesolimbic, tuberoinfundibular, and mesocortical. The nigrostriatal circuit, originating from A8 and A9 groups of dopamine cells, is well known from the impact of deficiencies. When these deficiencies occur naturally in the substantia nigra, Parkinson disease often develops with concomitant movement disorders, rigidity, and so forth, and when they occur as consequence of medications, the symptoms may be labeled as extrapyramidal symptoms.¹⁵ Neuroleptic-induced movement disorders or EPS are commonly encountered in humans after treatment with the typical antipsychotics.^2,12 The signs of EPS include Parkinsonism (i.e., tremor, rigidity), bradykinesia (abnormal slowness of movement), akinesia (difficulty in initiating and maintaining movement), dystonia (i.e., abrupt onset, sometimes bizarre muscular spasms affecting mainly the musculature of the head and neck), and akathisia (inner restlessness, compulsion to move).^12,16,18

Typical antipsychotics, such as fluphenazine, have a higher affinity for dopamine D₂ receptors than dopamine and as a consequence more frequently elicit Parkinsonism than the newer atypical antipsychotics that bind more loosely to the dopamine D₂ receptors.^14,17 The incidence of acute EPS associated with antipsychotics varies; however, most medical researchers agree that neuroleptic-induced EPS occurs in 50% to 75% of patients who take typical antipsychotics.^12,16 Most typical antipsychotics have a narrow therapeutic index, which means that the separation between the dose that produces efficacy and the one that produces EPS and other adverse effects in narrow.¹²

Dopamine D₂ receptor antagonists, such as fluphenazine, have also been shown to cause hyperprolactinemia.¹⁹ Hyperprolactinemia is commonly observed in women administered therapeutic doses of typical antipsychotics resulting in amenorrhea, gynecomastia, galactorrhea, and infertility.^15,16,19,20 Studies in humans taking long-term antipsychotic medications have also shown that they are at high risk of developing reduced bone mineral density as a consequence of hyperprolactinemia-induced hypogonadism.^19,20

4. Fluphenazine in Horses

Long-acting depot preparations of fluphenazine, such as fluphenazine decanoate and fluphenazine enanthate, have been administered off-label to horses for a long-lasting sedative effect^21,22 and as an anxiolytic and behavior modifier for horses in training and competition.^22-24 It is also been used in horses undergoing stall rest after surgery, ²⁵ in managing the behavior of young horses,²⁴ and for the treatment of fescue toxicosis in pregnant mares.²⁶  There are also anecdotal reports of its use for agalactia, head-shaking, and shivers.

Dowling (2004) stated that “before prescribing any drug for problem behavior in horses, the clinician should have (1) a reasonable diagnosis; (2) an appreciation for the mechanism of action of the drug; (3) a clear understanding of the potential side effects; (4) an understanding of how the drug will specifically alter the problem behavior; and (5) an understanding of the potential for abuse (unethical use).²² [...]