Download Adverse Side Effects in Horses Following the Administration of

MEDICINE I
Adverse Side Effects in Horses Following the
Administration of Fluphenazine Decanoate
John D. Baird, BVSc, PhD*; and George A. Maylin, DVM, MS, PhD
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 Antipsychotic 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 dialy-
NOTES
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MEDICINE I
Fig. 1.
Chemical structure of fluphenazine.
sis.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 halflife 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 con58
2011 Ⲑ Vol. 57 Ⲑ AAEP PROCEEDINGS
sequence of medications, the symptoms may be labeled as extrapyramidal symptoms.15 Neurolepticinduced 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 is 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 effect21,22 and as
an anxiolytic and behavior modifier for horses in
training and competition.21–24 It 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
MEDICINE I
5.
Reports of Adverse Reactions in Horses
Extrapyramidal side effects after the intramuscular
administration of fluphenazine decanoate, as reported in humans,5 have also been reported in the
horse.21,23–25 The doses of fluphenazine decanoate
administered to those horses that have shown EPS
have ranged from 25 mg25 to 50 mg21,23 to 125 mg.23
Extrapyramidal signs are usually observed between
24 and 36 hours after fluphenazine decanoate administration.21,23,25 A case has been reported in
which EPS signs were noticed 14 hours after the
intramuscular administration of 37.5 mg of fluphenazine enanthate24; another report described
signs that developed 72 hours after the administration of 50 mg fluphenazine decanoate.23
It is surprising that such severe and dramatic
EPS occur in horses (body weight, 400 to 450 kg)
after the administration of amounts of fluphenazine
decanoate that are within the standard dose of 25 to
50 mg administered to adult humans (body weight,
approximately 70 kg).1,23,24,27,28 Given this large
body weight difference, it would appear that the
horse may be very susceptible to adverse side effects
of fluphenazine decanoate.23,24 It has been proposed that horses might be more susceptible to fluphenazine-induced EPS because they may have a
more extensive extrapyramidal system than that in
humans.25 To the author’s knowledge, there are no
published studies on the pharmacokinetics of fluphenazine decanoate in the horse.
6.
Clinical Signs
Horses exhibiting extrapyramidal signs can be extremely dangerous to humans.22–25,29 The violent
behavior of these horses presents considerable diagnostic and therapeutic challenges.
The clinical signs result from a dopamine-acetylcholine imbalance in the extrapyramidal motor system. The signs of EPS in horses are characterized
by episodes of severe depression and somnolence
and the adoption of abnormal postures with intervals of extremely frantic, repetitive, compulsive,
manic movements.21,24,29,30 They may be reluctant
to move forward, and when they do, some have a
hypermetric gait.23,24,29 Muscle fasciculation has
been noted.23–25 When placed in a stall, they appear agitated and restless and may compulsively
circle the stall.21,23–25,29,31 Episodes of repetitive
and rhythmic neck flexion and head-tossing may
occur.23–25,29 Horses may show a rhythmic side-toside swaying of the head and neck23,25 (Fig. 2). Affected horses adopt abnormal postures and often
stand with their forelimbs extended forward and
may flex their head and neck ventrally and look
backward between their forelimbs.21
Horses affected with EPS may have intermittent
episodes of pawing that may become more frantic
and violent.21,23–25 These pawing episodes may
last for up to 1 to 2 minutes (Fig. 3). Horses have
also been reported to strike24,25 and rear.25 Profuse sweating may occur as a result of this abnormal
Fig. 2. Horse exhibiting abnormal posture and swinging of head
and neck after fluphenazine decanoate administration.
behavior.21,23,24 Horses may become laterally recumbent21,25,31 and may paddle while recumbent.25
There are reports of seizures,21 jaw champing,25 and
flank biting.23
Abnormal neurological signs have been observed
in neonatal foals nursing dams that have been administered fluphenazine decanoate. Fluphenazine
has been detected in the dam’s milk and serum of
the dam and her foal.
7.
Diagnosis
Determination of serum or plasma fluphenazine
concentrations can only be performed by a small
number of equine analytical laboratories in North
America and throughout the world. Unfortunately
results are usually available after a minimum of 2–3
weeks. This is not of great value when a veterinarian is confronted with a case of a horse exhibiting
extrapyramidal signs due to fluphenazine. However,
determination of fluphenazine in serum or plasma is
the “gold standard” and retrospectively is of value in
Fig. 3. Horse exhibiting frantic pawing after fluphenazine decanoate administration.
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MEDICINE I
confirming the diagnosis. For most veterinarians,
the history of fluphenazine administration within
the last 72 hours, as well as clinical signs of restlessness, agitation, bizarre behavior, violent and
frantic pawing, and abnormal movements of the
head and neck, are supportive of a diagnosis of EPS.
There have been wide variations in serum fluphenazine concentrations in horses with EPS.23–25
In severe EPS, fluphenazine concentrations as high
as 20.3 ng/mL24 and 39 ng/mL23 have been recorded,
but there are also cases with marked signs with
values of 3 to 4 ng/mL.23,25 Wide and highly fluctuating variations in serum or plasma fluphenazine
concentrations have also been observed in humans.6
Plasma fluphenazine concentrations in the range of
0.25 to 0.80 ng/mL have been considered to be probably adequate for maintenance therapy.6 As a result of the highly lipophilic nature of fluphenazine,
the tissue levels may be more important than
plasma or serum fluphenazine values. The author
is not aware of any studies on tissue levels after
fluphenazine decanoate administration to the horse.
8.
Differential Diagnoses
Differential diagnoses should include any disease
producing cerebrocortical dysfunction.28 The primary diagnostic rule-outs for fluphenazine-induced
EPS in a horse include rabies, equine herpes virus
(EHV)-1 myeloencephalopathy, equine protozoal
myeloencephalitis (EPM), Eastern equine encephalitis (EEE), Western equine encephalitis (WEE),
West Nile virus (WNV), and fumonisin toxicity (i.e.,
equine
leukoencephalomalacia).23,25,28 Because
many of the horses appear restless, agitated, with
constant walking and episodes of pawing, colic may
also be a diagnostic possibility. In the western
United States, nigropallidal encephalomalacia from
the chronic ingestion of yellow star thistle (Centaurea solstitialis) or Russian knapweed (Centaurea
repens) may also be considered as a possible diagnosis.24,30 However, many of these diseases may not
be considered primary rule-outs when the vaccination history and seasonal, environmental, and geographic conditions are taken into account. If the
severe signs exhibited by some horses are not recognized as being secondary to antipsychotic administration, it may lead to inappropriate euthanasia.29
9.
Treatment
Horses with EPS are often refractory to conventional tranquilizers such as xylazine, acepromazine,
or romifidine or they may result in a variable and
transient effect.23–25,31 An intravenous catheter
should be placed whenever possible to allow easy
venous access for repeated sedation and fluid
administration.
The principal treatment of fluphenazine-induced
EPS is based on the cholinergic-dopaminergic transmitter model.23–25,32 In the extrapyramidal system, especially in the basal ganglia, acetylcholine is
an excitatory transmitter, whereas dopamine is an
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2011 Ⲑ Vol. 57 Ⲑ AAEP PROCEEDINGS
inhibitory transmitter. Under normal conditions,
the cholinergic-dopaminergic system maintains
physiologic balance, resulting in coordinated neuromuscular activity.32 After the administration of
fluphenazine, blockage of the dopamine D2 receptors
occurs, especially in the nigrostriatal system. The
acetylcholine neurotransmitters become dominant
and overactive after the sudden withdrawal of dopaminergic inhibition, leading to an acute extrapyramidal reaction.17
Centrally acting anticholinergic drugs that restore an appropriate dopamine-acetylcholine balance, such as benztropine and diphenhydramine
hydrochloride, may be used to treat the extrapyramidal signs. Both drugs have been used in the
treatment of fluphenazine-induced EPS in the
horse.21,22–25,29,31
Diphenhydramine hydrochloride (0.67 to 1.0
mg/kg IV) administered as a bolus or over 20 minutes is the most widely used drug in the treatment of
EPS in the horse.23–25,31 If there is no response, a
second dose after an interval of approximately 15
minutes should be given.23,24 If there is still no
response, benztropine mesylate (0.018 mg/kg IV q
12 h or 0.04 mg/kg PO q 12 h) should be given.23
Benztropine mesylate is a synthetic compound containing the tropine portion of atropine and the
benzohydryl portion of diphenhydramine.32 Theoretically, benztropine mesylate should have stronger
antiparkinsonic and anticholinergic effects than
diphenhydramine.5,32 Benztropine mesylate has
both anticholinergic and antihistaminic effects.32
In horses, it has been recommended that treatment
with benztropine mesylate (0.035 mg/kg PO q 12 h)
should be continued for 7 to 10 days to prevent a
recurrence. In humans, a more rapid response has
been observed with antipsychotic-induced dystonic
reactions after treatment with benztropine mesylate
than with diphenhydramine.13,16,32
In some horses with EPS, neither diphenhydramine hydrochloride23,25 or benztropine mesylate
is effective.23 In these refractory cases, supportive
hypnotic therapy may be necessary. Intravenous
pentobarbital and phenobarbital has been found to
be useful in managing the maniacal behavior of
these horses.21,23,25,31 The ability to provide longterm sedation and control of fluphenazine-induced
central nervous system excitement without inducing
recumbency or anesthesia has been shown to be very
beneficial in managing these severe cases.21 Intravenous boluses or continuous-rate infusion of sodium pentobarbital (2.6 to 5.5 mg/kg IV) have been
given to provide rapid sedation.21,23 In some
horses, continuous-rate infusion of phenobarbital after a loading dose of 12 mg/kg administered in 1 L
over 20 to 30 minutes21,25 and oral phenobarbital
(10.6 mg/kg) has been used to manage these cases.25
While receiving barbiturates, horses with EPS need
close monitoring for a period of 5 to 10 days, and,
ideally, serum phenobarbital levels should be monitored to maintain the recommended therapeutic
MEDICINE I
range of 20 to 40 ␮g/mL.25 With improvement of
the horse’s mental status and behavior, the administration of phenobarbital may be gradually reduced.23,25 Intravenous chloral hydrate may be
used in place of barbiturates.31
Balanced electrolyte solutions, such as lactated
Ringer’s solution, should be given IV during hospitalization to provide renal diuresis.21,23,25 Observation of a response to anticholinergic treatments
(diphenhydramine, benztropine mesylate) for EPS
may place the viral encephalitides lower on the differential diagnostic list.
10.
Prognosis
The prognosis for the recovery of affected horses
tends to be good, and recovery is typically complete.28 The prognosis may depend on the dosage,
route of administration, frequency of administration, and interval(s) between doses. Considerable
difficulty may be involved in the treatment of these
horses. Transportation to a referral hospital is
recommended, but that may be difficult and hazardous.23,25 There are reports of horses being euthanized because of the severity of the behavioral
abnormalities and the lack of response to conventional tranquilizers and anticholinergics (diphenhydramine, benztropine mesylate).23 There are no
reports of the long-term continuation of EPS in the
horse, as reported in humans.12,16,25
11.
Testing for Fluphenazine
In 1997, a highly sensitive and specific high-performance liquid chromatographic method with coulometric detection was developed for the simultaneous
assay of fluphenazine and its metabolites in plasma.
The lower limit of quantification and detection of
fluphenazine and its metabolites in equine plasma is
0.1 ng/mL.1
The United States Equestrian Federation (USEF)
classifies fluphenazine as a forbidden substance and
warns that it is possible that long-acting forms of
fluphenazine or its metabolites may remain detectable in blood for long periods of time. For this
reason, a 90-day withdrawal time is recommended
to avoid inadvertent positive findings. Detection
depends on the formulation of the drug, dose or
doses administered, frequency of administration,
route of administration, weight of the horse or pony,
and health condition of the animal. Fluphenazine
testing was instituted by the USEF in 2003, and up
until 2010 there have been 48 positive tests in competition horses under the USEF jurisdiction. The
penalties imposed for a positive fluphenazine test
have ranged from $3000 to $6000 as well as suspension from competing or taking any part whatsoever
in recognized competitions as an exhibitor, participant, or spectator for periods of 3 to 6 months.
Any trophies, prizes, ribbons, and monies won by
these horses must also be returned.
From November 1, 2003, the New York Racing
and Wagering Board commenced post-race testing
for fluphenazine and reserpine. The New York
Racing and Wagering Board Rules of Racing that
pertain to these drugs for Thoroughbreds is Rule
4043.7 and for Harness horses is Rule 4120.11.
These rules state: “(a) Notwithstanding any inconsistent provision of this part, a finding by the laboratory that the drug reserpine or the drug
fluphenazine was present in the sample taken from
a horse shall result in the disqualification of the
horse from the race and from any share of the purse
in the race; and (b) The trainer of a horse which has
been the subject of a finding by the laboratory that
the drug reserpine or the drug fluphenazine was
present in the sample taken from that horse shall
not be subject to application of trainer’s responsibility based solely upon the finding by the laboratory
that the drug reserpine or the drug fluphenazine
was present in the sample.”
The Fédération Equestre Internationale classifies
fluphenazine as a prohibited substance, which
means a substance that has been deemed by the
Fédération Equestre Internationale to have no common legitimate use in equine medicine and/or have a
high potential for abuse. Positive drug tests have
been reported.
Equine veterinarians who are involved in prepurchase examinations may now request drug screening tests that include detection of fluphenazine.
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