(Adverse effect reported)
Chemistry - A butyrephone neuroleptic, azaperone occurs as a white to yellowish-white macrocrystalline powder with a melting point between 90 - 95°C. It is practically insoluble in water and 1 gram is soluble in 29 ml of alcohol.
Storage/Stability/Compatibility - Azaperone should be stored at room temperature (15-30°C) and away from light. No information was located regarding mixing azaperone with other compounds.
Pharmacology - The butyrephenones as a class cause tranquilization and sedation (sedation may be less so than with the phenothiazines), anti-emetic activity, reduced motor activity, and inhibition of CNS catecholamines (dopamine, norepinephrine). Azaperone appears to have minimal effects on respiration and may inhibit some of the respiratory depressant actions of general anesthetics. A slight reduction of arterial blood pressure has been measured in pigs after IM injections of azaperone, which is apparently due to slight alpha-adrenergic blockade. Azaperone has been demonstrated to prevent the development of halothane-induced malignant hyperthermia in susceptible pigs. Preliminary studies have suggested that the effects of butyrephenones may be antagonized by 4-aminopyridine.
Uses/Indications - Azaperone is officially indicated for the “control of aggressiveness when mixing or regrouping weanling or feeder pigs weighing up to 36.4 kg” (Package Insert, Stresnil® - P/M; Mallinckrodt). It is also used clinically as a general tranquilizer for swine, in aggressive sows to allow piglets to be accepted, and as a preoperative agent prior to general anesthesia or cesarian section with local anesthesia.
Azaperone has also been used as a neuroleptic in horses, but some horses develop adverse reactions (sweating, muscle tremors, panic reaction, CNS excitement) and IV administration has resulted in significant arterial hypotension in the horse. Because of these effects, most clinicians avoid the use of this drug in equines.
Pharmacokinetics - Minimal information was located regarding actual pharmacokinetic parameters, but the drug is considered to have a fairly rapid onset of action following IM injections in pigs (5-10 minutes) with a peak effect at approximately 30 minutes post injection. It has a duration of action of 2-3 hours in young pigs and 3-4 hours in older swine. The drug is metabolized in the liver with 13% of it excreted in the feces. At 16 hours post-dose, practically all of the drug is eliminated from the body.
Contraindications/Precautions - When used as directed, the manufacturer reports no contraindications for the drug. It should not be given IV as a significant excitatory phase may be seen in pigs.
Adverse Effects/Warnings - Transient salivation, piling, and shivering have been reported in pigs. Pigs should be left undisturbed after injection (for approximately 20 minutes) until the drug’s full effects have been expressed, as disturbances during this period may trigger excitement.
Azaperone has minimal analgesic effects and is not a substitute for appropriate anesthesia or analgesia. It is recommended that in large boars dosage not exceed 2 mg/kg IM.
Overdosage - No specific information was discovered regarding overdoses of azaperone, but it would be expected that symptoms would be an extension of its pharmacologic effects. It is suggested that treatment be supportive. Do not use epinephrine to treat cardiovascular symptoms. More work needs to done before 4-aminopyridine can be recommended as a reversal agent for azaperone.
Drug Interactions - No specific drug interactions have been reported for azaperone. The following interactions have been reported for the closely related compounds, haloperidol or droperidol: CNS depressant agents (barbiturates, narcotics, anesthetics, etc.) may cause additive CNS depression if used with butyrephenones.
a) For approved indication of mixing feeder or weanling pigs: 2.2 mg/kg deeply IM (see client information below) (Package Insert; Stresnil® — P/M; Mallinckrodt)
b) Preanesthetic: 2 - 4 mg/kg IM; Immobilizing agent: 5.3 - 8 mg/kg IM (Swindle 1985)
c) Sedation: 1 mg/kg IM
Reduction of aggressiveness: 2.5 mg/kg IM
Knock-down or immobilant: 5 - 10 mg/kg IM (Booth 1988a)
CAUTION! Sedative and anesthetic drug dosages for African elephants often vary from those for Asian elephants. Do not assume that the recommendations for one species can be applied to the other. Significant variation may also occur between individual elephants. Higher doses may be needed in wild or excited animals. The information provided here should be used as a guideline only. Consultation with experienced colleagues is advised
a) Total dose of azaperone for adult Asian captive elephants 80-100 mg; up to 140 mg for a large elephant. Induction in 20-30 minutes; duration 45-60 minutes (Cheeran et.al. 2002).
b) For capture of wild juvenile African elephants 4 mg etorphine and 60-80 mg azaperone; for capture of small calves (under 1 m shoulder height) 1 mg etorphine and 10 mg azaperone.
For transport of wild African elephants, the dose of azaperone varies with shoulder height: > 2.4 m (200 mg); 2.0-2.4 m (150 mg); all lactating females (150 mg); l .5-2.0 m (100 mg); 1.2-1.5 m (50 mg); 1.2 m (10-20 mg) (du Toit, 2001).
c) For standing sedation in captive African elephants, 0.056-0.107 mg/kg (median dose = 0.08 mg/kg; total dose 240-400 mg / animal; n=20). (Ramsey, 2000).
d) For capture of adult wild African elephants, azaperone in combination with etorphine or carfentanil as follows: adult females: 12 mg etorphine and 100 mg azaperone (or 10 mg carfentanil and 100 mg azaperone); adult males: 15 mg etorphine and 200 mg azaperone (or 13 mg carfentanil and 200 mg azaperone). For captive elephants, reduce dosage by 25 %.
For capture of wild African calves, (in combination with etorphine or carfentanil) according to shoulder height as follows:
Shoulder height 90-115 cm: etorphine 2 mg (or carfentanil 1 mg) and azaperone 20 mg
Shoulder height 116-140 cm: etorphine 5 mg (or carfentanil 3 mg) and azaperone 50 mg
Shoulder height 141-165 cm: etorphine 7 mg (or carfentanil 5 mg) and azaperone 70 mg
Shoulder height 166-200 cm: etorphine 9 mg (or carfentanil 7 mg) and azaperone 90 mg
For captive elephants, reduce dosage by 25 % (Raath, 1999).
e) Two African elephants (estimated weights 1000 and 1200 kg) were given 120 mg azaperone for transport (Stegmann, 1999).
f) For standing sedation in captive Asian elephants: 0.024-0.038 mg/kg for minor surgical procedures. Adverse effect noted – see info below (Schmitt, et.al. 1996).
g) For capture of wild African elephants ≤ 600 kg: etorphine 0.35 ± 0.13 µg/(kg/min) and azaperone 3.11 ± 1.10 µg/(kg/min)
For capture of wild African elephants > 600 kg: etorphine 0.23 ± 0.09 and azaperone 2.01 ± 0.8 µg/(kg/min)
Note: Total doses of etorphine and azaperone [µg/(kg/min)] were calculated as a sum of the induction (dart) dose and any following supplements divided by the elephant’s body mass and calculated anesthetic/recumbent time. Body mass of smaller elephants was determined by weighing. Body mass of larger elephants (>1000 kg) was estimated from shoulder height. See abstract below. (Still et.al. 1996).
h) Following immobilization for translocation of 670 elephants in family units in 1993, haloperidol (40 to 120 mg depending on body size) was used as a tranquilizer during transport. In addition, azaperone, (50-200 mg) was often administered to avoid aggression. Trilafon [perphenazine] (100-300 mg) was administered to keep animals calm after their release into bomas (Coetsee, 1996).
i) Azaperone (60-100 mg) was combined with etorphine (7-15 mg) and hyaluronidase 1500-3000 IU) in a translocation operation of 26 elephants in central Kenya. Induction time was 7-15 minutes. Five elephants died from metabolic changes unrelated to drugs doses administered.
(Njumbi et.al. 1996). (Author’s (Mikota) note: hyalase is incorrectly described as a tranquilizer in this article.
j) In the capture of wild African elephants, azaperone in combination with etorphine or carfentanil to reduce blood pressure decreases the occurrence of pink foam syndrome. See abstract below (Hattingh et.al. 1994).
k) 0.1 mg/kg azaperone IM for tranquilization of wild African elephants for transportation; For emergency treatment of pink foam syndrome 0.1 mg/kg IV as a vasodilator; reverse narcotic immediately. Pink foam syndrome is caused by pulmonary edema and capillary bleeding from high mean arterial pressure. It has been associated with opioids and manifests as pink froth from the trunk. Refer to the original work for azaperone doses for wild African calves and for further information and treatment of pink foam syndrome (Raath, 1993).
l) For sedation: 30-120 mg for babies, 120 mg for juveniles, 120-760 mg for adults. Species and route of
administration not specified (Kock et.al 1993). (Author’s (Mikota) note: The animal category and drug dose
column headings for azaperone are misaligned in this reference and may cause confusion. The doses listed here
are correctly matched to their respective age categories).
a) Cheeran,J.V., Chandrasekharan,K., and Radhakrishnan,K. 2002. Tranquilization and translocation of elephants. Journal of Indian Veterinary Association Kerala 7:(3):42-46
b) du Toit,J.G., 2001. Veterinary Care of African Elephants. Novartis, Pretoria, Republic of South Africa, 1-59 pp. Web/URL: www.wildlifedecisionsupport.com
c) Ramsay,E. 2000. Standing sedation and tranquilization in captive African elephants (Loxodonta africana). Proc. Am. Assoc. Zoo Vet. Pages: 111-114 Excerpt from abstract: Intramuscular azaperone was used to tranquilize seven animals (African) for a total of 20 immobilizations. Azaperone alone or in combination with local anesthesia (lidocaine blocks) was used 15 times. Reasons for tranquilization included treatment of tail folliculitis, treatment of abscesses, obtaining blood samples, intradermal tuberculin testing, and manual stimulation of ejaculation. Dosages for azaperone alone ranged from 0.056-0.107 mg/kg (median dosage = 0.08 mg/kg; total doses ranged from 240-400 mg/ animal). One animal, which received an initial dosage of 0.04 mg/kg required supplementation, to a total dosage of 0.056 mg/kg to be tractable enough, while in an elephant restraint device, for manual stimulation of ejaculation. All but one tranquilization were rated as good (sufficient tranquilization to accomplish the procedure) or excellent (sufficient tranquilization to perform the intended procedure and additional diagnostics). Tranquilized elephants stood, with minimal swaying, and did not make efforts to resist or pull away for the handler. Tranquilization of one female that received 0.075 mg/kg was rated as fair due to insufficient sedation for venipuncture. One tranquilization was rated good (dosage = 0.107 mg/kg) but a notation suggested that the elephant was “too deep, tried to buckle” and a lesser dosage was used more satisfactorily on that animal for subsequent immobilizations. Tranquilizations ranked as excellent were produced by dosages of 0.079- 0.0904 mg/kg (n=4). Times from initial darting to adequate sedation and to recovery (normal behavior) were infrequently recorded but the author’s impressions is that animals became sedate for handling approximately 20 minutes after the injection and recovered approximately 2 hr after initial dosing.
d) Raath,J.P., 1999. Relocation of African elephants. In: Fowler,M.E. and Miller,R.E. (Editors), Zoo and Wild Animal Medicine: Current Therapy 4. W.B. Saunders, Philadelphia, PA, USA pp. 525-533
e) Stegmann,G.F. 1999. Etorphine-halothane anaesthesia in two five-year-old African elephants (Loxodonta africana). Journal of the South African Veterinary Medical Association 70:(4):164-166 Abstract: Anaesthesia of 2 five-year-old female African elephants (Loxodonta africana) was required for dental surgery. The animals were each premedicated with 120 mg of azaperone 60 min before transportation to the hospital. Before offloading, 1 mg etorphine was administered intramuscularly (i.m.) to each elephant to facilitate walking them to the equine induction/recovery room. For induction, 2 mg etorphine was administered i.m. to each animal. Induction was complete within 6 min. Surgical anaesthesia was induced with halothane-in-oxygen after intubation of the trunk. During surgery the mean heart rate was 61 and 45 beats/min respectively. Systolic blood pressures increased to 27.5 and 25.6 kPa respectively, and were treated with intravenous azaperone. Blood pressure decreased thereafter to a mean systolic pressure of 18.1 and 19.8 kPa, respectively. Rectal temperature was 35.6 and 33.9 degrees C at the onset of surgery, and decreased to 35.3 and 33.5 degrees C, respectively, at the end of anaesthesia. Etorphine anaesthesia was reversed with 5 mg diprenorphine at the completion of 90 min of surgery.
f) Schmitt,D., Bradford,J., and Hardy,D.A. 1996. Azaperone for standing sedation in Asian elephants (Elephas maximus). Proceedings American Association of Zoo Veterinarians. Pages: 48-51 Abstract: Azaperone was used for standing sedation in four Asian elephants (Elephas maximus) in 93 trials at Dickerson Park Zoo (DPZ). Procedures including surgical artificial insemination, semen collection, and routine foot trimming were completed while utilizing azaperone as a sedative. All procedures were performed within an elephant restraint device. Azaperone has proven to be a safe and reliable drug for facilitation of routine health and reproductive-related procedures in captive Asian elephants when administered at 0.030 mg/kg. the procurement of azaperone in the United States has been difficult due to changing manufacturing and distribution procedures. The utilization of an Investigational New Animal Drug permit from the Food and Drug Administration is described, to facilitate procurement of azaperone from Canada for use in the United States. Additional excerpt: The sedative effects of azaperone in 93 trials were rated as good in 81 trials, fair in 12 trials, and poor in none. The calming initial effects of azaperone on the elephant could be seen in 10 to 15 min following injection. In most cases, appetite seemed to increase during this time. Maximum effect was attained in 15 to 25 min. Maximum effects were characterized by: a stuporous or somnolent mental state often accompanied by snoring, an unwillingness to move or respond to stimuli, diminished bowel movement, distended or relaxed penis or clitoris. No tendencies or desires to lie down have been noted. Maximum effects rapidly diminished after approximately 2 hr. Total duration of effects was approximately 3 hr. Repeated daily administration of azaperone during two to six day periods demonstrated no residual effects. * Adverse effect noted: Two abnormal responses were shown from the same cow during azaperone induction. The episodes of confused or hallucinatory behavior were responses to mild stimuli. Once maximum effect has been attained, no behavioral problems have been noted.
g) Still,J., Raath,J.P., and Matzner,L. 1996. Respiratory and circulatory parameters of African elephants (Loxodonta africana) anesthetized with etorphine and azaperone. Journal of the South African Veterinary Medical Association 67:(3):123-127 Abstract: Respiratory rate, heart rate, blood-gas tensions (PO2 and PCO2) and pH of arterial (a) and peripheral venous (v) blood, concentration of haemoglobin in arterial blood (Hb), saturation of arterial haemoglobin with oxygen and the end-expiratory concentration of oxygen were measured in 22 juvenile African elephants anaesthetized with etorphine and azaperone during 35 to 65 min after they assumed lateral recumbency. Based on these parameters the alveolar-arterial and arterial-peripheral venous differences of PO2 [P(A-a)O2 and P(a-v)O2, respectively], and oxygen content of arterial blood (CaO2) were calculated. Elephants with body mass of ≤ 600 kg showed significant changes in the following parameters compared with elephants with a body mass of more than 600 kg (x ± SD) : PO2 (64 ± 11 compared with 82 ± 8 mmHg), P(a-v)O2 (9 ± 5 compared with 22 ± 9 mmHg), P(A-a)O2 (37 ± 16 compared with 15 ± 8 mmHg) and Hb (148 ± 20 compared with 130 ± 10 g/litre) (p< 0.05). These findings suggested a tendency towards impaired oxygen exchange in the lungs, reduced peripheral extraction of oxygen and elevated oxygen-carrying capacity of arterial blood in smaller elephants. These changes were theoretically attributed to the respiratory-depressant and sympathomimetic effects of higher dosages of etorphine used in the smaller elephants to maintain a clinically acceptable anaesthetic plane. Individual elephants spent 35 to 150 min under anaesthesia and all recovered uneventfully after reversal of etorphine with diprenorphine.
h) Coetsee,C. 1996. Elephant Translocations. Pachyderm 22:81
i) Njumbi,S.T., Waithaka,J., Gachago,S., Sakwa,J., Mwathe,K., Mungai,P., Mulama,M., Mutinda,H., Omondi,P., and Litoroh,M. 1996. Translocation of elephants: the Kenyan experience. Pachyderm 22: 61-65
j) Hattingh,J. and Knox,C.M. 1994. Arterial blood pressure in anesthetized African elephants. South African Journal of Wildlife Research 24:(1/2) Abstract: A number of elephants previously captured in the Krueger National Park developed a pink frothy discharge from the external nares. Some of these elephants subsequently died and histopathological examinations indicated severe lung oedema. In view of the current hypothesis that high blood pressure could be a causative factor, arterial blood pressure was measured in elephants immobilized with etorphine alone (n=71) and with etorphine/azaperone (n=109) and with carfentanil/azaperone (n=26) mixtures. Arterial pressure was found to be significantly lower in the groups immobilized with azaperone mixtures than in the group immobilized with etorphine alone (p < 0.05). In addition, no cases of lung oedema were observed in animals immobilized with etorphine/azaperone and carfentanil/azaperone mixtures. It is strongly recommended, therefore, that azaperone be added to immobilization mixtures when elephants are subjected to herding prior to darting. Additional excerpt: all elephants in this study were juveniles 200 to 1300 kg. Group 1 (n=71) was immobilized with 4-8 mg etorphine; group 2 (n=109) was immobilized with 4-8 mg etorphine and 50-90 mg azaperone; and group 3 (n=26) was immobilized with 4-8 mg carfentanil and 50-90 mg azaperone.
k) Raath,J.P., 1993. Chemical capture of the African elephant.
In: The Capture and care manual : capture, care, accommodation and
transportation of wild African animals.
Wildlife Decision Support Services : South African Veterinary Foundation,
l) Kock,R.A., Morkel,P., and Kock,M.D., 1993. Current immobilization procedures used in elephants. In: Fowler,M.E. (Editor), Zoo and Wild Animal Medicine Current Therapy 3. W.B. Saunders Company, Philadelphia, PA, USA pp. 436-441
Dunlop,C.I., Hodgson,D.S., Cambre,R.C., Kenny,D.E., and Martin,H.D.
1994. Cardiopulmonary effects of three prolonged periods of isoflurane
anesthesia in an adult elephant. Journal of the American Veterinary
Medical Association 205:(10):1439-1444
Still,J. 1993. Etorphine-azaperone anaesthesia in an African elephant (Loxodonta africana). Journal of Veterinary Anaesthesia 20:54-55 Summary: Wild elephants ≤ 2000 kg were darted with a mixture of azaperone (30 to 100 mg) and etorphine (3 to 9 mg). No further drug dose detail provided. Respiratory parameters for one elephant monitored for 140 min are reported.
de Vos,V. 1978. Immobilization of free-ranging wild animals using a new drug. Vet Rec 103:(4):64-68 Abstract: Field trials were conducted with the potent morphine-like analgesic, R33799 (Janssen Pharmaceutica; Beerse, Belgium) in South African national parks on 217 free-ranging wild animals, representing 20 different species. The drug was found to be effective and safe for a wide range of ungulates and pachyderms and Burchell's zebra (Equus burchelli) did not react to expected dosage levels. A suggested dosage regime for 19 species is given. Recommended optimal dosage rates varies from about 1 microgram per kg for pachyderms to about 10 microgram per kg for most of the larger ungulates. Xylazine and azaperone were found valuable adjuncts to R33799 in dosage ratios of 10:1 and 30:1 respectively.
Silberman,M.S. 1977. Tranquilization of the African elephant (Loxodonta africana Blumenbach) with neuroleptic azaperone (R-1929). Journal of Zoo Animal Medicine 8:7-8
Monitoring Parameters -
1) Level of sedation
Client Information - Must be injected IM deeply, either behind the ear and perpendicular to the skin or in the back of the ham. All animals in groups to be mixed must be treated.
Dosage Forms/Preparations -
Veterinary-Approved Products: May not be currently marketed in the USA
Azaperone 40 mg/ml for Injection in 20 ml vials (6 vials/box); Stresnil®; (Schering-Plough) (Rx). Approved for use in pigs. There is no specific tolerance for residues published and there is no specified withdrawal time before slaughter.
Also known by the trade name Suicalm® in the United Kingdom.
Human-Approved Products: None
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