ACEPROMAZINE MALEATE

ACEPROMAZINE MALEATE

Chemistry

Acepromazine maleate (formerly acetylpromazine) is a phenothiazine derivative which occurs as a yellow, odorless, bitter tasting powder. One gram is soluble in 27 ml of water, 13 ml of alcohol, and 3 ml of chloroform. Acepromazine is also known as “ACE”, ACP, “Plegicil¨, “Notensil¨, & “Atravet¨.

Storage/Stability/Compatibility

Store protected from light. Tablets should be stored in tight containers. Acepromazine injection should be kept from freezing.

Although controlled studies have not documented the compatibility of these combinations, acepromazine has been mixed with atropine, buprenorphine, chloral hydrate, ketamine, meperidine, oxymorphone, and xylazine. Both glycopyrrolate and diazepam have been reported to be physically incompatible with phenothiazines. However, glycopyrrolate has been demonstrated to be compatible with promazine HCl for injection.

Pharmacology

Acepromazine is a phenothiazine neuroleptic agent. While the exact mechanisms of action are not fully understood, the phenothiazines block post-synaptic dopamine receptors in the CNS and may also inhibit the release of, and increase the turnover rate of dopamine. They are thought to depress portions of the reticular activating system which assists in the control of body temperature, basal metabolic rate, emesis, vasomotor tone, hormonal balance, and alertness.

Additionally, phenothiazines have varying degrees of anticholinergic, antihistaminic, antispasmodic, and alpha-adrenergic blocking effects.

The primary desired effect for the use of acepromazine in veterinary medicine is its tranquilizing action. Additional pharmacologic actions that acepromazine possess, include antiemetic, antispasmodic, and hypothermic actions. Some researchers have reported that acepromazine has anticonvulsant activity, but in veterinary medicine it is generally felt that phenothiazines should not be used in epileptic animals or those susceptible to seizures (e.g., post-myelography) as it may precipitate seizures.

Acepromazine may decrease respiratory rates, but studies have demonstrated that little or no effect occurs with regard to the blood gas picture, pH or oxyhemoglobin saturation. A dose dependent decrease in hematocrit is seen within 30 minutes after dosing in the horse and the dog. In horses, hematocrit values may decrease up to 50% of pre-dose values which is probably due to increased splenic sequestration of red cells.

Besides a lowering of arterial blood pressure in the dog, acepromazine causes an increase in central venous pressure, a vagally induced bradycardic effect and transient sinoatrial arrest. The bradycardia may be negated by a reflex tachycardic effect secondary to decreases in blood pressure.

Acepromazine also has antidysrhythmic effects. Acepromazine has been demonstrated to inhibit the arrhythmias induced by the ultra-short acting barbiturates, and protect against the ventricular fibrillatory actions of halothane and epinephrine. Other pharmacologic actions are discussed in the adverse effects section below.

Uses/Indications

Acepromazine is approved for use in dogs, cats, and horses. Approved indications for dogs and cats include: “...as an aid in controlling intractable animals.....alleviate itching as a result of skin irritation; as an antiemetic to control vomiting associated with motion sickness” and as a preanesthetic agent. In horses, “...as an aid in controlling fractious animals”, and in conjunction with local anesthesia for various procedures and treatments. It is also commonly used in horses as a pre-anesthetic agent, at very small doses to help control behavior. Although not approved, it is used as a tranquilizerin swine, cattle, rabbits, sheep and goats. Acepromazine has also been shown to reduce the incidence of halothane-induced malignant hyperthermia in susceptible pigs.

Pharmacokinetics

In horses: The drug has a fairly high volume of distribution (6.6 L/kg), and is more than 99% protein bound. The onset of action is fairly slow, requiring up to 15 minutes following IV administration, with peak effects seen in 30-60 minutes. The elimination half-life in horses approximately 3 hours. Acepromazine is metabolized in the liver with both conjugated and unconjugated metabolites eliminated in the urine. Metabolites may be found in equine urine for up to 96 hours after dosing.

Do not administer to racing animals within 4 days of racing.

Contraindications/Precautions

Animals may require lower dosages of general anesthetics following acepromazine. Cautious use and smaller doses of acepromazine should be given to animals with hepatic dysfunction, cardiac disease, or general debilitation. Because of its hypotensive effects, acepromazine is relatively contraindicated in patients with hypovolemia or shock.

Phenothiazines are relatively contraindicated in patients with tetanus or strychnine intoxication due to effects on the extrapyrimidal system.

Intravenous injections should be made slowly. Do not administer intra-arterially in horses; may cause severe CNS excitement/depression, seizures and death. Because of its effects on thermoregulation, use cautiously in very young or debilitated animals.

Acepromazine has no analgesic effects; treat animals with appropriate analgesics to control pain.

The tranquilization effects of acepromazine can be overridden and it cannot always be counted upon when used as a restraining agent. Do not administer to racing animals within 4 days of a race.

In dogs, acepromazine’s effects may be individually variable and breed dependent. In geriatric patients, very low doses have been associated with prolonged effects of the drug. Giant breeds and greyhounds may be extremely sensitive to the drug, while terrier breeds are somewhat resistant to its effects. Boxers are reported to very sensitive to the hypotensive and bradycardic effects of acepromazine and should be used cautiously and in small doses in this breed. Atropine is often suggested to be given with acepromazine to help negate its bradycardic effects.

In addition to the legal aspects (not approved) of using acepromazine in cattle, the drug may cause regurgitation of ruminal contents when inducing general anesthesia.

Adverse Effects/Warnings

Acepromazine’s effect on blood pressure (hypotension) is well described and an important consideration in therapy. This effect is thought to be mediated by both central mechanisms and also through the alpha-adrenergic actions of the drug. Cardiovascular collapse (secondary to bradycardia and hypotension) has been described in all major species. Dogs may be more sensitive to these effects than other animals.

In male large animals, acepromazine causes protrusion of the penis and corresponds to the sedative effects of the drug. In horses, this effect may last 2 hours. Stallions should be given acepromazine with caution as injury to the penis can occur with resultant swelling and permanent paralysis of the penis retractor muscle. Other symptoms that have been reported in horses include excitement, restlessness, sweating, trembling, tachypnea, tachycardia and, rarely, seizures and recumbency.

While acepromazine is a good tranquilizer, its effects of causing penis extension in horses and prolapse of the membrana nictitans in horses and dogs, may make its use unsuitable for show animals.

There are also ethical considerations regarding the use of tranquilizers prior to showing an animal or having the animal examined before sale.

Occasionally an animal may develop the contradictory symptoms of aggressiveness and generalized CNS stimulation after receiving acepromazine. IM injections may cause transient pain at the injection site.

Overdosage

The LD50 in mice is 61 mg/kg after IV dosage and 257 mg/kg after oral dose. Dogs receiving 20 - 40 mg/kg over 6 weeks apparently demonstrated no adverse effects. Dogs gradually receiving up to 220 mg/kg orally exhibited signs of pulmonary edema and hyperemia of internal organs, but no fatalities were noted.

Because of the apparent relative low toxicity of acepromazine, most overdoses can be handled by monitoring the animal and treating symptoms if they occur. Massive oral overdoses should definitely be treated by emptying the gut if possible. Hypotension should not be treated with epinephrine; use either phenylephrine or norepinephrine (levarterenol). Seizures may be controlled with barbiturates or diazepam. Doxapram has been suggested as an antagonist to the CNS depressant effects of acepromazine.

Drug Interactions

Acepromazine should not be given within one month of worming with an organophosphate agent as their effects may be potentiated. Other CNS depressant agents (barbiturates, narcotics, anesthetics, etc.) may cause additive CNS depression if used with acepromazine.

Quinidine when given with phenothiazines may cause additive cardiac depression.

Antidiarrheal mixtures (e.g., Kaolin/pectin, bismuth subsalicylate mixtures) and antacids may cause reduced GI absorption of oral phenothiazines. Increased blood levels of both drugs may result if propranolol is administered with phenothiazines.

Phenothiazines block alpha-adrenergic receptors and if epinephrine is given, can lead to unopposed beta-activity causing vasodilation and increased cardiac rate. Phenytoin metabolism may be decreased if given concurrently with phenothiazines.

Procaine activity may be enhanced by phenothiazines.

Doses

The manufacturer’s dose of 0.5 - 2.2 mg/kg for dogs and cats is considered by many clinicians to be 10 times greater than is necessary for most indications. Give IV doses slowly; allow at least 15 minutes for onset of action.

Dogs:

a) Premedication: 0.03 - 0.05 mg/kg IM or 1 - 3 mg/kg PO at least one hour prior to surgery (not as reliable).

b) Restraint/sedation: 0.025 - 0.2 mg/kg IV; maximum of 3 mg or 0.1 - 0.25 mg/kg IM.

Preanesthetic: 0.1 - 0.2mg/kg IV or IM; max. of 3 mg; 0.05 - 1 mg/kg IV, IM or SQ.

c) 0.1 mg/kg IM or IV q8h

d) 0.55 - 2.2 mg/kg PO or 0.55 - 1.1 mg/kg IV, IM or SQ

e) 0.55 - 2.2 mg/kg PO or 0.055 - 0.11 mg/kg IV, IM or SQ

Cats:

a) Restraint/sedation: 0.05 - 0.1 mg/kg IV, maximum of 1 mg

b) 0.1 mg/kg IM or IV once daily

c) 1.1 - 2.2 mg/kg PO, IV, IM or SQ

d) 0.055 - 0.11 mg/kg IM or SQ or 1.1 - 2.2 mg/kg PO

e) 0.11 mg/kg with atropine (0.045 - 0.067 mg/kg) 15-20 minutes prior to ketamine (22

mg/kg IM).

Rabbits:

a) As a tranquilizer: 1 mg/kg IM, effect should begin in 10 minutes and last for 1-2 hours

Cattle:

a) Sedation: 0.01 - 0.02 mg/kg IV or 0.03 - 0.1 mg/kg IM

b) 0.05 - 0.1 mg/kg IV, IM or SQ

c) Sedative one hour prior to local anesthesia: 0.1 mg/kg IM

Horses:

a) 0.04 - 0.1 mg/kg IV or IM

b) 0.044 - 0.088 mg/kg (2 - 4 mg/100 lbs. body weight) IV, IM or SQ

c) 0.02 - 0.05 mg/kg IM or IV as a preanesthetic

d) Neuroleptanalgesia:0.02 mg/kg given with buprenorphine (0.004 mg/kg IV) or xylazine

(0.6 mg/kg IV)

Swine:

a) 0.1 - 0.2 mg/kg IV, IM, or SQ

b) 0.03 - 0.1 mg/kg

c) For brief periods of immobilization: acepromazine 0.5 mg/kg IM followed in 30 minutes

by ketamine 15 mg/kg IM. Atropine (0.044 mg/kg IM) will reduce salivation and

bronchial secretions.

Sheep & Goats:

a) 0.05 - 0.1 mg/kg IM

Monitoring Parameters

1) Cardiac rate/rhythm/blood pressure if indicated and possible to measure

2) Degree of tranquilization

3) Male horses should be checked to make sure penis retracts and is not injured.

4) Body temperature (especially if ambient temperature is very hot or cold)

Client Information/FDA Approval Status

May discolor the urine to a pink or red-brown color; this is not abnormal.

Acepromazine is approved for use in dogs, cats, and horses not intended for food.

Dosage Forms/Preparations/FDA Approval Status/Withholding Times

Veterinary-Approved Products:

Acepromazine Maleate for Injection 10 mg/ml for injection in 50 ml vials; Approved for use in dogs, cats and horses not intended for food.

Acepromazine Maleate Tablets 5, 10, & 25 mg in bottles of 100 and 500 tablets; Approved for use in dogs, cats and horses not intended for food.

Human-Approved Products: None