Elephant specific information, if available, is in blue.

 

Chemistry – A benzodiazepine, diazepam is a white to yellow, practically odorless crystalline powder with a melting point between 131°-135°C and pKa of 3.4. Diazepam is tasteless initially, but a bitter after-taste develops. One gram is soluble in 333 ml of water, 25 ml of alcohol, and it is sparingly soluble in propylene glycol. The pH of the commercially prepared injectable solution is adjusted with benzoic acid/sodium benzoate to 6.2-6.9. It consists of a 5 mg/ml solution with 40% propylene glycol, 10% ethanol, 5% sodium benzoate/benzoic acid buffer, and 1.5% benzyl alcohol as a preservative.

 

Storage/Stability/Compatibility – All diazepam products should be stored at room temperature (15°-30°C). The injection should be kept from freezing and protected from light. The oral dosage forms (tablets/capsules) should be stored in tight containers and protected from light.

 

Because diazepam may adsorb to plastic, it should not be stored drawn up into plastic syringes. The drug may also significantly adsorb to IV solution plastic (PVC) bags and to the infusion tubing.  This adsorption appears to be dependent on several factors (temperature, concentration, flow rates, line length, etc.).

 

The manufacturers of injectable diazepam do not recommend the drug be mixed with any other medication or IV diluent. The drug has been successfully diluted to concentrations of 5 mg/50 ml or 5 mg/100 ml in normal saline, lactated Ringer’s and D5W. Differing results have occurred with different manufacturer’s products. Do not administer if a precipitate forms and does not clear.

 

Pharmacology – The subcortical levels (primarily limbic, thalamic, and hypothalamic) of the CNS are depressed by diazepam and other benzodiazepines thus producing the anxiolytic, sedative, skeletal muscle relaxant, and anticonvulsant effects seen. The exact mechanism of action is unknown, but postulated mechanisms include: antagonism of serotonin, increased release of and/or facilitation of gamma-aminobutyric acid (GABA) activity, and diminished release or turnover of acetylcholine in the CNS. Benzodiazepine specific receptors have been located in the mammalian brain, kidney, liver, lung, and heart. In all species studied, receptors are lacking in the white matter.

 

Uses/Indications – Diazepam is used clinically for its anxiolytic, muscle relaxant, hypnotic, appetite stimulant, and anticonvulsant activities. Refer to the dosage section for those and other suggested indications and doses for each species.

 

Pharmacokinetics – Diazepam is rapidly absorbed following oral administration. Peak plasma levels occur within 30 minutes to 2 hours after oral dosing. The drug is slowly (slower than oral) and incompletely absorbed following IM administration.

 

Diazepam is highly lipid soluble and is widely distributed throughout the body. It readily crosses the blood-brain barrier and is fairly highly bound to plasma proteins. In the horse at a serum of concentration of 75 ng/ml, 87% of the drug is bound to plasma proteins. In humans, this value has been reported to be 98-99%.

 

Diazepam is metabolized in the liver to several metabolites, including desmethyldiazepam (nordiazepam), temazepam, and oxazepam, all of which are pharmacologically active. These are eventually conjugated with glucuronide and eliminated primarily in the urine. Because of the active metabolites, serum values of diazepam are not useful in predicting efficacy. Serum half-lives (approximated) have been reported for diazepam and metabolites in dogs, cats, and horses:

 

 

	Dogs	Cats	Horses	Humans
Diazepam	2.5 – 3.2 hrs	5.5 hrs	7 – 22 hrs	20 – 50 hrs
Nordiazepam	3 hrs	21.3 hrs		30 – 200 hrs

 

 

Contraindications/Precautions – Slowly inject intravenously. This is particularly true when using a small vein for access or in small animals. Diazepam may cause significant thrombophlebitis. Too rapid of an injection of intravenous diazepam in small animals or neonates, may cause cardiotoxicity secondary to the propylene glycol in the formulation. Intra-carotid artery injections must be avoided.

 

Use cautiously in patients with hepatic or renal disease and in debilitated or geriatric patients. the drug should be administered to patients in coma, shock or with significant respiratory depression very cautiously.  It is contraindicated in patients with known hypersensitivity to the drug. Benzodiazepines may impair the abilities of working animals. If administering the drug IV, be prepared to administer cardiovascular or respiratory support.

 

Diazepam has been implicated in causing congenital abnormalities in humans if administered during the first trimester of pregnancy. Infants born of mothers receiving large doses of benzodiazepines shortly before delivery have been reported to suffer from apnea, impaired metabolic response to cold stress, difficulty in feeding, hyperbilirubinemia, hypotonia, etc. Withdrawal symptoms have occurred in infants whose mothers chronically took benzodiazepines during preg­nancy. The veterinary significance of these effects is unclear, but the use of these agents during the first trimester of pregnancy should only occur when the benefits clearly outweigh the risks associated with their use. Benzodiazepines and their metabolites are distributed into milk and may cause CNS effects in nursing neonates.

 

Adverse Effects/Warnings – In horses, diazepam may cause muscle fasiculations, weakness and ataxia at doses sufficient to cause sedation. Doses greater than 0.2 mg/kg may induce recumbency as a result of its muscle relaxant properties and general CNS depressant effects.

 

Cats may exhibit changes in behavior (irritability, depression, aberrant demeanor) after receiving diazepam. There have been recent reports of cats developing hepatic failure after receiving oral diazepam for several days; until this potential adverse effect is confirmed or refuted, use with caution in cats.

 

Dogs may exhibit a contradictory response (CNS excitement) following administration of diazepam. The effects with regard to sedation and tranquilization are extremely variable with each dog. Because of this individual variation, diazepam is not an ideal sedating agent for this species.

 

Overdosage – When administered alone, diazepam overdoses are generally limited to significant CNS depression (confusion, coma, decreased reflexes, etc). Hypotension, respiratory depression, and cardiac arrest have been reported in human patients, but apparently are quite rare.

 

Treatment of acute toxicity consists of standard protocols for removing and/or binding the drug in the gut if taken orally, and supportive systemic measures. The use of analeptic agents (CNS stimulants such as caffeine) are generally not recommended.

 

Drug Interactions – Metabolism of diazepam may be decreased and excessive sedation may occur if given with the following drugs: cimetidine, erythromycin, isoniazid, ketoconazole, propranolol, & valproic acid. If administered with other CNS depressant agents (barbiturates, narcotics, anesthetics, etc.) additive effects may occur. Antacids may slow the rate, but not the extent of oral absorption; administer 2 hours apart to avoid this potential interaction. The pharmacologic effects of digoxin may be increased; monitor serum digoxin levels or symptoms of toxicity. Rifampin may induce hepatic microsomal enzymes and decrease the pharmacologic effects of benzodiazepines.

 

Laboratory Interactions: Patients receiving diazepam, may show false negative urine glucose results if using Diastix® or Clinistix® tests.

 

Doses –

Horses:

For seizures:

a)   Foals: 0.05 – 0.4 mg/kg IV; repeat in 30 minutes if necessary;

Adults: 25 – 50 mg IV; repeat in 30 minutes if necessary. (Sweeney and Hansen 1987)

 

Treatment of seizures secondary to intraarterial injection of xylazine or other similar agents:

a)   0.10 – 0.15 mg/kg IV (Thurmon and Benson 1987)

 

As an appetite stimulant:

a)   0.02 mg/kg IV; immediately after dosing offer animal food. Keep loud noises and distractions to a minimum. If effective, usually only 2-3 treatments in a 24-48 hour period is required. (Ralston 1987)

 

Elephants:

 

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.  The information provided here should be used as a guideline only.  Consultation with experienced colleagues is advised. 

 

To control musth:

a) A 20 year-old African bull (weight not specified) was placed on the following regimen to reduce signs of musth:  400 mg diazepam in the a.m and 200 mg diazepam in the p.m for 5 days; concentrate feeds reduced by ½; a calming effect was noted; dose was tapered to 400 mg / day over a 5 day period; concentrates gradually increased; dose reduced to 100 mg / day for 10 days; concentrates increased; diazepam discontinued on day 20 and normal diet resumed (Thakuria and Barthakur, 1996).

 

b) To treat extrapyramidal signs associated with overdose of long-acting neuroleptics. Elephant-specific dose not listed (Ebedes et.al. 1995).

 

c) As an anti-convulsant in Asian elephants, 400 – 800 mg diazepam / animal IM (Cheeran et.al. 1995).

 

Elephant References:

a) Thakuria,D.B. and Barthakur,T. 1996. Management of musth in a male African elephant by chemical sedatives in the Assam state zoo, Guwahati. Indian Veterinary Journal 73:(3):339-340  Note: This article also discusses a successful regimen using lorazepam.

 

b) Ebedes,H.  1995. The use of long term neuroleptics in the confinement and transport of wild animals. Joint Conf AAZV/WDA/AAWV. Pages: 173-176

 

c) Cheeran,J.V., Chandrasekharan,K., and Radhakrishnan,K., 1995. Principles and Practice of Fixing Dose of Drugs for Elephants . In: Daniel,J.C. (Editor), A Week with Elephants; Proceedings of the International Seminar on Asian Elephants. Bombay Natural History Society; Oxford University Press, Bombay, India pp. 430-438

 

Monitoring Parameters – Horses should be observed carefully after receiving this drug.

 

Client Information – Keep out of reach of children and in tightly closed containers.

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

 

Veterinary-Approved Products: None

 

Human-Approved Products:

Diazepam oral tablets 2 mg, 5 mg, 10 mg; Valium®  (Roche); Generic; (Rx)

 

Diazepam timed-release oral capsules 15 mg; Valrelease®  (Roche); (Rx)

 

Diazepam oral solution 1 mg/ml in 500 ml containers and unit-dose (5 & 10 mg) 5 mg/ml in 30 ml dropper bottle; Diazepam Intensol® (Roxane); Generic (Rx)

 

Diazepam Injection 5 mg/ml in 2 ml amps & syringes & 1, 2, 10 ml vials, 2 ml Tel-E-Ject; Emulsified Injection: 5 mg/ml in 3 ml vials; Valium® (Roche); Zetran®  (Hauck);Dizac® (Ohmeda); Generic; (Rx)

 

Diazepam is a Class-IV controlled substance.