Veterinary Drug Handbook (VDH) is the reference veterinarians turn to when they want an independent source of information on the drugs that are used in veterinary medicine today.

DIAZEPAM

Chemistry - A benzodiazepine, diazepam is a white to yellow, practically odorless crystallinepowder 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 issparingly soluble in propylene glycol. The pH of the commercially prepared injectable solution isadjusted 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 alcoholas 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 dosageforms (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 - DIAZEPAM

The subcortical levels (primarily limbic, thalamic, and hypothalamic) of the CNSare depressed by diazepam and other benzodiazepines thus producing the anxiolytic, sedative, skeletal muscle relaxant, and anticonvulsant effects seen. The exact mechanism of action isunknown, but postulated mechanisms include: antagonism of serotonin, increased release of and/orfacilitation of gamma-aminobutyric acid (GABA) activity, and diminished release or turnover ofacetylcholine in the CNS. Benzodiazepine specific receptors have been located in the mammalianbrain, 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 othersuggested indications and doses for each species.

Pharmacokinetics - DIAZEPAM

Diazepam is rapidly absorbed following oral administration. Peak plasmalevels 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 crossesthe blood-brain barrier and is fairly highly bound to plasma proteins. In the horse at a serum ofconcentration of 75 ng/ml, 87% of the drug is bound to plasma proteins. In humans, this value hasbeen 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 areeventually conjugated with glucuronide and eliminated primarily in the urine. Because of the activemetabolites, 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
Diazepam2.5 - 3.2 hrs5.5 hrs7 - 22 hrs20 - 50 hrs
Nordiazepam3 hrs21.3 hrs30 - 200 hrs
Contraindications/Precautions - Slowly inject intravenously. This is particularly true whenusing 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. thedrug should be administered to patients in coma, shock or with significant respiratory depressionvery 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, beprepared to administer cardiovascular or respiratory support.
Diazepam has been implicated in causing congenital abnormalities in humans if administeredduring 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 firsttrimester of pregnancy should only occur when the benefits clearly outweigh the risks associatedwith their use. Benzodiazepines and their metabolites are distributed into milk and may cause CNSeffects in nursing neonates.

Adverse Effects, Warnings

In horses, diazepam may cause muscle fasiculations, weakness andataxia at doses sufficient to cause sedation. Doses greater than 0.2 mg/kg may induce recumbencyas a result of its muscle relaxant properties and general CNS depressant effects.
Cats may exhibit changes in behavior (irritability, depression, aberrant demeanor) after receivingdiazepam. There have been recent reports of cats developing hepatic failure after receiving oraldiazepam for several days; until this potential adverse effect is confirmed or refuted, use withcaution 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 inthe gut if taken orally, and supportive systemic measures. The use of analeptic agents (CNSstimulants such as caffeine) are generally not recommended.

Drug Interactions

Metabolism of diazepam may be decreased and excessive sedation may occurif 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 toavoid this potential interaction.
The pharmacologic effects of digoxin may be increased; monitor serum digoxin levels orsymptoms of toxicity.
Rifampin may induce hepatic microsomal enzymes and decrease the pharmacologic effects ofbenzodiazepines.
Laboratory Interactions: Patients receiving diazepam, may show false negative urine glucoseresults if using Diastix® or Clinistix® tests.
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