Chemicals / Complex Chemical Agents/ Chemical:

Diazepam (with special reference to Hedgehogs, Elephants, Bears, Lagomorphs, Ferrets, Great Apes and Cranes)

INFORMATION AVAILABLE

GENERAL CHEMICAL INFORMATION THERAPEUTIC INFORMATION [DOSE, FREQUENCY & ROUTE]

NUTRITIONAL INFORMATION

TOXICITY INFORMATION ENVIRONMENTAL INFORMATION
Information in this page has been entered to support the current volumes of Wildpro and further information will be added as new volumes are completed. This page is not intended to substitute for the manufacturer's data sheet and the information is not yet complete for all species, or for all contra-indications etc.

CAUTION: Before any pharmaceutical product is used, the manufacturer's data sheet, containing information on uses, dosage and administration, contra-indications, warnings etc., should always be consulted. It is important to remember that licensing of pharmaceutical products for use in a particular species/condition, as well as mandatory meat and milk withdrawal times for food-producing animals, varies between countries and changes with time. Withdrawal times also may vary between different pharmaceutical formulations and depending on route of administration. In the EU, the prescription cascade must be followed (see LCofC1.2H and W564.Apr05.w1); note that specific restrictions apply for food-producing animals. In the USA, FARAD may be consulted regarding residues and meat and milk withdrawal times.

General Chemical Information

Summary 
Benzodiazepine sedative-hypnotic agent. (B135.21.w21)

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Names and Formulae
Type Benzodiazepine. (B135.21.w21)
Alternative Names "Valium; 7-Chloro-1,3-Dihydro-1-Methyl-5-Phenyl-2H-1,4-Benzodiazepin-2-One; Valium R; T-quil; Valrelease; Vazepam; Apo-Diazepam; Diazemuls; Vivol; 7-chloro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one; 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one; 7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one; 7-chloro-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepine; 1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one; 7-chloro-1-methyl-3H-1,4-benziodiazepin-2(1H)-one; alboral; aliseum; alupram; amiprol; ansiolin; apaurin; apozepam; assival; atensine; atilen; bialzepam; calmocitene; calmpose; cercine; ceregulart; condition; diacepan; diapam; diazepan; diazetard; dienpax; Dipam; dipezona; domalium; duksen; Duxen; E-PAM; eridan; evacalm; faustan; freudal; frustan; gihitan; kiatrium; LA-III; lembrol; levium; liberetas; methyl diazepinone; morosan; neurolytril; NOAN; pacitran; Paranten; paxate; Paxel; plidan; quetinil; quiatril; quievita; relaminal; relanium; Relax; renborin; ro 5-2807; S.A. R.L.; saromet; sedapam; sedipam; seduksen; seduxen; serenack; serenamin; serenzin; setonil; sibazon; sonacon; stesolid; stesolin; tensopam; tranimul; tranqdyn; tranquase; tranquirit; tranquo-tablinen; umbrium; unisedil; usempax ap; Valeo; valitran; vatran; velium; Vival; wy-3467; Zipan; Solis; Tensium; Diazapam; Antenex; Ducene." (W324)
Chemical Formula C16H13ClN2O. (W324)
Chemical Structure (B135.21.w21)
Molecular Weight 284.7445. (W324)
Related Chemicals --

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Physical Properties / Chemistry
Appearance

White to yellow crystalline powder, practically odourless, with a bitter after-taste.(B263); off-white to yellow crystalline powder. (W324)

Melting point
Boiling point --
Density --
Water solubility
  • Insoluble. (B121)
  • One gram soluble in 333 mL water. (B263)
  • Insoluble; less than 0.1 g/100 mL at 20C. (W324)
Other solubility
  • One gram soluble in 25 ml alcohol. (B263)
  • Sparingly soluble in propylene glycol. (B263)
  • Lipid soluble. (B135.21.w21)
Acid/Base
  • Weak base. (B135.21.w21)
  • Commercially prepared injectable solution (5 mg/ml, with 40% propylene glycol, 10% ethanol, 5% sodium benzoate/benzoic acid buffer, 1.5% benzyl alcohol (as a preservative)): pH 6.2-6.9. (B263)

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Pharmacology & General Information
Pharmacology
  • Benzodiazepines potentiate neurotransmission involving GABA (gamma-aminobutyric acid), the main inhibitory neurotransmitter in the central nervous system. (B135.21.w21)
  • Benzodiazepines increase the efficacy of GABAergic synaptic inhibition (via membrane hyperpolarisation), leading to a decrease in the rate of firing of critical neurons in many brain regions. They appear to increase the frequency of GABA-gated ion channel opening events. (B135.21.w21)
  • They act at all levels including the spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex and cerebral cortex. (B135.21.w21)
  • Depression of the subcortical levels of the CNS (primarily limbic, thalamic and hypothalamic), resulting in anxiolytic, sedative, skeletal muscle relaxant and anticonvulsive effects. (B263)
  • Exact mechanism of action unknown; postulated mechanisms include serotonin antagonism, increased release or facilitation of GABA activity, diminished release/turnover of acetylcholine in the CNS. (B263)
  • Benzodiazepine-specific receptors have been located in the brain (not white matter), kidney, liver, lung, heart of mammals. (B263)
Storage / Stability
  • Store at room temperature (15-30 C), do not freeze, protect from light, store oral tablets/capsules in a tight container. (B263)
  • Do not store in plastic syringes: may adsorb to plastic including syringes, IV solution bags, infusion tubing. (B263)
Legal Category (In UK) --

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References

Associated Techniques

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ORGANISATIONS

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ELECTRONIC LIBRARY
(Further Reading)
Click image for full contents list of ELECTRONIC LIBRARY

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Authors Debra Bourne (V.w5); Gracia Vila-Garcia (V.w67)
Referees Suzanne I. Boardman (V.w6); Becki Lawson (V.w26); Susan Mikota (V.w72)

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Therapeutic Information

Uses/Indications
Activity
  • Anxiolytic, muscle relaxant, hypnotic, appetite stimulant (in cats), anticonvulsant. (B263)
  • Anticonvulsant activity. (B135.21.w21)(B121)
  • Minimal sedative or hypnotic effects in fit healthy dogs (B121)
    • In greyhounds, 2mg/kg may result in ataxia, lack of obvious sedation, and marked struggling on restraint. (B121)
  • At clinical dose rates, some muscular relaxation. (B121)
Appropriate Use
  • In the management of seizure states. (B135.21.w21)
    • e.g. for dog in status epilepticus, 5mg by slow intravenous injection followed if needed by another 5mg. (B121)
  • Anaesthetic premedication, increasing the length of action of other agents. (B121)
  • Anaesthetic premedication to reduce risk of convulsions. (B121)
  • For postoperative sedation. (B121)
  • Postoperative to reduce risk of convulsions following introduction of contrast media into the spinal canal. (B121)
  • As an anxiolytic, muscle relaxant, hypnotic, appetite stimulant, anticonvulsant. (B263)
  • In cats as an appetite stimulant. (B263)
Limitations --
Notes --

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Pharmacokinetics and Drug Interactions
Absorption /Bioavailability
  • Following oral administration, rapid absorption from the duodenum (high pH environment) reaching peak plasma levels in 30-120 minutes. (B135.21.w21, B263)
  • Following intramuscular injection absorption is slower than following oral administration and may be unreliable/incomplete. (B135.21.w21, B263)
Distribution
  • Highly lipid soluble; widely distributed through the body. (B263)
  • Readily crosses the blood-brain barrier. (B263)
  • Crosses the placenta. (B135.21.w21)
  • Distributed into milk and may affect nursing neonates. (B263)
Plasma Protein binding / Storage

Plasma protein binding:

  • Horse: 87% bound at a plasma concentration of 75ng/ml. (B263)
  • Humans: may be 98-99% plasma-protein bound. (B263)
Elimination Route
  • Metabolised in the liver; some metabolites (e.g. desmethyldiazepam (nordiazepam), temazepam, oxazepam) are pharmacologically active. (B135.21.w21, B263)
  • Eventual conjugation of metabolites with glucuronide and elimination mainly in urine. (B263)
  • Elimination half-life may be significantly increased in the very elderly and in individuals with severe liver disease; doses may need to be reduced. (B135.21.w21)
  • Enterohepatic recycling of diazepam/active metabolites is thought to occur as a rise in plasma concentration and return of clinical effects may be seen 6-8 hours after administration. (B121)
Elimination half-life / Clearance Rate Elimination half-life:
  • Human: 50-150 hours. (B135.21.w21)

Serum half-life:

  • Dogs 2.5-3.2 hours (nordiazepam 3 hrs).
  • Cat: 5.5 hours, (nordiazepam 21.3 hrs)
  • Horses: 7-22 hours. (B263)
  • Human: 20-50 hours (nordiazepam 30-200 hrs). (B263)
Drug Interactions
  • Physical incompatibilities: should not be diluted with water; should not be mixed with solutions of other drugs. (B121)
  • Manufacturers of injectable diazepam do not recommend mixing with other drugs or intravenous solutions. (B263)
  • Premedication with diazepam increases the length of action of other anaesthetic agents. (B121)
  • Various drugs, including cimetidine, erythromycin, isoniazid, ketoconazole, propanolol, metoprolol and valproic acid may decrease diazepam metabolism and therefore cause excessive sedation. (B263)
  • Additive effects may occur following administration with other CNS depressants such as barbiturates, narcotics and anaesthetics. (B263)
  • Rate of oral absorption may be reduced if antacids are administered concurrently: administer at least two hours apart. (B263)
  • Diazepam may increase the effects of digoxin; serum digoxin levels should be measured.(B263)
  • Hepatic microsomal enzymes may be induced by rifampin, thus reducing the effects of benzodiazepines such as diazepam. (B263)
  • Concurrent probenecid may interfere with hepatic metabolism of benzodiazepines, with resultant increased or prolonged effects. (B263)

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Administration
Formulations available UK:
  • e.g. Valium (Roche) (solution for injection) and non-proprietary tablets of various concentrations. (B201.6.w6)
Doses / Administration Routes / Frequencies

Use of Drugs (Medication):

  • Before administration of any pharmaceutical product the manufacturer's datasheet must be consulted regarding operator safety, relevant withdrawal times etc.
  • Many drugs are not registered for use in particular species and additional care should be taken in their use, with proper regard for possible toxic effects. 
  • Consideration should be given to relevant legislation regarding the use of drugs.
  • In the UK, guidelines regarding the use of drugs are set out in the Royal College of Veterinary Surgeons' Guide to Professional Conduct 2000: (See: LCofC1 - RCVS Guide to Professional Conduct 2000 - Choice of Medicinal Products).
Erinaceus europaeus - West European Hedgehog:
  • 1 mg/kg body weight intramuscular or intravenous injection. For sedation. (D93)
  • 1-3 mg/kg body weight intramuscular or intravenous injection. For control of seizures at higher dose range and sedation at lower dose range.(B284.6.w6)

Atelerix albiventris - Four-toed hedgehog:

  • 0.5-2.0 mg/kg intramuscularly. For mild sedation; may be administered with ketamine for anaesthesia. Also for seizures. (B267)
  • 0.5-2.0 mg/kg. (J204.59.w1)

"Hedgehog" (species not distinguished between Atelerix albiventris - Four-toed hedgehog or Erinaceus europaeus - West European Hedgehog):

  • Ketamine 5-20 mg/kg intramuscularly in combination with 0.5-1.0 mg/kg diazepam intramuscularly. (J34.24.w1)

In Elephants:

Elephas maximus - Asian Elephant

The following information is taken with permission directly from the Elephant Care International website (W580.Aug2005.w9):

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 ; 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

In Bears:

  • In general: "Domestic dog drugs and dosages are used to treat bears." (B336.51.w51)
  • 10-25 mg/kg was given to all bears once they were safe to handle, following initial sedation by oral Carfentanil. (J1.31.w11)

Lagomorphs - Oryctolagus cuniculus domesticus - Domestic rabbit:

  • 1.0 - 2.0 mg/kg intramuscularly or intravenously. (B373.Guide.w41)
  • 5 - 10 mg/kg intramuscularly. (J213.2.w3)
    • Note: can be reversed with flumazenil given intravenously at 1 part flumazenil per 13 parts diazepam. (J213.2.w3)
  • 1 - 2 mg/kg intravenously or intramuscularly. For sedation. N.B. this is not analgesic. (B600.4.w4)
  • 1.0 - 3.0 mg/kg intramuscularly or intravenously. (B602.41.w41)
  • 1.0 - 2.0 mg/kg intramuscularly or intravenously. (B603.5.w5)
  • 1.0 - 5.0 mg/kg intravenously, intramuscularly or intraperitoneally once. (B546)
  • 1.0 - 3.0 mg/kg intramuscularly. As a preanaesthetic or tranquiliser. (B548.w8)
  • 1.0 - 5.0 mg/kg intramuscularly or intravenously. As a preanaesthetic or tranquiliser. (B548.w8)
  • 1.0 mg/kg intravenous. For the treatment of seizures, as an alternative to intravenous injection. (B548.w8)

Ferrets - Mustela putorius furo - Ferret:

  • 1.0 - 2.0 mg/kg intramuscularly. (B602.41.w41, B626.App.w22)
    • Ketamine 10 - 20 mg/kg plus diazepam 1.0 - 2.0 mg/kg intramuscularly. (B602.41.w41)
    • Usually used in combination with ketamine: Ketamine 25 - 35 mg/kg plus diazepam 2.0 - 3.0 mg/kg intramuscularly. Suitable for minor procedures. (B626.App.w22)
  • 0.5 - 2.0 mg/kg intramuscularly or intravenously once; the effects may last four to six hours. Can also be used in combination with other agents for anaesthesia. (B631.22.w22)
    • Ketamine 10 - 20 mg/kg plus diazepam 1 - 2 mg/kg intramuscularly. Provides light anaesthesia and only poor analgesia. (B631.22.w22)
  • 3 mg/kg intramuscularly. (J213.3.w1)
    • Ketamine10 - 30 mg/kg plus diazepam 1.0 - 2.0 mg/kg intramuscularly. Can be combined in the same syring. This protocol may result in muscle rigidity, and complete analgesia is unlikely. (J213.3.w1)

Great Apes

  • 0.5 - 1.0 mg/kg (B336.39.w39)
    • This is used in combination with other drugs, in chemical restraint. (B336.39.w39)
    • Can be reversed with flumazenil, 0.02 - 0.1 mg/kg intravenously. (B336.39.w39)
  • Adult Pan troglodytes - Chimpanzee: 0.25 - 0.5 mg/kg intravenously or intramuscularly. (W768.Jun2012.w1)
  • Adult Pan troglodytes - Chimpanzee: 0.5 - 1.0 mg/kg orally. (W768.Jun2012.w1)
  • Primates: 1 mg/kg intravenously. (D425.3.15.w3o)

Cranes

  • 0.5- 1.0 mg/kg intramuscularly once. Used alone or with Ketamine. Effects last 2 - 6 hours. (B115.8.w4)
Monitoring parameters
  • Horses: careful observation. (B263)
  • Cats: pre-treatment hepatic tests, monitoring for emesis, lethargy, inappetance or ataxia, with repeat liver function tests and discontinuation of treatment. (B263)
  • Cats: for seizure control, it has been suggested that serum levels be monitored following five days of therapy. (B263)

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Withdrawal period / Withholding time
Notes Before the use of any pharmaceutical product in food-producing animals the label instructions for the product should be consulted regarding withdrawal requirements.

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Toxic Information

Toxic effects of Pharmaceutical Products
Contraindications / Precautions
  • Caution in debilitated or geriatric individuals. (B263)
  • Caution in individuals with hepatic disease or renal disease. (B263)
  • Caution if administering to individuals in coma, shock or with significant respiratory depression. (B263)
  • Contraindicated in individuals known to be hypersensitive to diazepam. (B263)
  • Caution in aggressive individuals: may remove anxiety which may be helping prevent aggressive behaviour. (B263)
  • Be prepared for cardiovascular or respiratory support if administering intravenously. (B263)
  • Not recommended for seizure control of cats following chlorpyrifos exposure: may potentiate the organophosphate toxicity. (B263)
Adverse Effects / Side Effects / Warnings
  • Thrombophlebitis may occur following intravenous injection. (B121)
    • Intravenous emulsion solution may not be irritant but has lower bioavailability. (B121)
    • Injection should be given slowly to reduce risk, particularly if into a small vein. (B263)
  • Rapid injection into small animals/neonates may result in cardiotoxicity due to the propylene glycol. (B263)
  • In horses: muscle-relaxant effect may induce panic. (B263)
  • In horses: doses sufficient to cause sedation may result in muscle fasciculations, weakness, ataxia. (B263)
  • Recumbency may result at doses greater than 0.2 mg/kg. (B263)
  • Cats: behavioural changes including irritability, depression, aberrant demeanour may be seen.
  • Cats: following several days of oral diazepam administration, hepatic failure has been reported with first sins after 5-11 days: baseline liver function tests should be carried out prior to diazepam therapy in this species, with therapy discontinued if emesis, lethargy, inappetance or ataxia develop. (B263)
  • Dog: CNS excitement may occur. (B263)
Operator Warnings Before the use of any pharmaceutical product the label instructions for the product should be consulted regarding operator safety/warnings.
Overdose / Acute Toxicity
  • Usually causes significant CNS depression with e.g. confusion, coma, decreased reflexes. (B263)
  • Rarely in humans hypotension, respiratory depression and cardiac arrest have been reported. (B263)
  • Overdose may be treated by standard protocols to reduce gut absorption (by removal or binding in the gut) and systemic supportive measures. (B263)

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Detailed Toxicological Information
Classification --
Acute Toxicity --
Chronic Toxicity
  • Dogs: low toxicity - large doses for prolonged periods do not produce changes in kidney function or liver function. (B121)
Reproductive effects
  • Implicated in congenital abnormalities in human infants following administration to the mother during the first trimester of pregnancy. (B263)
  • Withdrawal symptoms have been seen in infants of mothers who took benzodiazepines chronically during pregnancy. (B263)
  • Following large doses to mothers shortly before delivery, infants have been born reported with apnoea, impaired metabolic response to cold stress, difficulties in feeding, hyperbilirubinaemia, hypotonia and other signs. (B263)
Teratogenic effects --
Mutagenic effects --
Carcinogenic effects

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Organ toxicity --
Bird Toxicity --
Aquatic organism activity --
Other organism toxicity --

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Nutrient Information

Nutritional Data
Sources --
Biological Use --
Recommended Daily Allowance / Recommended level in food --
Stability in food (Storage time) --
Interactions --

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External / Environmental Information

External / Environmental Uses
Use --
Formulation --
Application method --
Application Concentration --
Persistence of Effect / Frequency of Application --

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Effects on the Environment
Effects in the aquatic environment

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Effects on land --

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Persistence in the Environment
Breakdown in soil and groundwater

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Breakdown in water --
Breakdown in vegetation --

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