Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 6 SEDATIVES
Benzodiazepines
EXAMPLES
Diazepam, midazolam, zolazepam (combined with
tiletamine in Telazol®, Zoletil®).
Clinical applications
Benzodiazepines are classed primarily as anxiolytic drugs
although high doses may cause sedation and hypnosis. A
wide range of benzodiazepines are available for use in
people. However, they are not used as frequently for
chemical restraint and premedication in veterinary patients
and are not specifically licensed for use in animals.
Benzodiazepines do not induce reliable sedation in
normal healthy animals and, indeed, their anxiolytic
action may increase excitement and render patients
more difficult to handle. However, in very young, very
old and critically ill patients benzodiazepines may
produce effective sedation and their relative lack of
adverse effects is an advantage in such ‘high-risk’ groups.
They have also been used to calm distressed or restless
patients in the postoperative period. It should be emphasized,
however, that benzodiazepines lack analgesic
activity and should not be used to compensate for inadequate
pain control.
Benzodiazepines may be used to induce general anesthesia
in combination with other agents, typically the
dissociative anesthetics. The anticonvulsant and musclerelaxant
properties of the benzodiazepines counteract
some of the less desirable effects of the dissociative
drugs, reducing muscle tone and decreasing the incidence
of seizures. A preparation that combines the dissociative
anesthetic tiletamine with zolazepam is
available in some countries (see Chapter 5).
Benzodiazepines may be used specifically for their
anticonvulsant action and diazepam is a drug of choice
in the treatment of status epilepticus (see Chapter 16).
The ability to relax skeletal muscles may also have
specific indications such as the treatment of tetanus
and relief of urethral spasm. Benzodiazepines will stimulate
appetite in a number of species and this property
has proved clinically useful in anorexic cats (see
Chapter 19).
All actions of the benzodiazepines can be reversed by
the specific benzodiazepine antagonist flumazenil.
Mechanism of action
The sedative and anticonvulsant properties of the benzodiazepines
have been attributed to the potentiation of
the inhibitory neurotransmitter GABA at GABA A receptors.
These receptors are linked to chloride channels,
opening of which causes hyperpolarization and a reduction
in membrane excitability. Benzodiazepines combine
with a regulatory site on the GABA A receptor, thereby
facilitating the binding of GABA and enhancing its
effect. Endogenous ligands for the benzodiazepine
receptor are believed to occur but the identity or function
of such agents has not been clearly established.
Endogenous benzodiazepines may have a role in the
pathophysiology of hepatic encephalopathy and the
benzodiazepine antagonist flumazenil has been shown
to reverse the signs of this condition in a proportion of
cases.
Formulations and dose rates
Diazepam
Dogs
• 0.1–0.5 mg/kg IV
• 2–10 mg/dog PO q.8 h for muscle relaxation
Cats
• 0.05–0.4 mg/kg IV
• 1.25–5 mg/cat PO q.8 h for muscle relaxation
Doses at the lower end of the range are used for sedation/premedication
(0.1–0.25 mg/kg) and appetite stimulation, while higher doses
may be required to control seizures (0.5 mg/kg).
Midazolam
Dogs
• 0.05–0.2 mg/kg IV or IM
• 0.2 mg/kg/h IV continuous infusion
Cats
• 0.05–0.2 mg/kg IV or IM
Zolazepam
Doses of Telazol® or Zoletil® are quoted in milligrams per kilogram
of combined product.
Dogs and cats
• 2–4 mg/kg IV for induction of anesthesia
• 2.5–5 mg/kg IM for sedation
The manufacturers recommend higher intramuscular doses of up to
15 mg/kg to produce heavy sedation or anesthesia in dogs and
cats.
Pharmacokinetics
The chemical structures of the benzodiazepines are as
follows.
● Diazepam: 7-chloro-1-methyl-5-phenyl-2,3-
dihydro-1 H-1,4-benzodiazepin-2-one
● Midazolam: 8-chloro-6-(2-fluorophenyl)-1-
methyl-4 H-imidazo (1,5-α)(1,4)benzodiazepine
Most of the benzodiazepines have a high oral bioavailability
and oral administration may be preferred
for long-term therapy. In dogs, reported values for the
oral bioavailability of diazepam range from 74% to
100%, while a figure of 89% has been quoted for
midazolam.
Diazepam is insoluble in water; therefore, solutions
for injection are prepared using propylene glycol,
sodium benzoate in benzoic acid and ethanol. These
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