Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 5 ANESTHETIC AGENTS
Emergence from anesthesia is rapid after a single dose
but can be prolonged in the animal that has received
multiple doses. Recovery may also be prolonged by
hypothermia, compromised organ function and concurrently
administered sedative, analgesic and inhalational
anesthetic agents. Emergence may also be delayed in
emaciated patients. Recovery is generally smooth in the
sedated animal but excitement may be seen in the
absence of sedation.
Mechanism of action
Thiopental enhances GABA-mediated inhibition of synaptic
transmission by opening membrane chloride channels,
causing cellular hyperpolarization. Thiopental
does not act directly on the GABA A receptor or the
chloride channel but binds to an allosteric site that
increases GABA action and prolongs the duration of
chloride-channel opening.
Formulations and dose rates
Thiopental is manufactured as a sodium salt that is soluble in water
and 0.9% saline. For use in small animals, suffi cient water or saline
is added to make a solution of 1.25–5% (2.5% is most commonly
used). The whitish-yellow crystalline powder is stable with a long
shelf-life but once in solution, it is stable for only about 2 weeks at
room temperature. The aqueous solution is strongly alkaline and is
incompatible with acidic drugs and oxidizing substances such as
analgesics, phenothiazines (e.g. acepromazine), adrenaline (epinephrine)
and some antibiotics and muscle relaxants.
• The dosage of thiopental required for induction of anesthesia in
the unpremedicated animal is approximately 20–25 mg/kg IV.
To avoid excitement during induction, one-half of this calculated
dose must be given as a bolus. Additional quarter-doses may
be required to obtain the necessary depth of anesthesia.
• Premedication is preferred and reduces the induction
requirement by 50–75%, i.e. to a dose of 10–12.5 mg/kg. An
initial bolus dose of one-quarter to one-half of the calculated
dose should be given, depending upon the depth of sedation.
• A single dose of thiopental provides anesthesia for about
10–15 min.
• Intravenous diazepam (0.25–0.5 mg/kg) given just before
thiopental administration reduces the barbiturate requirements
to 5–10 mg/kg and reduces the duration of effect to about
5–10 min.
• An unusual aspect of thiopental use is that the administration of
a 2.5% rather than a 5% solution markedly reduces the total
dose of drug needed to induce anesthesia.
• Because of its strong alkalinity, thiopental can cause severe
tissue reactions and must only be given by the intravenous
route.
Pharmacokinetics
Thiopental is highly lipid soluble and after intravenous
administration, concentrations sufficient to induce
unconsciousness occur in less than 30 seconds. The
thiopental concentration in all highly perfused organs
(brain, heart, liver, kidneys) is initially high but rapidly
falls. Muscle concentration of thiopental rises for about
20 min then begins to fall but fat continues to accumulate
thiopental for a further 3–6 hours. Uptake by muscle is
the dominant cause for the rapid fall in plasma thiopental
and peak muscle uptake corresponds to a lightening of
anesthesia that occurs about 10–15 min after administration.
Uptake by fat and hepatic metabolism also account
for some of the initial fall in plasma concentration.
Once the brain concentration falls below the effective
threshold, consciousness returns. Because redistribution is
the major factor causing recovery, prolonged anesthesia
can be seen with repeated doses as uptake sites become
saturated with drug. Drug that has been redistributed to
the tissues subsequently returns to the plasma and is gradually
metabolized by the liver into inactive compounds
that are excreted by the kidneys. The patient may appear
groggy during this ‘hangover’ period as significant quantities
of drug remain. Sighthounds (greyhound, Afghan,
saluki, whippet, borzoi) may sleep 2–4 times longer than
other breeds of dog because of a deficiency in the hepatic
enzyme required to cleave the sulfur molecule from the
thiopental, the first step in metabolism.
Thiopental is a weak acid. The ratio of ionized
to unionized drug will be influenced by plasma pH. Low
plasma pH, i.e. acidemia, will increase the concentration
of unionized drug. Since it is the unionized drug
that is active, this may enhance the anesthetic effect.
Thiopentone is highly protein bound (80–85%) and
an enhanced anesthetic effect is also possible in severely
hypoproteinemic patients or when other highly proteinbound
drugs (e.g. NSAIDs) are given concurrently.
Uremia may also augment the anesthetic effect by displacing
protein-bound drug.
Adverse effects
Central nervous system effects
● Thiopental produces a dose-dependent decrease in
cerebral oxygen requirements, cerebral blood flow
and intracranial pressure (ICP). The decrease in cerebral
oxygen requirements follows the neuronal
depression produced by thiopental and the fall in
blood flow occurs as a result of the decrease in
demand for oxygen. The effect of thiopental on ICP
makes this agent useful in patients with raised ICP
(head trauma, brain tumor, hydrocephalus).
● Thiopental is also an anticonvulsant, making it safe
in patients with epilepsy and those undergoing
myelography.
Cardiovascular effects
● Thiopental reduces blood pressure in a dosedependent
manner. Peripheral vasodilation is the
main mechanism involved and a compensatory rise
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