Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 5 ANESTHETIC AGENTS
and enhancing chloride conductance causing cellular
hyperpolarization. Alphaxalone ± alphadolone may also
activate chloride channels independently of GABA.
Formulations and dose rates
There are currently two different formulations of alphaxalone. A combination
of alphaxalone and alphadolone is manufactured as a clear
solution containing 9 mg/mL alphaxalone and 3 mg/mL alphadolone
(Saffan®). Cremophor EL (polyoxyethylated castor oil) is used as a
solvent. The solubility of alphaxalone in Cremophor EL is enhanced
by the addition of alphadolone, which has only weak hypnotic properties.
The Cremophor EL-based drug forms a viscid solution with a pH
of about 7. It is isotonic with blood and miscible with water. Cremophor
EL causes mild-to-moderate histamine release in the cat and
marked histamine release in the dog.
Alphaxalone is also marketed as a ‘ready-to-use’ 10 mg/mL solution
in hydroxylpropyl-β cyclodextrin, buffered to pH 7 by sodium
phosphate (Alfaxan®-CD). This solution contains no preservatives.
The recommended shelf-life after opening varies in different countries
(up to 7 days) but generally the solution should be used as quickly as
possible.
• The alphaxalone/alphadolone combination should only be used
in cats. The dosage is expressed as milligrams of total steroid
per kilogram. A dosage of 9 mg/kg IV provides 10–15 min of
anesthesia.
• Anesthesia can be prolonged by administering small boluses
of 2–3 mg/kg as needed or by providing an infusion of
0.2–0.25 mg/kg/min.
• It can also be given by the intramuscular route. An IM dose of
9 mg/kg produces light sedation and 12–18 mg/kg produces
light-to-moderate anesthesia.
• The response following intramuscular administration can be
variable unless the injection is given deep into the muscle.
Because of the large volumes required with intramuscular
administration, several sites may be necessary.
• Alphaxalone ± alphadolone is ineffective when given by the
subcutaneous route because of rapid metabolism.
• The alphaxalone solution that lacks Cremophor EL, i.e.
Alfaxan®-CD, can be used in cats and dogs. The dosage of
alphaxalone required for endotracheal intubation is 1–3 mg/kg
IV in dogs and 5 mg/kg in cats. Anesthesia can be prolonged by
administering small boluses of approximately 1 mg/kg as
needed (approximately every 10 minutes) or by providing an
infusion of 0.10–0.18 mg/kg/min. Doses at the higher end of
the range are required in cats and unpremedicated patients.
Pharmacokinetics
After intravenous administration, alphaxalone ± alphadolone
produces muscle relaxation within 9 seconds
and unconsciousness within 30 seconds. Intramuscular
injection takes about 6–12 min to have an effect and
lasts about 15 min. Alphaxalone is not highly protein
bound (30–50%) and hypoproteinemia has only a small
effect on the dosage required to induce anesthesia.
After IV administration a rapid fall in plasma
drug concentration occurs as a result of hepatic metabolism
and redistribution. Once plasma and brain
concentrations fall below the effective threshold, recovery
from anesthesia occurs. Because degradation is the
major factor causing termination of anesthesia, accumulation
is minimal and multiple doses can be given
without prolonging the duration of recovery. Metabolites
are excreted in urine.
Adverse effects
Central nervous system effects
● The cerebral depression produced by alphaxalone ±
alphadolone is similar to that of thiopental. Cerebral
metabolic oxygen requirement, cerebral blood flow
and intracranial pressure are all decreased, making
this agent useful in the patient with cerebral disease.
● Disturbing a cat during recovery can result in paddling
and twitching, and violent convulsant-like
activity may occur with rough handling.
Cardiovascular effects
● Alphaxalone ± alphadolone decreases arterial blood
pressure in a dose-dependent manner. The fall in blood
pressure appears to be due to a decrease in myocardial
contractility and stroke volume. Heart rate usually
increases and central venous pressure falls. Low doses
(≤5 mg/kg) of alphaxalone have a mild transient effect
on blood pressure, whereas larger doses (10 mg/kg)
cause a moderate hypotension that persists for up to
40 min after a single dose. Clinical doses (8–9 mg/kg)
of the alphaxalone/alphadolone combination cause
the greatest decrease in blood pressure and the decrease
may last for over 60 min. Much of the cardiovascular
depression associated with alphaxalone ± alphadolone
may be due to the Cremophor EL base rather than the
active ingredients, as alphaxalone in cyclodextrin
appears to produce less cardiovascular depression. In
the cat alphaxalone ± alphadolone provides some
protection against adrenaline (epinephrine)-induced
cardiac arrhythmias.
● Perivascular administration of alphaxalone ± alphadolone
does not cause any irritation or pain.
Respiratory effects
● Respiratory depression is minimal after alphaxalone
± alphadolone administration. Transient postinduction
apnea can occur but is considered rare.
Other effects
● Cremophor EL causes marked histamine release and
hypotension in dogs, making alphaxalone ± alphadolone
unsuitable for anesthesia in this species.
– In cats Cremophor EL also appears to cause histamine
release, although it is less severe than that
seen in dogs.
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