Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 1 PRINCIPLES OF CLINICAL PHARMACOLOGY
Inter- and intraspecies differences
Between-species differences
It is perhaps surprising that, although dogs and cats
have evolved independently, when drug dose rates are
scaled according to bodyweight the majority of drugs
behave similarly in both species. However, there are a
number of notable differences and it is prudent therefore
to consider that, in the absence of information to
the contrary, each species should be treated as unique.
The principal pharmacological differences between
dogs and cats can be classified as pharmacokinetic,
pharmacodynamic and behavioral.
Pharmacokinetic differences
While there are differences in enteric and dermal absorption,
distribution and elimination, the most notable
pharmacological differences are in metabolism. Cats
have a slow rate of hepatic phase II glucuronidation,
resulting in decreased clearance of drugs that depend on
this means of biotransformation prior to elimination.
Important clinical examples include the metabolism of
acetylsalicylic acid (aspirin) and morphine. While the
dose rate of aspirin is the same in the dog and cat
(10 mg/kg) as the drug has similar volumes of distribution,
the dosage interval to allow maintenance of a
therapeutic concentration is 12 hours in the dog and 48
hours in the cat. This reflects the significant differences
in half-life of elimination (8.6 hours in the dog and 37.6
hours in the cat) as a result of the reduced clearance and
rate of metabolism in the cat.
In contrast to cats, dogs are deficient in hepatic phase
II acetylation, reducing the dog’s ability to metabolize
aromatic amines. This can be beneficial to the dog when
treated with sulfonamides, as acetylated metabolites
produced in species with active acetylation pathways
are less soluble than the parent compound and more
likely to precipitate and cause damage in the renal
tubules. Alternative metabolic pathways for aromatic
amines include glucuronidation and hydroxylation.
Other drugs displaying pharmacokinetic differences
include succinylcholine, which is metabolized more
slowly in the cat than in the dog, presumably because
of reduced blood pseudocholinesterase activity.
Pharmacodynamic differences
Differences between dogs and cats with respect to drug
receptor distribution and affinity have been described,
with morphine representing the archetypal example. In
addition to a slower rate of biotransformation because
of the deficiency of glucuronidation in the cat, morphine
is associated with CNS stimulation (CNS depression in
the dog), centrally mediated emesis at much reduced
sensitivity compared to the dog (dog requires dose 1/740
that of cat) and pupillary dilation (miosis in the dog).
However, at a dose rate of 0.1 mg/kg subcutaneously
(compared with 0.1–2 mg/kg in the dog), morphine provides
effective analgesia in the cat.
Other examples of drugs subject to pharmacodynamic
differences include xylazine and febantel (which induce
emesis much more readily in cats than dogs), digitalis
glycosides (the cat is less tolerant than the dog, presumably
because of increased sensitivity of feline cardiac
Na + ,K + -ATPase to inhibition) and drugs affecting oxidative
processes such as some of the sulfonamides, nitrofurans
and sulfones (cat erythrocytes more sensitive to
oxidative challenge than those of dogs). The increased
sensitivity of cats to the toxic effects of permethrin and
chlorpyrifos may also be due to pharmacodynamic differences
between cats and dogs.
Behavioral differences
The grooming behavior of cats increases the likelihood
that topically applied medications will be ingested.
Advantage can be taken of this behavior by applying
medications intended for ingestion to accessible parts of
the cat’s body (e.g. anthelmintic or antibiotic paste
preparations). However, cats are at greater risk of exposure
to purposefully or adventitiously applied topical
toxicants such as disinfectants (particularly phenolics,
which are principally candidates for glucuronidation) or
pesticides. Indeed, concentrated preparations of permethrin
applied topically to cats can be lethal when
ingested.
Within-species differences
There are many real and potential factors that influence
the clinical pharmacology of a drug within an individual
(see Table 1.3).
● Age, bounded by the extremes of the pediatric and
geriatric patient. In many cases metabolic enzymes
have not reached full activity in neonatal animals.
The aged frequently have increased pharmacodynamic
sensitivity of the cardiovascular and central
nervous systems.
● Sex. With the exception of the reproductive hormones,
surprising little impact of sex has been
described to account for within-species differences in
drug pharmacology.
● Disease. Febrile state; dysfunction of organs of
metabolism and excretion; cardiovascular and renal
dysfunction affecting water balance and drug distribution;
and gastrointestinal disorders affecting drug
absorption can all account for significant withinspecies
differences. Adjustment of dosage regimens
or avoidance of use of particular drugs may be necessary
in patients with particular disease states.
● Physical state. Pregnancy, obesity and lean or malnourished
states can all have effects on drug distribu-
18