Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

FACTORS THAT INFLUENCE TYPE A ADVERSE DRUG REACTIONS
O: Unclassified. There is insufficient information available
on which to reasonably draw any conclusion.
N: Unlikely to be drug related. Sufficient information is
available and investigation has established beyond
reasonable doubt that the suspected drug is not causally
related to the observed events.
Causality categorization is generally open to change as
further relevant information becomes available, including
the benefits derived from additional reports and
further pathophysiological or pharmacoepidemiological
studies.
FACTORS THAT INFLUENCE TYPE
A ADVERSE DRUG REACTIONS
It is important to understand the factors that modify the
effects of drugs and their dosage in order to anticipate
when a patient may be at increased risk of a Type A
ADR. Many factors modify the effects of drugs in the
individual patient. Some factors result in qualitative
differences in the effects of the drug and may preclude
its safe use in that patient. Other factors may produce
a quantitative change in the usual effects of the drug
that can be offset by appropriate adjustment in dose.
Factors that may be important in modifying the effects
of a drug in an individual include the following.
Species
In veterinary medicine we have to deal with animals of
different species, different ages and, within one species,
animals that may vary enormously in weight, e.g. a 2 kg
chihuahua versus a 80 kg rottweiler. Therefore in order
to individualize dosing regimens it is particularly important
that we are aware of particular species peculiarities
in drug metabolism, the effect of body size on dosing
recommendations and, most importantly, that we
understand that drug doses cannot necessarily be
extrapolated between cats and dogs even if they are of
similar weights.
Species differences in drug disposition may occur due
to differences in absorption (due to differences in the
anatomy of the gastrointestinal tract), differences in
metabolism, distribution and excretion as well as many
other factors.
Dogs versus cats
Of particular relevance to small animal clinical pharmacology
are the potential differences between cats and
dogs in how they handle drugs.
Although cats and dogs are physiologically similar in
many respects and dosing regimens recommended for
dogs can frequently be extrapolated to cats, there are
some important differences in drug disposition between
the two species that can have a profound influence on
dosing recommendations. The majority of differences
relate to pharmacokinetic differences in drug metabolism.
However, differences in hemoglobin structure,
receptors and behavioral differences may also account
for differences in drug disposition between the two
species.
Absorption and distribution
The kinetics of drug absorption appear to be similar in
dogs and cats regardless of the route of administration.
There are minor differences in factors that influence
drug distribution between dogs and cats. For example,
cats have a smaller blood volume per kg (66–70 mL/kg
bodyweight) than dogs (90 mL/kg) and therefore plasma
drug concentrations may differ between the two species
for drugs which are confined to the plasma compartment.
As understanding of drug transport proteins
increases, further species differences may become
evident.
Metabolism
Cats tend to be deficient in some glucuronyl transferases
which are important for glucuronidation. They have
substantially reduced ability to conjugate drugs such as
acetominophen and aspirin with glucuronic acid. As a
result hepatic clearance of aspirin in the cat is very
prolonged, leading to a half-life of 37.5 hours compared
with 8.5 hours in dogs. However, the drug can be used
safely provided the dosage interval is appropriately
extended. In contrast, acetaminophen is extremely toxic
to cats and cannot be used under any circumstances
because alternative metabolic pathways to glucuronidation
produce toxic metabolites. Other drugs which are
metabolized more slowly in cats include dipyrone,
chloramphenicol, morphine and hexachlorophene.
This is not a problem for all drugs that are glucuronidated
as cats are only deficient in certain families of
glucuronyl transferases. A drug normally metabolized
by glucuronidation may have a wide safety margin or
the drug may be metabolized by a different route in cats
(although this can result in toxicity for some drugs such
as acetaminophen). For example, sulfation is well developed
in cats compared to dogs and acetylation, which
is deficient in dogs, appears to be well developed
in cats.
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.
Dogs have a significantly reduced ability to acetylate
drugs. Where this pathway is responsible for drug inactivation,
e.g. sulfonamides, the drug will have a longer
duration of action than in other species.
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