Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 3 ADVERSE DRUG REACTIONS
at increased risk of sulfonamide toxicity as NAT is a
key enzyme in sulfonamide detoxification. By contrast
with dogs, a study in cats has shown that while most
species have at least two genes that code for NAT
(NAT1 and NAT2), the cat has only one gene that codes
for a NAT1-like enzyme.
Thiopurine S-methyltransferase
Thiopurine S-methyltransferase (TPMT) activity has
been shown to be polymorphic in both cats and dogs.
The clinical significance of this variability in enzyme
activity is that TPMT is a key enzyme in the metabolism
and inactivation of thiopurine analogs such as
azathioprine and 6-mercaptopurine. Low TPMT activity
increases the risk of myelosuppression in treated
animals while high TPMT activity can be associated
with poor antineoplastic efficacy.
Immune response genes
It has been hypothesized that variation in response to
vaccines (for example, rabies and parvovirus vaccines)
may be related to genomic differences in immune
response genes of the major histocompatibility complex,
consistent with the observation of unique breed-related
haplotypes (Day 2006).
P-glycoprotein
P-glycoprotein (P-gp) or multidrug resistance protein 1
(Mdr1) is a member of the ATP binding cassette (ABC)
superfamily of transmembrane transport proteins and
in the dog is encoded by the gene Mdr1. P-gp is an
important drug efflux transporter that has a significant
impact on the gastrointestinal absorption, distribution,
metabolism, excretion and toxicity of its substrates.
Mutations of Mdr1 have been observed in 10 dog breeds
(see Table 3.5), with dogs that are homozygous for
the mdr1-1∆ allele displaying nonfunctional P-gp. The
pharmacological impact of homozygous mutants is the
ability of ivermectin to pass the blood–brain barrier and
achieve toxic concentrations within the brain two orders
of magnitude higher than in dogs with functional P-gp.
The identification of this mutation in collies and related
breeds finally explains the well-known sensitivity of
these breeds to the macrocyclic lactone class of
parasiticides.
Drug interactions
A drug interaction can occur if one member of a class
of drugs alters the intensity of the pharmacological
effects of another drug given concurrently. The net
result of a drug interaction may be: enhancement of
effects of one or other drug (hence increasing the risk
Table 3.5 P-glycoprotein polymorphism in dogs
Dog breed distribution of mdr1-1D
Collie
Australian shepherd
Border collie
English shepherd
German shepherd
Long-haired whippet
McNab
Old English sheepdog
Shetland sheepdog (shelty)
Silken windhound
P-gp substrates
Acepromazine a
Butorphanol a
Dexamethasone a
Digoxin a
Doramectin a
Doxorubicin a
Doxorubicin a
Ivermectin a
Ketoconazole c (inhibitor)
Loperamide a
Mexiletine a
Moxidectin a
Ondansetron c
Progesterone c
Quinidine b (inhibitor)
Selamectin a
Vinblastine b
Vincristine a
a Clinical evidence or b nonclinical evidence in dogs that these
drugs can cause adverse effects if recipient is homozygous for
mdr1-1∆. c Possible substrate for canine P-gp.
Neff et al 2004; Schwab et al 2003; Mealey 2006.
of an ADR occurring); development of totally new
effects not seen when either drug is used alone; inhibition
of effect of one drug by another; no change in the
net result despite the kinetics or metabolism of one or
both drugs being substantially altered.
Drug interactions may be classified as:
● pharmaceutical – interactions that occur prior to
administration (for example, mixing of a base and
an acid for systemic or enteral use, such as a penicillin
and an aminoglycoside). Most pharmaceutical
interactions result in inactivation of one or both
drugs. Rarely, a toxic interaction can arise
● pharmacokinetic – defined as an alteration in the
absorption, distribution, metabolism or excretion of
one drug by another. This is the most common type
of drug interaction
● pharmacodynamic – where the drug affects the action
or effect of the other drug.
Drug interactions can involve: direct chemical or physical
interaction; interactions in gastrointestinal absorption;
competition between drugs for protein-binding
sites; interactions at receptor sites; interaction due
to accelerated metabolism; inhibition of metabolism;
alteration of renal excretion; and alteration of pH or
electrolyte concentrations. While many drug interactions
lead to increased risk of ADRs, other interactions
may be beneficial, as for example when probenecid is
combined with penicillin or clavulanic acid with
amoxicillin.
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