Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 3 ADVERSE DRUG REACTIONS
an appropriate dosage for nonlipid-soluble drugs even
if using body surface area. Drugs which have a narrow
margin of safety and are not lipid soluble include digoxin
and the aminoglycoside antibiotics. For lipid-soluble
drugs, increased body fat can act as a sink and reservoir,
leading to protracted drug elimination if metabolism to
a more water-soluble form is not involved.
Age
Neonates have a reduced capability for drug biotransformation
and have underdeveloped hepatic and renal
excretory mechanisms. Hence the increased sensitivity
to, and prolonged recovery from, barbiturate anesthetics
that may be observed in dogs and cats younger than
4 months. Other factors that influence drug disposition
in the pediatric patient include increased gastrointestinal
permeability, differences in body water and protein
binding (greater percentage of body water, less extensive
protein binding) and increased blood–brain barrier
permeability.
Older animals may have reduced hepatic or renal
function, less body water and reduced lean body mass
and therefore often require lower doses of drugs compared
to younger animals. However, it is important to
be aware that the aging process varies greatly between
individuals. Patient-specific physiological and functional
characteristics are probably more important than age
per se in predicting the predisposition to ADRs in
patients.
Sex
During pregnancy or lactation, caution should be
observed in administration of drugs that might affect the
fetus or neonate. Drugs that should be avoided or used
with caution in pregnant animals include corticosteroids,
cytotoxic drugs, griseofulvin, ketoconazole, prostaglandins,
salicylates, sex hormones, tetracyclines and
live vaccines. Drugs which may adversely affect lactation,
causing agalactia, include atropine, bromocriptine
and furosemide. Adverse drug reactions occur more
commonly in female humans but it is not known if this
phenomenon occurs in domestic animals.
Pathology
Dosage recommendations are usually based on pharmacokinetic
data obtained from healthy animals under
controlled conditions even though many drugs will be
given to diseased animals. Drug absorption, distribution,
metabolism and excretion may be adversely
affected by pathology of various organs, in particular
the gastrointestinal tract, liver and kidney. Adjustment
in dosage may be required, depending on changes in
volume of distribution and clearance as influenced by
the site of metabolism and route of elimination of the
particular drug.
Drugs and the liver
The liver is the major site of metabolism of many drugs
and thus the clinician is rightly concerned about the
safety of administering drugs to patients with hepatic
disease. Hepatocellular dysfunction can alter the bioavailability
and disposition of a drug as well as influencing
its pharmacological effects. In addition, the impact
of hepatic pathology on drug disposition can relate to
the effect of the clinical consequences of liver disease
such as anorexia, pyrexia, hypoproteinemia and
jaundice.
Hepatic extraction and the first-pass effect
When a drug is absorbed across the gut wall, it is delivered
via portal blood to the liver prior to entry into the
systemic circulation. Drug metabolism most commonly
occurs in the liver prior to the drug reaching the systemic
circulation although it can also occur in gut wall
and portal blood. The liver may also excrete the drug
into bile, allowing enterohepatic recycling.
The effect of first-pass elimination on bioavailability
(the proportion of administered dose that reaches the
systemic circulation unchanged) is expressed as the
extraction ratio ER
CL liver
= where CL liver is clearance
Q
by the liver and Q is hepatic blood flow. This equation
would predict that if clearance of a drug by the liver is
reduced because of hepatocellular dysfunction causing
reduced drug metabolism or decreased biliary excretion,
then the ER will be reduced and systemic availability of
the drug will rise when the drug is given orally. The
equation also predicts that if hepatic blood flow is
reduced then ER will also increase.
Studies in horses have demonstrated that acute submaximal
exercise increases the elimination half-life of
bromosulfan, possibly due to decreased splanchnic and
hepatic blood flow. Whether this has clinical relevance
for animals that are exercised to a far greater degree
than the ‘normal’ pet is unknown.
Hepatic diseases that are accompanied by substantial
intrahepatic or extrahepatic shunting (such as cirrhosis,
congenital portacaval shunts) will result in increased
bioavailability of drugs with high extraction ratios such
as verapamil, pethidine, propranolol and several tricyclic
antidepressants. Clearance of drugs which have
intermediate extraction ratios such as aspirin, codeine
and morphine may also be affected. Clearance of these
drugs will also be prolonged by poor hepatic perfusion
(e.g. in heart failure, in shock and with propranolol
administration). Liver blood flow also tends to be
reduced in older patients. In contrast, there will be little
change in bioavailability of drugs that are poorly
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