Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 2 CLINICAL PHARMACOKINETICS
repeatedly, the usual aim of therapy is to maintain a
(relatively) constant drug concentration at the site of
effect.
This ‘steady-state’ concentration (C ss ) is determined
by the dose (D), the bioavailability (F), the dosing frequency
(T) and the clearance of the drug (Cl). Mathematically
this is defined as:
C ss = F × D/T/Cl
Using the equation:
● when the dose (D) is increased, concentration at
steady state (C ss ) is increased
● when the dosing frequency (T) is decreased (e.g.
every 12 h rather than every 8 h), C ss decreases
● when clearance (Cl) decreases, C ss increases
● a decrease in clearance (Cl) will need to be
balanced by a decrease in dose/frequency (D/T) to
keep C ss constant
● either a decrease in dose (D) or an increase in
dosing frequency (T) or both will lead to a
decrease in D/T
● decreases in drug clearance may occur frequently as
a result of renal and liver diseases
● significant increases in drug clearance are
uncommon in small animal practice.
Example
If a D/T of 100 mg/h is required, this could be achieved
by:
● a dose of 1000 mg given every 10 h
● a dose of 100 mg given every hour
● a dose of 1 mg given every 36s.
The effect of the choice between these three options is
considerable. The first option would result in a very
high plasma concentration initially (perhaps toxic),
therapeutic concentrations for a certain period of time
and very low concentrations (perhaps subtherapeutic)
before the next dose. Such fluctuations may be suitable
for certain drugs (e.g. concentration-dependent antibiotics).
The third option would result in constant therapeutic
plasma concentrations throughout the dosing
period (as with a constant infusion), but would be
impractical for long-term therapy.
So, the dosing interval and the magnitude of the dose
given at each time will determine the fluctuations in
plasma concentrations. Most importantly, if you suspect
that the clearance of a drug may be decreased as a result
of liver or renal disease, then D/T can be manipulated
to compensate for the decrease in drug clearance, so that
plasma drug concentrations can be kept within the
therapeutic range. If you estimate that drug clearance
may be decreased by 50%, then D/T will need to be
decreased by 50%. Taking the above example of a D/T
required of 100 mg/h (in normal animals), a D/T of
50 mg/h could be achieved by halving the dose (keeping
the interval constant) or doubling the dosing interval
(keeping the dose constant). Usually, since clearance is
expected to be halved, the dosing interval is doubled
rather than the dose halved.
Important clinical syndromes in which
pharmacokinetic knowledge is critical
Liver disease/failure
Liver disease may affect the following pharmacokinetic
variables.
● Bioavailability of oral drugs
● Binding of drugs to serum albumin (if hepatic
albumin production decreases)
● Metabolism of prodrugs to active metabolites
● Hepatic metabolism and/or clearance of drugs.
There are no satisfactory indices of liver dysfunction in
veterinary laboratory medicine that can be used to
predict the magnitude of changes in hepatic clearance
of drugs.
For drugs that have high plasma protein binding and
are predominantly cleared by the liver, liver disease
would be expected to result in an increase in the volume
of distribution of the drug and decrease drug clearance.
Thus, loading doses may need to be increased and
dosing intervals may need to be lengthened to compensate
for these changes. Close clinical monitoring will be
required to aid individualization of the dose regimen
and to match changes to the patient’s needs.
Whether the use of certain drugs should be avoided
in animals experiencing liver dysfunction is controversial.
Ultimately it depends on whether that drug
leads to toxicity at concentrations close to therapeutic
concentrations and whether alternative drugs are
available.
The effect of liver disease on drug disposition is
discussed further in Chapter 3 on Adverse Drug
Reactions.
Renal disease/failure
Renal disease may affect the following processes.
● Glomerular filtration of drugs
● Active tubular secretion of drugs
● Passive reabsorption of drugs
● Total body water
● Plasma albumin concentration
● Protein binding in the presence of uremia
There are few indices of renal dysfunction in veterinary
laboratory medicine that can be used to predict the
magnitude of changes in renal clearance of drugs.
Although blood (plasma/serum) urea and creatinine are
commonly used to assess renal function, they may not
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