Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 2 CLINICAL PHARMACOKINETICS
release formulations, many drugs when administered by
constant intravenous infusion and many drugs administered
by transdermal patches.
Some drugs that are eliminated by zero-order processes
in some species include ethanol, salicylate, phenytoin
(in humans but not in dogs), propranolol in some
species, phenylbutazone in the horse at some dose rates
and paracetamol (acetaminophen) in the cat. Zero-order
elimination is usually due to saturation of metabolism
or excretion processes.
In summary, zero-order rates remain constant irrespective
of the concentration of drug present.
In contrast, a first-order process is one where the
change in concentration of drug in the body fluid is
proportional to the concentration of the drug in that
fluid at that time. δC/δt = kC (i.e. the rate of change of
C over time equals a constant proportion of C). The
exponent of C is one, leading to the description, first
order.
The vast majority of drugs used at therapeutic doses
in veterinary clinical practice conform to first-order
pharmacokinetics with respect to their elimination from
the body, but there are some drugs that are absorbed
and eliminated by zero-order processes.
In order to discuss manipulation of drug dose and
dosing frequency, some pharmacokinetic characteristics
must be introduced and described mathematically. The
most useful clinically (and referred to later in this
chapter) are as follows.
● F (the fraction absorbed): the extent of a drug’s
systemic availability (bioavailability) after administration,
usually considered as the percentage of
unchanged drug absorbed that reaches the systemic
circulation, e.g. F = 80% means that 80% of the
administered drug reaches the blood in comparison
with intravenous bioavailability which is usually
accepted as being 100%.
● Cl, the plasma clearance, is the volume of plasma
cleared of drug per unit time. Clearance is a measure
of the efficiency of removal of drug from the blood
by all means, though principally hepatic and renal
processes. Plasma clearance is expressed in units
of flow (e.g. mL/min). Clearance determines the
maintenance dose rate required to achieve a target
plasma concentration at steady state. Maintenance
rate (mg/min) = Cl (mL/min) × [target concentration
(mg/mL)].
● V d : the apparent volume of distribution of a drug. V d
is expressed in units of volume (e.g. mL). It does not
have physiological meaning but is useful in predicting
the loading dose.
● Elimination half-life (t 1/2 ): the time taken for the
plasma concentration to halve, e.g. if the plasma
concentration of a drug decreases from 8 µg/mL to
4 µg/mL in 4 hours, the half-life of the drug is 4
hours. Half-life is a hybrid term, being a function of
both Cl and V d .
– t 1/2 = kV/Cl (k = 0.693). As V increases, t 1/2
increases. As Cl increases, t 1/2 decreases. If both
parameters vary together, t 1/2 can remain
unchanged.
– Half-life determines duration of action after a
single dose, time needed to reach steady state with
repeated dosing and dosing frequency required to
avoid large fluctuations in plasma concentration
during the dosing interval. As a general rule,
when the effect is related to drug concentration,
doubling the dose adds one half-life to the duration
of effect.
In summary, the volume of distribution and bioavailability
are important for determining the first drug
dose, clearance is important for the maintenance dose
and half-life is important for determining the time
needed to reach steady state and the dosing interval.
These concepts are explored further in the Appendix to
this chapter (p. 38).
Individualization of dosage regimens
When a veterinarian is considering drug therapy in an
animal patient, critical questions include:
● What drug?
● What dose?
● What dosing interval and frequency?
Within each animal species, each drug is expected to
have a predictable absorption, distribution, metabolism
and excretion in normal animals and dosing regimens
suggested in textbooks reflect this ‘predictability’.
However, there can be substantial individual variation
in drug kinetics in individual dog and cat patients to
which additional variability may be presented by pharmacodynamic
processes. In addition, certain diseases
may alter the pharmacokinetics of a drug. This variability
is greater for some drugs than for others and has
clinical importance when concentrations that are associated
with toxicity are similar to therapeutic concentrations
(e.g. drugs with low therapeutic margin such as
digoxin, many cytotoxic drugs).
The variability in how the body ‘deals’ with the drug
can be very difficult to predict. While approaches to
alter the inherent pharmacokinetic nature of a drug in
an individual animal are limited, veterinarians can
manipulate the dose and dosing frequency of a drug to
compensate for expected pharmacokinetic changes.
Such manipulations can be made on a trial-and-error
basis where the effects of the drug are closely monitored.
Unfortunately, for many drugs used in small
animal practice, drug effects cannot readily be measured,
so monitoring the effectiveness of a dosing
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