Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

FACTORS THAT MODIFY DRUG EFFECTS AND DOSAGE
● Solvated state. Crystal solvates are substances that
contain a solvent as a defined part of their lattice
network structure. Crystal hydrates include the most
commonly encountered examples. There are significant
differences in stability, solubility and bioavailability
between solvated and solvent-free crystals.
Drugs that can exist in either state are numerous and
include ampicillin, amoxicillin, phenobarbital, theophylline,
prednisolone and morphine.
● Particle size. Both particle size and particle size
distribution can influence solubility and bioavailability,
principally by changes in surface area of
the drug. Clinically important examples of active
constituents in solid or aqueous dosage forms include
mebendazole, digoxin and nitroscanate, the bioavailability
of all being increased as particle size is
reduced. Penicillin and erythromycin suffer reduced
oral bioavailability with reduced particle size as a
greater surface area is exposed to acid degradation
in the stomach. It should be noted that, for parenterally
administered oily suspensions, the converse is
observed: the smaller the particle size, the slower the
absorption.
● Salt form. Salt forms of drugs generally exhibit a
higher dissolution rate than the corresponding acid
or base and if the rate of absorption is dissolution
limited, then salts will provide improved bioavailability.
While different salts frequently have
similar pharmaceutical characteristics, this is not
always the case. The relative order of dissolution
rates and plasma C max for penicillin V was potassium
salt > calcium salt > free acid > benzathine salt. It
should be noted, however, that the stability of different
salt forms may vary. For example, the thermal
stability of the sodium and potassium salts of penicillin
G is superior to that of the procaine salt. The
calcium salt of penicillin V is less hygroscopic than
the sodium salt.
● Excipients. Excipients are the pharmaceutically
important but (generally) pharmacologically inactive
components of a formulation that in great part determine
the physical form, release characteristics and
stability of the dosage form. In solid dosage forms
excipients function to control the rate of disintegration
and dissolution, which may also be influenced by
both the compression characteristics of tablets and
any special coatings that may be applied (e.g. pHsensitive
enteric coatings). Excipients act as binders
(sucrose, methylcellulose), disintegrants, lubricants
(magnesium stearate), glidants (talc), wetting agents,
adsorbents, buffers, surfactants, micellization
agents, solvents, cosolvents, emulsifiers, suspending
agents, viscosity enhancers, desiccants, flavor enhancers,
coloring agents, antioxidants, preservatives and
fillers. While the relative proportions may be constant
and controlled within any one defined dosage form,
there may be subtle or extreme differences between
products, all potentially influencing bioavailability
either positively or negatively.
● Physiological effects. Depending on both the active
constituent and the formulation, there may be significant
physiological effects on the recipient of the
dosage form. These include pain and tissue damage
from injections (intravenous, intra-articular, intramuscular
and subcutaneous), skin damage from
topical preparations, increased tear production from
ophthalmic products, emesis and mucosal irritation
from oral dosage forms. All of these physiological
effects can impair the bioavailability of the drug and
lead to variation in clinical response between and
within individuals.
Compliance
There is little published data on patient (client) compliance
in veterinary medicine but some guidelines exist
from human studies and unpublished work. Studies
have shown that a substantial proportion of human
patients comply poorly with drug therapies prescribed
by physicians. Limited observations suggest that noncompliance
is also important in veterinary medicine. In
two canine studies, only 27% of owners gave the prescribed
number of doses each day during short-term
antibiotic treatment. Other reported examples of poor
compliance apply to long-term prophylaxis of heartworm
with daily or monthly preparations, insulin
administration in diabetic patients and chronic administration
of behavior-modifying drugs. In one additional
case of compliance failure, veterinary support staff
withheld postoperative opioid treatment or substituted
another analgesic agent in dogs displaying pain because
of concern about possible adverse effects.
Errors of compliance include the following.
● Omission of treatment, including ‘drug holidays’.
● Incorrect treatment administration, e.g. oral products
given with food when fasting was required
or, in dermatological therapy, dipping technique
may be inadequate to penetrate the hair or the preparation
may be rinsed out of the hair coat instead of
being left to dry; dips for scabies may miss the ears
and face; shampoos may not be left on long
enough.
● Dosage: under- or overdosing.
● Timing or sequence: for example, a recommendation
for morning treatment may not be observed; dosing
may be after feeding instead of before feeding.
● Addition of medications that were not prescribed.
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