Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

FACTORS THAT MODIFY DRUG EFFECTS AND DOSAGE
administration of aspirin on an empty stomach instead
of with food or injecting melarsomine into the caudolateral
thigh rather than the epaxial musculature) or
applying a bad rule. Slips and lapses are defects in
unconscious processes and can result from slips of
action (illegibly writing amoxicillin, which is then
misread as digoxin) or lapses of memory (administering
penicillin and forgetting that you have already been
advised that the patient is allergic).
Latent conditions are the inevitable consequences of
the systems operating to define the work environment.
The most notable example is the error-provoking conditions
induced by time pressure, understating, fatigue,
inadequate equipment and inexperience. Clearly, the
combination of latent conditions and active failures is
an excellent recipe for error.
While all clinicians will have experienced and recognized
errors, it is unfortunate that systematic reporting
and analysis is rare to nonexistent. Encouragement of
nonpunitive, protected, voluntary incident reporting
combined with case review and auditing of diagnoses
would help to identify errors and limit their relentless
reproduction.
With respect to variability in clinical response to
treatment, medical errors should be actively sought and
corrected before adjusting therapeutic plans.
Feeding
There are many potential interactions of food and drugs
in companion animals; however, the clinical significance
of many of these effects is still under investigation.
While it is of some importance with short-term dosing,
when administering drugs chronically it is a therapeutic
goal that the pharmacokinetics (and bioavailability) of
the drug remain constant, predictable and reproducible,
as this will be reflected in the response of the patient.
Differences in feeding regimens may be one source of
variation in drug behavior. The degree of variation that
is clinically acceptable will depend on:
● the need to exceed a minimum plasma
concentration for as long as possible or to attain a
maximum plasma concentration (particularly
important for antibiotics)
● the therapeutic index of the drug being
administered (e.g. the digitalis glycosides, mitotane
and many antineoplastic agents have a low
therapeutic index and the likelihood of adverse
effects can only be reduced by minimizing
pharmacokinetic variability)
● the seriousness of the condition being treated.
The interaction of food and drugs is principally manifested
as effects on drug absorption, the rate and extent
of which can be decreased, delayed, less commonly
increased or be unaffected. There are also possible
effects of food on drug metabolism. Advantage can be
taken of the interaction of food and drugs in minimizing
tissue irritation (useful with a number of acidic drugs
such as ibuprofen and aspirin) and in reducing the likelihood
of toxicity by delaying absorption to produce a
reduced C max (e.g. digoxin).
The mechanisms by which food can interact with a
drug include effects on the following.
● Gastric emptying. Most absorption of orally administered
drugs takes place in the small intestine. The
rate at which drugs reach the small intestine is dependent
on the rate of gastric emptying, which in turn
is dependent on the presence or absence of food,
meal size, energy content, form of meal (solid or
liquid) and particle size distribution. In the fasting
state, drugs usually leave the stomach rapidly but
exit is dependent on the time of administration in
relation to the gastroileal contractile waves of the
interdigestive migrating motor complex. Intestinal
transit time is relatively constant and little influenced
by feeding, but may be affected by disease.
● Dissolution of dosage forms. Changes in gastric
emptying rate combined with changes in gastric pH
induced by food can significantly impact the rate and
extent of dosage form disintegration and drug dissolution.
Gastric acid promotes the dissolution and
absorption of basic drugs and accelerates the degradation
of acid-labile compounds. Increased gastric
dissolution of carbamazepine and phenytoin will
increase the drug available for absorption by the
small intestine. By contrast, some drugs (e.g. penicillin
G) are susceptible to degradation in low pH
environments and, if dosage forms disintegrate and
release their drug content, less drug will be available
for absorption.
● Bile acid activity. The absorption of some insoluble
(fenbendazole) or lipid-soluble (griseofulvin and
mitotane) drugs can be enhanced by coadministration
of a high-fat meal, which increases the biliary
output of bile acids. However, with some drugs
(e.g. kanamycin and polymyxin) bile salts may form
stable complexes, reducing their bioavailability.
● Pancreatic and intestinal mucosal enzyme activity.
The presystemic metabolism of drugs susceptible to
enzymatic biotransformation by pancreatic proteases,
lipases and other enzymes can be affected.
While prodrugs may be activated and bioavailability
increased (particularly with esters of active drugs),
many peptide drugs will be inactivated.
● Splanchnic blood flow. Splanchnic blood flow
increases in response to feeding and a greater proportion
of blood flow bypasses the liver, thus allowing
drugs subject to first-pass hepatic metabolism (e.g.
clomipramine) to avoid this process, with an apparent
increase in systemic bioavailability.
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