Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

FACTORS THAT MODIFY DRUG EFFECTS AND DOSAGE
than speculative and theoretical scaremongering guesswork,
hallowed by repeated quotation’.
When studied, the incidence of drug interactions
has been found to be much lower than would be anticipated
on the basis of the frequency of use of multiple
drugs. However, clinicians should always be conscious
of the possibility of drug interactions whenever more
than one drug is administered, considering both prescribed
treatment and concurrent owner-initiated
medications. Interactions can be serious, but a critical,
objective and investigative mind should be retained, as
it is important always to endeavor to determine the
cause of any unintended clinical outcomes in order
that future prescribing decisions can be modified
appropriately.
Interactions may be:
● physicochemical or pharmaceutical, generally interacting
prior to administration
● pharmacokinetic, leading to alterations in the absorption,
distribution, metabolism or elimination of one
drug by another
● pharmacodynamic, whereby one drug affects the
action of another drug.
The net outcome of the interaction may be:
● enhancement of the effects of one or other drug
● development of totally new effects not seen when
either drug is used alone
● inhibition of effect of one drug by another
● no change in net result despite the pharmacokinetics
of one or both drugs being substantially
altered.
Mechanisms of interactions
● Direct chemical or physical interactions, e.g. inactivation
and precipitation of penicillin when mixed in
the same syringe or infusion set with phenytoin or B
complex vitamins. Similarly with carbenicillin and
gentamicin.
● Interactions in gastrointestinal tract (GIT)
absorption:
– physical interactions (tetracyclines or fluoroquinolones
given with milk (calcium) or iron;
levothyroxine (thyroxine) complexed to coadministered
colestyramine)
– altered GIT motility by one drug (metoclopramide
can decrease and propantheline can increase the
absorption of digoxin)
– change in pH by one drug (reduced ketoconazole
absorption due to reduced dissolution when
administered with antacids or H 2 blockers)
– alteration in bacterial flora can cause dysbiosis
and altered GIT motility; in addition, antimicrobial
drugs can eliminate the flora that may be
necessary to activate (e.g. sulfasalazine) or inactivate
(e.g. digoxin) a drug, leading to decreased
and increased bioavailability respectively.
● Protein binding. Many drugs bind to plasma proteins.
Acidic drugs bind to albumin while basic drugs
bind to α 1 -acid glycoprotein. Competition between
drugs for binding sites depends on the affinity of each
drug for the binding sites and drug concentration.
Usually only the free (nonbound) portion of the drug
is able to exert a pharmacological effect. If the drug
is highly protein bound (>95%), even a minor percentage
change in the extent of binding will lead to
a large change in the concentration of free drug. The
free drug is immediately available for distribution
and elimination and a new equilibrium of free and
bound drug is established, rendering this type of
interaction more hypothetical and perceived than
real and of clinical importance.
● Interactions at receptor sites by:
– agonist and antagonist will negate an effect,
which may be beneficial (organophosphate
and pralidoxime, naloxone and morphine, vitamin
K and coumarin anticoagulant) or harmful
(α 2 -adrenoceptor agonist and α 2 -adrenoceptor
blocker)
– multiple agonists or antagonists may lead to
increased effect (increased likelihood of ototoxicity
with concurrent use of aminoglycosides and
furosemide (frusemide), potentiation of effects of
nondepolarizing muscle relaxants with concurrent
use of aminoglycosides).
● Interaction due to accelerated metabolism after
induction of drug-metabolizing enzymes, especially
hepatic (e.g. phenobarbital significantly decreases
the half-life of quinidine and digoxin; other
enzyme inducers include phenytoin, griseofulvin and
carbamazepine).
● Inhibition of metabolism by chloramphenicol,
phenylbutazone, azole antifungal agents, cimetidine
and verapamil can be associated with prolonged
action, accumulation and toxicity of concurrent
medications that would normally be cleared by
hepatic biotransformation.
● Alteration of renal excretion. Increased digoxin
concentrations have been associated with use of
aminoglycosides and consequent renal impairment.
Probenecid reduces the renal clearance of penicillin
by competitively inhibiting renal tubular secretion.
● Alteration of urine pH by alkalinizing agents (sodium
bicarbonate and acetazolamide and other carbonic
anhydrase inhibitors) or acidifying agents (ascorbic
acid or ammonium chloride) can hasten or delay the
excretion of drugs. Renal clearance of basic drugs
(e.g. amfetamine) is increased in acid urine while
clearance of acidic drugs (e.g. aspirin and barbiturates)
is enhanced in alkaline urine.
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