Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 8 ANTIBACTERIAL DRUGS
In animals, the half-lives of sulfonamides and trimethoprim
differ (in contrast to humans) but the combination
is clinically effective as there is a relatively broad
range of drug ratio over which synergism occurs.
Sulfonamides are extensively metabolized and
excreted primarily by renal excretion; therefore large
amounts of drug are present in urine. Trimethoprim is
more lipid soluble than sulfonamides and reaches higher
concentrations in lungs and prostate.
Sulfonamides are bound to plasma proteins to an
extent varying from 15% to 90%. There are differences
between species in binding of individual sulfonamides.
Extensive protein binding (>80%) increases half-life. In
any one species the extent of protein binding, apparent
volume of distribution and half-life vary widely between
sulfonamides.
In most species, sulfonamides undergo acetylation
prior to renal elimination but in the dog they are eliminated
by glucuronidation and renal filtration. They are
also excreted in milk, feces, bile, sweat and tears. The
acetyl derivative of most sulfonamides (except sulfapyrimidines)
is less soluble in water than the parent compound
and may increase the risk of damage to renal
tubules due to precipitation.
Renal elimination involves glomerular filtration of
free drug, active carrier-mediated proximal tubular
excretion of nonionized unchanged drug and metabolites
and passive reabsorption of nonionized drug from
distal tubular fluid. The extent of reabsorption is determined
by the pKa of the sulfonamide and the pH of the
distal tubular fluid. Urinary alkalinization increases
both the fraction of the dose eliminated unchanged in
urine and the solubility of sulfonamides in urine.
Topical wound powders containing sulfonamides are
not useful because blood, pus and tissue breakdown
products impede antibacterial effectiveness and wound
healing can be delayed.
Adverse effects
Hypersensitivity reactions (dogs)
Abnormalities that may occur with hypersensitivity
reactions to sulfonamides include polyarthritis and
fever, cutaneous eruptions, thrombocytopenia, leukopenia
and hepatitis.
The sulfonamide molecule is too small to be immunogenic.
It is thought that hypersensitivity reactions occur
because of hydroxylamine metabolites that are formed
from oxidation of the para-amino group. These are cytotoxic
and capable of binding covalently to protein.
Doberman pinschers are predisposed to sulfonamide
hypersensitivity. This may be because of a reduced
ability to detoxify hydroxylamine groups compared
with mixed-breed dogs. Also, dobermans and other
breeds of dogs commonly affected with von Willebrand’s
disease (Scottish terriers, German shepherds) may not
tolerate sulfonamides well. These drugs probably should
be avoided in dobermans.
Keratoconjunctivitis sicca (KCS)
This may occur with prolonged use of some sulfonamides.
It is probably most often associated with sulfasalazine,
as this drug is used for long-term treatment
of ulcerative colitis. However, KCS has also been
reported within the first week of treatment in a small
proportion of dogs treated with trimethoprimsulfadiazine.
The dogs all weighed less than 12 kg, suggesting
that care should be taken with dose calculations
for smaller dogs.
Renal effects
Crystalluria, hematuria and urinary tract obstruction
can occur as a result of concentration of sulfonamides
in renal tubules and acid pH. Ensure that animals receiving
sulfonamides are well hydrated.
Excessive salivation
Cats often foam at the mouth if given oral sulfonamide
drugs, particularly if enteric-coated tablets are broken.
Other effects
● Trimethoprim-sulfonamides have been reported to
cause idiosyncratic severe hepatic necrosis on rare
occasions.
● Aplastic anemia and thrombocytopenia may occur
but are rare.
● It has been postulated but not proven that trimethoprim-sulfonamides
are a risk factor for acute
pancreatitis.
● Sulfonamides at high doses (30 mg/kg twice daily)
can profoundly alter thyroid physiology. They cause
decreased iodinization of colloid and decreased concentrations
of thyroxine and thyronine. Clinically
relevant decreased thyroid function is apparent by 3
weeks of therapy and will return to normal within 3
weeks of therapy being discontinued.
FLUOROQUINOLONES
The fluoroquinolones are synthetic antibacterial agents
derived from the 4-quinolone molecule, which was first
synthesized in the early 1960s. Nalidixic acid, the first
quinolone marketed for clinical use, had limited effectiveness
because of poor absorption, narrow spectrum
of activity and toxicity. The first fluoroquinolone, norfloxacin,
developed in the early 1980s, had greater
absorption, better antibacterial activity and reduced
toxicity.
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