Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 10 ANTIPARASITIC DRUGS
Formulations and dose rates
• 2.2 mg/kg by careful IV injection, q.12 h for 2 d. Effi cacy is
improved if four injections are administered within 36 h
• Expected effi cacy is in the range of 50–100% reduction in adult
heartworm
• If adverse effects prevent completion of the four-dose program,
treatment should be repeated in full when the dog has
recovered and at least 2 weeks later. Retreated dogs will not
necessarily experience adverse effects again
Pharmacokinetics
Following IV administration of thiacetarsamide, the
plasma half-life of arsenic is 177 min, with a volume of
distribution of 2.2 L/kg and mean residence time of only
75 min. Some 50% and 85% of the administered dose
is eliminated within 24 h and 48 h respectively, principally
in the feces. Arsenic is widely distributed, with
significant binding to erythrocytes, and concentrations
are highest in liver and kidney, target organs of toxicity.
The active form of the drug is not clear but it does not
appear to be arsenic per se, as orally administered thiacetarsamide
providing equivalent blood arsenic concentrations
to IV drug is not effective. Efficacy against
macrofilariae appears to be more related to the duration
of exposure to a minimum effective drug concentration
rather than to short periods of high concentrations.
Efficacy is also related to the age of heartworms (infections
2 or 24 months of age are better controlled than
those between these ages) and their sex (female worms
are much more tolerant than males).
Adverse effects
● Around 15% of dogs can be expected to react
adversely. The most serious effects include pulmonary
thromboembolism, hepatotoxicity, nephrotoxicity
and perivascular inflammation and necrosis.
Common signs include:
– vomiting
– anorexia
– icterus
– lethargy
– fever.
● Thiacetarsamide is irritant if injected perivascularly
and will cause local tissue necrosis.
Contraindications and precautions
Thiacetarsamide should not be administered to dogs
with severe heartworm disease.
Special considerations
● To minimize the impact of pulmonary thromboembolism,
after treatment dogs should be rested.
● Microfilariae are not eliminated by thiacetarsamide
and appropriate treatment (commonly an ML)
should be instituted.
Melarsomine hydrochloride
[4-[(4,6-diamino-1,3,5-triazon-2-yl)amino] phenyldithioarsenite
of di(2-aminoethyl) dihydrochloride.
Clinical applications
Melarsomine is used as a Dirofilaria immitis macrofilaricide
in dogs. Use in cats has not been defined,
although the dog dosage regimen appears
inappropriate.
Melarsomine dihydrochloride contains 14.9% As 3+
and is believed to provide a greater degree of convenience,
efficacy and safety for macrofilarial control than
thiacetarsamide if used strictly as directed. However,
serious adverse reactions have been reported when
the drug is not used according to the manufacturer’s
strict guidelines in relation to clinical staging of the
patient. This may relate to the greater efficacy of
melarsomine in killing adult heartworms in comparison
with thiacetarsamide, resulting in increased risk of
thromboembolism.
Formulations and dose rates
2.5 mg/kg IM (into lumbar muscles), two doses on alternate sides
24 h apart. In dogs with advanced clinical signs of dirofi lariosis (class
3), an alternative regimen has been recommended, whereby a single
IM dose of 2.5 mg/kg (which is expected to kill around 50% of worms)
is followed, when the condition of the dog improves 1–2 months later,
by the standard protocol.
Pharmacokinetics
Following melarsomine injection into the lumbar epaxial
musculature of dogs, the drug is rapidly absorbed,
reaching maximum blood arsenic concentrations in
around 11 min. The terminal elimination half-life is
approximately 3 h, with a mean residence time of 7 h.
These parameters compare very favorably with those of
thiacetarsamide and demonstrate that parasite exposure
to arsenic will be significantly longer after treatment
with melarsomine.
Macrofilarial efficacy appears to be related to sustained
exposure to blood arsenic concentrations of at
least 0.1 mg/L. Melarsomine dosage regimens provide
such a pharmacokinetic profile, resulting in high and
reproducible efficacy. Indeed, 90% of male and 10%
of female worms are killed in response to a single
injection.
218