Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS
Formulations and dose rates
There is a large interpatient variation in dose response to warfarin. A
20-fold variability in dose response has been reported in humans, and
veterinarians using warfarin clinically have observed signifi cant variability
in cats. Thus careful patient monitoring is essential and initial
hospitalization while the dose is being stabilized is recommended.
One-stage prothrombin time is the most common coagulation test
used to monitor warfarin therapy. Time of drug administration and
blood sampling should be standardized to optimize interpretation of
results. Veterinarians are advised to consult relevant references to
ensure they are familiar with appropriate protocols for monitoring
warfarin therapy.
Warfarin is available in tablet and injectable formulations. The initial
dose in cats is 0.5 mg q.24 h PO. If used in dogs to prevent thromboembolism,
an initial dose of 0.1–0.2 mg/kg PO has been
recommended.
Pharmacokinetics
Pharmacokinetic data for warfarin in cats have not been
determined. In humans it is rapidly and completely
absorbed after oral administration. It is highly protein
bound (approximately 99% in humans) but there are
wide species variations in the degree of protein binding
– for example, it is less protein bound in horses than in
rats, sheep and swine. Comparative data are lacking for
companion animal species.
Warfarin is predominantly metabolized in the liver to
inactive metabolites that are excreted in urine and bile.
Metabolites excreted in bile undergo enterohepatic recycling
and are eventually eliminated in urine. The plasma
half-life may be several hours to several days, depending
on the patient and possibly on the species.
Adverse effects
Dose-related hemorrhage can be a serious
complication.
Known drug interactions
Numerous drugs interact with warfarin and may affect
the patient’s response to the drug.
● In humans potentiated anticoagulant effects may
occur with:
– anabolic steroids
– several antimicrobial drugs (chloramphenicol,
erythromycin, metronidazole, tetracycline,
trimethoprim/sulfamethoxazole)
– several antifungal drugs (fluconazole,
ketoconazole, miconazole)
– antiulcer drugs (cimetidine and omeprazole)
– thyroid medication (levothyroxine (thyroxine),
propylthiouracil)
– amiodarone
– danazol
– NSAIDs
– quinidine.
● In humans decreased anticoagulant effects may
occur with:
– barbiturates
– carbamazepine
– corticosteroids
– griseofulvin
– estrogen-containing products
– rifampicin (rifampin)
– spironolactone
– sucralfate
– vitamin K
– mercaptopurine.
ANTIPLATELET DRUGS
EXAMPLES
Aspirin, thienopyridines (clopidogrel (Plavix®), ticlopidine
(Ticlid®))
ASPIRIN
See Chapter 13.
THIENOPYRIDINES
These agents induce specific irreversible platelet membrane
ADP receptor antagonism. They are direct antiplatelet
drugs and inhibit primary and secondary platelet
aggregation in response to many agonists and thus
prolong mucosal bleeding times. Antiplatelet effects are
greater than those with aspirin. The ADP-induced
conformational change of glycoprotein IIb/IIIa complex
is also inhibited which reduces binding of fibrinogen
and von Willebrand factor. Platelet release action is
also impaired, decreasing the release of proaggregation
and vasoconstrictive agents (e.g. serotonin, ADP,
thromboxane).
Clopidogrel
Clopidogrel is a second-generation agent with increased
potency relative to ticlopidine. A short-term pharmacodynamic
study in normal cats reported that clopidogrel
caused inhibition of platelet aggregation to ADP and
serotonin by >90% and a 3.9-fold increase in mucosal
bleeding time at 18.75, 37.5 and 75 mg/cat PO q.24 h.
Maximum effects were present by 3 d and were lost 7 d
following discontinuation of drug administration. No
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