Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

ANTICOAGULANTS
– NSAIDs
– warfarin.
● Heparin may antagonize the effects of:
– corticosteroids
– insulin
– ACTH.
● Heparin may increase the plasma concentration of
diazepam.
● Heparin’s actions may be partially antagonized by
– antihistamines
– intravenous nitroglycerin
– propylene glycol
– digoxin
– tetracyclines.
● Heparin decreases TSH and levothyroxine
(thyroxine) concentrations, possibly as a result of
interference with the binding of these hormones to
proteins.
Low molecular weight heparins (LMWH)
EXAMPLES
Dalteparin (Fragmin®), enoxaparin (Lovenox®)
The LMWH or fractionated heparins represent an alternative
to unfractionated heparin. These agents are
similar in size to heparin but maintain a peptide sequence
that prevents the activation of factor X. They inhibit
thrombin IIa to a lesser degree and are frequently
expressed as anti-Xa:anti-IIa activity ratios. Because
they have less activity towards factor IIa, the PT will
not be prolonged significantly and monitoring is not
required. Instead, anti-Xa activity can be monitored.
LMWH has a higher bioavailability and longer half-life
than heparin in people, allowing q.12–24 h dosing.
LMWH have minimal antiplatelet effects in humans
compared to heparin. They do, however, exhibit fewer
although similar proaggregating effects in humans with
hypersensitive platelets. They are more expensive than
heparin but can be administered subcutaneously. Both
dalteparin and enoxaparin have been used in cats at
100 IU/kg SQ q.24–12 h and 1.0–1.5 mg/kg SQ q.24–
12 h respectively. Efficacy can be monitored by determination
of anti-Xa:anti-IIA ratios. The ratios for
dalteparin and enoxaparin are 2:1 and 3:1 respectively.
As with heparin, the most common side effect is
bleeding.
One study reported the pharmacokinetics of dalteparin
in normal cats. A dose of 100 IU/kg SQ q.24 h for
5 d achieved an anti-Xa activity in the human therapeutic
range by 4 h after the dose was given and fell below
the human therapeutic range by 4–8 h. Another study
reported the effects of enoxaparin at 1 mg/kg SQ q.12 h
and dalteparin at 100 IU/kg SQ q.12 h. Peak anti-Xa
activity occurred by 4 h and returned to baseline by 8 h.
However, peak anti-Xa activity was not within the
human therapeutic range. Together, these studies suggest
that a dosing interval of 8 h may be optimum. However,
the correlation between thrombus prevention and therapeutic
range of anti-Xa activity is not strong. Thus to
better evaluate these agents in cats at risk for aorticothromboembolism
(ATE), anti-Xa effects would need to
be evaluated in this patient population and ultimately a
prospective clinical trial would be required. One retrospective
study failed to demonstrate a significant reduction
in recurrence rate or improved survival in cats at
risk for ATE receiving warfarin or dalteparin.
Warfarin
Clinical applications
Warfarin is used prophylactically to prevent thromboembolism
in cats with hypertrophic and unclassified
cardiomyopathy.
Mechanism of action
Warfarin interferes with the cyclic interconversion of
vitamin K and vitamin K epoxide by inhibiting epoxide
reductase (Fig. 17.2), thus inhibiting the production of
vitamin K-dependent coagulation factors (II, VII, IX,
X). These factors require activation from precursor
coagulation proteins to activated coagulation proteins.
Activation occurs via γ-carboxylation by carboxylase
enzymes located in hepatocytes; vitamin K is an essential
cofactor for this reaction.
LIVER
Precursor
coagulation
proteins
Vitamin K
hydroquinone
A
B
Vitamin K
quinone
SOURCE
C
Activated
coagulation
proteins
(II, VII, IX, X)
Vitamin K
epoxide
Fig. 17.2 Metabolic pathway for vitamin K. A, reductase
reaction; B, linked g-carboxylation and epoxidation
reaction; C, epoxide reductase reaction.
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