Page 630 - Basic _ Clinical Pharmacology ( PDFDrive )

616 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

be changed to an alternative form of anticoagulation (eg, daily for their hypoprothrombinemic interaction are a stereoselective
injections of LMW heparin or one of the newer oral anticoagu- inhibition of oxidative metabolic transformation of S-warfarin
lants). Warfarin resistance is most commonly seen in patients with (the more potent isomer) and displacement of albumin-bound
advanced cancers, typically of gastrointestinal origin (Trousseau’s warfarin, increasing the free fraction. For this and other reasons,
syndrome). LMW heparin is superior to warfarin in preventing neither phenylbutazone nor sulfinpyrazone is in common use in
recurrent venous thromboembolism in patients with cancer. the United States. Metronidazole, fluconazole, and trimethoprim-
sulfamethoxazole also stereoselectively inhibit the metabolic
Drug Interactions transformation of S-warfarin, whereas amiodarone, disulfiram,
and cimetidine inhibit metabolism of both enantiomorphs of
The coumarin anticoagulants often interact with other drugs and warfarin (see Chapter 4). Aspirin, hepatic disease, and hyper-
with disease states. These interactions can be broadly divided into thyroidism augment warfarin’s effects—aspirin by its effect on
pharmacokinetic and pharmacodynamic effects (Table 34–2). platelet function and the latter two by increasing the turnover rate
Pharmacokinetic mechanisms for drug interaction with warfarin of clotting factors. The third-generation cephalosporins eliminate
mainly involve cytochrome P450 CYP2C9 enzyme induction, the bacteria in the intestinal tract that produce vitamin K and, like
enzyme inhibition, and reduced plasma protein binding. Phar- warfarin, also directly inhibit vitamin K epoxide reductase.
macodynamic mechanisms for interactions with warfarin are Barbiturates and rifampin cause a marked decrease of the
synergism (impaired hemostasis, reduced clotting factor synthesis, anticoagulant effect by induction of the hepatic enzymes that
as in hepatic disease), competitive antagonism (vitamin K), and transform racemic warfarin. Cholestyramine binds warfarin in the
an altered physiologic control loop for vitamin K (hereditary intestine and reduces its absorption and bioavailability.
resistance to oral anticoagulants). Pharmacodynamic reductions of anticoagulant effect occur
The most serious interactions with warfarin are those that with increased vitamin K intake (increased synthesis of clotting
increase the anticoagulant effect and the risk of bleeding. The factors), the diuretics chlorthalidone and spironolactone (clotting
most dangerous of these interactions are the pharmacokinetic factor concentration), hereditary resistance (mutation of vitamin
interactions with the mostly obsolete pyrazolones phenylbu- K reactivation cycle molecules), and hypothyroidism (decreased
tazone and sulfinpyrazone. These drugs not only augment the turnover rate of clotting factors).
hypoprothrombinemia but also inhibit platelet function and may Drugs with no significant effect on anticoagulant therapy
induce peptic ulcer disease (see Chapter 36). The mechanisms
include ethanol, phenothiazines, benzodiazepines, acetamino-
phen, opioids, indomethacin, and most antibiotics.
TABLE 34–2 Pharmacokinetic and
pharmacodynamic drug and body Reversal of Warfarin Action
interactions with oral anticoagulants.
Excessive anticoagulant effect and bleeding from warfarin can be
Increased Prothrombin Time Decreased Prothrombin Time reversed by stopping the drug and administering oral or parenteral
vitamin K (phytonadione), fresh-frozen plasma, prothrombin
Pharmacokinetic Pharmacokinetic 1
complex concentrates, and recombinant factor VIIa (rFVIIa). A
Amiodarone Barbiturates four-factor concentrate containing factors II, VII, IX, and X (Pro-
Cimetidine Cholestyramine thrombin Complex Concentrate, [Human]; Kcentra) (4F PCC)
Disulfiram Rifampin is available. The disappearance of excessive effect is not correlated
Fluconazole 1 with plasma warfarin concentrations but rather with reestablish-
ment of normal activity of the clotting factors. A modest excess of
Metronidazole 1 anticoagulant effect without bleeding may require no more than
Phenylbutazone 1 cessation of the drug. The warfarin effect can be rapidly reversed
Sulfinpyrazone 1 in the setting of severe bleeding with the administration of pro-
Trimethoprim-sulfamethoxazole thrombin complex or rFVIIa coupled with intravenous vitamin K.
It is important to note that due to the long half-life of warfarin, a
Pharmacodynamic Pharmacodynamic
single dose of vitamin K or rFVIIa may not be sufficient.
Drugs Drugs
Aspirin (high doses) Diuretics ORAL DIRECT FACTOR Xa
Cephalosporins, third-generation Vitamin K INHIBITORS
Heparin, argatroban, dabigatran,
rivaroxaban, apixaban
Oral Xa inhibitors, including rivaroxaban, apixaban, and edoxa-
Body factors Body factors ban represent a new class of oral anticoagulant drugs that require
Hepatic disease Hereditary resistance no monitoring. Along with oral direct thrombin inhibitors
Hyperthyroidism Hypothyroidism (discussed below) this new class of direct oral anticoagulant
(DOAC) drugs is having a major impact on antithrombotic
1 Stereoselectively inhibits the oxidative metabolism of the S-warfarin enantiomorph
of racemic warfarin. pharmacotherapy.