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394 Part V: Therapeutic Principles Chapter 25: Antithrombotic Therapy 395

TABLE 25–1. Types and Function of Antithrombotic TABLE 25–2. Effect of Drugs on Warfarin Response
Agents POTENTIATE EFFECT
Anticoagulants—decrease fibrin formation by inhibiting α-Methyldopa Indomethacin
thrombin or thrombin formation
Agents Acetaminophen Isoniazid
Oral—warfarin and other vitamin K antagonists, dabigatran Acetohexamide Mefenamic acid
(direct thrombin inhibitor) and oral direct X inhibitors (rivarox- Allopurinol Methimazole
a
aban, apixaban, edoxaban) Androgenic and anabolic Methotrexate
Parenteral—heparin, low-molecular-weight heparins, steroids
fondaparinux, direct thrombin inhibitors (argatroban, desirudin,
bivalirudin) Antibiotics that disrupt Methylphenidate
Antiplatelet agents—inhibit platelet function intestinal flora (tetracyclines, Nalidixic acid
streptomycin, erythromycin,
Agents kanamycin, nalidixic acid, Nortriptyline
Aspirin, clopidogrel, prasugrel, dipyridamole, abciximab, eptifi- neomycin) Oxyphenbutazone
batide, tirofiban, vorapaxar
Fibrinolytic agents—plasminogen activators and accelerate clot Cephaloridine p-Aminosalicylic acid
lysis Chloral hydrate Paromomycin
Agents Chloramphenicol Phenylbutazone
Streptokinase, urokinase, alteplase, reteplase, tenecteplase Chlorpromazine Phenyramidol
Chlorpropamide Phenytoin
Cimetidine Propylthiouracil
PHARMACOLOGY Clofibrate Quinidine
The coumarins are competitive inhibitors of vitamin K. They inhibit Diazoxide Salicylate
γ-carboxylation reactions required for synthesis of several coagula-
tion proteins, including factors II, VII, IX, and X, as well as proteins C Disulfiram Sulfinpyrazone
and S, which are involved in inhibitory regulation of hemostasis. The Ethacrynic acid Sulfonamides
synthesis of these proteins requires a posttranslational modification of Glucagon Thyroid hormone
several glutamic acid residues, converting them to γ-carboxylated glu-
tamic acid (Gla), which is required for proper membrane interaction Guanethidine Tolbutamide
and biologic activity (Chap. 115). The carboxylation reaction requires DEPRESS EFFECT
3,4
reduced vitamin K, which is converted to vitamin K epoxide in the Antipyrine Glutethimide
reaction. Vitamin K epoxide subsequently undergoes reduction by an
enzyme that is inhibited by warfarin. Therefore, treatment with war- Azathioprine Griseofulvin
5–7
farin causes reduced γ-carboxylation, leading to synthesis of molecules Barbiturates Haloperidol
with impaired activity. 8–10 Carbamazepine Phenobarbital
Warfarin preparations consist of a racemic mixture of S and R
enantiomers in approximately equal proportion in an oral formula- Digitalis Prednisone
tion with high bioavailability. Warfarin is water soluble and rapidly Ethanol Rifampin
absorbed after oral administration, reaching a peak concentration Ethchlorvynol Vitamin K
after 60 to 90 minutes. An intravenous preparation is also available for
patients who cannot take oral medications or who have malabsorption.
It is tightly bound to plasma proteins with a half-life of 35 to 45 hours,
with only the free, nonbound form having biologic activity. Warfarin is hypometabolic states may also alter sensitivity. Hereditary resistance to
metabolized through the cytochrome P450 (CYP) system, the activity of warfarin has been described and related to specific mutations in vita-
12
which is influenced by environmental factors and also by genetic poly- min K epoxide reductase. Many drug interactions can influence the
morphisms that alter the structure of common enzymes. Other vitamin pharmacodynamics of warfarin by altering synthesis or clearance of
K antagonists have similar activities but exhibit differences in absorp- vitamin K–dependent coagulation factors or interfering with warfarin
tion and elimination. metabolism, and patients should be advised to consult their physician
Because warfarin is a vitamin K antagonist, its action is influenced or pharmacist about effects on anticoagulation when changing drug
11
by the vitamin K content of the diet. Naturally occurring vitamin K is therapy or starting new medications (Table 25–2). Other commonly
found in a variety of vegetables, and changes in diet can affect the vita- used drugs affecting hemostasis, such as aspirin, nonsteroidal antiin-
min K availability and warfarin effect. This may be seen particularly in flammatory agents, heparins, and other anticoagulants can add to the
11
patients receiving warfarin who are on strict weight-reduction diets or antihemostatic effects of warfarin and can lead to bleeding.
in those with little oral intake because of illness. Also, diarrhea can affect
vitamin K availability, as can administration of broad-spectrum anti-
biotics leading to marked warfarin sensitivity in hospitalized patients. ADMINISTRATION AND MONITORING
Ingestion of vitamin K in dietary supplements or vitamins also affects The anticoagulant effect of warfarin is the result of decreased levels of
sensitivity to warfarin. Liver disease can increase sensitivity to warfa- vitamin K–dependent coagulation factors, and their concentration rep-
rin because of impaired synthesis of coagulation factors, and hyper- or resents a balance of synthesis and metabolism. Warfarin administration

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