DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 30–2
Frequencies of CYP2C9 Genotypes and VKORC1 Haplotypes in Different Populations and Their Effect on Warfarin
Dose Requirements
863
DOSE REDUCTION
GENOTYPE/
FREQUENCY (%)
COMPARED WITH
HAPLOTYPE CAUCASIANS AFRICAN AMERICANS ASIANS WILD-TYPE (%)
CYP2C9
*1/*1 70 90 95 —
*1/*2 17 2 0 22
*1/*3 9 3 4 34
*2/*2 2 0 0 43
*2/*3 1 0 0 53
*3/*3 0 0 1 76
VKORC1
Non-A/Non-A 37 82 7 —
Non-A/A 45 12 30 26
A/A 18 6 63 50
Source: Ghimire and Stein, 2009.
currently known genetic factors on warfarin dose requirements.
However, it is not clear whether genotyping patients and modifying
warfarin therapy accordingly will improve the quality of anticoagulation
as determined by such clinically important outcomes as time
to therapeutic INR, time spent within the target INR range, and rates
of serious bleeding. Large randomized controlled trials comparing
genotype-based therapy with standard care are under way to define
the clinical impact of incorporating genetic information into clinical
practice.
Drug and Other Interactions. The list of drugs and other
factors that may affect the action of oral anticoagulants is
prodigious and expanding (Hirsh et al., 2003). Any substance
or condition is potentially dangerous if it alters:
• The uptake or metabolism of the oral anticoagulant
or vitamin K
• The synthesis, function, or clearance of any factor
or cell involved in hemostasis or fibrinolysis
• The integrity of any epithelial surface
Patients must be educated to report the addition or deletion
of any medication, including nonprescription drugs
and food supplements.
Some of the more commonly described factors
that cause a decreased effect of oral anticoagulants
include:
• Reduced absorption of drug caused by binding to
cholestyramine in the GI tract
• Increased volume of distribution and a short t 1/2
secondary
to hypoproteinemia, as in nephrotic syndrome
• Increased metabolic clearance of drug secondary to
induction of hepatic enzymes, especially CYP2C9, by
barbiturates, carbamazepine, or rifampin
• Ingestion of large amounts of vitamin K-rich foods
or supplements
• Increased levels of coagulation factors during
pregnancy
The PT can be shortened in any of these cases.
Frequently cited interactions that enhance the risk of hemorrhage
in patients taking oral anticoagulants include decreased metabolism
due to CYP2C9 inhibition by amiodarone, azole antifungals,
cimetidine, clopidogrel, cotrimoxazole, disulfiram, fluoxetine, isoniazid,
metronidazole, sulfinpyrazone, tolcapone, or zafirlukast, and
displacement from protein binding sites caused by loop diuretics or
valproate. Relative deficiency of vitamin K may result from inadequate
diet (e.g., postoperative patients on parenteral fluids), especially
when coupled with the elimination of intestinal flora by
antimicrobial agents. Gut bacteria synthesize vitamin K and are an
important source of this vitamin. Consequently, antibiotics can cause
excessive PT prolongation in patients adequately controlled on warfarin.
In addition to an effect on reducing intestinal flora,
cephalosporins containing heterocyclic side chains also inhibit steps
in the vitamin K cycle. Low concentrations of coagulation factors
may result from impaired hepatic function, congestive heart failure,
or hypermetabolic states, such as hyperthyroidism; generally, these
conditions increase the prolongation of the PT. Serious interactions
that do not alter the PT include inhibition of platelet function by
agents such as aspirin and gastritis or frank ulceration induced by
anti-inflammatory drugs. Agents may have more than one effect;
e.g., clofibrate increases the rate of turnover of coagulation factors and