**4.2. Heparin**

carriers of CYP2C9 poor metaboliser alleles experience a rate of major bleeding that is 3.68-

The frequency of CYP2C9 alleles is ethnically related [82, 86]. Approximately 20% of the Caucasian population carries one of the loss-of-function CYP2C9 alleles, and it is estimated that 1% of Caucasian carry two such alleles [71]. The frequency of the CYP2C9\*2 allele re‐ portedly ranges from 8-13% in different Caucasian populations. CYP2C9\*2 is present in 4% of African-Americans and is rare among Japanese individuals [87, 88]. The frequency of CYP2C9\*3 is 6-10% among Caucasian populations and 3.8% in Japanese populations [88, 89]. This data suggests that a substantial fraction of the Caucasian patient population may carry at least one defective CYP2C9 allele. In this group, the usual prescription dosage of warfarin

Warfarin is commonly prescribed in combination with selective serotonin reuptake inhibi‐ tors (SSRIs), as depression often coexists with cardiovascular disease. Case reports suggest that some SSRIs can interact with warfarin to increase the likelihood of bleeding [90]. SSRIs cause adverse effects in isolation [91, 92] and can interact with other medications by inhibit‐ ing various isoenzymes of the CYP450 enzyme group [93, 94]. It has been shown that metro‐ nidazole and cimetadine increase the prothrombin time in patients on warfarin therapy. Chloramphenicol enhances warfarin's effect by inhibiting the action of the hepatic P450 sys‐ tem [71]. Some authors [95], [96] have warned that antidepressants with a known or predict‐ able interaction with warfarin, such as fluoxetine and fluvoxamine, should be avoided in

Drug-drug interaction is a main concern in adverse drug reactions. The primary complica‐ tion occurring with warfarin treatment is bleeding. SSRIs may increase the risk of bleeding during warfarin therapy by hindering platelet aggregation through depletion of platelet se‐ rotonin levels [97-99]. Some SSRIs may also inhibit the oxidative metabolism of warfarin by

It has been shown that concurrent use of selective serotonin reuptake inhibitors and warfar‐ in increases the risk of hospitalisation due to haemorrhage [90, 98]. Drugs which affect sero‐ tonin may have a detrimental effect on platelet function, as drugs which inhibit the reuptake of serotonin may decrease platelet serotonin levels leading to a reduction in serotonin-medi‐ ated platelet aggregation. Potential drug interactions can involve modification in either of these mechanisms and may result in pharmacodynamic interference or enhancement of war‐

It was shown that major and moderate drug-drug interactions with warfarin are very common in inpatients and are associated with INR results outside the therapeutic range. The most common drugs involved in the increase of anticoagulation effect were enoxaparin, simvastatin, omeprazole and tramadol. Multivariate analysis showed that age, length of hospital stay, exposure to >/=4 major or moderate drug interactions, and refusal of pharmacist recommendations contribute significantly to the patient's INR re‐

fold higher than the rate seen in patients with the wild type genotype.

may lead to major or even life-threatening haemorrhage.

patients receiving warfarin because of the risk of adverse outcomes.

CYP 2C9 [95].

84 Drug Discovery

farin's action.

sult >5 [100].

One of the preventative treatments of thromboembolic disease in patients is a prescription of heparin. However, heparin induced thrombocytopenia (HIT) is one of the most serious adverse reactions. HIT consequences can include thromboembolic complications and death.

An association between the Fc receptor gene and the risk for HIT has been found in some studies and it was demonstrated that the homozygous 131Arg/Arg genotype occurred sig‐ nificantly more often in patients with HIT than in the healthy volunteers' group [102] [103] ; however, another group have found no association [104]. Results are very preliminary and more evidence are needed before it may be possible to genotype candidates for heparin ther‐ apy to identify those at risk for drug-induced thromboembolic complications.
