Ethnicity and adverse drug reactions

It is a matter of debate whether ethnicity is an important contributor to the outcome of drug treatment. Research evidence is limited in quantity and variable in quality. Too often patients' ethnicity is classified by using poorly defined criteria or an inadequate scientific basis. Indeed, both skin colour and self identification of ethnic origin seem to be poorly correlated with molecular genetics, and most genetic variability is found within, rather than among, continental populations. In addition, ethnic differences in drug response might originate from cultural or environmental factors.

In a recent meta-analysis McDowell and colleagues systematically reviewed the literature and summarised consistent findings about ethnicity and adverse drug reactions to cardiovascular drugs. They found, among other interesting results, a threefold higher risk of angioedema in black compared to non-black patients when taking angiotensin converting enzyme inhibitors as well as a doubled risk of intracranial bleeding from thrombolytic therapy.

A simple message to doctors in clinical practice must be an increased awareness of these adverse drug reactions in black patients (although with the caution that ethnicity was inconsistently defined in different studies). This might contribute to more accurate risk assessment in individual cases.

The reported differences in risk of adverse drug reaction would probably not be enough to justify offering other forms of treatment or information to different ethnic groups. Perhaps the greatest impact of this study will be to direct future research on the underlying mechanisms and pharmacogenetics of these specific adverse reactions. Population based differences in drug response are an adequate basis for extensive molecular comparisons, as exemplified in earlier studies.

There is a growing body of evidence from detailed pharmacogenetic studies that various populations may differ significantly in the distribution of allelic variants of important enzymes that determine drug disposition or variants of drug receptors.  Such information about individual genotype could lead to dose optimisation, thus avoiding concentration dependent toxicity caused by drugs such as oral anticoagulants or antiarrhythmic drugs.

Finding genetic markers for severe adverse drug reactions would help to identify patients at high risk before the start of specific treatment. Such findings would also serve as valuable support in establishing causality in complex cases where patients have taken more than one suspect drug.

Some challenging findings on genetic markers of idiosyncratic drug toxicity have been reported recently. Two years ago, a striking association was described in a Han Chinese population between the human leukocyte antigen HLA-B^*1502 and induction of Stevens-Johnson syndrome (a severe skin reaction) by the anticonvulsant carbamazepine.

Every patient in this study with the syndrome carried the B^*1502 allele, compared with less than 5% of those who tolerated carbamazepine.  In a smaller follow-up study from Europe, where the allele frequency of HLA-B^*1502 is significantly lower, it became clear that only a minority of patients with Stevens-Johnson syndrome induced by carbamazepine carried that particular haplotype, and interestingly enough, these four patients were of Asian descent. These data might imply that East Asians testing negative for HLA-B^*1502 have almost no risk of Stevens-Johnson syndrome from carbamazepine, whereas the same is not true in Europe—where it might be more relevant to test for other genetic risk markers, unknown at this stage.

An analogous situation concerns a relatively frequent general hypersensitivity reaction to the HIV drug abacavir, for which the described risk allele, HLA-B^*5701, represents a highly specific and more sensitive marker in white people than in black people.

The discovery of unique markers of adverse drug reactions will require validation in different populations before such evidence can be applied widely to practice. Even deeper knowledge about the mechanisms involved in severe reactions should not only lead to more qualified—and more widely applicable—predictions of which individuals are at increased risk, but also to development of safer drugs.

Even with improved methods to predict an individual's risk of specific adverse drug reactions, the overall clinical value of patient screening will depend on the frequency and severity of adverse reactions and on other means to estimate and possibly avoid drug toxicity in individual patients. "Personalised" drug treatment will continue, therefore, to rely on good clinical judgment. The meta-analysis by McDowell and colleagues is one more important piece of information to consider in the clinical assessment of the benefits and risks of specific cardiovascular drugs.

Web: Source

Back to top

Gynaecological infection

A randomised controlled trial was set up to ascertain whether a clinically important difference exists in the incidence of gynaecological infection between surgical management and expectant or medical management of miscarriage.

This was carried out in the early pregnancy assessment units of seven hospitals in the United Kingdom in women of less than 13 weeks' gestation, with a diagnosis of early foetal demise or incomplete miscarriage.

Expectant management with no specific intervention was compared with  medical management; a vaginal dose of misoprostol preceded, for women with early foetal demise, by oral mifepristone 24-48 hours earlier and surgical management (surgical evacuation).

The main outcome measures were confirmed gynaecological infection at 14 days and eight weeks.  1200 women were recruited. No differences were found in the incidence of confirmed infection within 14 days between the expectant group (3%) and the surgical group (3%) or between the medical group (2%) and the surgical group.

Compared with the surgical group, the number of unplanned hospital admissions was significantly higher in both the expectant group and the medical group. Similarly, when compared with the surgical group, the number of women who had an unplanned surgical curettage was significantly higher in the expectant group  and the medical group .

The authors concluded that the incidence of gynaecological infection after surgical, expectant, and medical management of first trimester miscarriage is low (2-3%), and no evidence exists of a difference by the method of management.

However, significantly more unplanned admissions and unplanned surgical curettage occurred after expectant management and medical management than after surgical management.

Web: Source

Back to top