During pregnancy the distribution volume changes due to an expansion of total body water and an increase in renal plasma flow and glomerular filtration. Its clinical relevance varies as organ blood flow is redistributed, drug-binding proteins change as well as circulating sex-hormones. For some drugs such as lamotrigine, an anti-epileptic drug, repeated adaptations in dosing are required during pregnancy, for others such as carbamazepine no change in dosing is needed [7, 12, 13, 28].

Use of oral contraceptives can affect the pharmacokinetics of many drugs, with for instance a higher clearance for benzodiazepines, phenytoin, and cyclosporine and a lower clearance for other drugs such as corticosteroids, amitriptyline and caffeine. Both estrogens and progestins undergo intestinal absorption and hepatic metabolism during enterohepatic recycling [14].

Hormonal changes during the menstrual cycle usually have limited effect on the pharmacokinetics of drugs. An exception is for drugs which induce QT prolongation (Table 14.2). This especially accounts for the ovulatory phase of the menstrual cycle. Whether this is due to pharmacokinetic or pharmacodynamic hormone-induced changes is unclear [15].

Concerning other drugs, such as corticosteroids, women are more sensitive to cortisol suppression than men which may lead to an enhanced sensitivity during treatment with corticosteroids. There are several other hormonal systems showing differences between men and women, for example the renin angiotensin system (RAS). Estrogens increase the availability of angiotensinogen and plasma levels of angiotensin II, but decrease renin and ACE activities and the expression of angiotensin receptor 1, whereas androgens upregulate the RAS system [8]. There are also indications that women have a greater cardiac-specific sympathetic activation than men [29], whereas they are less responsive to sympathetic vasoconstrictor activity [30]. This may be due to an increase in β2-adrenoreceptor sensitivity [31], and a higher β2-adrenoreceptor density in lymphocytes [32]. Estrogens and progesterone inhibit the cardiac expression of β1-adrenoceptors and reduce β-adrenergic-mediated stimulation exerting a cardio-protective effect. Thus, gender-specific differences in the pharmacodynamics of β- blockers might be expected [33, 34]. However, meta-analyses of the big clinical trials have not shown sex-differences in outcomes [35].

Most pharmacotherapeutic studies include both men and women, although in many therapeutic areas relevant sex analyses are not performed and presented. For example Weinberg et al. found that of 150 published randomized controlled trials (RCTs) on treatment for depression, 15% did not report the number of women included in the study and 50% did not analyze outcomes by gender [36]. This is also true for many studies of cardiovascular treatment in the areas of ischemic heart disease, dyslipidemia, hypertension, heart failure and atrial fibrillation. Sex-distribution is often skewed as upper age limits exclude more women than men. Thus, there is still much to learn about sex-differences in pharmacodynamics. The Food and Drug Administration (FDA) and National Institutes of Health (NIH) as well as the Canadian Institutes of Health Research (CIHR) have recently released recommendations for improvement [37].

An Adverse Drug Reaction (ADR) is defined as all undesired effects of a drug in general, women report more ADRs than men and the causes of this are still debated [16, 17]. One explanation is that doses are not weight-adjusted resulting in more women than men being treated with too high doses. Another reason might be that women seek more health care and use more medications. According to Swedish data 70% of all Swedish women, compared to 59% of all men, were dispensed at least one prescription during a year [2]. The risk of experience an ADR increases with the number of medications used. Also, the risk of interactions and a higher risk of an ADR increase with number of medications, which could be another cause for more ADRs in women than men.

Most of reported ADRs are probably dose-dependent and can be explained by the mode of action of drugs, but differences in anatomy, pathophysiology, symptoms, sex-hormones and pharmacogenetics may also play a role.

Some examples of more frequent occurring ADRs in women are the following:

Patient compliance depends on many factors: perceived seriousness of the treated condition, financial costs, adverse events or perceived risk of adverse events, age of the patient, length of treatment, goal of treatment (prevention, curative, symptomatic), and socioeconomic factors such as age and sex. Studies show varying results of compliance to pharmacological treatment depending on geographic/cultural setting and the type of treatment that was studied. It is debated whether there is a systematic difference in compliance in women compared to men: some studies show higher adherence in men, while other show better adherence in women [21]. In a review of 51 studies covering 19 different disease categories, 771 individual factor items were identified related to non-adherence to chronic therapies of which most were determinants of implementation, and only 47 were related to persistence with medication [54]. Factors with an unambiguous effect on adherence were further grouped into 8 clusters of socio-economic-related factors, 6 of health care team and system related factors, 6 of condition related factors, 6 of therapy related factors, and 14 of patient related factors. The lack of standardized definitions and poor measurement methods however have resulted in many inconsistencies [54]. Despite, some studies show that patient-related factors such as older age, female gender, higher income, and higher education have positive, if rather small, effect on adherence to therapy [55]. Medication non-adherence is therefore affected by multiple determinants. The prediction of non-adherence in the individual patients is difficult however and suitable measurement and multifaceted interventions may be the most effective answer towards unsatisfactory adherence. The limited number of publications assessing determinants of persistence with medication, and lack of those providing determinants of adherence to short-term treatment, are areas where future research is needed. In general, a well-informed motivated patient who has been involved in the decision of treatment which is also affordable are key-factors that increase drug compliance.

The need of medication during pregnancy is rather common. Pregnant women suffer chronic diseases as well as acute disease and pregnancy complications may require treatment. There are several concerns with drug treatment during pregnancy, related to the unborn child such as the risk of a teratogenic effect of the drug, exposure of the fetus to the drug and withdrawal syndromes in the fetus after delivery. There are also concerns about treatment of pregnant women in relation to their increased plasma volume, higher renal clearance and liver enzyme activity. While there is a wish of keeping the fetus’ exposure of the drug as low as possible the pharmacokinetic changes due to pregnancy might also require increased doses to maintain the desired effect in the pregnant woman. To avoid over- or under-treatment, it is important to reconsider appropriate dosing during pregnancy as this may change throughout pregnancy and post-partum [13, 14, 28].