Pharmacokinetics describes what happens to a drug after it has been administered. This includes drug absorption, distribution and elimination or excretion [10, 11]. The goal of any therapeutic agent is to enhance efficacy and minimize toxicity [10, 11]. Therefore pharmacokinetics allows us to safely manage medications by predicting the concentrations in the body and maintaining appropriate therapeutic efficacy.

In order for a medication to reach its site of action, the medication needs to be absorbed. Medication absorption is affected by many different factors including route. Differences in drug route could play a role in the amount of drug that is allowed into the body and the length of time in which a drug takes to reach its desired target organ or receptor. The oral route is much slower compared to other routes such as intravenous or sublingual. For example, consider the use of nitroglycerin for a patient that is experiencing angina. At the first sign of chest pain sublingual nitroglycerin may be given to ensure continued and appropriate blood flow to the heart. By applying the medication under the tongue rather than digesting the tablet orally we allow for quicker response of nitric oxide release therefore faster onset of action and greater efficacy. Oral nitrate tablets have shown much slower time to effect.

Absorption times can be affected by other factors other than route. When comparing absorption rates, women have longer gastrointestinal transit times compared with men, approximately 91.7 h in women and 44.8 h in men and therefore bioavailability of a medication may be greater in women [12–14]. Women also appear to have less gastric acidity therefore absorption of certain medications may be altered. Due to the difference in acidity, there will be decrease absorption for weak acids and increase absorption for weak bases in women [15]. Additionally, women have a smaller body surface and less cardiac output compared to men which may decrease absorption of some medications as well [15]. Once a medication is absorbed, it needs to travel to its site of action. The concept of a medication getting to its site of action is volume of distribution. Factors that affect volume of distribution are protein binding, molecular size of medications, and whether a medication is lipophilic or hydrophilic. In general, no differences have been found between men and women in regards to protein binding [15]. However it has been shown that volume of distribution is decreased in women compare to men. This decrease is thought to be secondary to women having lower total body water, lower intra- and extracellular water, and lower total blood volume. Therefore there will be higher concentrations of water soluble medications in females and potentially an increase in a woman’s clinical response to a water soluble medication [15, 16]. An example of this is atenolol which has been shown to have better blood pressure lowering effects compared to men secondary to the lower volume of distribution [10]. Furthermore, women have a higher percentage of body fat in relationship to total body weight compared to men [17]. In general, body weight increases from young adulthood to the age of 60. After 60, the overall body size decreases and fat in women increases [18]. Therefore, lipid soluble medications, such as benzodiazepines, could distribute to more areas of the body and thereby increasing the effect of the medication in women [12, 16].

After a medication is distributed it is metabolized to allow it to exert its effect. The main site of metabolism is the liver via the cytochrome 450 systems; however other sites of metabolism include the lungs, kidneys, skin, and gastrointestinal tract [13]. There is conflicting information about gender differences in drug metabolism. Even though there is large variation in metabolism of medications, most gender related differences appear to be eliminated by controlling for height, weight, surface area, and body composition [13]. One study by Bebia et al. indicates that the CYP1A system showed decrease clearance of up to 10–20 % in women compared to men. However, another study showed no difference in clearance [5]. Given the conflicting findings, it is postulated that other environmental factors may explain the difference seen in this system. Factors such as diet, smoking, and alcohol use indeed seem to play a role. Furthermore, no consistent gender-related difference in clearance in regards to CYP2C pathway has been shown. The CYP2D6 system has been shown to manifest slower clearance in women compared to men and therefore it has been suggested that the dose of medications that are metabolized through this pathway may need to be reduced by 10–20 %. The CYP3A system was shown by Wolbold et al. to have 15–35 % faster clearance in women suggesting that medications metabolized by this enzyme such as verapamil, nifedipine, and amlodipine may need higher dosing [5, 13, 14, 18]. Table 20.3 summarizes these findings.

Once the medication has been used by the body, it needs to be removed. Excretion is final route by which drug metabolites are removed from the body and is primarily handled by the kidneys [13]. The primary technique by which excretion is measured is called clearance. Clearance is defined as a hypothetical volume of distribution of the unmetabolized drug which is cleared per unit of time (ml/min or ml/h) by any pathway of drug removal (renal, hepatic (or) other pathway of elimination) [19]. It has well been established that renal clearance decreases with age. Similarly, several drug trials have shown that women have lower clearance at all ages compared to men [13]. Werner and colleagues also demonstrated that women have less elimination of certain loop diuretics, torsemide specifically, thus leading to higher adverse reactions (ADRs) in women compared to men [20]. For example in a German Pharmacovigilance Project, 66 % of hospitalizations due to torasemide ADRs occurred in women [20]. It is thus critically important to consider women’s decreased renal clearance when prescribing medications that are primarily eliminated by the kidney, especially if a toxic metabolite is formed when the medication is metabolized.

Pharmacokinetic studies have shown metabolism of medications via the cytochrome P450 system are altered during pregnancy as summarized in Table 20.4 [21]. As pregnancy progresses, metabolism progressively decreases through the 1A2 pathway. In the third trimester 1A2 and 2C19 activity decreases, 60 and 50 % respectively. However 2A6 increases 54 %, 2A9 increases 20 %, 2D6 increase 50 %, and 3A4 increases 50–100 %. In addition renal metabolism increases 20–65 % in each trimester [21].

A review by Anderson and Carr in the late 1980s and early 1990s estimated that approximately 12 % of women had hypertension during pregnancy [21]. It is expected that this number has increased significantly and therefore the amount of medications used to treat hypertension has also increased. The primary medication used to treat hypertension is methyldopa due to its decreased risk on the fetus (pregnancy category B) [22]. Other treatments which are used less frequency are clonidine, hydralazine, beta blockers and calcium channel blockers [17]. Since atenolol, furosemide and methyldopa are greater than 90, 60–90 and 50 % renally eliminated respectively, we would anticipate that there would be less effect on blood pressure with higher renal clearance as the pregnancy progresses. Nevertheless given decreased fetal risk, methyldopa is favored for BP control during pregnancy. Furthermore, diltiazem and nifedipine are mainly metabolized by CYP 3A4 and metoprolol is mainly metabolized by 2D6, therefore these medications may have less effect of blood pressure during the third trimester since the 3A4 and 2D6 pathways have increased activity during the third trimester [21].

Genetic Polymorphism may modify drug response. In the cardiovascular field, this has been associated with the metabolism of beta blockers and calcium channel blockers and response to ACE inhibitors. Some cardiovascular phenotypes are associated with autosomal gene polymorphisms that have been shown to manifest gender differences in drug response [23]. Examples of these are shown in Table 20.5. Genes located in the X chromosome are also good candidates to account for some gender differences. Carrel and Willard among others have extensively studied how mutations in these genes or functionally related polymorphisms might be better compensated in women [24]. For example genes for Angiotensin Converting Enzyme −2 (ACE-2) and angiotensin II receptor (ATR2) are located in the X chromosome [25]. The AT2R has been shown to modulate left ventricular hypertrophy in women with HCM independently of the circulating RAS but this has not been shown in men. Studies have suggested that LV mass in women is in part regulated by number of specific alleles of the AT2R gene [26]. In Transgenic mice models a more severe cardiovascular phenotype was seen in male rather than female animals and this correlated to earlier development of and faster progression to heart failure [27]. Interestingly, a variety of factors and complex interactions ranging from diet, sex hormonal influences, removal of ovaries and administration of exogenous estrogen, or age, seem to change gene expression adding to the complexity of the pathways that lead to gender differences in drug responses [28].

Estrogens and progestins interacts with a large number of cardiovascular drugs possibly by inhibiting CYP enzymes or increasing drug glucuronidation [5]. Menstrual cycle, pregnancy, and menopause can modify this interaction due to variation of levels of estrogen and other hormones, alterations in total body water due to renal plasma flow variations and changes in glomerular filtration during these specific periods for women. For example, it has been reported that menstruation, pregnancy and, ovariectomy can modulate CYP2D6 activity [29]. The clinical relevance of these changes is not clear. Interactions with exogenous hormone therapy such as hormone replacement therapy (HRT) and oral contraceptives must also be taken into account. Estrogens seem to interfere with the synthesis of Angiotensinogen in the liver and also with the expression of Angiotensin I receptor (ATR-1) in the myocardium [30]. On the other hand estrogens appear to increase the expression of AT2R in the myocardium. In the cardiovascular system, progesterones appear to have a partially synergistic and/ or antagonistic relationship with estrogens [31]. In some animal models (ovariectomized rabbits), progesterone was seen to exert a direct inhibitory effect on the atheroprotective action of estrogen [31], while in other models (ischemic rats) progesterone has been shown to have cardioprotective effects but only in female ischemic rats. These findings suggest complex interactions with endogenous estrogen.

Gender differences in drug metabolism can in part be explained by the dismorphic expression of CYP450 and other liver-expressed genes (females predominantly express CYP3A4). This expression is in part regulated by GH (Growth Hormone) release by the pituitary gland which shows significant gender difference in its pattern of release [32]

Pharmacodynamics describes the principle of drug action and its resulting effect at its target site, i.e. receptor or membrane [10]. This concept is often used to examine overall maximum effect of a drug and/or the sensitivity of the target area to the drug concentration [11]. Current literature regarding differences of pharmacodynamics between men and women is limited. Most pharmacodynamic data deals primarily with the elderly. Despite the lack of pharmacodynamic studies in women we can hypothesize that there may be differences in drug response due to gender by evaluating adverse drug reports.

Currently, the Food and Drug Administration (FDA) holds a database in which patients and providers can voluntarily document adverse events. The reporting system is known as FAERS (FDA Adverse Event Reporting System) which allows the FDA to monitor medication and report post-marketing data to the public [33]. A study by Moore et al. examined adverse event data from FAERS between 1998 and 2005. In their analysis they found that more women had adverse events (55.5 %) compared to men (45.5 %) and the adverse effects were more serious in women [15]. When age was closely examined patients between 45 and 64 years old had 33.7 % of the events which accounted for 22.2 % of the total population. Individuals that were greater than or equal to 65 years old were found to have 33.6 % of the adverse events but only accounted for 12.6 % of the total population. Of the cardiovascular drugs that totaled 500, more adverse events in any year were reported in women. HMG-CoA reductase inhibitors (statins) were associated with the most issues. Cerivastatin, which was later withdrawn from the market, was found to have 1,573 events [34]. Furthermore, out of 10 medications that were withdrawn from market during 1997 and 2000, 8 were withdrawn secondary to greater adverse effects in women [15]. In general women have a 1.5- to 1.7-fold greater risk of developing an adverse drug reaction. The reasons for this increased risk are not entirely clear but include gender-related differences in pharmacokinetics already discussed, immunological and hormonal factors as well as differences in the use of medications by women compared with men, polypharmacy and increasing age.