Differential Drug Dosing

Although individuals vary, men and women differ significantly in body size and composition, with women, in general, having a higher percentage of body fat and lower total mass. Recommended drug dosages for medications are currently calculated for the “average” 70-kilogram healthy male. With significant differences noted between men and women in regard to size and composition, the single-dosing approach leads to the potential for higher concentrations and more adverse effects occurring in women (Franconi et al. 2012).

Drug–Drug Interactions

Drug–drug interactions are an increasing focus of pharmacology and a major cause of morbidity. Perhaps the most common interaction for which the patient’s sex is a factor involves oral contraceptive pills (OCPs).

OCPs are the most commonly prescribed medication for women of reproductive age (Services 2013). These medications undergo both absorption and metabolism within the gastrointestinal tract via gastric CYP3A4, followed by hepatic metabolism through oxidation by hepatic CYP3A4 and hepatobiliary cycling. Studies researching drug metabolism of OCPs have generated mixed results with the metabolism of some drugs being inhibited, unaffected, or even enhanced (Schwartz 2003).

The combined use of anticonvulsants (e.g., phenytoin, primidone, and carbamezipine) or anti-tuberculars (e.g., rifampin) with OCPs increases drug clearance and leads to decreased OCP serum concentrations with decreased efficacy. Conversely, the coadministration of antifungals (e.g., ketoconazole, fluconazole, itraconazole, and griseofulvin) or warfarin with OCPs may lead to decreased OCP clearance and increased OCP concentrations. OCP concentrations are also increased in the presence of antibacterials such as penicillin, ampicillin, tetracyclines, and cephalosporins because of inhibited enterohepatic recirculation (Schwartz 2003).

OCPs may lead to alterations in the concentrations of coadministered drugs as well. In the presence of OCPs, benzodiazepines, clofibric acid, cyclosporine, phenytoin, rifampin, and warfarin demonstrate increased drug clearance, thus, lower serum concentrations and decreased efficacy. Conversely, OCPs lead to decreased drug clearance of imipramine, amitriptyline, caffeine, corticosteroids, selegiline, and theophylline and result in increased concentration as well as effect.

Placebo Effect

The placebo effect may play an important role in therapeutic management (Franconi 2013) and its effect may vary with sex. Studies on the efficacy of placebo have found women to be either less responsive (Franconi et al. 2007; Compton et al. 2003; Wilcox et al. 1992) or more responsive (Franconi et al. 2007; Pud et al. 2006; Saxon et al. 2001) than men. However, women report more side effects to medications than men with either active or inactive drugs, while men only reported adverse effects with the active pharmaceutical (Rickels 1965; Franconi et al. 2007).

Absorption

Pharmaceutical absorption may be somewhat slower in women than men, although this effect is not consistently reported (McGilveray 2011; Schwartz 2003). The absorption of medications is dependent on multiple variables; some of which are dependent on the drug’s characteristics, while others are due to the route of administration (Marazziti et al. 2013). Absorption depends on the pH differences between the lumen and the mucosal, surface area of the pharmaceutical, perfusion to the absorptive villi, available digestive enzymes within bile, and the integrity of the gastrointestinal epithelium.

Women tend to have higher gastric pH levels, leading to rapid absorption of basic medications (e.g., benzodiazepines and tricyclic antidepressants) and with subsequently higher peak concentrations (Hamilton 1996; Franconi and Campesi 2014; Grossman et al. 1963; Marazziti et al. 2013; Pollock 1997). Women have less active gastric enzymes in general, which may lead to higher drug concentrations. For example, women have lower concentrations of gastric alcohol dehydrogenase than men, which leads to higher alcohol concentrations even after equivalent weight-based dosing. Men and women differ in regard to the composition of bile acids, which may explain the differential absorption of several medications. Chenodeoxycholic acid, found in higher concentration in women when compared to men, inhibits CYP450 enzymes involved in the metabolism of aniline, benzo (a) pyrene, 7-ethoxy-coumarin, p-nitroanisole, aminopyrine, and testosterone (Kawalek 1979; Marazziti et al. 2013). Women also have slower gastric as well as intestinal transit times than men (Franconi and Campesi 2014; Frezza et al. 1990; Hamilton 1996; Marazziti et al. 2013; Rao et al. 1987). Many of these noted differences may be accounted for by progesterone and estrogen effects, as reflected by changes occurring in relation to the menstrual cycle as well as pregnancy (Franconi and Campesi 2014).

These effects are supported by a review of bioequivalence studies submitted to the FDA between 1977 and 1995. In these studies with equivalent per kilogram dosing, the maximum concentration (Cmax) of medication in women was higher than in men 87% of the time, while the area under the curve (AUC) for women was higher 71% of the time (Chen et al. 2000; Marazziti et al. 2013; McGilveray 2011).

Respiratory tract delivery of medications has also been found to be affected by sex differences. Limited studies have noted that both ribavirin and cyclosporine have decreased absorption via the inhaled route when administered to women. This may potentially lead to alterations in management of medical conditions treated in this manner such as asthma, chronic obstructive pulmonary disease, and pulmonary infections (Schwartz 2003).

Ethanol

Since antiquity, it has been known that women are more sensitive to the clinical effects of ethanol ingestion. These effects are in part due to a lower body mass leading to higher blood concentrations with equivalent doses (McGilveray 2011). Clinical evaluation of male and female subjects has found that the AUC after equivalent weight-based doses was 28% higher in women compared to men (Ammon et al. 1996; McGilveray 2011). Body mass is not the only factor; a study conducted in 2001 revealed that lower gastric alcohol dehydrogenase (ADH) activity plays a dominant role in the noted sex difference in alcohol metabolism (Baraona et al. 2001; McGilveray 2011). Other contributors to the observed sex difference include lean body mass and gastric emptying as well as hepatic oxidation, all of which are influenced by sex hormones, liver volume, ethnicity, and genetic polymorphisms of both ADH and aldehyde dehydrogenase (McGilveray 2011; Ramchandani et al. 2001).

Distribution

Distribution of a medication after absorption is best described by the volume of distribution, the theoretical body volume that would be occupied by the drug given the measured serum concentration. The volume of distribution for medications is dependent on several factors: body mass, body fat composition, local perfusion, and protein binding, all of which differ between men and women (Marazziti et al. 2013).

Women tend to have a lower body mass and lower blood volume when compared to men. Given that adult drug dosing is generally not weight based, the average woman when compared to the average man will have higher drug concentrations. The higher percentage of body fat found in women may lead to initially lower drug concentrations of lipid soluble compounds, but it places them at risk for bioaccumulation within fatty tissue, leading to prolonged half-lives of elimination. For example, women who receive propofol infusions have lower serum concentrations and wake up faster than men given the same weight-based dose (Ward et al. 2002). Elderly women are at an increased risk of accumulation and therefore higher elimination half-lives because of body fat percentage increases with age (Marazziti et al. 2013).

Plasma protein binding is important in the determination of drug effects. Non-protein-bound (“free”) drugs are responsible for clinical effects, whereas medications that are bound to protein cannot penetrate tissues or bind to receptor sites. Women have lower protein-binding capacity and, therefore, higher concentrations of free drug, which may contribute to their increased rate of adverse effects (Marazziti et al. 2013).

Metabolism

Medication metabolism involves many enzymatic processes. Sex differences are responsible for slower rates of both glucuronidation and hydrolyzation in women when compared to men. These slower rates result in higher concentrations of active substances in women, thus, the potential for greater clinical effects as well as the potential for more adverse effects (Marazziti et al. 2013).

Elimination

Drug elimination takes place for the most part via hepatic, renal, and pulmonary routes, with minor contributions through exocrine secretion into sweat, tears, and breast milk (Marazziti et al. 2013).

Hepatic clearance of medications depends on both blood flow as well as intrinsic hepatic enzyme activity. Women have lower hepatic blood flow; thus, they have less medication made available for elimination by the liver. As previously discussed, sex differences in hepatic enzymes also put women at risk of differential drug effects compared to men (Marazziti et al. 2013). Of particular concern is the role of hormones in the expression of P-glycoprotein. These proteins regulate the biliary excretion of drugs and have been found to be 2.4-fold lower in women when compared to men (Marazziti et al. 2013; Nicolas et al. 2009; Schuetz et al. 1995).

Renal clearance accounts for the majority of excretion of both the parent drug as well as metabolites. Women have lower rates of glomerular filtration (10% lower) (Anderson 2002) passive diffusion and active secretion and therefore lower elimination than men (Marazziti et al. 2013). Thus, adjustments for renal clearance may reduce the amount of adverse effects of drugs that are renally excreted.

Drug Transporters

Molecular drug transporters have been found to alter pharmacokinetics by influencing absorption, distribution, and excretion of pharmaceuticals. The most commonly recognized drug transporter is P-glycoprotein. This transporter is the gene product of human multidrug resistance gene 1. Studies looking at sex differences have found that women express one-third to one-half of the hepatic protein concentrations that men express (Meibohm et al. 2002; Schuetz et al. 1995). The implications of reduced expression affect several steps in medication metabolism. Low levels of P-glycoprotein have been found to affect absorption by leading to reduced gastrointestinal transit time, thus decreased intestinal wall metabolism via CYP3A4 and increased concentration and effect. Decreased P-glycoprotein levels within the liver lead to increased CYP3A4 metabolism (Benet et al. 1999; Lown et al. 1997; Meibohm et al. 2002), as noted by the metabolism of both alfentanil and nifedipine, which are substrates of CYP3A4 and are found in lower concentration in women because of their more extensive metabolism (Franconi et al. 2007; Krecic-Shepard et al. 2000b; Lemmens et al. 1990).

Pharmacodynamics

Pharmacodynamics refers to the effects that a medication has on the individual and involves both the clinical effect as well as adverse effects. Unfortunately, there is limited data on sex-related effects on pharmacodynamics

Women are more likely to take medications, in particular hormonal contraceptives and replacement, but also psychotropics and opioids, when compared to men. Available data indicate that this may be due to sex-related differences in drug responses. Antipsychotics have been reported to lead to a more pronounced response in women (Marazziti et al. 2013). This effect may be due to hormonal influences leading to higher dopamine uptake in the striatum (Cohen et al. 1999; Franconi et al. 2007). In regard to antidepressants, women are more likely to respond to selective serotonin reuptake inhibitors (SSRI), while men are more likely to respond to tricyclic antidepressants (Brose 1993; Kornstein et al. 2000; Marazziti et al. 2013; Parker et al. 2003). This response has been attributed to women’s ability to increase tryptophan, while at the same time reducing cortisol in the setting of SSRI exposure (Bano et al. 2004; Marazziti et al. 2013).

Illicit drugs also appear to have sex-related differences. Women are more responsive to both cocaine and methylphenidate (Dafny and Yang 2006; Franconi et al. 2007; Kosten et al. 1996), but they are less responsive to amphetamines because of the release of lower amounts of dopamine from the striatum (Franconi et al. 2007; Munro et al, 2006). In addition, the subjective effects of cocaine and amphetamine are reduced by hormonal influences during the luteal phase of the menstrual cycle. Women are less susceptible to toxicity resulting from methamphetamine and have even demonstrated fewer electroencephalographic (EEG) changes when compared to men (Dluzen et al. 2003; Franconi et al. 2007; King et al. 2000).

It is clear that women have a higher rate and more severe adverse drug reactions (Baggio et al. 2013; Franconi and Campesi 2014; Franconi et al. 2012; Patel et al. 2007; Pirmohamed et al. 2004), but whether these are primarily pharmacokinetic or pharmacodynamic effects or a combination is not yet clear.

Site of Action Effects

Although limited data are available, some site of action effects that appeared to be enhanced in women include

Adverse Effects

All of the previously described pharmacodynamic changes help explain the higher risk (50%–70%) of adverse effects experienced by women (Spoletini et al. 2012). Adverse reactions commonly experienced by women include rashes, immune reactions, and drug-induced liver injury (Anderson 2008).

General Concepts

Although men and women attempt suicide at similar rates (Crosby et al. 2011b), men are more likely to complete suicide by more immediate and violent methods (Crosby et al. 2011a; Henderson et al. 2005), while women are significantly more likely to use medication overdose as their method of suicide (Henderson et al. 2005). There is little comprehensive literature on sex differences in acute overdoses; however, some patterns are evident in overdoses of acetaminophen and opioids.

Acetaminophen

Acetaminophen-induced liver failure and liver injury are more common in men after overdose, and men have a longer duration of hospital stay. The cause of this inequity may be that men ingest larger doses of acetaminophen and present later to health care (Zyoud et al. 2010), although animal data suggests that hepatic glutathione handling may be a contributing factor (Dai et al. 2006; Masubuchi et al. 2011).

Opioids

In the past two decades, opioid use, abuse, and dependence have increased significantly with several interesting sex differences emerging. While the rate of substance abuse disorders is higher in men for most drugs, the rate of opioid abuse is roughly equivalent among men and women (Parsells Kelly et al. 2008). Several factors may contribute to this: women are more likely than men to be prescribed opioid pain medication (Parsells Kelly et al. 2008), women more commonly treat negative affective and somatic complaints with opioids (McHugh et al. 2013), and women are more likely to have depression (McHugh et al. 2013). In regard to accidental deaths from prescription opioids in the United States, deaths are 1.5 times more common in men (McHugh et al. 2013).

Intravenous Lipid Emulsion

Intravenous lipid emulsion is being used in the treatment of severe toxicity of lipid-soluble medications. Its use is currently standard therapy for local anesthetic toxicity, but animal data suggest that it may also be effective for other lipid-soluble medications, such as propranolol and verapamil.

Data are limited regarding sex differences in the use of intravenous lipid emulsion therapy. Animal research shows differences in lipid metabolism. When rats received a bolus of 0.2 g/kg of 10% fat emulsion, females have faster clearance rates when compared to males, likely because of greater activity of postheparin lipoprotein lipase. Increases in females’ metabolism may lead to potentially faster rebound of pharmaceutical concentrations because of dissociation of the agent from the lipid or might lead to lower concentrations because of enhanced liver delivery (Jesmok et al. 1981).

HIV

Infection with the human immunodeficiency virus is a unique situation in which there appear to be significant sex-related differences. Women are more vulnerable to infections than males because of higher surface area and trauma during intercourse (Floridia et al. 2008). Once infected, hormones are influential, with estrogen inhibiting the action of tumor necrosis factors responsible for viral replication, leading to lower viral loads (Athreya et al. 1993; Floridia et al. 2008).

In HIV, drug dosing is currently administered in standard doses rather than weight based. Given the previously discussed sex differences, women are at increased risk of adverse effects including rashes, lipodystrophic changes, hepatoxicity, and dyslipidemias (Bonfanti et al. 2003; Clark 2005; Currier et al. 2000; Floridia et al. 2008; Mazhude et al. 2002; Pacifici et al. 1996; Pernerstorfer-Schoen et al. 2001). Sex differences in the expression of cellular kinases leads to the variable effects of nucleoside reverse transcriptase inhibitors (NRTIs). These differences may lead to an increased frequency of lactic acidosis, an adverse effect more commonly encountered in obese women (Floridia et al. 2008; Moyle et al. 2002). Protease inhibitors (PI) including saquinavir and ritonavir have lower clearances and increased concentrations in women when compared to men (Floridia et al. 2008; Pai et al. 2004). Women exposed to evirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), or the other NNRTIs are at higher risk of adverse effects such as rash and hepatotoxicity when compared to men (Floridia et al. 2008; Sanne et al. 2005; van Leth et al. 2005).

Another unique situation for women affected with HIV is the management of their disease in the setting of pregnancy. Drugs that should be avoided include efavirenz due to the risk of birth defects, stavudine and didanosine due to lactic acidosis, as well as tenofovir due to effects on developing bone (Clumeck et al. 2008; Floridia et al. 2008).

Treatment may also increase the risk of premature delivery, with studies both in Europe and the United States finding a rate of premature delivery of 25% (Cotter et al. 2006; Floridia et al. 2008; Ravizza et al. 2007; Schulte et al. 2007; Townsend et al. 2007). Antiretrovirals also place the mother as well as the pregnancy at increased risk of commonly encountered complications such as fatty liver, diabetes, cholestasis, and preeclampsia (Floridia et al. 2008).

Pregnancy has also been shown to alter the pharmacokinetics of antiretrovirals. Both PI and NNRTI affect the CYP450 system. The use of ritonavir leads to decreased levels of nevirapine, indanavir, saquinavir, and nelfinavir likely the result of enhanced CYP3A4 activity in pregnancy (Floridia et al. 2008).