Sex & Gender in Acute Care Medicine

1. Sex & Gender in Acute Care Medicine Chapter 5: Sex, Drugs, and Toxicology

2. Chapter 5: Sex, Drugs, and Toxicology Annette Lopez Robert G. Hendrickson

3. Case Study • A 30-year-old female presented via EMS after being involved in a single-vehicle crash • She was found by police, restrained, resting her head on the steering wheel with her car in a ditch • When awokened, she appeared to be in a dreamlike state • On arrival to the ED, she had normal vital signs

4. Case Study • Patient was well-appearing but difficult to arouse • Exam revealed no signs of trauma • On arousal, patient had no recollection of the events leading to the collision • She recalled waking up, getting ready, and being on her way to work

5. Case Study • Patient denied any drug or alcohol use the previous night • She was found to have a negative blood alcohol concentration and negative urine drug test • Prescription drug history was significant for use of zolpidem 10mg at bedtime

6. Case Study • In January 2013, the FDA notified the public of concerns for next morning impairment after use of zolpidem • The agency was particularly concerned about slower elimination of the drug in women compared to men • This notice was followed in May 2013 by label changes to zolpidem dosing • New label dosing reduced the starting dose of the immediate-release formulation from 10mg to 5mg

7. Introduction • Sex and gender influence the effects of pharmaceuticals on an individual, including: • drug dosing • rate of drug-drug interaction • the body’s ability to absorb, distribute, metabolize, and excrete medications • differences in time course and intensity of adverse effects

8. Introduction • Women account for the majority of acute overdose ingestions • They also have a higher rate of adverse effects • Sex is also responsible for the generation of special populations, pregnant and breastfeeding women, in which drugs have unique effects • Unique effects have also been noted for women when exposed to certain medications related to chronic conditions such as HIV and cancer

9. Introduction • Unfortunately, research on sex differences has only recently become a priority • The FDA issued the first guideline for the evaluation of sex differences in drug trials in 1993 • It allowed more women to be included in clinical trials, with further enforcements demanding equal participation in 1998

10. Introduction • In 2004, the FDA produced a draft guideline addressing pharmacokinetics in pregnancy • Reviews of participation after these guidelines revealed increasing involvement of women • Yet continued underrepresentation in early phases of clinical trials • Concerns of teratogenicity are likely responsible • However, this goes against the current FDA recommendation

11. A note on terminology • Sex and gender are commonly interchangeable terms • However, “sex” refers to the physiological differences between males and females that are most heavily influenced by hormones and anatomy

12. A note on terminology • “Gender” is a societally ascribed term that reflects environmental, cultural, and behavioral differences • In this chapter, we will use the term “sex differences” given that the available pharmacologic data reflects mostly hormonal rather than environmental or behavioral differences

13. Pharmacology • Sexual hormones can lead to direct and indirect effects on the pharmacology of drugs • Hormones can have direct effects on drug response • They can also lead to modifications in the intrinsic hormonal sequences

14. Differential Drug Dosing • Although individuals vary, men and women differ significantly in body size and composition • In general, women have a higher percentage of body fat and lower total mass • Recommended drug dosages are currently calculated for the “average” 70 kg male • Single-dosing approach leads to the potential for higher concentrations and more adverse affects in women

15. Drug-Drug Interactions • Drug-drug interactions are 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 medications for women of reproductive age

16. Drug-Drug Interactions • Studies researching drug metabolism of OCPs have generated mixed results with the metabolism of some drugs being inhibited, unaffected, or even enhanced • The combined use of anticonvulsants (e.g., carbamazepine) or anti-tuberculars with OCPs increases drug clearance and leads to decreased OCP serum concentrations with decreased efficacy

17. Drug-Drug Interactions • Conversely, coadministration of antifungals or warfarin with OCPs may lead to decreased OCP clearance and increased OCP concentrations • OCP concentrations are also increased with antibacterials such as penicillin, ampicillin, tetracyclines, and cephalosporins due to inhibited enterohepatic recirculation

18. Drug-Drug Interactions • OCPs may lead to alterations in the concentrations of coadministered drugs • In the presence of OCPs, benzodiazepines, clofibric acid, cyclosporin, phenytoin, rifampin, and warfarin demonstrate increased clearance, lower serum concentrations, and decreased efficacy

19. Drug-Drug Interactions • Conversely, OCPs lead to decreased drug clearance of: • Imipramine • Amitriptyline • Caffeine • Corticosteroids • Selegiline • Theophylline

20. Placebo Effect • May play an important role in therapeutic management and its effect may vary with sex • Studies on the efficacy of placebo have found women to be either less responsive or more responsive than men • Women report more side effects to medication than men with either active or inactive drugs • While men only report adverse effects with the active pharmaceutical

21. Pharmacokinetics - Absorption • Pharmaceutical absorption may be somewhat slower in women than in men, although this effect is not consistently reported • Absorption of medications depends on multiple variables, some of which are dependent on drug characteristics • Others are due to the route of administration

22. Absorption • Absorption depends on: • pH differences between the lumen the mucosa, • surface area of the pharmaceutical, • perfusion to the absorptive villi, • available digestive enzymes within bile, • and the integrity of the gastrointestinal epithelium

23. Absorption • Women tend to have higher gastric pH levels, leading to rapid absorption of basic medications (e.g., benzodiazepines) • Women have less active gastric enzymes, which may lead to higher drug concentrations • For example, lower concentrations of gastric alcohol dehydrogenase in women leads to higher alcohol concentrations even after equivalent weight-based dosing

24. Absorption • Men and women differ in regard to the composition of bile acids • This may explain differential absorption • Chenodeoxycholic acid, found in higher concentration in women than men, inhibits CYP450 enzymes involved in the metabolism of aniline, benzo(a)pyrene, 7-ethoxy-coumarin, p-nitroanisole, aminopyrine, and testosterone

25. Absorption • In a review of bioequivalence studies submitted to the FDA from 1977-1995, the maximum concentration (Cmax) of medication in women was higher than in men 87% of the time • The area under the curve (AUC) for women was higher 75% of the time • Respiratory tract delivery of medications has also been found to be affected by sex differences

26. Ethanol • Since antiquity, it has been known that women are more sensitive to the clinical effects of ethanol ingestion • Body mass is not the only factor • A 2001 study revealed that lower gastric alcohol dehydrogenase (ADH) activity plays a dominant role in the noted sex difference in alcohol metabolism

27. Ethanol • Other contributors to the observed sex difference include lean body mass, gastric emptying, and hepatic oxidation • All of which are influenced by sex hormones, liver volume, ethnicity, and genetic polymorphisms of both ADH and aldehyde dehydrogenase

28. 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 • Volume of distribution depends on many factors: • Body mass, body fat composition, local perfusion, and protein binding • All of which differ between men and women

29. Distribution • Women tend to have a lower body mass and blood volume compared to men • Given that adult drug dosing is generally not weight-based, the average women will have higher drug concentrations compared to the average man • The higher percentage of body fat found in women may lead to initially lower drug concentrations of lipid soluble compounds

30. Distribution • However, this places women 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

31. Distribution • Plasma protein binding is important in the determination of drug effects • Non-protein-bound (“free”) drugs are responsible for clinical effects • Drugs 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 adverse effects

32. Metabolism • Medication metabolism involves many enzymatic processes • Sex differences are responsible for slower rates of both glucuronidation and hydrolyzation in women 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 more adverse effects

33. CYP450 • The majority of hepatic metabolism occurs via the CYP450 system, comprised of more than 30 isoenzymes • It has been theorized that sex-related pharmacokinetic differences may be due to hormonal influences causing differential expression and altered activity of multiple isoforms

34. CYP System and Sex Effects

35. CYP450 • There is conflicting evidence for many of these agents • The data presented here are consensus data from various sources • CYP3A4 accounts for about 60% of all metabolic activities due to the CYP450 sytem • It also accounts for the most important sex-related differences noted in drug metabolism

36. CYP450 • This particular isozyme is influenced by sex as well as age • With 20-40% higher CYP3A4 activity in young women when compared to both men and elderly women • Thus young women will metabolize certain medications more quickly, leading to lower concentrations of the medication and less efficacy

37. CYP450 • Women have greater CYP2C19 activity than men, leading to faster metabolism and lower drug concentrations • Although this enzyme’s activity may fluctuate in the presence of other medications • Studies in both Sweden and the Netherlands found CYP2C19 activity to be 40% greater in men and 61% lower in women taking OCPs

38. CYP450 • The CYP2D6 isoform metabolizes many drugs • It is commonly implicated in drug-drug interactions • Men tend to have higher enzyme expression • Pregnancy increases the activity of CYP2D6 • Thus, it may be under the influence of sex steroids, although there has been no supporting data of their role in changing drug concentrations

39. Elimination • Drug elimination takes place for the most part via hepatic, renal, and pulmonary routes • Hepatic clearance of medications depends on both blood flow and intrinsic hepatic enzyme activity • Women have lower hepatic blood flow; thus, they have less medication made available for elimination by the liver

40. Elimination • Of particular concern is the role of hormones in expression of P glycoproteins • These proteins regulate biliary excretion of drugs • P glycoproteins have been found to be 2.4-fold lower in women when compared to men • Women also have lower rates of glomerular filtration • Adjustments for renal clearance may reduce the adverse effects of renally excreted drugs

41. Drug Transporters • Molecular drug transporters have been found to alter pharmacokinetics by influencing absorption, distribution, and excretion • The most commonly recognized drug transporter is p-glycoprotein • Studies looking at sex differences have found that women express 1/3 to 1/2 the hepatic protein concentrations that men express

42. Drug Transporters • Reduced expression affects several steps in medication metabolism • Low levels of p-glycoprotein affect absorption by leading to reduced gastrointestinal transit time • Thus decreased intestinal wall metabolism via CYP3A4 and increased concentration and effect • Decreased p-glycoprotein in the liver leads to increased CYP3A4 metabolism • As noted by the metabolsim of both alfentanil and nifedipine

43. Pharmacodynamics • Refers to the effects a medication has on the individual, including both the clinical effect and adverse effects • Unfortunately, there is limited data on sex-related effects on pharmacodynamics • Women are more likely to take medications when compared to men • Available data indicate that this may be due to sex-related differences in drug responses

44. Pharmacodynamics • Antipsychotics have been reported to create a more pronounced response in women • This effect may be due to hormonal influences leading to higher dopamine uptake in the striatum • Women are more likely to respond to selective serotonin reuptake inhibitors (SSRIs), while men are more likely to respond to tricyclic antidepressants

45. Pharmacodynamics • Illicit drugs also appear to have sex-related differences • Women are more responsive to both cocaine and methylphenidate, • but less responsive to amphetamines • In addition, the subjective effects of cocaine and amphetamine are reduced by hormonal influences during the luteal phase of the menstrual cycle

46. Pharmacodynamics • Women are less susceptible to toxicity from methamphetamine • Women have even demonstrated fewer EEG changes when compared to men • It is clear that women have a higher rate and more severe adverse drug reactions • Whether these are primarily pharmacokinetic or pharmacodynamic effects or a combination of both is not yet clear

47. Site of Action Effects • Although limited data are available, some site of action effects appear to be enhanced in women: • Hemorrhagic consequences with anticoagulation and thrombolytics • Diuretic-induced electrolyte abnormalities • Myopathy in the setting of statins • Cough from angiotensin converting enzyme (ACE) inhibitor therapy

48. QTc Effects • Prolongation of the QT interval has been shown to increase the risk of sudden tachydysrhythmias, specifically polymorphic ventricular tachycardia (torsades de pointes) • Women account for more than 70% of all cases of drug-induced polymorphic ventricular tachycardia • Multiple medications have been shown to prolong the QT interval

49. QTc Effects • QT interval length is directly proportional to the flow of potassium through potassium channels • Cellular production of potassium channels is enhanced by testosterone • When boys’ testosterone concentration increases at puberty, the QTc (rate corrected QT) shortens due to increased production of potassium channels

50. QTc Effects • Conversely, QTc gradually increases in women • QTc durations in men and women become similar as testosterone concentrations in men decrease with age • Decreased testosterone in women also enhances the effect of QT-prolonging drugs • For example, women may develop a proportionately longer increase in QT compared to men when given an identical per weight dose of a QT-prolonging medication