RxP International presents Gender and Psychiatric Drugs
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This powerpoint presentation is presented by RxP International to provide information for mental health and medical professionals pertaining to gender differences in pharmacokinetics, pharmacodynamics, disease prevalence, adverse drug reactions and theories about why women are more likely to present with disease. Differences in drug metabolism, distribution and elimination are included. Impact of oral contraceptives are reviewed.
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RxP International presents Gender and Psychiatric Drugs
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- 2. OverviewOverview Introduction Pharmacology Gender-Specific Disorders Hormonal Contraceptives Pregnancy and Lactation Menopause Wrap Up 2
- 3. IntroductionIntroduction Gender Differences in Life SpanGender Differences in Life Span Life Expectancy at Birth, by Race and Sex, 1970 - 2008 3
- 4. IntroductionIntroduction Gender Differences in Life SpanGender Differences in Life Span ◦ “Men die from disease, Women live with disease” 4
- 5. IntroductionIntroduction Gender Differences in Life SpanGender Differences in Life Span
- 6. IntroductionIntroduction Gender Differences in PrescribingGender Differences in Prescribing 6
- 7. IntroductionIntroduction Gender Differences in Prescribing ◦ Why are women more likely to be diagnosed and given prescriptions for psychotropics? ◦ Popular Hypotheses: Morbidity Reporting Stereotyping Prescribing bias 7
- 8. IntroductionIntroduction Gender Differences in Prescribing ◦ Morbidity Hypothesis “Epidemiology studies in the U.S and world-wide consistently show higher incidence of mood and anxiety disorders in women compared to men” Estradiol and progesterone influence synthesis, metabolism and turnover of CNS NTs (5HT, NE, DA) associated with changes in mood Estrogen influences NT, neuroendocrine, neuromodulatory systems, circadian rhythms, density of receptors in CNS 8
- 9. IntroductionIntroduction Gender Differences in Prescribing ◦ Reporting Hypothesis Women report their symptoms more frequently Morbidity studies often rely on self-report measures and women are more likely to share both physical and emotional symptoms than men Men more likely to suffer from Alexithymia experience depression as irritability Treat with alcohol 9
- 10. IntroductionIntroduction Gender Differences in Prescribing ◦ Stereotyping Hypothesis Professional journal advertisements Disease Model: Physicians work on model of pathology with expression of “negative” emotions (nervousness, worry, sadness/tearfulness) as signs of disease Masculine- “stiff upper lip” and stoicism as normal Female- crying as pathological/intolerable Classic depression 10
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- 15. PharmacologyPharmacology Pharmacokinetics ◦ What the body does to the drug: “ADME” ◦ In order for a drug to work Reach the right target (receptor) in the right concentration Too much—Adverse Effects Too little—No or minimal effect Right amount is still no guarantee—Why? 15
- 16. PharmacologyPharmacology Pharmacokinetics ◦ Women develop more adverse effects and fatal reactions to medicines than men 8/10 drugs withdrawn from market Jan 1997-Jan 2001 due to greater risks in women ◦ The FDA evaluated sex differences in bioequivalence from 1977-1995 Cmax greater in women 87% of the time AUC greater in women 71% of the time 16
- 18. PharmacologyPharmacology Changes Childhood Pediatrics Changes Menstrual Cycle Changes Pregnancy Changes Elder Years Changes based on Sex Absorption ⇓Gastric pH ⇑ Skin absorption (infants) ⇑Rectal pH ⇓Gastric emptying time (premenstrually) ⇓Gastric emptying time Gastric pH⇑ ⇓Motility and intestinal blood flow ⇑Gastric pH ⇓Gastric emptying time ⇓ GI blood flow ⇓ Gastric emptying time ⇓Alchohol dehydrogenase 18 Adapted from: Women's Health Across the Lifespan: A Pharmacotherapeutic Approach, Laura Marie Borgelt, Mary Beth O'Connell, Judith Ann Smith, Karim Anton Calis, 2010. Pharmacokinetics Female Lifespan Factors -Absorption
- 19. PharmacologyPharmacology Changes Childhood Pediatrics Changes Menstrual Cycle Changes Pregnancy Changes Elder Years Changes based on Sex Distribution ⇑Vd for hydrophilic drugs ⇓Protein binding ⇑Vd for hydrophilic drugs due to increase in TBW ⇑ Blood volume ⇓Serum Albumen ⇑Crossover between fetal maternal barrier ⇓Vd for hydrophilic drugs ⇑Vd for lipophilic drugs ⇓Protein binding ⇑Vd for lipohilic drugs ⇓Vd for hydrophilic drugs 19 Adapted from: Women's Health Across the Lifespan: A Pharmacotherapeutic Approach, Laura Marie Borgelt, Mary Beth O'Connell, Judith Ann Smith, Karim Anton Calis Pharmacokinetics: Female Lifespan Factors - Distribution
- 20. PharmacologyPharmacology Pharmacokinetics: Female Lifespan Factors - Metabolism 20 Changes Childhood Pediatrics Changes Menstrual Cycle Changes Pregnancy Changes Elder Years Changes based on Sex Metabolism Phase I and II below 100% until age 2 Variable effects Phase I ⇑Hydrolysis ⇓Oxidation ⇓CYP1A2 ⇓CYP2C19 ⇑CYP2A6 ⇑CYP2D6 (3rd trimester) ⇑CYP3A4 Phase II: no change Phase I variable changes on CYP activity Phase II: No change Phase I ⇑Oxidation ⇑CYP1A2 ⇑CYP2D6 ⇑CYP3A4 induction (e.g., 90% vs⇑ 50% men for St John’s Wort) Phase II: ⇓Conjugation Adapted from: Women's Health Across the Lifespan: A Pharmacotherapeutic Approach, Laura Marie Borgelt, Mary Beth O'Connell, Judith Ann Smith, Karim Anton Calis
- 21. PharmacologyPharmacology Pharmacokinetics: Female Lifespan Factors - Elimination 21 Changes Childhood Pediatrics Changes Menstrual Cycle Changes Pregnancy Changes Elder Years Changes based on Sex Elimination GFR reaches adult level by age 2 ⇑GFR in luteal phase ⇓GFR in early follicular phase ⇑Renal blood flow ⇑GFR ⇓Creatinine clearance ⇓Creatinine clearance Adapted from: Women's Health Across the Lifespan: A Pharmacotherapeutic Approach, Laura Marie Borgelt, Mary Beth O'Connell, Judith Ann Smith, Karim Anton Calis
- 22. Adapted from: Psychiatric disorders in women: psychopharmacologic treatments. Fanhauser, M.P. J American Pharm Assoc. 1997 22
- 23. Adapted from: Psychiatric disorders in women: psychopharmacologic treatments. Fanhauser, M.P. J American Pharm Assoc. 1997 PharmacologyPharmacology Antipsychotics 23
- 25. PharmacologyPharmacology 25 1. Kornstein, et al., 2000 and Hildebrandt et.al., 2003)
- 26. PharmacologyPharmacology Clinical Psycopharmacology Differences in Bone Cortical Densities 26
- 27. PharmacologyPharmacology Clinical Psycopharmacology ◦ Gender and Mood Stabilizers Men More likely to experience tremor with lithium treatment Women More likely to develop hypothyroidism with lithium Factor most predictive of hypothyroidism was weight gain during the first year Carbamazepine, Oxcarbazepine, Topiramate may lower the efficacy of oral contraceptives 27
- 28. PharmacologyPharmacology Clinical Psycopharmacology ◦ Gender and Neuroleptics Women Estrogen may have antidopaminergic properties by binding to DA receptor Significantly higher plasma concentrations of APs (CPZ, Fluphenazine, Olanzapine, Clozapine) Require lower doses and show more dyskinesias Greater risk for TD with long term neuroleptic use Men Require up to 2x dose as women for maintenance with APs (Milkerson, Hulting, & Rane, 2001) 28
- 29. PharmacologyPharmacology Clinical Psycopharmacology ◦ Gender and Benzodiazepines Panic disorder occurs disproportionately in women 29 •Adapted from: Psychiatric disorders in women: psychopharmacologic treatments. Fanhauser, M.P. J American Pharm Assoc. 1997
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Hinweis der Redaktion
- Gender, a social construct, is expressed in terms of masculinity and femininity. It is defined by the way people perceive themselves and how they expect others to behave. Gender is largely determined by culture. Sex differences result from the classification of organisms based on genetic composition as well as reproductive organs and function [6].
- Men greater tendency for risk taking, have poorer health compliance, ingest more alcohol, and smoke more than women
- (Soldin, Chung & Matisson, 2001) 4x more likely to complete suicide(Bigos et. al., 2009) Asthma, Arthritis Osteoporosis, Dementia, Hypothroid 2- to 10-fold incidence and severity of autoimmune/inflammatory diseases in females Most autoimmune diseases are detected in females of childbearing age Men higher rates of mortality: Coronary Vascular Disease, Cancer, Injuries More Comorbid Alcohol/Drug Abuse 4x more likely to complete suicide Increased levels of estrogen and progesterone alter hepatic enzyme activity, which can increase drug accumulation or decrease elimination of some drugs. Female steroid hormones and prolactin play a role in autoimmunity. Regulation of immunity and interactions between the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes contribute to the 2- to 10-fold incidence and severity of autoimmune/inflammatory diseases in females compared to males. Most autoimmune diseases are detected in females of childbearing age. Metabolic changes can also depend on hormone levels that change during the menstrual cycle, with use of oral contraceptives, throughout pregnancy, or during menopause. For example, some asthmatic women have worsening symptoms before or during menstruation [109]. An increase in oxidative stress in females has been described during intensive physical exercise, particularly in postmenopausal women [110]. Moreover, sex hormone levels throughout the menstrual cycle are associated with the activation of specific hepatic enzymes and the rate of clearance of certain drugs. Caffeine and theophylline clearance, for example, is higher during the early follicular phase and prolonged during the mid-luteal phase Although women can expect to live 5 years longer than men on average, women experience more physically and mentally unhealthy days than men. In 2007–2009, women reported an average of 4.0 days per month that their physical health was not good and 3.9 days per month that their mental health was not good, compared to an average of 3.2 physically unhealthy and 2.9 mentally unhealthy days per month reported among men. Due to their longer life expectancy, women are more likely than men to have certain age-related conditions like Alzheimer’s disease. Regardless of age, however, women are more likely to have asthma, arthritis, osteoporosis, and activity limitations. For example, 9.2 percent of women had asthma in 2007–2009, compared to 5.5 percent of men.Men, nonetheless, bear a disproportionate burden of other health conditions, such as HIV/AIDS, high blood pressure, and coronary heart disease. In 2008, for instance, the rate of newly reported HIV cases among adolescent and adult males was more than 3 times the rate among females (32.7 versus 9.8 per 100,000, respectively). Despite the greater risk, however, a smaller proportion of men had ever been tested for HIV than women (36.1 versus 41.0 percent, respectively). In addition, men were more likely than women to lack health insurance and less likely to have received a preventive check-up in the past year. Sarcopenia is defined as the age-related loss of muscle mass.9–11 Besides the decline in testosterone, sarcopenia has multiple causes, including decreased intake of protein, decreased physical activity, peripheral vascular disease, cytokine excess (especially interleukin-6), decreased growth hormone and insulin growth factor-1, and reduced motor neuron innervation.12,13 Replacement of testosterone using selective androgen receptor molecules improves muscle strength.14,15 A recent study showed that a combination of testosterone and a high calorie protein supplement reduced hospitalizations.16
- Overall use of psychiatric medications among adults grew 22% from 2001 to 2010. The new figures, released Wednesday, are based on prescription-drug pharmacy claims of two million U.S. insured adults and children reported by Medco Health Solutions Inc., a pharmacy-benefit manager. The patterns are consistent with, but more pronounced than, published findings from national government data, which tend to have a lag time. A recent Archives of General Psychiatry paper looking at data before 2005 found that about 10% of the population took an antidepressant. Wednesday's data found that about 10% of adult men used antidepressants in 2010, but 21% in adult women did. Psychiatric medications are among the most widely prescribed and biggest-selling class of drugs in the U.S. In 2010, Americans spent $16.1 billion on antipsychotics to treat depression, bipolar disorder and schizophrenia, $11.6 billion on antidepressants and $7.2 billion on treatment for ADHD, according to IMS Health, which tracks prescription-drug sales.
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- Area Under the Curve (AUC): The area under the plot of plasma concentration of drug (not logarithm of the concentration) against time after drug administration. The area is conveniently determined by the “trapezoidal rule”: the data points are connected by straight line segments, perpendiculars are erected from the abscissa to each data point, and the sum of the areas of the triangles and trapezoids so constructed is computed. When the last measured concentration (Cn, at time tn) is not zero, the AUC from tn to infinite time is estimated by Cn/kel. The AUC is of particular use in estimating bioavailability of drugs, and in estimating total clearance of drugs (ClT). Following single intravenous doses, AUC = D/ClT, for single compartment systems obeying first-order elimination kinetics; alternatively, AUC = C0/kel. With routes other than the intravenous, for such systems, AUC = F · D/ClT, where F is the bioavailability of the drug. The ratio of the AUC after oral administration of a drug formulation to that after the intravenous injection of the same dose to the same subject is used during drug development to assess a drug’s oral bioavailability. The FDA evaluated sex differences in bioequivalence among 26 studies submitted to the agency between 1977 and 1995 [20, 24]. It is a major concern that over a 20-year period, only 26 studies submitted to the FDA had data addressing sex differences in drug absorption. Among the 26 studies, there were 47 datasets addressing sex differences in maximum concentration (Cmax) and AUC. None of the datasets had more than 20 individuals of each sex. Most had no more than 10 men or women, so the sample size available to assess sex differences in bioavailability was limited. However, among these studies, the Cmax was greater in women 87% of the time and AUC was greater in women 71% of the time. Reason For Difference Pharmacologic Reason Pharmacologic Factor Women are Overdosed Pharmacokinetics Absorption Vd Differences in protein binding Metabolism (Phase I and II) Elimination Women are More Sensitive Pharmacodynamics Drug targets -receptor number -receptor binding -signal transduction s/p receptor binding Women on Polypharmacy Drug-drug interactions Competition for receptors (protein binding) Induction/Inhibition
- Routes of absorption occur across body surfaces, such as the gastrointestinal tract, respiratory tract, or skin, which differ in males and females. For example, drug absorption occurs at different sites throughout the gastrointestinal tract, and rate of absorption is influenced by gut transit times, lipid solubility of the agent, pH at the site of absorption, and the ionization and molecular weight of the agent [5]. Transit times differ significantly in men and women, with mean transit times being shorter in men (44.8 hours) than in women (91.7 hours) [22]. While fiber ingestion decreases transit time, female gut transit times are consistently longer [22]. Sex differences have also been noted in bile acid composition, which may impact the solubility of various drugs. Men have higher concentrations of cholic acid, while women have higher concentrations of chenodeoxycholic acid [23].
- ⇓Gastric emptying time occurs when progesterone levels are high results in increased absorption of some medications pH effect on bioavilability depends on weak acid, weak base, ionic characteristics of drug Psychotropics are weak bases
- More fat larger Vd for lipophillic Once drug is absorbed into the blood, it begins to distribute to tissues The amount of drug that partitions into tissues depends on . . . Lipophilicity Protein binding The partitioning of drug between blood and tissues is expressed quantitatively as the Volume of Distribution Drugs with low Vd are contained mostly in the plasma, because . . . They are highly water soluble (plasma water content is higher than tissues), or They are highly protein bound (which prevents them from freely diffusing into tissues Drugs with high Vd are mostly in tissues, and plasma levels may not reflect body burden Factors that can affect Vd Body fat index (men vs. women) Tissue perfusion (CHF or edema) Concentration of plasma proteins
- Routes of absorption occur across body surfaces, such as the gastrointestinal tract, respiratory tract, or skin, which differ in males and females. For example, drug absorption occurs at different sites throughout the gastrointestinal tract, and rate of absorption is influenced by gut transit times, lipid solubility of the agent, pH at the site of absorption, and the ionization and molecular weight of the agent [5]. Transit times differ significantly in men and women, with mean transit times being shorter in men (44.8 hours) than in women (91.7 hours) [22]. While fiber ingestion decreases transit time, female gut transit times are consistently longer [22]. Sex differences have also been noted in bile acid composition, which may impact the solubility of various drugs. Men have higher concentrations of cholic acid, while women have higher concentrations of chenodeoxycholic acid [23].
- A recent review on sex differences in pharmacokinetics of antidepressants highlights possible hormone-drug competition for hepatic metabolic enzymes. Since estrogen is a substrate for CYP3A4 and CYP1A2, antidepressant metabolism may be significantly impacted during the late luteal phase of the menstrual cycle or with estrogen replacement therapy [45]. K. L. Bigos, B. G. Pollock, B. A. Stankevich, and R. R. Bies, “Sex differences in the pharmacokinetics and pharmacodynamics of antidepressants: an updated review,” Gender Medicine, vol. 6, no. 4, pp. 522–543, 2009. The paucity of research on gender-specific differences related to antidepressants is a significant public health deficiency and represents an understudied and necessary research area. The current data suggest that the pharmacokinetics of antidepressant drugs can be substantially different between men and women as a result of differences in both the metabolizing enzymes and the expression of P-glycoprotein MDR1.17,18 The data suggest that different pharmacodynamic responses are observed between premenopausal women and men. Women are more likely to respond better to an MAOI antidepressant compared to men. In addition, men respond better to TCAs than women in this age group, but differences diminish after menopause.
- Goldman: Goldman's Cecil Medicine, 24th ed Cortical bone mineral density versus age in men and women. Women have lower peak cortical bone density than men and experience a period of rapid bone loss at menopause, thus reaching the fracture threshold (the level of bone density at which the risk of developing osteoporotic fractures begins to increase) earlier than men.
- Onset of bipolar disorder during the fifth decade of life is also more common in women than men Women appear to be more prone to a depressive diathesis of bipolar disorder compared with men [6] . Women are more likely to present with an initial depressive episode, to have depressive episodes before hypomania or mania, to follow a bipolar type II (mainly depressive) course, and to be considered unipolar depressed longer than men [3] . Lamotrigine, an established anticonvulsant, may have antidepressant and mood-stabilizing properties in the treatment of patients with bipolar disorder [35] [36] [37] [38] . In a double-blind, placebo-controlled, 6-month maintenance study in patients with rapid-cycling bipolar disorder, lamotrigine monotherapy resulted in a significantly greater percentage of patients stable without relapse compared with placebo, a difference that was driven by improvement in bipolar II patients [24] . Therefore, lamotrigine may be a useful treatment for bipolar II patients with rapid cycling. However, there was a high prevalence of depression in patients reaching the study endpoint in both lamotrigine-treated patients (37%) and patients on placebo (45%) and a high prevalence of depression requiring additional pharmacotherapy. These results again demonstrate the treatment-refractory nature of depressive episodes that occur as part of the rapid-cycling course of bipolar disorder [24] . Other medications studied in the treatment of rapid-cycling bipolar disorder include the atypical antipsychotics, clozapine, risperidone, and quetiapine for which there are open data supporting their possible efficacy in this group of patients [39 Gabapentin and Lamotrigine, Pregabalin, Vigabatrin, levetiracetam do not lower oral contraceptives [