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Supplemental Table 1. Gender differences in absorption, distribution, metabolism, and excretion Parameter Drug bioavailability1-12 Absorption Gastric acid secretion Gastric emptying Gastrointestinal transit times Gut metabolism Body composition1-14 Body surface area Organ (heart) size Organ blood flow Total body water Plasma volume Body fat content Cardiac output Pulmonary function Drug distribution1-14 Volume of distribution Plasma protein binding to - Albumin7,8,15,16 - 1-acid glycoprotein16,17 - Globulins18 Sex differences M>W M > W > P1-3. Decreases absorption of weak acids but increases absorption of weak bases in M M > W > P3-9. E inhibit gastric empting7 M=W M > P > W. Absorption increases when body surface are is larger M > W. Greater blood flow to skeletal muscle and liver in M; greater to adipose tissue in W. Blood flow increases during P M>P>W P > M > W. Varies during the menstrual cycle and . W>M M > P > W. Increase rate of distribution in M M > P > W. Increase pulmonary elimination in M W > M. Higher Vd for lipophilic drugs in W M > W. Higher Vd of hydrophilic drugs in M M = W. P and OC reduce plasma albumin and increases free drug plasma levels. M > W. E, OC and P decrease its plasma levels E increase sex-hormone binding, corticosteroid-binding and thyroxine-binding globulin. Parameter Drug transporters Hepatic P-glycoprotein OCT2 OATP1B1-3 1 Sex differences M > W10,19,20 M > W21,22. E downregulates OTC2 M > W21 Drug metabolizing enzymes and transporters Phase I metabolic reactions CYP1A2: M > W23-27. Decreases in pregnancy and by (hydrolysis, oxidation, reduction) OCP mediated via cytochrome P450 (CYP) CYP2B6: W > M27 isoforms CYP2C9: M = W21,27,28 CYP2C19: M = W29 Decreases in pregnancy and by OCP30,31 CYP3A4: W > M27,32,33. Increases by OCP CYP2D6: M > W23,31,34. E induces35-37 and OCP decreases CYP2D6 activity31 CYP2E1: M > W38. Increases by OCP Phase II metabolism - Uridine diphosphate - M > W. Increase by OCP and E and during gluronosyltransferases (UGTs 1/ 2) pregnancy28,37,39 - N-Acetyltransferases (NAT) - M = W24 - M > W40 - Catechol-O-methyltransferase - Acetyl-/Butiryl-cholinesterase - M > W41 - Xantine-oxidase - F > M24,25 - Gastric alcohol dehydrogenase - M > F. Higher alcohol plasma levels in W42,43 Drug excretion12,44,45 - Renal blood flow M > W. Renal Cl increases during P - Glomerular filtration rate Drugs actively secreted by the kidney may show sex - Tubular secretion/ reabsorption differences in renal excretion Cl: clearance. E: estrogens. GFR: glomerular filtration rate. GI: gastrointestinal. M: men. OCP: oral contraceptives. P: pregnancy. P-gp: P-glycoprotein. Vd: volume of distribution. W: women. 2 References 1. Soldin OP, Chung S, Mattison. Sex differences in drug disposition. J Biomed Biotechnol 2011;2011:187103. 2. Soldin OP, Mattison. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2009;48:143-158. 3. Freire AC, Basit AW, Choudhary R, Piong CW, Merchant HA. Does sex matter? The influence of gender on gastrointestinal physiology and drug delivery. Int J Pharm 2011;415:15-28. 4. Kimura T, Higaki K. Gastrointestinal transit and drug absorption. Biol Pharm Bull 2002;25:149-164. 5. Mearadji B, Penning C, Vu MK, van der Schaar PJ, van Petersen AS, Kamerling IM, Masclee AA. Influence of gender on proximal gastric motor and sensory function. Am J Gastroenterol 2001;96:2066–2073. 6. Sadik R, Abrahamsson H, Stotzer PO. Gender differences in gut transit shown with a newly developed radiological procedure. Scand J Gastroenterol 2003;38:36–42. 7. Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995;50:222-239. 8. Beierle I, Meibohm B, Derendorf H. Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther 1999;37:529–547. 9. Legato M. Gender and the heart: sex-specific differences in normal anatomy and physiology. J Gend Specif Med 2000;3:15–18. 10. Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics? Clin Pharmacokinet 2002;41:329-342. 11. Anderson GD. Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J Womens Health (Larchmt) 2005;14:19–29. 12. Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF. Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol 2004;44:499-523. 13. Nicolas J-M, Espie P, Molimard M. Gender and interindividual variability in pharmacokinetics. Drug Metabolism Rev 2009;41:408-421. 14. Franconi F, Campese I. Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women. Br J Clin Pharmacol 2014;171:580-594. 15. Haram K, Augensen K, Elsayed S. Serum protein pattern in normal pregnancy with special reference to acute phase reactants. Br J Obstet Gynaecol 1983;90:139-144. 16. Succari M, Foglietti MJ, Percheron F. Microheterogeneity of alpha 1-acid glycoprotein: variation during the menstrual cycle in healthy women, and profile in women receiving estrogenprogestogen treatment. Clin Chim Acta 1990;187:235–241. 17. Kishino S, Nomura A, Itoh S, Nakagawa T, Takekuma Y, Sugawara M, Furukawa H, Todo S, Miyazaki K. Age- and gender-related differences in carbohydrate concentrations of alpha1acid glycoprotein variants and the effects of glycoforms on drug binding capacities. Eur J Clin Pharmacol 2002;58:621–628. 18. Wiegratz I, Kutschera E, Lee JH, Moore C, Mellinger U, Winkler UH, Kuhl H. Effect of four different oral contraceptives on various sex hormones and serum-binding globulins. Contraception 2003;67:25-32. 19. Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 1995;275:1011-1018. 20. Davis M. Gender differences in p-glycoprotein: drug toxicity and response. J Clin Oncol 2005;23:6439–6440. 3 21. Schwartz JB. The current state of knowledge on age, sex, and their interactions on clinical pharmacology. Clin Pharmacol Ther 2007;82:87‑96. 22. Urakami Y, Okuda M, Saito H, Inui K. Hormonal regulation of organic cation transporter OCT2 expression in rat kidney. FEBS Lett 2000;473:173. 23. Bock KW, Schrenk D, Forster A, Griese EU, Mörike K, Brockmeier D, Eichelbaum M. The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDPglucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes. Pharmacogenetics 1994;4:209-218. 24. Relling MV, Lin JS, Ayers GD, Evans WE. Racial and gender differences in Nacetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther 1992;52:643-658. 25. Kashuba AD, Nafziger AN. Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet 1998;34:203–218. 26. Oertelt-Prigione S, Regitz-Zagrosek V. Gender aspects in cardiovascular pharmacology. J Cardiovasc Trans Res 2009;2:258-266. 27. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138:103-141. 28. Anderson GD. Sex differences in drug metabolism: cytochrome P-450 and uridine diphosphate glucuronosyltransferase. J Gend Specif Med 2002;5:25-33. 29. Lucas D, Menez C, Girre C, Berthou F, Bodenez P, Joannet I, et al. Cytochrome P450 2E1 genotype and chlorzoxazone metabolism in healthy and alcoholic Caucasian subjects. Pharmacogenetics 1995;5:298–304. 30. Laine K, Tybring G, Bertilsson L. No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. Clin Pharmacol Ther 2000;68:151–159. 31. Hagg S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol 2001;51:169-173. 32. Cotreau MM, von Moltke LL, Greenblatt DJ. The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet 2005;44:33-60. 33. Wolbold R, Klein K, Burk O, Nüssler AK, Neuhaus P, Eichelbaum M, Schwab M, Zanger UM. Sex is a major determinant of CYP3A4 expression in human liver. Hepatology 2003;38:978– 988. 34. Labbé L, Sirois C, Pilote S, Arseneault M, Robitaille NM, Turgeon J, Hamelin BA. Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates. Pharmacogenetics 2000;10:425–438. 35. Hogstedt S, Lindberg B, Rane A. Increased oral clearance of metoprolol in pregnancy. Eur J Clin Pharmacol 1983;24:217–220. 36. Wadelius M, Darj E, Frenne G, Rane A. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther 1997;62:400–407. 37. Jochmann N, Stangl K, Garbe E, Baumann G, Stangl V. Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases. Eur Heart J 2005;26:1585–1595. 38. Franconi F, Carru C, Malorni W, Vella S, Mercuro G. The Effect of Sex/Gender on Cardiovascular Pharmacology. Curr Pharm Des 2011;17:1095-1107. 39. Court MH, Duan SX, von Moltke LL, Greenblatt DJ, Patten CJ, Miners JO, Mackenzie PI. Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDPglucuronosyltransferase isoforms. J Pharmacol Exp Ther 2001;299:998-1006.. 4 40. Boudikova B, Szumlanski C, Maidak B, Weinshilboum R. Human liver catechol-Omethyltransferase pharmacogenetics. Clin Pharmacol Ther 1990;48:381–389. 41. Zimmer KR, Lencina CL, Zimmer AR, Thiesen FV. Influence of physical exercise and gender on acetylcholinesterase and butyrylcholinesterase activity in human blood samples. Int J Environ Health Res 2010;22:279–286. 42. Baraona E, Abittan CS, Dohmen K, Moretti M, Pozzato G, Chayes ZW, Schaefer C, Lieber CS. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res 2001;25:502-507. 43. Frezza M, di Padova C, Pozzato G, Terpin M, Baraona E, Lieber CS. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and firstpass metabolism. N Engl J Med 1990;322:95-99. 44. Berg UB. Differences in decline in GFR with age between males and females: reference data on clearances of inulin and PAH in potential kidney donors. Nephrol Dial Transplant 2006;21:2577-2582 45. Davison JM, Dunlop W. Renal hemodynamics and tubular function normal human pregnancy. Kidney Int 1980;18:152-161. 5 Supplemental Table 2. Sex-related differences in drug pharmacokinetic parameters Drug class Outcomes in females Anesthetics: Propofol Alcohol Plasma propofol levels decline more rapidly in W at the end of infusion1-5. Lower gastric alcohol dehydrogenase activity in W. Higher plasma concentrations in W as compared to M following an equivalent drink6. Antidepressants Higher AUC and Cmax in W7. H1-Antihistamines Slower metabolism and elimination in W8,9. Antipsychotic drugs (1) Higher plasma levels and Vd and lower Cl in W10-12. Reduce the dosage in F or increase dosage in M. Olanzapine is more rapidly eliminated in M than in W13. Aspirin Higher bioavailability and plasma levels of aspirin and salicylate are higher in W possibly due to lower activity of aspirin esterase, larger Vd and lower Cl in W than in M14-16. Differences disappear with OCP14. Benzodiazepines Lower initial plasma levels due to larger Vd, and possibly higher Cl, in W17-21. OC reduce their Cl. Higher plasma levels of free diazepam in W21. Beta-receptor agonists W are less sensitive4. Beta blockers: W have higher plasma levels due to a smaller Vd and slower Cl22-24. Drug Metoprolol, propranolol exposure to metoprolol increases by OC25. Renal Cl of atenolol and metoprolol increases during P due to enhanced hepatic metabolism26,27. Calcium channel Faster Cl of verapamil28, and nifedipine29 in W. Increased bioavailability and blockers decreased clearance of oral verapamil in W compared to M30,31. Digoxin W have higher serum digoxin concentrations due to reduced Vd and lower Cl32,33. Drug Cl increases during P34. Glucocorticoids Oral Cl and Vd of prednisolone are higher M. Prednisolone clearance was reduced by OC35-37. Heparin W had higher plasma levels and APTT values than M due to a lower Cl8,38-40. Iron Oral absorption of iron is greater in W than in M41. Isosorbide Mononitrate W had significantly higher serum plasma concentrations compared to men, probably due to the lower body weights in females42 . Labetalol Labetalol concentrations are 80% higher in W43. Lidocaine W has a larger Vd and may require a higher i.v. bolus dose than M. Higher free plasma levels in W receiving OCP, as alpha 1-acid glycoprotein levels are reduced by oestrogens21. Slower onset and offset of action in W2,4,44. -opioid (OP3) receptor agonists (2) Neuromuscular Lower Vd, higher plasma levels, faster onset and prolonged duration in W blocking drugs (3) due to the higher body fat and lower Vd4,45-50. Paracetamol Lower plasma levels and higher Cl in M due to increased activity of the glucuronidation pathway51,52. OCP increase drug clearance52. Procainamide Plasma levels are higher (30%) in W due to a lower BMI and Vd53. Quinidine Plasma protein binding decreases during P54. Selective serotonin W present higher plasma levels, probably related to sex-related activity of reuptake inhibitors (4) various CYP enzymes7,55-57. Statins Higher plasma levels of lovastatin and simvastattin in W58. Theophylline Metabolism is faster and half-life is shorter in W than in M59. Plasma protein binding decreases and the Vd increases during P. Torasemide Higher Cmax and lower Cl in W than in M60,61. 6 Tricyclic antidepressants Verapamil Vorapaxar Warfarin Zolpidem Free plasma concentrations of imipramine, clomipramine and nortriptyñine are higher in W and in pregnant women7,62. Faster Cl in i.v. W probably due to the higher activity of CYP3A4 or lower activity of P-gp; lower Cl in W after oral administration28,30,63. The Cmax and AUC were 30% higher in women but no dose adjustement is required64. Higher free plasma levels in W8,65. Plasma levels and AUC are higher, and clearance is lower in W66 Abbreviations: AUC: area under the curve. BMI: body mass index. Cl: clearance. Cmax: peak plasma drug concentrations. CYP: cytochrome P450 isoforms. i.v.: intravenous. M: men. OC: oral contraceptives. P: pregnancy. P-gp: P-glycoprotein. Vd: volume of distribution. W: women. (1): olanzapine, clozapine, pimozide, haloperidol. (2): fentanyl, morphine, pentazocine, ramifentanil. (3): atracurium, pancuronium, rocuronium vecuronium. (4): citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline References 1. Apfelbaum JL, Grasela TH, Hug CC Jr, McLeskey CH, Nahrwold ML, Roizen MF, Stanley TH, Thisted RA, Walawander CA, White PF. The initial clinical experience of 1819 physicians in maintaining anesthesia with propofol: characteristics associated with prolonged time to awakening. Anesth Analg 1993;77(4 Suppl):S10-S14. 2. Ciccone GK, Holdcroft A. Drugs and sex differences: a review of drugs relating anaesthesia. Br J Anesthes 1999;82:255-265. 3. Vuyk J, Oostwouder CJ, Vletter AA, Burm AG, Bovill JG. Gender differences in the pharmacokinetics of propofol in elderly patients during and after continuous infusion. Br J Anaesth 2001;86:183-188. 4. Pleym H, Spigset O, Kharasch ED, Dale O. Gender differences in drug effects: implications for anesthesiologists. Acta Anaesthesiol Scand 2003;47:241-259. 5. Hoymork SC, Raeder J. Why do women wake up faster than men from propofol anaesthesia? 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Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology 2000;93:1245-1254. 45. Xue FS, Tong SY, Liao X, Liu JH, An G, Luo LK. Dose-response and time course of effect of rocuronium in male and female anesthetized patients. Anesth Analg 1997;85:667-671. 46. Xue FS, Liao X, Liu JH, Tong SY, Zhang YM, Zhang RJ, An G, Luo LK. Dose-response curve and time-course of effect of vecuronium in male and female patients. Br J Anaesth 1998;80:720-724. 47. Xue FS, An G, Liao X, Zou Q, Luo LK. The pharmacokinetics of vecuronium in male and female patients. Anesth Analg 1998;86:1322-1327. 48. Xue FS, Zhang YM, Liao X, Liu JH, An G. Influences of age and gender on dose response and time course of effect of atracurium in anesthetized adult patients. J Clin Anesth 1999;11:397-405. 49. Takaya T, Takeyama K, Miura M, Takiguchi M. Influence of body fat on the onset of vecuronium induced neuromuscular blockade. Tokai J Exp Clin Med 2001;26:107-111. 50. Ueno K. Gender differences in pharmacokinetics of anesthetics. Jap J Anesthesiol 2009;58:51-58. 51. Abernethy DR, Divoll M, Greenblatt DJ, Ameer B. Obesity, sex, and acetaminophen disposition. Clin Pharmacol Ther 1982;31:783-790. 52. Miners JO, Attwood J, Birkett DJ. Influence of sex and oral contraceptive steroids on paracetamol metabolism. Br J Clin Pharmacol 1983;16:503-509. 53. Koup JR, Abel RB, Smithers JA, Eldon MA, de Vries TM. Effect of age, gender and race on steady state procainamide pharmacokinetics after administration of procanbid sustained-release tablets. Ther Drug Monit 1998;20:73-77. 54. El-Eraky H, Thomas SH. Effects of sex on the pharmacokinetic and phar-macodynamic properties of quinidine. Br J Clin Pharmacol 2003;56:198-204. 55. Hiemke C, Härtter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther 2005;85:11-28. 56. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors: an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 1997;32(Suppl. 1):1-21. 9 57. Härtter S, Wetzel H, Hammes E, Torkzadeh M, Hiemke C. Nonlinear pharmacokinetics of fluvoxamine and gender differences. Ther Drug Monit 1998;20:446-449. 58. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607-1621. 59. Nafziger AN, Bertino Jr JS. Sex-related differences in theophylline pharmacokinetics. Eur J Clin Pharmacol 1989;37:97-100. 60. Werner D, Werner U, Meybaum A, Schmidt B, Umbreen S, Grosch A, Lestin HG, Graf B, Zolk O, Fromm MF. Determinants of steady-state torasemide pharmacokinetics: impact of pharmacogenetic factors, gender and angiotensin II receptor blockers. Clin Pharmacokinet 2008;47:323-332. 61. Werner U, Werner D, Heinbüchner S, Graf B, Ince H, Kische S, Thürmann P, König J, Fromm MF, Zolk O. Gender is an important determinant of the disposition of the loop diuretic torasemide. J Clin Pharmacol 2010;50:160-168. 62. Yonkers KA, Brawman-Mintzer O. The pharmacologic treatment of depression: is gender a critical factor? J Clin Psychiatry 2002;63:610-615. 63. Dadashzadeha SB, Javadiana B, Sadeghianb S. The Effect of Gender on the Pharmacokinetics of Verapamil and Norverapamil in Human. Biopharm. Drug Dispos 2006;27:329-334. 64. Prescribing information for vorapaxar. https://www.merck.com/product/usa/ pi_circulars/z/zontivity/ zontivity_pi.pdf. [Accessed September 17th, 2016.] 65. Yacobi A, Stoll RG, DiSanto AR, Levy G. Intersubjeet variation of warfarin binding to protein in serum of normal subjects. Res Commun Chem Pathol Pharmacol 1976;14:743-746. 66. Greenblatt DJ, Harmatz JS, von Moltke LL, Wright CE, Durol AL, Harrel-Joseph LM, Shader RI. Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: evaluation of sex-dependent differences. J Pharmacol Exp Ther 2000;293:435-443. 10 Supplemental Table 3. Sex differences in drug pharmacodynamics Drug class Alcohol Anesthetics: Propofol ACEIs Antidepressants Antipsychotic drugs: Aspirin Benzodiazepines Beta-blockers Digoxin Glucocortioids Outcomes Higher vulnerability of W to acute and chronic complications of alcoholism1 W are less sensitive to propofol2. W wake up faster and require higher doses than M for the same effect2-6 No mortality benefit in W with asymptomatic LV systolic dysfunction7 W respond better to selective serotonin/noradrenaline uptake inhibitors. M respond better to TCA and MAO inhibitors than W8-15 More effective in W. They require lower doses to control symptoms16-18 It has a better protective effect against stroke in W and against MI in M19. Aspirin is more active in vitro in male platelets20,21. Aspirin resistance is more frequent in W22 Diazepam impairs psychomotor skills to a greater extent in W. They should be initiated at lower dosages in W23 Greater reduction in blood pressure and heart rate in W treated with metoprolol and propranolol24 W with HF have an increased risk of mortality on digoxin therapy. W require lower doses and lower plasma levels (< 0.8 ng/ml)25-27 Females are more sensitive to the effects of methylprednisolone on cortisol suppression28 Heparin Ibuprofen Lidocaine -opioid (OP3) and * (OP2) receptor agonists (1) Neuromuscular blocking drugs (2) Paracetamol rt-PA SSRIs (3) Verapamil Warfarin Zolpidem W had increased partial thromboplastin time, even after weight-adjusted dosing, suggesting an increased sensitivity29 Less effective in W30 W may require a higher i.v. bolus doses to achieve the same plasma concentration31 W experience more pain and are more sensitive to morphine and receptor agonists2,32-37. M require 30-60% greater dose of morphine and receptor agonists for the same pain relief23,33-35,38 W are more sensitive and require lower (20-30%) doses than M due to a smaller Vd2,39-44. If a rapid onset of action is required the dose should be increased in M W displayed lower Cl and Vd compared to M45. Oral contraceptives increase drug clearance18,46 W with acute ischemic stroke obtein more benefit from rtPA than M47-51 W respond better than M, being the preferred therapy8-10,15 Greater reduction in blood pressure and heart rate in W52 W need less warfarin per week than M53,54. Doses should be modified to reduce the risk of excessive anticoagulation in F The recommended initial dose is lower in W55 Abbreviations: ACEIs: angiotensin-converting enzyme inhibitors. E: estrogens. HF: heart failure. M: men. MI: myocardial infartion. OCP: oral contraceptives. rt-PA: recombinant tissue plasminogen activator. SSRIs SSRIs: selective serotonin reuptake inhibitors. (1) alfentanyl, butorphanol*, fentanyl, morphine, nalbuphine* pentazocine*, remifentanyl. (2) atracurium, pancuronium, rocuronium and vecuronium. (3): citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline 11 References 1. Freire AC, Basit AW, Choudhary R, Piong CW, Merchant HA. Does sex matter? The influence of gender on gastrointestinal physiology and drug delivery. Int J Pharm 2011;415:15-28. 2. Ueno K. Gender differences in pharmacokinetics of anesthetics. Jap J Anesthesiol 2009;58:5158. 3. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 1998;339:489-497. 4. Hoymork SC, Raeder J. Why do women wake up faster than men from propofol anaesthesia? Br J Anaesth 2005;95:627-633. 5. Buchanan MR, Rischke JA, Butt R, Turpie AG, Hirsh J, Rosenfeld J. The sex-related differences in aspirin pharmacokinetics in rabbits and man and its relationship to antiplatelet effects. Thromb Res 1983;29:125-139 6. Gan TJ, Glass PS, Sigl J, Sebel P, Payne F, Rosow C, Embree P. Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 1999;90:12831287. 7. Shekelle PG1, Rich MW, Morton SC, Atkinson CS, Tu W, Maglione M, Rhodes S, Barrett M, Fonarow GC, Greenberg B, Heidenreich PA, Knabel T, Konstam MA, Steimle A, Warner Stevenson L. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol 2003;41:1529-1538. 8. Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Davis SM, Harrison WM, Keller MB.Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry 2000;157:1445-1452. 9. Baca E, Garcia-Garcia M, Porras-Chavarino A. Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:57-65. 10. Berlanga C, Flores-Ramos M. Different gender response to serotonergic and noradrenergic antidepressants. A comparative study of the efficacy of citalopram and reboxetine. J Affect Disord 2006;95:119-123. 11. Parker G, Parker K, AustinMP, Mitchell P, Brotchie H. Gender differences in response to differing antidepressant drug classes: two negative studies. Psychol Med 2003;33:1473-1477. 12. Khan A, Brodhead AE, Schwartz KA, Kolts RL, Brown WA. Sex differences in antidepressant response in recent antidepressant clinical trials. J Clin Psychopharmacol 2005;25:318-324. 13. Yonkers KA, Brawman-Mintzer O. The pharmacologic treatment of depression: is gender a critical factor? J Clin Psychiatry 2002;63:610-615. 14. Yonkers KA. Special issues related to the treatment of depression in women. J Clin Psychiatry 2003;64(Suppl.18):8-13. 15. Bano S, Akhter S, Afridi MI. Gender based response to fluoxetine hydrochloride medication in endogenous depression. J Coll Physicians Surg Pak 2004;14:161-165. 16. Yonkers KA, Kando JC, Cole JO, Blumenthal S. Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication. Am J Psychiatry 1992;149:587-595. 17. Melkersson KI, Hulting AL, Rane AJ. Dose requirement and prolactin elevation of antipsychotics in male and female patients with schizophrenia or related psychoses. Br J Clin Pharmacol 2001;51:317-324. 18. Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol 2001;2:349351. 19. Berger JS, Roncaglioni MC, Avanzini F, Pangrzzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sexspecific meta-analysis of randomized controlled trials. JAMA 2006;295:306-313. 12 20. Escolar G, Bastida E, Garrido M, Rodríguez-Gómez J, Castillo R, Ordinas A. Sex-related differences in the effects of aspirin on the interaction of platelets with subendothelium. Thromb Res 1986;44:837-847 21. Harrison MJ, Weisblatt E. A sex difference in the effect of aspirin on “spontaneous” platelet aggregation in whole blood. Thromb Haemost 1983;50:773-774. 22. Bailey A, Scantlebury DC, Smyth SS. Thrombosis and antithrombotic therapy in women. Arterioscler Thromb Vasc Biol 2009;29:284-288. 23. Pleym H, Spigset O, Kharasch ED, Dale O. Gender differences in drug effects: implications for anesthesiologists. Acta Anaesthesiol Scand 2003;47:241-259. 24. Luzier AB, Killian A, Wilton JH, Wilson MF, Forrest A, Kazierad DJ. Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 1999;66:594-601. 25. Luxford AM, Kellaway GS. Pharmacokinetics of digoxin in pregnancy. Eur J Clin Pharmacol 1983;25:117-121. 26. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403-1411. 27. Regitz-Zagrosek V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov 2006;5:425-438. 28. Lew KH, Ludwig EA, Milad MA, Donovan K, Middleton E Jr, Ferry JJ, Jusko WJ. Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1993;54:402-414. 29. Granger CB, J Hirsh, R.D Califf. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial. Circulation 1996:93;870-878. 30. Walker JS, Carmody JJ. Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen. Anesth Analg 1998;86:1257-1262. 31. Routledge PA, Stargel WW, Kitchell BB, Barchowsky A, Shand DG. Sex-related differences in the plasma protein binding of lignocaine and diazepam. Br J Clin Pharmacol 1981;11:245-250. 32. Sarton E, Olofsen E, Romberg R, den Hartigh J, Kest B, Nieuwenhuijs D, Burm A, Teppema L, Dahan A. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology 2000;93:1245-1254. 33. Gear RW, Gordon NC, Heller PH, Paul S, Miaskowski C, Levine JD. Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett 1996;205:207-209. 34. Gear RW, Gordon NC, Hossaini-Zadeh M, Lee JS, Miaskowski C, Paul SM, Levine JD. A subanalgesic dose of morphine eliminates nalbuphine antianalgesia in postoperative pain. J Pain 2008;9:337-341. 35. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD. Kappa-opioids produce significantly greater analgesia in women than in men. Nat Med 1996;2:1248-1250. 36. Cepeda MD, Carr D. Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesthesia and Analgesia 2003;97:1464-1468. 37. Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, Meyer CR, Koeppe RA, Stohler CS. mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci 2002;22:5100-5107. 38. Craft RM. Sex differences in drug and non-drug-induced analgesia. Life Sci 2003;72:2675-2688. 39. Xue FS, Liao X, Liu JH, Tong SY, Zhang YM, Zhang RJ, An G, Luo LK. Dose-response curve and time-course of effect of vecuronium in male and female patients. Br J Anaesth 1998;80:720-724. 40. Xue FS, Tong SY, Liao X, Liu JH, An G, Luo LK. Dose-response and time course of effect of rocuronium in male and female anesthetized patients. Anesth Analg 1997;85:667-671. 41. Xue FS, Zhang YM, Liao X, Liu JH, An G. Influences of age and gender on dose response and time course of effect of atracurium in anesthetized adult patients. J Clin Anesth 1999;11:397-405. 13 42. Takaya T, Takeyama K, Miura M, Takiguchi M. Influence of body fat on the onset of vecuronium induced neuromuscular blockade. Tokai J Exp Clin Med 2001;26:107. 43. Gan TJ, Glass PS, Sigl J, Sebel P, Payne F, Rosow C, Embree P. Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 1999;90:12831287. 44. Semple P, Hope DA, Clyburn P, Rodbert A. Relative potency of vecuronium in male and female patients in Britain and Australia. Br J Anaesth 1994;72:190-194. 45. Abernethy DR, Divoll M, Greenblatt DJ, Ameer B. Obesity, sex, and acetaminophen disposition. Clin Pharmacol Ther 1982;31:783-790. 46. Miners JO, Attwood J, Birkett DJ. Influence of sex and oral contraceptive steroids on paracetamol metabolism. Br J Clin Pharmacol 1983;16:503-509. 47. Weaver WD, White HD, Wilcox RG, Aylward PE, Morris D, Guerci A, Ohman EM, Barbash GI, Betriu A, Sadowski Z, Topol EJ, Califf RM; for the GUSTO-I Investigators. Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy. GUSTO-I Investigators. JAMA 1996;275:777-782. 48. Moscucci M, Fox KA, Cannon CP, KleinW, López-Sendón J, Montalescot G, et al. 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Gender-specific effects on verapamil pharmacokinetics and pharmacodynamics in humans. J Clin Pharmacol 2000;40:219230. 53. Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest 2005;127:2049-2056. 54. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E.. The pharmacology and management of the vitamin K antagonists: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. Chest Guidelines 2004;126:204S-233S. 55. Ambien® Prescribing Information. www.accessdata.fda.gov/drugsatfda_docs/label/2008/019908s027lbl.pdf. Accessed: November 4th, 2016. 14 Supplemental Table 4. Examples of sex differences in adverse drug reactions (ADRs) Drug class Analgesic drugs Anaphylactic shock Anesthetic drugs Angiotensin converting enzyme inhbitors Anorectics Antiarrhythnmic drugs Anticoagulants: H1-Antihistamines Antiplatelets Antipsychotics Aspirin Beta blockers Benzodiazepines Calcium channel blockers Digoxin Diuretics Drug-induced TdP GPIIb/IIIa inhibitors Heparins Opioid receptor agonists NSAIDs Paracetamol Procainamide Skin diseases Statins Thiazides Thiazolidinediones Thrombolytics Unfractioned heparin Zolpidem Outcomes in females W report more adverse effects to perioperative analgesic drugs1. Anaphylactic shock induced by neuromuscular blocking agents, hypnotics, opioids and benzodiazepines is more frequent in W2. W are more prone to ADR postoperatively2-4 Dry cough is 2-3 times more frequent in W5-7. No gender preference for angioedema/urticaria8. Cardiac valvulopathy is more frequent in W exposed to phentermine, dexfenfluramine or fenfluramine9. Higher risk of QT prolongation and TdP in W10. More frequent and severe bleedings in W11-19 W are more vulnerable to sedation and drowsiness20-22 More frequent and severe bleedings in W23 W present more extrapyramidal and anticholinergic effects and QTc prolongation. M reported more sexual problems24-27 Increased risk of bleeding in W28. More ulcer complications in M29 Enhanced BP lowering and heart rate reduction with metoprolol in W30. Diazepam impaired the psychomotor skills more in W than in M31. Dependency is more frequent in W26 Higher risk of edema in W32. Women taking OCP and diazepam during menstruation become relatively intoxicated33 Higher mortality in F with heart failure34. Digoxin plasma levels < 0.8 ng/mL are recommended in W35 Higher rates of hospitalizations due to hypo-osmolarity, hypokalemia and hyponatremia and higher risk of arrhythmias in W15,35-39 W have a longer QTc intervals and devep TdP more frequently than M40-44 W experience more bleeding than M23,45 W present higher bleeding risk12,46,47 W experience more ADRs (nausea and vomiting, respiratory depression) despite smaller dose requirements for pain control48-52 M display a higher prevalence of ADRs than W29,53-55 Acute liver failure die to paracetamol overdose is more common in W56 Systemic lupus erythematosus more common in W57,58 W > M (systemic lupus erythematosus and photosensitivity57,59 Myopathy is more frequent in older W with low body weight60,61 More hyponatremia and hypokalemia in W62 Double the risk of fractures among diabetic F, but not among M63-66 Higher risk of bleeding67-69 and intracranial hemorrhagic in W70,71 W develop higher plasma levels and higher bleeding risk12,19 To reduce the risk of morning-after activity impairment decrease the dose of zolpidem by 50% in W72 Abbreviations: ACEIs: angiotensin-converting enzyme inhibitors. E: estrogens. HF: heart failure. 5-HTTT: serotonin transporter. ADR: adverse drug reactions. BP: blood pressure. CV: cardiovascular. GP: glycoprotein. NSAID: non-steroidal anti-inflammatory drugs. OC: oral contraceptives. QTc: corrected QT interval. TdP: torsades de pointes. W: women. 15 References 1. Richardson J, Holdcroft A. Results of forty years Yellow Card reporting for commonly used perioperative analgesic drugs. Pharmacoepidemiol Drug Saf 2007;16:687-694. 2. Ciccone GK, Holdcroft A. Drugs and sex differences: a review of drugs relating anaesthesia. Br J Anesthes 1999;82:255-265. 3. Kando JC, Yonkers KA, Cole JO. Gender as a risk factor for adverse events to medications. Drugs 1995;50:1-6. 4. Buchanan MR, Rischke JA, Butt R, Turpie AG, Hirsh J, Rosenfeld J. The sex-related differences in aspirin pharmacokinetics in rabbits and man and its relationship to antiplatelet effects. Thromb Res 1983;29:125-139. 5. Os I, Bratland B, Dahlof B, Gisholt K, Syvertsen JO, Tretli S. 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