INTRODUCTION:

Clinical pharmacology seeks to understand how to optimise drug use in order to reduce therapeutic side events while increasing therapeutic effectiveness. Both can be accomplished by studying the pharmacodynamics (PD) and pharmacokinetics (PK) of the medications in the various populations for which they are designed¹.

The physiological differences between males and females have a profound impact on the prevalence and consequences of illness. For comparison, Males are less likely than females to experience thyroid problems, depression, hepatitis, migraines, multiple sclerosis, irritable bowel syndrome, cataracts, and rheumatoid arthritis. Myocardial infarction (MI) is more common in men, women, on the other hand, are more probable to die a year following a MI. Women consistently outlive men despite being more susceptible to many diseases. Differences in sex also have significant effects on the pharmacokinetics (A, D, M, E) and pharmacodynamics of drugs².

Figure 1: Pathways of pharmacokinetics and pharmacodynamics

Pharmacokinetic Differences:

Pharmacokinetics is the study of how pharmaceuticals move through the body, including their uptake, transfer between body compartments, biological transformation, and elimination. Many physiological variations between men and women may account for pharmacokinetic variances, which may have an effect on dose for drugs with narrow therapeutic indices³.

Absorption:

Factors such as stomach acidity, enzyme activity, and gastrointestinal motility all play a role in how well an oral medicine is absorbed. Women often have slower GI transit speeds and produce less stomach acid than men. Therefore, absorption of those drugs that need an acidic environment to absorb, like ketoconazole, may have reduced bioavailability in the female body. A drug's effectiveness may be diminished if it is not taken with an acidic beverage⁴. Metoprolol, theophylline, and verapamil can all have their absorption reduced by an extended gastrointestinal transit time^5,6. According to one study, women who had just eaten a meal had a delayed absorption of enteric-coated aspirin⁷. Medications that need to be taken on an empty stomach should be postponed by women until after they have eaten. Some common examples are captopril, ampicillin, tetracycline, felodipine, loratadine, cilostazol and demeclocycline⁸. The rate at which men and women consume alcohol is also different. Women will have a greater blood alcohol concentration (BAC) than men after consuming the same amount of ethanol. The faster breakdown of ethanol by the digestive enzyme alcohol dehydrogenase in males than in females accounts for the gender gap in ethanol absorption and bioavailability⁹. Transdermal absorption, on the other hand, is equivalent between the sexes¹⁰.

Distribution:

Variations in drug distribution have been linked to changes in body composition, Body Mass Index (BMI), plasma protein-binding capacities, and plasma volume. In general, men outsize women in terms of weight, BMI, and organ size. When figuring out loading or bolus doses, these variations should be taken into account¹¹.To reduce unneeded adverse drug responces, women should receive lower doses. Aminoglycosides, class I and III antiarrhythmics, digoxin, chemotherapeutics, heparin, thrombolytics, and lidocaine (xylocaine) are medications that need loading-dose estimates^3,11. Women have more adipose tissue than men do, which might increase the medicine's volume of distribution if the drug has hydrophilic qualities and decrease it if the drug is hydrophobic. Because women have more adipose tissue than men do, lipophilic drugs like benzodiazepines and neuromuscular blockers have longer-lasting effects when taken by women. Women require lower doses of benzodiazepineand neuromuscular blockers and are 30 percent more sensitive to them than males^12,13. Hydrophilic drugs, such as alcohol and fluoroquinolone antibiotics have greater initial plasma concentrations and more profound effects in women because they diffuse in smaller quantities^3,14,15.

Table 1 Depicts the ADME differences according to sex^{3,4,9,11,16,17}

Parameter	Sex differences
Drug bioavailability
Absorption	Men>Women
Gastric acid secretion	Men>Women>Pregnant women. Decreases weak acid absorption while increasing weak base absorption in humans.
Gastric emptying	Men>Women> Pregnant women. Gastric emptying is inhibited by oestrogen.
Gut metabolism	Equal in Men and Women
Body composition
Body surface area	Men> Pregnant women > Woman. Larger body surfaces result in more absorption.
Organ (heart) size	Men>Women
Organ blood flow	Increased blood flow to the skeletal muscles and liver in men. Adipose tissue in the women received more blood flow. During Pregnant women, blood flow rises.
Total body water	Men> Pregnant women>Women
Plasma volume	Pregnant women>Men>Women. Pregnant women and the menstrual cycle cause alterations.
Body fat content	Women>Men
Cardiac output	Men> Pregnant women>Women. Men has an increased rate of distribution.
Pulmonary function	Men> Pregnant women>Women. Man has an increased pulmonary elimination.
Drug distribution
Volume of distribution	Women>Men. Higher Volumeof distribution for hydrophobic drugs in Women. Men>Women. Higher Volumeof distribution for hydrophilic drugs in Men.
Drug metabolism
Phase I (Cytochrome P450 isoenzyme - CYP1A2)	Men>Women> Pregnant women or women with contraceptive pill.
Phase I (Cytochrome P450 isoenzyme - CYP2B6)	Women>Men.
Phase II (Uridinediphosphateglucuronosyltransferases)	Men>Women> Pregnant women or women with contraceptive pill.
Phase II (Catechol-O-ethyltransferase)	Men>Women
Alcohol dehydrogenase	Men>Women
Acetyl-cholinesterase	Men>Women
Drug excretion
Renal blood flow	Men>Women. Pregnant women has an increased renal clearance.
Glomerular filtration rate	Drugs that the kidney actively secretes may exhibit sex variations in renal excretion.

Metabolism:

In the first phase of metabolism, molecules undergo oxidation, reduction, or hydroxylation through the cytochrome P450 system. Most drugs are broken down in the liver during phase I metabolism; however, warfarin is one of the rare medications where the dosage varies by gender. According to studies, women require 2.5 to 4.5mg less of warfarin per week than men^16,18. Phase II metabolism converts the parent drug or phase I metabolite into a polar conjugate for renal excretion by glucuronidation, sulfation, acetylation, or methylation. Some medications, such as acetaminophen, caffeine, digoxin, doxorubicin (adriamycin), fluorouracil, levodopa, mercaptopurine, and propranolol, clear more quickly in males because of these accelerated metabolic processes^3,19–22.

Excretion:

There are three mechanisms involved in kidney clearance: glomerular filtration, tubular secretion, and tubular reabsorption. Body weight, sexual orientation, and serum creatinine are frequently used to determine the glomerular filtration rate (GFR). Even though adjusting for weight eliminates some differences between men and women, GFR is consistently higher in males.Women process medications more slowly when they are excreted unaltered in the urine³. GFRs in women are 10 to 25 percent9 slower after correcting for body size¹⁷. For instance, digoxin and methotrexate, whose main routes of elimination are the kidneys, respectively, have 13 percent and 17 percent delayed clearance in women. Aminoglycosides, cephalosporins, fluoroquinolones, and vancomycin, as well as pregabalin and gabapentin (Neurontin), have all been linked to reduced renal clearance in female patients (Lyrica). Women should take these medications in lower dosages depending on their GFR to account for variations in clearance^3,17,23. The distribution of a medicine may be affected by a number of factors, including the patient's physiology and pharmacokinetic (PK) profile. Most differences in PK between sexes are eliminated when dosing considerations for body weight, height, and glomerular filtration rate (GFR) are made¹¹.

Table 2: depicts sex-related differences in drug pharmacokinetic parameters

Class of drugs	Outcomes	References
Anaesthetics: propofol	After the infusion, the plasma levels of propofol in women decrease more quickly.	24
Alcohol	Women have lower alcohol dehydrogenase activity in the body. Women's plasma concentrations were greater than men's after the same amount of alcohol was consumed.	9
Antidepressants	AUC (Area Under Curve) and Cmax are higher in women.	25
Antipsychotic drugs	In women, plasma Volume of distribution (V)_d and Clarence (Cl) levels are higher. Increase the dosage for men while decreasing it for women. In comparison to women, men eliminate olanzapine more quickly.	26
Aspirin	Due to a lower aspirin esterase activity, an increased V_d, and a decreased Cl in women compared to men, aspirin and salicylate have higher bioavailability and plasma levels in women. With OC, differences disappear.	27,28
Benzodiazepines	Lower initial plasma levels since the woman's Vd is higher and her Cl is presumably higher. Oral contraceptives (OC) reduced Cl and raised free diazepam plasma levels in women.	12
Beta-receptor agonists	Less sensitive in a woman.	29,30
Beta-blockers: metoprolol, propranolol	Because of a smaller V_d and a slower Cl, women have higher plasma levels. Metoprolol drug exposure rises by OC. Due to accelerated hepatic metabolism during pregnency, atenolol, and metoprolol, renal Cl increases.	22,31
Calcium channel blockers	Verapamil and nifedipine work more quickly in women. When compared to men, women have a higher bioavailability and a lower elimination of oral verapamil.	32,33
Digoxin	Due to lower V_d and Cl, women have higher serum digoxin concentrations. During pregnency, the drug Cl rises.	21
Paracetamol	As a result of enhanced glucuronidation pathway activity, there are lower plasma levels and more Cl in men. OC boost drug Cl.	24
Verapamil	Women show higher Cl of verapamil after intravenous delivery, perhaps as a result of higher CYP3A4 activity or lower P-glycoprotein (P-gp) activity: lower Cl in Women after oral administration.	32,34
Warfarin	Greater plasma-free levels in women.	29

PHARMACODYNAMIC DIFFERENCES:

Pharmacodynamics is the scientific study of the relationship between the concentration of a medication and the quantity and speed with which it produces a pharmacologic effect. Therefore, for any particular blood concentration, a medication may produce a range of responses, including changes in effectiveness and safety²⁹.

Antidepressants and Antipsychotics:

Antidepressant and antipsychotic drugs affect men and women differently. Women usually respond better to sertraline (Zoloft) therapy than tricyclic antidepressants like imipramine when taking selective serotonin reuptake inhibitor (SSRI) therapy, although there does not appear to be a difference in the severity of depression symptoms (Tofranil)^35,36. This may be because when receiving SSRI therapy, women make more tryptophan and less cortisol. In contrast, tricyclic antidepressants work better on males than SSRIs^36,37. The pharmacodynamics of antipsychotic drugs can also be affected by gender. Symptoms appear and worsen at various times in men and women; men are more likely to be hospitalised and remain there for longer²⁶^,³⁸. Popular antipsychotic medicines like haloperidol and perphenazine work better in women, whereas men require double the amount to manage symptoms. This may be explained by differences in drug metabolism between the sexes³⁹.

Opioids:

Pain perception, medication response, and pain pathways are all known to be affected by estrogen. Women, who typically have higher estrogen levels than men, are more sensitive to pain and report higher degrees of discomfort in response to standardized stimuli⁴⁰. Opioids provide a greater analgesic effect in females. Men need between 30 and 40 percent more morphine than women to experience a comparable level of pain relief⁴¹. Sexual dimorphism has been related to differences in central opioid metabolism and cellular-level opioid activity. The respiratory depression and increased sedation caused by opioids are also more noticeable in women⁴².

Table 3: depicts sex-related differences in drug pharmacodynamics

Class of drugs	Outcomes	References
Alcohol	Women are more prone to both acute and chronic alcoholic consequences.	9
Antidepressants	Selective inhibitors of serotonin and noradrenaline absorption work better in women. TCA and MAO inhibitors work better on men than on women.	35,36
Antipsychotic drugs	More efficient in females. Lower dosages are needed for them to control symptoms.	26
Aspirin	When it comes to heart attacks, men do better, whereas women have greater safety from strokes. Aspirin has a greater effect on male platelets. Aspirin resistance is more prevalent in women.	43,44
Beta-blockers	Women receiving metoprolol with propranolol saw greater declines in blood pressure and heart rate.	31
Ibuprofen	Fewer benefits for women	42
Paracetamol	Cl and V_d were both lower in women than in men. The effectiveness of the medication CL is increased by OC.	24
Warfarin	Compared to men, women require less warfarin weekly. To lower the risk of excessive anticoagulation in women, doses should be changed.	18,45

Beta Blockers:

Metoprolol is a beta-blocker that has a more pronounced effect on women than men. The elimination half-life is similar in men and women, although the systolic blood pressure and heart rate reduction in women who take metoprolol while exercising are larger. These differences are due to increased plasma medication concentrations in female patients³¹.

Calcium Channel Blockers:

Verapamil and Nifedipine gender-specific PK differences were identified, but Amlodipine does not. Women had quicker clearance and lower plasma levels of nifedipine and verapamil after intravenous treatment^17,46,47. However, clearance after oral administration was slower in women than in men³³. This difference may be attributable to gender-related differences in body mass, CYP3A4 activity, and P-gp (P-glycoprotein) activity^47,48. Women’s verapamil clearance declines as they mature, which accounts for why older women exhibit a stronger antihypertensive response³. In an open 18-week study, amlodipine reduced BP and edema incidence more in women than in men. However, significant calcium channel blocker hypertension trials revealed no proof of gender-specific outcome differences⁴⁹. Compared to women, males had a smaller reduction in risk with a diastolic BP aim of 85 mmHg, according to a sub-analysis of the HOT (Hypertension Optimal Treatment) trial⁵⁰.

Nitrates:

Due to their reduced body weight, women have higher isosorbide-5-mononitrate Cmax and AUC. Dosing based on dose/kg or titration is recommended for optimal clinical effect⁵¹.

NSAIDs:

When it comes to preventing major cardiovascular events, the therapeutic profile of NSAIDs, especially aspirin, has been shown to vary. In one analysis, aspirin significantly reduced the risk of stroke, but women taking it suffered MI at the same rate as those taking a placebo. However, males who took aspirin had a dramatic decrease in MI and no change in stroke rates. Both males and females taking aspirin experienced more bleeding incidents⁴³. Another study found that aspirin usage in women was associated with a lower rate of total platelet inhibition when administered for secondary prophylaxis after a cardiovascular incident. Hormone treatment in women and the effects of testosterone in men might account for these findings⁴⁴.

Sex-Differences in Adverse drug Reaction:

An adverse drug reaction is 50–75 percent more likely to occur in women than in men⁵²^,⁵³. These variations might be brought on by rising polypharmacy, drug use, and medicine sensitivity. More women than men get the life-threatening medication side effect known as torsade de pointes. Torsade de pointes is more common in women since they have a longer QT interval⁵⁴^,⁵⁵^,⁵⁶. Antiarrhythmics (such as amiodarone and disopyramide), antibiotics (such as erythromycin and moxifloxacin), antidepressants (such as imipramine and amitriptyline), and antipsychotics (such as chlorpromazine) are among the medications that have been shown to prolong the QT interval and possibly cause torsade de pointes^52,54^,⁵⁷. Digoxin uses increased in a subset of heart failure patients following the publication of the 1997 Digitalis Investigation Group study⁵⁸. Later post-hoc sub-analyses confirmed that the mortality risk for women using digoxin was statistically higher than that for those receiving a placebo⁵⁹. There was no evidence of this result in males. Women who were given digoxin had a greater risk of death from any cause than men who were given digoxin (5.8percent absolute rate) or a placebo46. Lower serum concentrations of less than 0.8 ng per mL (1.02nmol per L) are advised, while the origins of the higher mortality risk in women are unclear⁶⁰. In addition, nevirapine (Viramune) and efavirenz (Sustiva), medications for human immunodeficiency virus, cause drug-induced dermatitis in women six to eight times more frequently than in men, and antiepileptic medications cause more drug-induced liver disease in women than in men. These differences may be explained, at least in part, by the fact that females often have superior immune systems and manufacture greater quantities of immunologic products like antibodies²³.

Table 4: depicts examples of sex-differences in ADR^{23,48,49,50,51,61,62}

Class of drugs	Outcomes
Analgesics	To perioperative analgesic drugs, women report higher adverse effects on their bodies.
Anesthetics	Postoperative ADR is more likely to take place in women.
Antiarrhythmic	Increased risk oftorsades de pointes and QT prolongation in women.
H1-Antihistamines	Women are more prone to being sedated and falling asleep.
Antipsychotics	Women have higher extrapyramidal, anticholinergic, and QTc-extending effects. The male reported more sex-related concerns.
Aspirin	Greater risk of bleeding in women. Men have more problems with ulcers.
Beta-blockers	Metoprolol facilitates a woman to decrease her blood pressure and heart rate more effectively.
Calcium channel blockers	Oedema risk is higher in women. When using OC and diazepam during their periods, women experience mild intoxication.
Diuretics	Hospitalization rates for hypoosmolarity, hypokalaemia, hypernatremia, and arrhythmias in women are greater.
NSAIDS	ADRs are more common in men than in women.
Paracetamol	Acute liver failure from aoverdose of paracetamol affects more women than men.
Thiazides	Woman has more hypernatremia and hypokalaemia.
Analgesics	To perioperative analgesic drugs, women report higher adverse effects on their bodies.
Anaesthetics	Postoperative ADR is more likely to take place in women.

CONCLUSION:

Women and men may have distinct reactions to pharmaceuticals due to variations in body composition, the pharmacokinetic and pharmacodynamic features of certain drugs, and changes in endogenous sex hormone levels (pregnancy, the menstrual cycle). Furthermore, adverse medication responses are more common in women than men, and when they do occur, they tend to be more severe in females. Higher plasma levels and potential overdoses in women may occur when fixed dosages are used instead of doses adjusted for body weight. Identifying gender variations in medicine dose, efficacy, and safety is the first step in tailoring therapy to the individual. There has been no investigation into the potential therapeutic significance of gender-based PD/PK differences in medicines. This should encourage both basic and applied research into how sex affects the pharmacodynamics and pharmacokinetics (PD and PK) of drugs in response to pathological circumstances, as well as how sex affects the efficacy and safety of different treatments. The assessment of outcomes by gender requires a cost-effectiveness analysis and the incorporation of quality-of-life measures. Drug selection for the prevention and treatment of various symptoms and illnesses, as well as an improved knowledge of sex-related differences in these factors, would greatly benefit from this data. Dosage recommendations based on gender are no longer mentioned on medicine labels, despite a 40% PK difference between males and females. However, making and using sex-specific pharmaceutical prescriptions is the most effective technique for preventing the higher occurrence of ADR in women.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this review.

REFERENCES:

1. Patrick, K. S. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th Edition Edited by J. G. Hardman, L. E. Limbird, and A. G. Gilman. McGraw Hill, New York. 2001. Xxvii + 2148 Pp. 21 × 26 Cm. ISBN 0-07-1354469-7. $125.00. J. Med. Chem. 2002; 45 (6): 1392–1393. https://doi.org/10.1021/jm020026w.

2. Bren, L. Does Sex Make a Difference? FDA Consum.2005; 39(4): 10–15.

3. Schwartz, J. B. The Influence of Sex on Pharmacokinetics. Clin. Pharmacokinet. 2003; 42(2): 107–121. https://doi.org/10.2165/00003088-200342020-00001.

4. Fletcher, C. V.; Acosta, E. P.; Strykowski, J. M. Gender Differences in Human Pharmacokinetics and Pharmacodynamics. J. Adolesc. Health. 1994; 15(8): 619–629. https://doi.org/10.1016/S1054-139X(94)90628-9.

5. Kimura, T.; Higaki, K. Gastrointestinal Transit and Drug Absorption. Biol. Pharm. Bull. 2002; 25(2): 149–164. https://doi.org/10.1248/BPB.25.149.

6. Fleisher, D.; Li, C.; Zhou, Y.; Pao, L. H.; Karim, A. Drug, Meal and Formulation Interactions Influencing Drug Absorption after Oral Administration. Clinical Implications. Clin. Pharmacokinet. 1999; 36(3): 233–254. https://doi.org/10.2165/00003088-199936030-00004.

7. Mojaverian, P.; Rocci, M. L.; Conner, D. P.; Abrams, W. B.; Vlasses, P. H. Effect of Food on the Absorption of Enteric-Coated Aspirin: Correlation with Gastric Residence Time. Clin. Pharmacol. Ther. 1987; 41(1): 11–17. https://doi.org/10.1038/CLPT.1987.3.

8. Gandhi, M.; Aweeka, F.; Greenblatt, R. M.; Blaschke, T. F. Sex Differences in Pharmacokinetics and Pharmacodynamics. Annu. Rev. Pharmacol. Toxicol. 2004; 44: 499–523. https://doi.org/10.1146/ANNUREV.PHARMTOX.44.101802.121453.

9. Baraona, E.; Abittan, C. S.; Dohmen, K.; Moretti, M.; Pozzato, G.; Chayes, Z. W.; Schaefer, C.; Lieber, C. S. Gender Differences in Pharmacokinetics of Alcohol. Alcohol. Clin. Exp. Res. 2001; 25(4): 502–507. https://doi.org/10.1111/J.1530-0277.2001.TB02242.X.

10. 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(16): 1585–1595. https://doi.org/10.1093/EURHEARTJ/EHI397.

11. Schwartz, J. B. The Current State of Knowledge on Age, Sex, and Their Interactions on Clinical Pharmacology. Clin. Pharmacol. Ther. 2007; 82(1): 87–96. https://doi.org/10.1038/SJ.CLPT.6100226.

12. Ochs, H. R.; Greenblatt, D. J.; Divoll, M.; Abernethy, D. R.; Feyerabend, H.; Dengler, H. J. Diazepam Kinetics in Relation to Age and Sex. Pharmacology. 1981; 23(1): 24–30. https://doi.org/10.1159/000137524.

13. Xue, F. S.; Tong, S. Y.; Liao, X.; Liu, J. H.; An, G.; Luo, L. K. Dose-Response and Time Course of Effect of Rocuronium in Male and Female Anesthetized Patients. Anesth. Analg. 1997; 85(3): 667–671. https://doi.org/10.1097/00000539-199709000-00033.

14. Wedel, M.; Pieters, J. E.; Pikaar, N. A.; Ockhuizen, T. Application of a Three-Compartment Model to a Study of the Effects of Sex, Alcohol Dose and Concentration, Exercise and Food Consumption on the Pharmacokinetics of Ethanol in Healthy Volunteers. Alcohol Alcohol. 1991; 26(3): 329–336. https://doi.org/10.1093/OXFORDJOURNALS.ALCALC.A045119

15. Sowinski, K. M.; Abel, S. R.; Clark, W. R.; Mueller, B. A. Effect of Gender on the Pharmacokinetics of Ofloxacin. Pharmacotherapy. 1999; 19(4): 442–446. https://doi.org/10.1592/PHCO.19.6.442.31044.

16. Whitley, H. P.; Fermo, J. D.; Chumney, E. C. G.; Brzezinski, W. A. Effect of Patient-Specific Factors on Weekly Warfarin Dose. Ther. Clin. Risk Manag. 2007; 3(3):499.

17. Anderson, G. D. Sex and Racial Differences in Pharmacological Response: Where Is the Evidence? Pharmacogenetics, Pharmacokinetics, and Pharmacodynamics. J. Womens. Health (Larchmt). 2005; 14(1): 19–29. https://doi.org/10.1089/JWH.2005.14.19.

18. Garcia, D.; Regan, S.; Crowther, M.; Hughes, R. A.; Hylek, E. M. Warfarin Maintenance Dosing Patterns in Clinical Practice: Implications for Safer Anticoagulation in the Elderly Population. Chest2005;127(6):2049–2056. https://doi.org/10.1378/CHEST.127.6.2049.

19. Dobbs, N. A.; Twelves, C. J.; Gillies, H.; James, C. A.; Harper, P. G.; Rubens, R. D. Gender Affects Doxorubicin Pharmacokinetics in Patients with Normal Liver Biochemistry. Cancer Chemother. Pharmacol. 1995; 36(6): 473–476. https://doi.org/10.1007/BF00685796.

20. Walter Bock, K.; Schrenk, D.; Forster, A.; Griese, E. U.; Mörike, K.; Brockmeier, D.; Eichelbaum, M. The Influence of Environmental and Genetic Factors on CYP2D6, CYP1A2 and UDP-Glucuronosyltransferases in Man Using Sparteine, Caffeine, and Paracetamol as Probes. Pharmacogenetics. 1994; 4(4): 209–218. https://doi.org/10.1097/00008571-199408000-00005.

21. Yukawa, E.; Honda, T.; Ohdo, S.; Higuchi, S.; Aoyama, T. Population-Based Investigation of Relative Clearance of Digoxin in Japanese Patients by Multiple Trough Screen Analysis: An Update. J. Clin. Pharmacol.1997;37(2):92–100. https://doi.org/10.1002/J.1552-4604.1997.TB04766.X.

22. Walle, T.; Walle, U. K.; Cowart, T. D.; Conradi, E. C. Pathway-Selective Sex Differences in the Metabolic Clearance of Propranolol in Human Subjects. Clin. Pharmacol. Ther. 1989; 46(3): 257–263. https://doi.org/10.1038/CLPT.1989.136.

23. Anderson, G. D. Gender Differences in Pharmacological Response. Int. Rev. Neurobiol. 2008; 83: 1–10. https://doi.org/10.1016/S0074-7742(08)00001-9.

24. Campesi, I.; Fois, M.; Franconi, F. Sex and Gender Aspects in Anesthetics and Pain Medication. Handb. Exp. Pharmacol. 2012; 214(214): 265–278. https://doi.org/10.1007/978-3-642-30726-3_13.

25. Kokras, N.; Dalla, C.; Papadopoulou-Daifoti, Z. Sex Differences in Pharmacokinetics of Antidepressants. Expert Opin. Drug Metab. Toxicol. 2011; 7(2): 213–226. https://doi.org/10.1517/17425255.2011.544250.

26. Seeman, M. V. Gender Differences in the Prescribing of Antipsychotic Drugs. Am. J. Psychiatry. 2004; 161(8): 1324–1333. https://doi.org/10.1176/APPI.AJP.161.8.1324.

27. Buchanan, M. R.; Rischke, J. A.; Butt, R.; Turpie, A. G. G.; 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(2): 125–139. https://doi.org/10.1016/0049-3848(83)90134-2.

28. Ho, P.; Triggs, E.; Bourne, D.; Heazlewood, V. The Effects of Age and Sex on the Disposition of Acetylsalicylic Acid and Its Metabolites. Br. J. Clin. Pharmacol. 1985; 19(5): 675–684. https://doi.org/10.1111/J.1365-2125.1985.TB02695.X.

29. Tamargo, J.; Rosano, G.; Walther, T.; Duarte, J.; Niessner, A.; Kaski, J. C.; Ceconi, C.; Drexel, H.; Kjeldsen, K.; Savarese, G.; Torp-Pedersen, C.; Atar, D.; Lewis, B. S.; Agewall, S. Gender Differences in the Effects of Cardiovascular Drugs. Eur. Hear. J. - Cardiovasc. Pharmacother. 2017; 3(3): 163–182. https://doi.org/10.1093/EHJCVP/PVW042.

30. Sheykh, M.; Ostadrahimi, P.; Havasian, M. R.; Rostami-Estabragh, K.; Mahmoodi, Z. Evaluation of Gender Differences in the Prevalence of Coronary Risk Factors in Patients with Acute Intractable Syndrome Hospitalized in CCU of Amir-Almomenin Hospital, Zabol. Res. J. Pharm. Technol. 2017; 10(9): 2883–2886. https://doi.org/10.5958/0974-360X.2017.00509.1.

31. Luzier, A. B.; Killian, A.; Wilton, J. H.; Wilson, M. F.; Forrest, A.; Kazierad, D. J. Gender-Related Effects on Metoprolol Pharmacokinetics and Pharmacodynamics in Healthy Volunteers. Clin. Pharmacol. Ther. 1999; 66(6): 594–601. https://doi.org/10.1053/CP.1999.V66.103400001.

32. Krecic-Shepard, M. E.; Barnas, C. R.; Slimko, J.; Jones, M. P.; Schwartz, J. B. Gender-Specific Effects on Verapamil Pharmacokinetics and Pharmacodynamics in Humans. J. Clin. Pharmacol. 2000; 40(3): 219–230. https://doi.org/10.1177/00912700022008883.

33. Krecic-Shepard, M. E.; Park, K.; Barnas, C.; Slimko, J.; Kerwin, D. R.; Schwartz, J. B. Race and Sex Influence Clearance of Nifedipine: Results of a Population Study. Clin. Pharmacol. Ther. 2000; 68(2): 130–142. https://doi.org/10.1067/MCP.2000.108678.

34. Rajaram, C. U. Review of Captopril Drug Formulation, Mechanism of Action, Dosage, Use and Adverse Drug Reactions. Res. J. Pharm. Dos. Forms Technol. 2021; 13(2): 157–160. https://doi.org/10.52711/0975-4377.2021.00028.

35. 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(1):57–65. https://doi.org/10.1016/S0278-5846(03)00177-5.

36. Kornstein, S. G.; Schatzberg, A. F.; Thase, M. E.; Yonkers, K. A.; McCullough, J. P.; Keitner, G. I.; Gelenberg, A. J.; Davis, S. M.; Harrison, W. M.; Keller, M. B. Gender Differences in Treatment Response to Sertraline versus Imipramine in Chronic Depression. Am. J. Psychiatry. 2000; 157(9): 1445–1452. https://doi.org/10.1176/APPI.AJP.157.9.1445.

37. Bano, S.; Akhter, S.; Afridi, M. Gender Based Response to Fluoxetine Hydrochloride Medication in Endogenous Depression. J. Coll. Physicians Surg. Pak. 2004.

38. Yanagisawa, H. Relation between the Chaos Equation and Gender Differences of the Human Brain- Nightingale’s Brain Was the Fixed Type. Asian J. Nurs. Educ. Res. 2017; 7(3): 273–277. https://doi.org/10.5958/2349-2996.2017.00056.8.

39. Melkersson, K. I.; Hulting, A. L.; Rane, A. J. Dose Requirement and Prolactin Elevation of Antipsychotics in Male and Female Patients with Schizophrenia or Related Psychoses. Br. J. Clin. Pharmacol. 2001; 51(4): 317–324. https://doi.org/10.1046/J.1365-2125.2001.01352.X.

40. Berkley, K. J. Sex Differences in Pain. Behav. Brain Sci. 1997; 20(3): 371–380. https://doi.org/10.1017/S0140525X97221485.

41. Pleym, H.; Spigset, O.; Kharasch, E. D.; Dale, O. Gender Differences in Drug Effects: Implications for Anesthesiologists. Acta Anaesthesiol. Scand. 2003; 47(3): 241–259. https://doi.org/10.1034/J.1399-6576.2003.00036.X.

42. Craft, R. M. Sex Differences in Drug- and Non-Drug-Induced Analgesia. Life Sci. 2003; 72(24): 675–2688. https://doi.org/10.1016/S0024-3205(03)00178-4.

43. Berger, J. S.; Roncaglioni, M. C.; Avanzini, F.; Pangrazzi, I.; Tognoni, G.; Brown, D. L. Aspirin for the Primary Prevention of Cardiovascular Events in Women and Men: A Sex-Specific Meta-Analysis of Randomized Controlled Trials. JAMA. 2006; 295(3): 306–316. https://doi.org/10.1001/JAMA.295.3.306.

44. Cavallari, L. H.; Helgason, C. M.; Brace, L. D.; Viana, M. A. G.; Nutescu, E. A. Sex Difference in the Antiplatelet Effect of Aspirin in Patients with Stroke. Ann. Pharmacother. 2006; 40(5): 812–817. https://doi.org/10.1345/APH.1G569.

45. Valer’evich, B. V.; Vladimirovna, B. A.; Andreevich, L. K.; Isaakovich, V. A.; Vasil’evich, U. V. Distribution and Transmembrane Transport as the Basis of Proper Pharmacodynamics of an Antithrombotic Drug – An Indolinone Derivative. Res. J. Pharm. Technol. 2022; 15(3): 1241–1244. https://doi.org/10.52711/0974-360X.2022.00207.

46. Krecic-Shepard, M. E.; Barnas, C. R.; Slimko, J.; Schwartz, J. B. Faster Clearance of Sustained Release Verapamil in Men versus Women: Continuing Observations on Sex-Specific Differences after Oral Administration of Verapamil. Clin. Pharmacol. Ther. 2000; 68(3): 286–292. https://doi.org/10.1067/MCP.2000.109356.

47. Kang, D.; Verotta, D.; Krecic-Shepard, M. E.; Modi, N. B.; Gupta, S. K.; Schwartz, J. B. Population Analyses of Sustained-Release Verapamil in Patients: Effects of Sex, Race, and Smoking. Clin. Pharmacol. Ther. 2003; 73(1): 31–40. https://doi.org/10.1067/MCP.2003.21.

48. Dadashzadeh, S.; Javadian, B.; Sadeghian, S. The Effect of Gender on the Pharmacokinetics of Verapamil and Norverapamil in Human. Biopharm. Drug Dispos. 2006; 27(7): 329–334. https://doi.org/10.1002/BDD.512.

49. Manteuffel, M.; Williams, S.; Chen, W.; Verbrugge, R. R.; Pittman, D. G.; Steinkellner, A. Influence of Patient Sex and Gender on Medication Use, Adherence, and Prescribing Alignment with Guidelines. J. Womens. Health (Larchmt). 2014; 23(2): 112–119. https://doi.org/10.1089/JWH.2012.3972.

50. Kjeldsen, S. E.; Kolloch, R. E.; Leonetti, G.; Mallion, J. M.; Zanchetti, A.; Elmfeldt, D.; Warnold, I.; Hansson, L. Influence of Gender and Age on Preventing Cardiovascular Disease by Antihypertensive Treatment and Acetylsalicylic Acid. The HOT Study. Hypertension Optimal Treatment. J. Hypertens. 2000; 18(5): 629–642. https://doi.org/10.1097/00004872-200018050-00017.

51. Vree, T. B.; Dammers, E.; Valducci, R. Sex-Related Differences in the Pharmacokinetics of Isosorbide-5-Mononitrate (60 Mg) after Repeated Oral Administration of Two Different Original Prolonged Release Formulations. Int. J. Clin. Pharmacol. Ther. 2004; 42(8): 463–472. https://doi.org/10.5414/CPP42463.

52. Rademaker, M. Do Women Have More Adverse Drug Reactions? American Journal of Clinical Dermatology. 2001. https://doi.org/10.2165/00128071-200102060-00001.

53. Rajput, M. D.; Rajput, Y. B.; Rajput, L. D. A Review on Adverse Drug Reaction. Asian J. Pharm. Res. 2020; 10(3): 221–225. https://doi.org/10.5958/2231-5691.2020.00038.6.

54. Drici, M. D.; Clément, N. Is Gender a Risk Factor for Adverse Drug Reactions? The Example of Drug-Induced Long Qt Syndrome. Drug Saf. 2001; 24(8): 575–585. https://doi.org/10.2165/00002018-200124080-00002/METRICS.

55. Abubakar, A. R.; Simbak, N. Bin; Haque, M. Adverse Drug Reactions: Predisposing Factors, Modern Classifications and Causality Assessment. Res. J. Pharm. Technol. 2014; 7(9): 1091–1098.

56. Dutta, M.; Prashad, L. Prevalence and Risk Factors of Polypharmacy among Elderly in India: Evidence from SAGE Data. Int. J. Public Ment. Heal. Neurosci.2015;2.

57. Menaka, K.; Sarumathy, S.; Sivakumar, T. Study on the Adverse Reactions of Antipsychotics and Therapeutic Drug Monitoring of Olanzapine in Psychiatric Patients. Res. J. Pharm. Technol. 2016; 9(6): 687–690. https://doi.org/10.5958/0974-360X.2016.00128.1.

58. The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure. N. Engl. J. Med. 1997; 336(8): 525–533. https://doi.org/10.1056/NEJM199702203360801.

59. Rathore, S. S.; Wang, Y.; Krumholz, H. M. Sex-Based Differences in the Effect of Digoxin for the Treatment of Heart Failure. N. Engl. J. Med. 2002; 347(18): 1403–1411. https://doi.org/10.1056/NEJMOA021266.

60. Regitz-Zagrosek, V. Therapeutic Implications of the Gender-Specific Aspects of Cardiovascular Disease. Nat. Rev. Drug Discov. 2006; 5(5): 425–439. https://doi.org/10.1038/NRD2032.

61. Goud, C. M.; Ghazanfar, S. M. Nimesulide – A Drug to Be Banned Completely. Asian J. Pharm. Res. 2021; 11(2): 132–137. https://doi.org/10.52711/2231-5691.2021.00025.

62. Kumar, S.; Badruddeen; Singh, S.; Akhtar, J.; Khan, M.; Ahmad, M.; Ahmad, U. Assessment of Analgesics Induced Adverse Drug Reactions in a Tertiary Care Hospital. Res. J. Pharm. Technol. 2020; 13: 4861–4864. https://doi.org/10.5958/0974-360X.2020.00855.0.

Received on 04.07.2023 Modified on 06.09.2023

Res. J. Pharmacology and Pharmacodynamics.2023;15(4):179-185.

DOI: 10.52711/2321-5836.2023.00032