Gender Pharmacology Dictionary

Chemical formula
C9H13NO3

Compound Information

Adrenaline is a naturally occurring neurotransmitter hormone produced by the adrenal glands and can be administered intravenously, intramuscularly, or subcutaneously. The pharmacological form is better known as epinephrine. It is a sympathomimetic drug that primarily acts on adrenergic receptors, mimicking the effects of the sympathetic nervous system, particularly in situations of stress and emergency, which induce the "fight or flight" response. Additionally, it promotes gluconeogenesis and glycogenolysis, increasing blood glucose levels to provide rapid energy to the body during emergencies. Its effects are mainly due to the activation of alpha (α1, α2) and beta (β1, β2, β3) receptors, each of which has a specific impact on the body:

• Alpha-1 receptors (α1): vasoconstriction and increased blood pressure;

• Beta-1 receptors (β1): increased heart rate (positive chronotropic effect), contraction force (positive inotropic effect), and conduction speed (positive dromotropic effect);

• Beta-2 receptors (β2): bronchodilation, improving respiration in conditions like asthma or bronchospasm, vasodilation, and reducing diastolic blood pressure (DBP);

• Beta-3 receptors (β3): stimulate lipolysis, which is the mobilization of fats from adipose tissue, and promote the relaxation of smooth muscle, such as in the urinary tract and uterus.
  
  

Epinephrine undergoes extensive biotransformation, primarily in the liver, kidneys, and other extraneuronal tissues. The main metabolic enzymes involved in its metabolism are monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), which degrade epinephrine into inactive metabolites, particularly vanillylmandelic acid. After intravenous administration, epinephrine is rapidly distributed throughout the body. The pharmacokinetic profile shows a rapid decline in plasma concentrations, with a steady-state typically reached within 10-15 minutes when administered as a continuous infusion. Most epinephrine is eliminated via metabolic pathways, with only a small fraction excreted unchanged in the urine. The liver plays a dominant role in epinephrine clearance, significantly contributing to its removal from the bloodstream. Additional contributions to the elimination process come from the kidneys, skeletal muscle, and mesenteric organs, all vital in clearing the drug from circulation. Metanephrine is the main metabolite derived from the methylation of adrenaline, catalyzed by COMT, and present at 40% in the metabolites of adrenaline excreted through urine. The same percentage of vanillylmandelic acid is found among these. There is then 7% of 3-methoxy-4-hydroxyphenylglycol and 2% of 3,4-dihydroxyphenylacetic acid. The remaining 1% of adrenaline's urinary metabolites consists of its acetylated derivatives. The adverse effects of adrenaline depend on the dose and individual response to the drug, including:

• Tachycardia;

• Hypertension;

• Arrhythmias;

• Angina;

• Anxiety;

• Tremors;

• Dizziness;

• Light-headedness;

• Headache;

• Shortness of breath;

• Weakness;

• Nausea.
  
  

Uses
Adrenaline is mainly used in the treatment of hypersensitivity reactions and in medical emergencies (CPR), to prolong the action of infiltrated anesthetics. Since 1987, the EpiPen has made adrenaline available in a form suitable for self-administration, especially for patients with severe allergies: adrenaline works quickly by constricting blood vessels, increasing blood pressure, and relaxing the muscles of the airways to facilitate breathing. It can also be used to treat asthma attacks, as adrenaline also acts as a bronchodilator, relaxing the muscles of the airways, reducing inflammation, and allowing better airflow to the lungs.

Gender Differences
Epinephrine as a drug may have different responses between men and women due to hormonal and physiological variations between the sexes. Women tend to be more sensitive to the effects of epinephrine and may respond to lower doses than men: estrogen, which is more prevalent in women, increases sensitivity to adrenergic receptors, enhancing the effect of epinephrine. Although there are no significant differences in therapeutic recommendations based on sex, cardiovascular and metabolic responses may vary, requiring appropriate monitoring and dose adjustments. Therefore, while both sexes produce adrenaline in response to stressful situations, women tend to experience a longer and more complex response, while men respond more quickly and for a shorter period.

Chemical formula
C₆₄₄₄H₉₉₆₄N₁₇₁₂O₂₀₁₈S₄₄

Compound information
Anifrolumab is a human monoclonal antibody of immunoglobulin G1 kappa (IgG1κ), produced in murine myeloma cells (NS0) using recombinant DNA technology.

Usage
Anifrolumab is indicated as an add-on therapy for the treatment of adult patients with active systemic lupus erythematosus (SLE), autoantibody-positive, with moderate to severe forms, despite standard therapy.

Gender differences

• Basal type I interferon activity: Women have higher basal type I interferon activity compared to men, which may lead to increased susceptibility to the side effects associated with the use of anifrolumab.

• Influence of estrogens: Estrogens may modulate the action of anifrolumab, influencing the therapeutic response and safety profile of the drug in women.

• Body composition and weight: Differences in body composition and weight between men and women may influence the absorption and metabolism of anifrolumab, potentially altering its effectiveness and the risk of side effects.

Special considerations for pregnancy and fertility

• Anifrolumab is classified as Category C for use in pregnancy, indicating that animal studies have shown adverse effects on the fetus, but there are no adequate and well-controlled studies in pregnant women.

• It is recommended to avoid the use of anifrolumab during pregnancy unless the benefits outweigh the potential risks.

• It is not known whether anifrolumab is excreted in breast milk; therefore, a decision should be made whether to discontinue breastfeeding or the treatment, considering the importance of the drug for the mother.

Chemical Formula
C25H29I2NO3

Compound Information
A Class III antiarrhythmic agent, commercially known as Cordarone.

• It inhibits potassium channels, leading to a prolongation of the repolarization phase III of the action potential and an increase in the refractory period.

• It has negative chronotropic and inotropic effects, as it reduces heart rate and the strength of cardiac contraction.

• It can exert a suppressive action on the autonomic sympathetic system, being a non-competitive antagonist of alpha and beta-adrenergic receptors.

Uses
It is used in the treatment of various types of cardiac arrhythmias, particularly in patients with dilated or ischemic cardiomyopathy and arrhythmias refractory to other drugs, with the goal of restoring sinus rhythm.

Gender Differences

• Hepatic metabolism of amiodarone in females is slower, as estrogens can influence the enzymatic activity of cytochrome P450, contributing to increased plasma concentrations of the drug, its toxicity, and consequently, the side effects.

• The greater accumulation in women is also potentiated by the higher percentage of body fat present in females.

• For these reasons, the risk of developing bradycardia and hypotension is also increased.

Chemical Formula

C25H25N5O4

Compound Information

This is a pyrazolopyridine, a member of piperidones that acts as:

• A new-generation oral anticoagulant

• A direct and reversible inhibitor of factor Xa

• An interferer with the conversion of prothrombin into thrombin

• A factor for preventing the formation of reticulated fibrin clots.

Usage

• Prevention and treatment of the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation

• Prophylaxis of deep vein thrombosis to prevent blood clot formation leading to pulmonary embolism in patients undergoing hip or knee replacement surgery

• Treatment of patients with irregular heartbeats (atrial fibrillation) and at least one additional risk factor.

• Gender Differences

Regarding the female gender:

• Increased risk of bleeding during pregnancy (but no increased risk of fetal malformations)

• Interactions with contraceptive drugs and drugs used during pregnancy and childbirth

• Interactions with antineoplastic chemotherapeutics like cisplatin, typically used to treat breast cancer (more common in females)

• Higher incidence of bleeding in women with acute venous thromboembolism

• Some studies on lactating female rats suggest that the active ingredient apixaban may be excreted in breast milk and, as a result, ingested by offspring, causing clotting episodes and a risk of bleeding in them. However, no studies have been conducted on humans. Nevertheless, it is advisable for breastfeeding women to discontinue the therapy as a precaution.

• Evidence in transgender individuals → Negative interactions have been observed between apixaban and the administration of estrogen and testosterone used during the transition phase.

Chemical Formula

C₃₃H₃₅FN₂O₅

Compound Information

This belongs to the class of statins.

Usage

• Treatment of high cholesterol and reduction of the risk of stroke, heart attack, and cardiovascular complications.

• Reduction of LDL (low-density lipoprotein) cholesterol.

• Reduction of triglycerides.

• Increase in HDL (high-density lipoprotein) cholesterol.

• Reduction of the risk of: Stroke, heart attack, atherosclerosis, cardiovascular and coronary diseases, cardiovascular complications (in patients with type 2 diabetes, coronary diseases, or other risk factors for heart and artery health).

Gender differences

1. Adverse effects: 

• • • Some adverse effects, such as toxic damage to skeletal muscle and the incidence of diabetes mellitus, appear to be more frequent in women.

    • The prescription rate of statins in women is lower compared to the male counterpart.

    • Cardiovascular diseases are more common in the male population.

    • The mortality rate due to coronary heart diseases is higher in the female population.

    • Coronary heart disease is more frequent in men before menopause; thereafter, the incidence rate reverses.

    • Lipid profile abnormalities are more common in females.

2. Atorvastatin absorption:

• • • Women: Reduced gastrointestinal motility.

    • Men: Faster gastric emptying rate.

3. Atorvastatin distribution:

• • • Better distribution in women due to the lipophilic nature of statins.

4. Metabolism:

• • • Statin metabolism appears to be faster in females.

    • Drug efficacy is higher in males.

5. Pharmacokinetic differences:

• • • CYP3A4 enzyme: Women express double the amount of cytochrome P450 compared to men, leading to faster and more extensive statin metabolism.

    • Body composition: Women tend to have lower body mass and more adipose tissue than men, influencing drug distribution volume and prolonging drug half-life, thereby increasing efficacy.

    • Glomerular filtration: Slower rate in women, with a possible need for dosage adjustment to avoid side effects.

6. Adverse effects:

• • • Higher risk of discontinuing or changing therapy in women due to greater side effects compared to men.

    • Type 2 diabetes: Increased risk by 33% in women over 75.

Chemical Formula

C₁₆H₁₉N₃O₅S±3H₂O

Compound Information

Augmentin is composed of the combination of amoxicillin (a semisynthetic derivative of aminopenicillin) and clavulanic acid (a beta-lactamase inhibitor), which allows it to have a bactericidal effect while protecting amoxicillin from the action of bacterial beta-lactamases.

Usage

Augmentin is indicated for the treatment of infectious diseases caused by microorganisms sensitive to amoxicillin and for surgical prophylaxis to prevent bacterial contamination.

The drug is effective in treating the following infections:

• Respiratory infections

• Intestinal infections

• Spleen infections

• Septicemia

• Endocarditis

• Peritonitis

• Listeria meningitis

• Typhoid and paratyphoid fever

• Actinomycosis

Gender Differences

• Sex does not seem to have a significant impact on the pharmacokinetics of the drug.

• In Pregnancy → Animal studies have not revealed any harmful effects, either direct or indirect, related to pregnancy, embryonic/fetal development, childbirth, or postnatal development. Limited human data on the use of amoxicillin/clavulanic acid during pregnancy do not indicate an increased risk of congenital malformations. However, usage during pregnancy should be avoided unless otherwise directed by a healthcare provider.

• Breastfeeding → Both substances in the drug are excreted in breast milk. However, the potential effects on the infant are not yet well known. Diarrhea and fungal infections of the mucous membranes may occur. In these cases, breastfeeding should be discontinued.

Chemical Formula

C₉H₈O₄

Compound Information

Cardioaspirin is an antithrombotic based on acetylsalicylic acid. It acts by blocking the synthesis of prostaglandins, which are responsible for pain perception.

Usage

Cardioaspirin is used for the prevention of major atherothrombotic events, reocclusion of aortocoronary bypasses and percutaneous transluminal coronary angioplasty, cardiovascular events, reducing the risk of cardiovascular death, risks related to myocardial infarction/cerebral stroke, and reducing platelet adhesion after carotid endarterectomy. It is also administered for the treatment of fever, pain, inflammation, and flu, as well as the treatment of cardiovascular thromboembolism and angina pectoris.

Gender Differences

• Absorption: women may experience delayed gastric emptying, which can influence the absorption rates of orally administered NSAIDs.

• Distribution: NSAIDs are highly protein-bound drugs. Women have slightly lower plasma albumin levels, leading to higher free drug concentrations, making them more prone to developing side effects.

• Metabolism: women have lower levels of certain liver enzymes (e.g., cytochrome P450) involved in drug metabolism, which may cause slower clearance.

• Excretion: women generally have slower renal clearance for NSAIDs, thus prolonging the half-life of the drug, increasing both its efficacy and the risk of side effects.

Additionally, regarding Cardioaspirin:

• Women show a faster absorption rate.

• Women are more commonly subject to drug resistance.

• Women experience more side effects (hemorrhagic strokes, bleeding, thrombotic events).

• The female population shows significantly higher levels of acetylsalicylic acid and salicylic acid, across all age groups, compared to men, and these levels remain elevated even after normalizing body weight. This is due to the fact that the enzymes to metabolize NSAIDs are lower in women.

• Salicyluric acid levels are higher in men than in women, especially in young women who do not take oral contraceptives, which are responsible for increasing these metabolic pathways.

• Studies show that low doses of aspirin reduce platelet reactivity similarly in both genders, although platelet reactivity in women remains higher after aspirin.

• In men, Cardioaspirin may help combat impotence and erectile dysfunction.

• The antithrombotic action is greater in the male population.

• The drug helps prevent stroke in women and myocardial infarction in men, but overall, the reduction of cardiovascular events is significant and very similar between the sexes.

• An increased risk of intracranial and extracranial bleeding is observed in both women and men, but cerebral hemorrhages are more prevalent in men.

• Cardiovascular protection:

  • • In men: greater efficacy in preventing myocardial infarction (MI).

    • In women: more effective in reducing the risk of ischemic stroke rather than MI.

• Pain and inflammation: mixed evidence has been found regarding sex differences in the efficacy of analgesics and anti-inflammatory drugs.

• Platelet inhibition: women may exhibit reduced platelet responsiveness to aspirin compared to men.

• Gastrointestinal (GI) effects: women tend to have more gastrointestinal issues related to NSAIDs (nausea, dyspepsia, ulcerations, etc.), linked both to delayed gastric emptying and hormonal factors.

• Cardiovascular side effects: the cardiovascular risks related to COX-2 inhibitors are more prominent in women due to variations in blood pressure regulation and lipid profile (due to hormonal factors). Women reporting contraindications were 20.5% of those in the study group, compared to 12.5% of men.

• Dosage recommendations: current guidelines may not always account for sex-specific pharmacological differences. Indeed, individual patient factors are still preferred due to the lack of data regarding sex and gender specificity.

• Aspirin tends to be more effective in reducing the risk of myocardial infarction in men.

• Women have a higher risk of experiencing gastrointestinal bleeding due to hormonal differences and the fact that they are more likely to have other diseases that increase the risk of bleeding (e.g., anemia).

• Women, on average, report higher pain intensity, so they may require higher doses to achieve the same pain relief as men.

In Pregnancy: cardioaspirin is contraindicated because the inhibition of prostaglandin synthesis can negatively affect embryonic development. It is also not recommended during breastfeeding unless prescribed by a healthcare provider.

Chemical Formula
C₂₆H₃₇N₅O₂

Compound Information
Cabergoline is a dopamine agonist that works by inhibiting the secretion of prolactin. It has a relatively long half-life, ranging from 63 to 110 hours, and is usually administered orally once or twice a week, at a dosage between 0.25 and 0.5 mg per week.

Uses
It is used to reduce prolactin levels and shrink prolactinomas, proving to be highly effective in approximately 70–90% of cases by lowering prolactin levels and reducing tumor size.

Sex-Based Differences
Some studies show that women tend to respond better to treatment than men, exhibiting a greater decrease in prolactin levels. However, the drug may cause side effects: women may experience changes in sexual desire, while in men there is an increased risk of hypersexuality and behavioral disturbances.

Sources

Chemical Formula

C₁₈H₁₉ClN₄

Compound Information

It belongs to the chemical class of benzodiazepines and has a cholinergic action.

Usage

• This is an antipsychotic drug, primarily indicated for the treatment of treatment-resistant schizophrenia. It is recommended for patients who show a poor response to standard antipsychotic drugs. 

• It reduces delusions, the perception of persecution, hallucinations, disorganized thoughts/language, and bizarre motor coordination. 

• Clozapine has also been shown to significantly reduce the suicide rate. It can be administered to patients with Parkinson's disease. The advantage of clozapine is that it shows reduced extrapyramidal effects, resulting in a better tolerability profile.

Gender Differences

Most studies on treatment response have been focused on the male population, neglecting female subjects and not considering the complexity of their different hormonal status. Depending on specific phases of the female reproductive cycle, prescriptions should be made with particular attention.

Among other differences, women generally:

• Have a better outcome than men in terms of neurological and psychotic diseases such as schizophrenia.

• Are less likely to be hospitalized than men.

• Are less prone to legal problems.

• Have better relationships with their families.

• Are more at risk of weight gain, especially after menopause.

• May need an increased dose following menopause.

There are also theoretical reasons why effective doses of antipsychotics for women might need to be lower than the recommended guidelines for men, especially concerning olanzapine and clozapine. However, with so many variables impacting antipsychotic response, it is challenging to provide definitive guidance.

Chemical Formula

C₂₄H₂₉NO₃

Compound Information

Donepezil is a selective and reversible acetylcholinesterase inhibitor. In Italy, it is available in various authorized pharmaceutical forms. The main formulations include film-coated tablets (available in 5 mg and 10 mg doses) and orodispersible tablets (also 5 mg and 10 mg), which dissolve quickly in the mouth without the need for water—making them easier to take for patients with swallowing difficulties. Donepezil was first approved by the FDA in 1996, and an extended-release formulation in combination with memantine (an NMDA receptor antagonist) was approved in 2014 to manage moderate to severe Alzheimer’s disease. A transdermal delivery system for donepezil was approved by the FDA in March 2022 for the treatment of Alzheimer’s dementia. However, transdermal formulations are not yet available in Italy. Patches like Adlarity are approved in the United States. The LD50 (lethal dose for 50% of a test population under controlled conditions, typically in lab animals) of donepezil in rats is 32.6 mg/kg. Signs and symptoms of overdose in humans with cholinesterase inhibitors like donepezil may include:

• Severe nausea and vomiting

• Bradycardia

• Hypotension

• Sweating

• Seizures

• Muscle weakness

• Respiratory depression

• Collapse
  
  

Significant muscle weakness can be fatal if respiratory muscles are involved in the overdose. To treat an overdose, anticholinergic agents such as atropine can be used as antidotes. It is currently unknown whether donepezil can be removed from the body via dialysis.

Use

Donepezil is used to treat symptoms of Alzheimer’s disease, including confusion, memory loss, and agitation. While it does not alter disease progression, it improves cognitive and behavioral symptoms. It is also used off-label for conditions such as:

• Vascular dementia: caused by damage to cerebral blood vessels. Though benefits are less established than in Alzheimer’s, some studies suggest cognitive and memory improvements.

• Dementia with Lewy bodies (DLB): used to improve cognitive and behavioral symptoms like hallucinations, cognitive fluctuations, and parkinsonian symptoms.

• Parkinson’s disease dementia (PDD): helps improve attention and memory by increasing acetylcholine in the brain.

• Post-stroke cognitive deficits

• Down syndrome

• Adult ADHD

• Post-traumatic stress disorder (PTSD)

• Schizophrenia
  
  

Off-label use of donepezil must be carefully evaluated by the physician, as efficacy and safety in these conditions are not always supported by definitive clinical studies.

Pharmacokinetics

Donepezil is slowly absorbed through the gastrointestinal tract after oral administration.

• Tmax (time to reach maximum plasma concentration) is approximately 3–4 hours, with 100% bioavailability.

• Steady-state concentrations are reached within 15–21 days of administration.

• A pharmacokinetic study determined a mean Tmax of 4.1 ± 1.5 hours.
  
  

Donepezil is widely distributed in extravascular compartments. It binds to plasma proteins at around 96%, particularly albumin and alpha-1-glycoprotein. It crosses the blood-brain barrier. Donepezil undergoes first-pass metabolism in the liver, primarily via cytochrome P450 enzymes, especially CYP3A4, and to a lesser extent CYP2D6. In a study involving radiolabeled donepezil in healthy adults:

• 57% of the measured radioactivity was excreted in the urine

• 5% was found in the feces.

The half-life (time for plasma concentration to decrease by 50%) is approximately 70 hours, according to various FDA studies. One pharmacokinetic study found a mean terminal half-life of 81.5 ± 22.0 hours.

Mechanism of Action

Donepezil is a selective and reversible acetylcholinesterase inhibitor, which increases the availability of acetylcholine in the central nervous system, enhancing cholinergic transmission. By inhibiting the enzyme acetylcholinesterase, donepezil improves cognitive and behavioral symptoms of Alzheimer’s disease, which may include apathy, aggression, confusion, and psychosis. Acetylcholine is a key neurotransmitter for neural signaling, essential for memory, learning, and attention. The widely accepted cholinergic hypothesis suggests that part of the cognitive and behavioral decline in Alzheimer’s is due to reduced cholinergic transmission in the brain. Donepezil’s main pharmacological effects result from this enzymatic inhibition, leading to increased acetylcholine availability and improved symptoms of dementia.

Gender-Specific Differences

Although no specific studies have been conducted on sex and gender differences for donepezil, inferences can be made based on established biological knowledge. Women have lower gastric pH and intestinal motility, which may affect drug absorption. Women generally show reduced hepatic clearance, potentially leading to higher drug exposure.
Higher plasma concentrations of donepezil in women may occur due to body composition differences: women typically have more body fat, affecting drug distribution. Lower average body weight in women can also contribute to higher concentrations at equivalent doses. Women tend to have reduced renal excretion, increasing the risk of accumulation with repeated dosing, although donepezil’s long half-life must also be considered. Treatment responses may vary between men and women due to factors like neuroprotective effects of estrogen, and differences in absorption, distribution, metabolism, and elimination. This highlights the need for personalized treatment approaches to optimize efficacy and minimize risk. Ideally, future drug development should aim for gender-specific dosing regimens.

Bibliography

Chemical Formula

C17H21NO.C7H7ClN4O2

Compound Information

It belongs to the class of medication called antihistamines and works by preventing problems with body balance. 

Usage

It's used to prevent and treat nausea, vomiting, vertigo and motion sickness. It reduces intestinal motility, having an anticholinergic effect at high doses. It may also have sedative effects and cause euphoria and concentration problems. It is also used to treat labyrinthitis. 

Gender Differences

Sedative properties are enhanced in women, as estrogen increases the permeability of the Blood Brain Barrier. Furthermore, women may experience greater adverse effects. 

Chemical Formula

C27H29NO11

Compound Information

Doxorubicin is an antibiotic antineoplastic drug belonging to the anthracycline family with antitumor action.

Usage

It is used for the treatment of various cancers, including carcinomas, lymphomas, sarcomas, leukemias, myelomas, neuroblastomas, and Wilms tumor.

Gender Differences

In Men:

• Infertility may occur in males.

• Individuals of the male sex are advised to avoid conception during treatment and for 6 months after.

In Women:

• Fertile women must use effective contraception during doxorubicin treatment and for 6 months after the therapy.

Chemical formula
C₁₇H₁₆Cl₃N₃O₃

Compound information
Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in combination therapy for the treatment of HIV-1. It works by inhibiting the reverse transcriptase enzyme, which is essential for viral replication and integration into the host's DNA.

Usage
Efavirenz is used as part of a combination therapy with other antiretroviral drugs to treat HIV-1 infection in adults and pediatric patients. It is administered to suppress viral load and improve immune function.

Gender-specific differences

• Higher plasma drug levels in women: women experience more frequent and severe side effects from efavirenz, likely due to higher plasma drug levels compared to men. This is related to differences in body weight and fat distribution between the sexes.

• Reduced efficacy in women: there is evidence suggesting reduced efficacy of efavirenz in women, with a potential increase in the risk of vertical HIV transmission, although further studies are needed to confirm this.

• Teratogenic risk: efavirenz has potential teratogenic effects, especially during the first trimester of pregnancy. However, recent studies suggest a lower risk of neural tube defects than initially thought.

• Pregnancy: pregnancy may alter the pharmacokinetics of efavirenz, requiring careful monitoring and possible dose adjustments during pregnancy.

• Interactions with oral contraceptives: efavirenz may reduce the efficacy of combined oral contraceptives (COCs) by increasing their metabolism, thereby reducing their effectiveness. This interaction was highlighted in a study involving Ugandan women living with HIV.

• Hormonal therapy in transgender women: efavirenz may reduce the bioavailability of estradiol, a hormone used in hormone replacement therapy for transgender women, due to the induction of CYP3A4, which accelerates estradiol metabolism.

• Special considerations for pregnancy and fertility
  Efavirenz is not recommended during pregnancy, especially in the first trimester, due to its potential teratogenic effects.

• If taken during pregnancy, close monitoring is required.
  Efavirenz may also affect reproductive health, impacting fertility and pregnancy outcomes.

• Women who are pregnant or planning a pregnancy should consult their healthcare provider regarding

Chemical formula

C17H18F3NO

Information about the compound

Commonly referred to as the "happiness pill," fluoxetine is a second-generation antidepressant classified as a selective serotonin reuptake inhibitor (SSRI). It is known for its role in regulating the circadian rhythms, controlling appetite and eating behavior, and influencing sexual behavior and social relationships, among many other biological functions.

Usage

Frequently prescribed for managing depressive disorders, fluoxetine is also used for the treatment of:

• Bulimia nervosa

• Obsessive-compulsive disorder (OCD)

• Premenstrual dysphoric disorder (PMDD)

• Panic disorder

• Bipolar disorder

Gender Differences

• Numerous studies have indicated that individuals of the female sex exhibit a stronger response to the medication compared to those of the male sex.

• Some studies have shown that women treated with fluoxetine have higher rates of relapse compared to men.

• The prevalence of suicidal behavior was higher in men treated with fluoxetine than in women, according to a large study in the British registry.

• No studies have been published on gender differences in the pharmacokinetics of fluoxetine in healthy adult men and women.

• A small study on elderly subjects (aged 65-85 years; 11 men, 14 women) found no sexual differences in plasma concentrations, half-life, or clearance of fluoxetine. However, women had levels that were 17% higher and slower elimination of the active metabolite norfluoxetine.

• In a study involving children and adolescents diagnosed with major depressive disorder, obsessive-compulsive disorder, or generalized anxiety disorder (24 boys, 50 girls; aged 10-17 years), average doses and average serum concentrations were higher in girls compared to boys (week 8: 26.6 vs. 18.5 mg/day; 111.4 vs. 61.7 ng/ml). However, other studies on children and adolescents using average doses of 20 mg/day did not show gender differences in serum concentrations of fluoxetine and its active metabolite, norfluoxetine.

During Pregnancy

Fluoxetine can be used during pregnancy but should be prescribed with caution, especially in the late stages of pregnancy or just before the onset of labor, as neonates have been reported to experience effects such as irritability, tremors, hypotonia, persistent crying, and difficulty sleeping. It is known that fluoxetine is also excreted in human breast milk. Adverse events have been reported in breastfed neonates. If fluoxetine treatment is deemed necessary, consideration should be given to discontinuing breastfeeding or reducing the dose to a minimum.

Chemical formula

C₄H₃FN₂O₂

Usage

Used in the treatment of:

• Actinic keratosis

• Basal cell carcinoma

• Palliative treatment for breast, colon, rectum, stomach, and pancreatic carcinoma

• Pediatric patients

• Elderly patients

• Polichemotherapy treatment protocols.

Gender Differences

• Women, having a slower gastric emptying and a greater volume of distribution for lipophilic drugs, exhibit a 1.7-fold increase in adverse effects. However, the longer half-life provides a survival benefit.

• Men undergoing chemotherapy with 5-fluorouracil have a shorter average overall survival and an unfavorable outcome.

• Women are more sensitive to toxicity, especially in the gastrointestinal and mucosal regions when treated with 5-fluorouracil. They may experience symptoms such as alopecia, constipation, "hand-foot" syndrome, and epigastralgia.

• In a meta-analysis published on March 15, 2005, which included four clinical trials with 1,074 patients with colorectal cancer, women had more hematological side effects compared to men, and moderate to severe mucositis was more frequent in women than in men.

• 5-fluorouracil therapy can lead to loss of fertility in both men and women and has a teratogenic effect on the fetus.

• Episodes of nausea and vomiting are much more frequent in males than in females, partly due to the lower effectiveness of antiemetic drugs.

Chemical formula

C13H18O2

Indications for the Compound
This is a non-steroidal anti-inflammatory drug (NSAID) characterized by anti-inflammatory and analgesic properties, owing to its action in inhibiting the production of prostaglandins in the central nervous system. The pharmacodynamic action of ibuprofen is based on biochemical mechanisms that involve the inhibition of key enzymes involved in the synthesis of inflammatory mediators, called prostaglandins.

Usage
It is used to alleviate acute pain, such as headaches, neuralgias, menstrual cramps, musculoskeletal pain (e.g., neck pain), traumatic pain (e.g., associated with bruises, sprains, muscle strains), post-partum pain, and post-operative pain. It is also used to treat symptoms of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Furthermore, it also exhibits antipyretic properties.

Gender Differences

• Men show a greater analgesic response compared to women. This phenomenon may be related to various physiological and hormonal factors. 

• However, women may experience a stronger analgesic response due to the influence of estrogen and progesterone on the expression of COX-2, which modulates the inflammatory response and pain sensitivity.

• Older men and those with coronary heart disease are identified as high-risk groups for prolonged ibuprofen use.
  Frequent and prolonged use may contribute to the development of hypogonadism in the male population.

• Women, on the other hand, if taking it for extended periods, present a higher risk of auditory damage, a condition potentially linked to drug sensitivity.

• During the luteal phase of the menstrual cycle, the analgesic effect may be enhanced because pain receptors are more sensitive. In general, estrogens can potentiate the anti-inflammatory response by modulating the expression of prostaglandins.

• Gastric pH and gastrointestinal motility are reduced in women compared to men, and both are influenced by hormones. As a result, these factors may vary during the menstrual cycle and pregnancy.

• The 0.5 unit pH reduction observed in women can alter the dissolution rate of pharmaceutical forms that depend on pH, leading to a higher risk of gastrointestinal bleeding in women.

• Reduced intestinal motility in women may require a longer interval between drug intake and food consumption.

• Prolonged use of ibuprofen may increase the risk of cardiac damage, especially in men with pre-existing conditions such as coronary heart disease.

• Ibuprofen use in women who are trying to conceive or during the first two trimesters of pregnancy should be limited and taken only when strictly necessary. The administration of prostaglandin synthesis inhibitors, such as ibuprofen, can negatively impact fetal development, particularly: it may increase the risk of miscarriage, cardiac malformations, and gastroschisis if taken in the early stages of pregnancy. Additionally, there are effects on the fetus in the third trimester: the use of prostaglandin inhibitors during this phase can cause premature closure of the ductus arteriosus and pulmonary hypertension in the fetus, as well as renal dysfunctions such as oligohydramnios (reduced amniotic fluid). During ibuprofen use in pregnancy, the mother may also experience prolonged bleeding time due to the anticoagulant effect and inhibition of uterine contractions, which may delay labor.

Chemical formula

C256H387N65O79S6

Information about the compound

Insulin is a protein-based hormone, and its name comes from the Latin word "insula," meaning island, as it is produced by groups of endocrine cells in the pancreas known as the islets of Langerhans.

Usage
Insulin is the quintessential anabolic hormone, and through its action, it: facilitates the transfer of glucose from the blood to the cells, thus exerting a hypoglycemic effect (lowers blood glucose levels). Inhibits the release of sugars by the liver. Facilitates the uptake of potassium into cells. Stimulates the utilization of glucose for energy production.

Gender Differences

• The male population tends to develop insulin resistance more easily, as they have metabolically active visceral fat mass. Insulin resistance is also linked to particularly high testosterone levels.

• Estrogens, on the other hand, provide protection against insulin resistance: after menopause, when estrogen levels decline, this risk can increase.

• Insulin therapy is commonly administered for the treatment of diabetes during pregnancy, as it has been found to be safe since it cannot cross the placenta, However, because the physiological course of blood glucose levels during pregnancy is not uniform, it will be necessary to adjust the amount of insulin administered over the course of gestation to maintain glycemic standards, which are essential for both the mother's and the baby's health.

Chemical formula

C20H28O2

Information about the compound

This is a drug derived from vitamin A.

Usage

It is used in the treatment of severe acne. Sometimes, it is also used in the treatment of certain types of cancer (skin, head, and neck).

Gender differences

Like other derivatives of vitamin A, isotretinoin has been shown to be teratogenic and embryotoxic. There are therapeutic consequences for administering it to patients of childbearing age, pregnant individuals, or those who are breastfeeding, unless all conditions specified by the Pregnancy Prevention Program are met.

In the case of transgender individuals undergoing testosterone therapy, isotretinoin is recommended for the treatment of severe, nodular, or recalcitrant acne.

Chemical formula

C16H14O3

Information about the compound

It is one of the non-steroidal anti-inflammatory drugs (NSAIDs).

Usage

An analgesic and anti-inflammatory drug used in cases of:

• Rheumatoid arthritis

• Ankylosing spondylitis

• Painful osteoarthritis

• Extra-articular rheumatism

• Post-traumatic inflammation

• Painful inflammatory conditions in dentistry

• Otorhinolaryngology

• Urology

• Pneumology

Gender differences

At the moment, no specific gender differences are known, but some studies have shown that the use of NSAIDs inhibits ovulation in women who take them for mild musculoskeletal pain. This suggests that NSAIDs may have a negative effect on fertility. In fact, it is now known that NSAIDs slow down ovulation and interfere with the menstrual cycle, sometimes leading to amenorrhea.

Chemical formula

C₁₄H₁₀BrN₃O

Information about the compound

Lexotan is a psychotropic drug belonging to the benzodiazepine class. It possesses anxiolytic, sedative-hypnotic, anticonvulsant, muscle relaxant, and anesthetic properties. It should be taken with caution because it can lead to physical and psychological dependence, which may be greater in individuals with a history of alcohol or drug abuse.

Usage

It is used in the treatment of severe anxiety disorders and insomnia.

Gender differences

To date, scientific evidence shows few gender differences. However, some differences have been observed:

• The absorption of the drug is better in women, both due to the peculiar isoform of cytochrome P450 and because of the lower pH (which tends to be lower in the female population and therefore better absorbs basic substances, such as benzodiazepines).

• Pregnancy and Breastfeeding: Several studies have shown an increased risk of developing congenital malformations and Lexotan withdrawal syndrome, characterized by tremors, bradycardia, diarrhea, etc. It is advisable not to breastfeed as the drug can be excreted in breast milk.

Chemical formula

C8H14N2O2

Information about the compound

It belongs to the class of pyrrolidines.

Usage

Levetiracetam is used in the treatment of epilepsy and various other disorders characterized by seizures.

Gender differences

• Levetiracetam is not extensively metabolized in humans.

• Studies have shown that men are more likely to experience toxic effects after administration.

• According to recent studies, women are more prone to developing treatment-resistant epilepsy, a hypothesis confirmed by age-stratified studies as well.

Chemical Formula

C₁₅H₁₀Cl₂N₂O₂

Information about the compound

This is a short-acting benzodiazepine.

Usage

Sedative and anxiolytic.

Gender Differences

Firstly, it should be noted that women are prescribed benzodiazepines twice as often as men, and there is evidence of gender differences in the therapeutic response to benzodiazepines. The distribution of benzodiazepines is more efficient in the female gender, due to a higher lipid percentage.

Moreover, Lorazepam interacts with Oral Contraceptive Steroids in female individuals.

Chemical Formula

C₄H₁₁N₅

Information about the compound

Oral hypoglycemic agent.

Usage

Used in the treatment of hyperglycemia in people with type 2 diabetes mellitus.

Gender Differences

• Metformin induces a favorable effect on cardiac metabolism in women but an unfavorable one in men.

• The beneficial musculoskeletal effects of the drug appear to be more pronounced in women than in men.

• Generally, women are prescribed lower drug doses than men, but they report more gastrointestinal side effects.

• During pregnancy, recent studies show that metformin, although it is not commonly used, is a safe drug as no connection has been found between the use of the drug and congenital malformations in the newborn.

Chemical Formula

C15H25NO3

Information about the compound

It is a beta-blocker, an antagonist of beta receptors (responsible for the uptake of adrenaline and noradrenaline).

Usage

Metoprolol is used in the treatment of cardiovascular disorders such as heart failure, angina, and arrhythmias. It is also employed in patients with migraine, diabetes, anxiety, and tremors.

Gender Differences

• In males:

Higher drug levels may be needed to achieve the same result observed in the female population.

• In females:

Elevated levels of plasma metoprolol are associated with a below-average heart rate.

Chemical Formula

C20H22N8O5

Information about the compound

Methotrexate is a folate analogue with the following properties:

• Interferes with the growth of some rapidly reproducing cells in the body: Methotrexate acts as an inhibitor of dihydrofolate reductase and thymidylate synthase, preventing the synthesis of purine and pyrimidine bases. This blocks the production of DNA and RNA, hindering the growth and proliferation of rapidly replicating cells.

• Reduces the activity of the immune system: The drug has the ability to suppress the immune system, the body's defense mechanism. This property makes it useful in the treatment of autoimmune conditions where the immune system mistakenly attacks healthy cells in the body.

• Anti-inflammatory effects: Methotrexate also has anti-inflammatory properties, making it effective in the treatment of rheumatological diseases and other conditions characterized by inflammation and cell proliferation.

Methotrexate is absorbed into cells through the same folate carrier, and once inside the cell, it undergoes modifications to become polyglutamate. Its inhibitory action on dihydrofolate reductase and thymidylate synthase contributes to interfering with DNA and RNA synthesis, making it effective in managing conditions such as cancer and autoimmune diseases. However, it's important to note that methotrexate is not selective for tumor cells, acting on all actively replicating cells.

Usage

Methotrexate is an antineoplastic, anti-inflammatory, and immunosuppressive drug.

Gender Differences

Methotrexate can cause reproductive alterations in both male and female patients. In non-oncological indications, effective contraceptive methods must be used during and for at least six months after treatment in sexually mature patients, as this drug is highly teratogenic.

In women, it can lead to menstrual dysfunction, amenorrhea, abortion, and fetal malformations. Therefore, administering it during pregnancy is contraindicated for women with rheumatoid arthritis or psoriasis. Even in women with neoplastic diseases, the drug should only be used if the potential benefits are deemed greater than the risks to the fetus. Methotrexate is excreted in breast milk and can cause toxic effects and severe adverse reactions in the nursing infant. Therefore, breastfeeding women should not take the drug. As women are more prone to developing autoimmune diseases such as rheumatoid arthritis, they may be more exposed to the toxic effects of methotrexate compared to men.

In men, it affects spermatogenesis and is genotoxic to sperm cells. Therefore, they should not donate seminal fluid during the therapy and for six months after discontinuation of methotrexate therapy. Due to reduced liver and kidney function and diminished folate reserves in elderly patients, lower doses should be considered, and these patients should be closely monitored for early signs of toxicity.

Chemical Formula
C₁₇H₁₉NO₃

Compound Information
Morphine was discovered in 1803 by the German chemist Friedrich Sertürner: it is an alkaloid metabolite derived from the Papaver Somniferum plant. It functions as an opioid agonist, meaning it is a narcotic substance capable of reducing pain sensation, altering mood, and inducing sleep. Morphine works by blocking nociceptive signal transmission, binding to opioid receptors found both in the brain and spinal cord. It has low oral bioavailability (25-30%) due to first-pass metabolism in the liver. However, when administered intravenously or intramuscularly, its bioavailability is much higher (almost 100%). Morphine is rapidly distributed in tissues, particularly in the central nervous system, where it exerts its analgesic effect. It achieves this because it binds well to plasma proteins. It is metabolized in the liver into morphine-6-glucuronide and morphine-3-glucuronide. Both morphine and its metabolites are primarily eliminated through the kidneys. Its half-life is generally around 2-4 hours.

Uses
In its hydrochloride form, the drug is indicated for the treatment of pain when other analgesic treatments have not been effective. Specifically, it is indicated for the treatment of pain caused by tumors (neoplasms), heart problems (myocardial infarction), following surgery, or due to lung issues (acute pulmonary edema). It can also be used for acute and chronic dyspnea and palliative sedation. Common side effects include:

• Drowsiness

• Sedation

• Constipation

• Nausea

• Dizziness

• Headache
  
  

It is advisable to avoid taking morphine in the following conditions:

• Respiratory failure/chronic respiratory problems

• Severe asthma

• Intestinal blockages
  
  

• Reduced liver function

• Head trauma

• Pregnancy (absolutely avoid)

• Breastfeeding

• Substance dependence issues
  
  

Additionally, it is important to carefully assess the possibility of morphine use if simultaneously taking antidepressants, other opioids, and central nervous system depressants, as these drug classes can enhance its side effects and toxicity.

• Gender Differences

The analgesic effect of morphine administered intravenously varies by sex. 

• The EC50 in men is 76 ng/mL, while in women it is 22 ng/mL.

• Women are more prone to respiratory depression following opioid analgesic therapy.

• In terms of drug response, clinical studies indicate that males require a higher dose of morphine (about 60% more) to achieve adequate pain relief. This is believed to be influenced by sex hormones.

• During pregnancy, morphine use is not recommended unless absolutely necessary. It can cause respiratory problems in the newborn or withdrawal symptoms. Furthermore, morphine is excreted in breast milk, so in breastfeeding women, careful evaluation of the benefit/risk ratio is needed.

Compound Information
A medication containing the active ingredients Bupropion-Naltrexone, belonging to the category of metabolic weight-loss drugs. Bupropion is a norepinephrine/dopamine reuptake inhibitor (NDRI), which exerts its pharmacological effect by weakly inhibiting the enzymes involved in the reuptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, thereby prolonging their action within the neuronal synapse and enhancing their effects. More specifically, it binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT), inhibiting their reuptake and increasing their concentration in the central nervous system, thus producing an antidepressant effect. However, its exact mechanism of action is not yet fully understood. It is known that it does not affect serotonin, which results in fewer side effects related to sexual dysfunction, sedation, and weight gain compared to other antidepressants. In Mysimba, bupropion is formulated for sustained and prolonged release over 12 hours, allowing for only two daily doses. However, the tablets must not be crushed, as this could lead to too rapid a release and increase the risk of side effects. Bupropion is rapidly absorbed, although the time to reach peak concentration depends on the formulation (which may differ from that of Mysimba). For Mysimba, peak concentration is reached approximately 3 hours after intake. Because it is quickly absorbed, it has a volume of distribution of 19 L. Once metabolized, it is eliminated primarily through the urine (88%). Due to its stimulating effects and selective activity on dopaminergic and adrenergic receptors, bupropion carries a potential risk of abuse. Additionally, it has effects similar to amphetamines, increasing blood pressure and thus the risk of hypertension, which can be serious in individuals with cardiovascular conditions or who smoke, potentially promoting events such as stroke and heart attack. In cases of overdose, toxicity may occur, with symptoms such as seizures, hallucinations, loss of consciousness, and tachycardia, potentially leading to cardiac arrest.

Naltrexone is a µ-opioid receptor antagonist and is used as an antidote in the treatment of opioid poisoning and overdose: it blocks the effects of opioids in the central nervous system by blocking the receptors. It may cause side effects during the initial days of treatment and has particularly low toxicity. It may cause side effects in the gastrointestinal tract and central nervous system. More rarely, it can lead to severe hepatic or allergic reactions, seizures, and psychiatric disorders. For these reasons, the use of naltrexone should be avoided in individuals with liver problems, those dependent on opioids, and during pregnancy.

When Bupropion and Naltrexone are used together, they appear to act on areas of the brain that control food intake regulation, such as the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine pathway, involved in the brain’s reward processes. Some studies have shown that the combined activity of these two compounds increases the firing rate of pro-opiomelanocortin (POMC) neurons in the hypothalamus and blocks the POMC auto-inhibition, which is mediated by opioid receptors. This is associated with a reduction in food intake and an increase in energy expenditure.

Usage
Prescribed for individuals suffering from obesity to control hunger and food intake.

Gender Differences
There is currently no data available regarding gender differences.

References

Information about the compound

This is a drug composed of monoclonal antibodies belonging to the class of antitumor medications, specifically within the category of immunotherapeutic drugs.

Usage

It restores the functionality of the immune system. Specifically, it can serve the following purposes:

• Adjuvant therapy for individuals who have recovered from cancer, with the goal of preventing tumor recurrence or metastasis.

• Neoadjuvant therapy for individuals who still have the tumor, aimed at reducing the tumor mass as much as possible before surgical removal.

• It is used as a therapy for certain types of cancer, including melanoma, advanced renal cell carcinoma, classical Hodgkin lymphoma, urothelial carcinoma, mesothelioma, colorectal cancer, esophageal and gastroesophageal junction cancer, adenocarcinoma, and non-small cell lung cancer.

Gender Differences

• In the male population, the treatment with Nivolumab appears to have a worse outcome. Men tend to experience more severe adverse reactions than women. Regarding disease recurrence, the trend is somewhat similar, although studies have shown a negative association between progression-free survival and treatment response in men.

• In patients with advanced or metastatic forms of melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck cancers, the reduction in the risk of death following treatment is twice as high in the male population compared to the female population.

Chemical Formula

C43H66N12O12S2

Information about the compound

Oxytocin is a pleiotropic nonapeptide hormone obtained by extraction from the posterior lobe of the pituitary gland of healthy pigs or cattle.

Usage

Recombinant oxytocin is used to induce or strengthen uterine contractions in pregnant women to facilitate labor and childbirth or to control postpartum bleeding. It can be used to induce labor in cases of uterine inertia, Rh sensitization, maternal diabetes, term or near-term preeclampsia, when labor is indicated due to premature rupture of membranes, and as an adjunct therapy for managing incomplete or inevitable abortion.

Gender Differences

A recent study conducted by researchers at the University of California, San Diego, has highlighted that oxytocin, when administered via nasal spray, produces a significant improvement in sexual functions in the male population. In particular, it may provide benefits in terms of libido, erections, and orgasmic sensation. It can amplify both sexual desire and arousal. However, the precise mechanism of action of this hormone has not yet been fully clarified.

Chemical Formula

C₁₆H₁₅F₂N₃O₄S

Information about the compound

Pantoprazole is an active ingredient belonging to the class of gastroprotective drugs that works by inhibiting the secretion of hydrochloric acid in the stomach.

Usage

It is primarily used in the treatment of symptoms of gastric reflux, the treatment and prevention of gastric and duodenal ulcers, and in specific conditions such as Zollinger-Ellison syndrome.

Gender Differences

A higher incidence of heartburn, constipation, and abdominal pain has been observed in the female population undergoing treatment with pantoprazole.

Chemical Formula

C19H20FNO3

Information about the compound

1. Paroxetine is a derivative of phenylpiperidine, capable of increasing the local concentration of neurotransmitters at synaptic and extracellular spaces by blocking the serotonin transporter.

2. It is an antidepressant mainly used in the treatment of major depressive disorder, anxiety disorders, and vasomotor symptoms of menopause.

Gender differences

1. Absorption:

2. • • Greater availability of the drug in women, as they have lower gastric acidity.

     • Faster intestinal transport for men.

2. Distribution:

2. • • Being lipophilic, paroxetine distributes better in the female body.

     • Hormonal variations due to the ovarian cycle can interfere with the drug's action.

     • During pregnancy, paroxetine may be less effective, requiring higher doses.

     • Paroxetine is more effective in women following menopause.

     • Oral contraceptive pills may interfere with paroxetine.

     • The drug can reduce the production and functionality of sperm, so its use is not recommended in men intending to conceive.

Chemical Formula

C28H29F2N3O

Information about the compound

Pimozide is an antipsychotic drug derived from diphenylbutylpiperidine.

Usage

It is used to treat motor and vocal tics in patients with Tourette syndrome. It is no longer prescribed for schizophrenia.

Gender Differences

• Adverse events due to the use of pimozide vary between the male and female populations:

• In men, it can cause impotence or erectile dysfunction, galactorrhea, and gynecomastia.

• In women, it can cause amenorrhea and galactorrhea.

• Some studies suggest that young girls may respond better (and may require lower doses) compared to males.

• Not recommended during pregnancy and breastfeeding.

Chemical Formula

C12H18O

Information about the compound

Propofol belongs to the category of intravenous anesthetics.

Usage

It is usually administered to induce general anesthesia and for continuous infusion when used to maintain general anesthesia. It is sometimes used in the management of refractory epileptic states.

Gender Differences

• Men are more sensitive to propofol than women. It may be necessary to reduce the propofol dose by 30-40% in the male population to achieve similar recovery times between the two sexes.

• Men wake up more slowly than women and have less postoperative nausea, vomiting, and pain.

• Taking propofol is not recommended during pregnancy unless strictly necessary, as it can cross the placenta and cause neonatal depression.

• During breastfeeding, it is advisable to discard one's milk for the 24 hours following Propofol administration.

Chemical formula: 

C21H25N3O2S

Information about the compound:

Quetiapine acts as an antagonist on the following receptors:

• Dopamine type 2 (D2)

• Serotonin type 2A (5HT2A)

In relation to bipolar disorder and major depression, Quetiapine also plays the role of a norepinephrine transporter inhibitor.

Usage:

Quetiapine is a psychotropic antipsychotic agent used in the management of:

• Bipolar disorder

• Schizophrenia

• Major depressive disorder

• Treatment of post-traumatic stress disorder (PTSD)

• Generalized anxiety disorder

• Psychosis associated with Parkinson's disease

Gender differences:

The administration of quetiapine in rats has resulted in various effects, including:

• Reduced sperm concentration

• Decreased serum levels of LH and testosterone in subjects receiving 20 and 40 mg/kg of quetiapine

• Decreased activities of catalase and superoxide dismutase in testicular tissue

In the case of pregnancy, quetiapine should be administered only if the benefit justifies the potential risks. Cases of withdrawal in newborns have been observed following the intake of this drug by pregnant women, as quetiapine is excreted in breast milk. There also appear to be correlations between gestational diabetes and the use of atypical antipsychotics, but articles on this topic are still conflicting to date.

Chemical formula

C22H30N6O4S

Usage

Treatment of erectile dysfunction.

Gender Differences

In pregnant women, sildenafil is indicated for the treatment of pulmonary arterial hypertension.

Sildenafil is not recommended for women of childbearing age unless appropriate contraceptive measures are also used.

Chemical Formula

C26H29NO

Information about the compound

Tamoxifen is an anti-hormonal chemotherapeutic antiestrogenic drug that acts on DNA to induce apoptosis in cancer cells. It is a non-steroidal SERM (Selective Estrogen Receptor Modulator). Commercial names include Nolvadex® and Soltamox®. It was synthesized in 1962 by Dora Richardson as a potential contraceptive, and by the late 1960s, it was recognized for its anti-estrogenic properties in breast cancer. In 1977, it was approved by the FDA for the treatment of metastatic ER+ breast cancer in women. In 1990, it was recognized as a selective estrogen receptor modulator (SERM) with tissue-specific effects. In 1993, the FDA also approved it for use in men with breast cancer. In 1998, it was selected for preventive oncology indication (DCIS), and in 2000, new therapeutic prospects were investigated. Tamoxifen is well absorbed in the intestine following oral administration, with an oral bioavailability near 100% and minimal first-pass metabolism. After administration, the peak plasma concentration is reached within 3 to 7 hours. For a single 40 mg dose, the peak plasma concentration is approximately 65 ng/mL. The volume of distribution is very high, ranging from 50-60 L/kg, and clearance is estimated between 1.2 and 5.1 L/hour. It is widely distributed in tissues, particularly in estrogen-sensitive tissues such as the breast, uterus, ovaries, but also in the liver, kidneys, lungs, and pancreas. Plasma protein binding is over 99%, primarily to albumin (98.8%). Tissue concentrations are significantly higher than plasma concentrations: in the breast, they can be up to 10 times higher, while in the uterus, they are about 2–3 times higher. Pharmacokinetically, tamoxifen is metabolized in the liver by various cytochrome P450 enzymes, particularly CYP3A4, CYP2C19, and CYP2D6. Some of its metabolites include:

• N-demethyltamoxifen, an active metabolite but with low affinity for estrogen receptors (ER).

• 4-hydroxytamoxifen (also known as afimoxifene), an active metabolite.

• Endoxifene, the most potent metabolite.
  
  

The genetic variability of CYP2D6 can significantly impact clinical treatment efficacy, as plasma levels of endoxifene, the key metabolite, are 5–10 times higher than those of afimoxifene in normal metabolizers (average values: 10.8–15.9 ng/mL). The clinical efficacy of tamoxifen treatment depends on the concentration of circulating endoxifene. However, some SSRIs (Selective Serotonin Reuptake Inhibitors) may reduce conversion to endoxifene, compromising the effectiveness of tamoxifen itself. Some studies suggest increased mortality or recurrence in patients taking potent CYP2D6 inhibitors. Therefore, it is advisable to avoid, if possible, the use of strong CYP2D6 inhibitors in patients on tamoxifen therapy. For patients requiring antidepressants, SSRIs with minimal CYP2D6 inhibition, such as citalopram or venlafaxine, are preferable. Enzyme inducers and transporters, on the other hand, accelerate the drug's metabolism via alternative pathways (such as ABCC1 and ABCC2), diverting metabolism toward other reactions that do not form endoxifene, thereby reducing the production of active metabolites. This results in decreased tamoxifen efficacy. The enzymatic activity of CYP2D6 is highly variable due to genetic polymorphisms, including SNPs (single nucleotide polymorphisms) and variations in the number of gene copies. Over 80 genetic variants have been identified that reduce or abolish the enzyme's activity. Patients with reduced enzymatic activity (termed "poor metabolizers") are at higher risk of not responding adequately to tamoxifen treatment. Finally, the frequency of CYP2D6 genetic variants varies among different ethnic groups, which may influence therapeutic response to tamoxifen.

The half-lives of elimination are relatively long:

• Tamoxifen: 5–7 days (range 4–11 days).

• Afimoxifene: approximately 14 days.

• Endoxifene: 50–70 hours (about 2–3 days).
  
  

These prolonged half-lives are due to high protein binding and enterohepatic recirculation. After discontinuing treatment, tamoxifen and its active metabolites may persist in the bloodstream for more than six weeks. The elimination route is primarily biliary/fecal.

Use

Tamoxifen is used to treat estrogen receptor-positive (ER+) breast cancers and to prevent breast cancer incidence in high-risk populations. It also has significant non-genomic effects in the neuropsychiatric field, independent of estrogen receptors. One of the most studied effects is its inhibitory action on protein kinase C (PKC), a family of enzymes involved in various cellular processes. PKC is highly expressed in the brain and plays a key role in functions like cell cycle regulation, neuronal survival, apoptosis, and synaptic plasticity. In patients with bipolar disorder (BD), during manic phases, a significant increase in PKC activity has been observed, both in the brain and in platelets. This hyperactivity is associated with abnormal neuroplasticity and mood dysregulation. Clinical and preclinical studies indicate that tamoxifen can reduce PKC activity and improve cognitive functions compromised during manic episodes. Additionally, it modulates neuronal activity in the prefrontal cortex, a crucial brain region for executive functions and mood regulation. These findings support the potential use of tamoxifen as a mood stabilizer, either alone or in combination with drugs like lithium and valproate, which also indirectly affect PKC. 

Mechanism of Action
Tamoxifen is an antagonist of estrogen receptors (ER) in breast tissue but acts as a partial agonist in other tissues like the endometrium, bones, and liver. Its molecular action is based on several mechanisms:

• Competitive binding to estrogen receptors (ERα and ERβ), preventing estrogen action on the receptor.

• Blocking the translocation of the receptor to the nucleus, preventing activation of estrogen-regulated genes.

• Inhibiting the binding of the receptor-estrogen complex to DNA, thus reducing the transcription of estrogen-dependent genes.
  
  

In breast tissue, tamoxifen competes with estrogen for binding to estrogen receptors, reducing the stimulation of tumor growth in ER-positive breast cancers. This effect is crucial in the treatment and prevention of breast cancer because it blocks estrogen's proliferative effect. In bone tissue, tamoxifen acts as a partial agonist, activating estrogen receptors and mimicking estrogen's protective effect against bone loss. This is particularly important in postmenopausal women as it helps prevent osteoporosis. In the hypothalamic system, tamoxifen acts as an agonist in premenopausal women, stimulating estrogenic activity. This leads to an increase in gonadotropins (FSH and LH), which can induce ovulation, with potential effects on fertility. Overall, tamoxifen blocks estrogen-dependent gene activation, reducing cell proliferation and slowing the cell cycle. This makes it a cytostatic agent (inhibiting cell growth) but not cytotoxic (not causing cell death). Through these mechanisms, tamoxifen exerts an antitumor effect in ER-positive breast cancers, limiting the growth of estrogen-dependent tumors. Tamoxifen’s action on protein kinase C occurs through direct mechanisms that are still being studied but are well documented in experimental models. The main proposed mechanisms include:

• Competitive blockage of the enzyme’s active site, preventing its normal catalytic activity.

• Modification of the lipid environment of the membrane, necessary for PKC activation.

• Inhibition of intracellular translocation of PKC, which is essential for the enzyme to reach the membrane and perform its function.
  
  

Studies on animal models and in vitro show that tamoxifen reduces PKC activity induced by pharmacological stimuli, improves performance in cognitive tests compromised by stress or PKC hyperactivity, and modulates neuronal excitability, neurotransmitter release, and dendritic spine morphology in the prefrontal cortex. Chronic stress, through the activation of α1 adrenergic receptors by norepinephrine, stimulates the phosphatidylinositol pathway and enhances PKC activity, contributing to cognitive dysfunction. Inhibition of this pathway by tamoxifen may reverse these effects, providing potential therapeutic benefits in mood disorders characterized by prefrontal dysregulation.

Gender Differences
Most studies focus on women, leaving many uncertainties regarding effects in men. However, tamoxifen is used in the treatment of male breast cancer (which is less common than in women), infertility, and idiopathic gynecomastia. Given the differences in endogenous estradiol levels, distribution of estrogen receptors in the body, and drug metabolism between men and women, it is reasonable to assume that adverse effects may differ by sex. However, appropriate studies are still lacking. In some cases, tamoxifen use in men has been associated with cardiovascular, gastrointestinal disturbances, and in fewer cases, reduced libido, sleep disorders, anxiety, depression, and mood swings. Among men treated with tamoxifen, over 60% experience at least one adverse effect, with the most common being mood alterations (38%), reduced libido (29%), weight gain (25%), and hot flashes (21%). However, despite the frequency of these symptoms, fewer than 5% have discontinued treatment due to toxicity, suggesting good overall tolerance of the drug. The profile of side effects can vary depending on the condition for which tamoxifen is administered. For example, in prostate cancer patients, particularly in later stages, the most frequently reported side effects include gastrointestinal and cardiovascular disturbances, while reproductive and breast-related issues like gynecomastia and sexual dysfunction are less frequent, although still present. It is important to consider that natural estrogens, such as estradiol, estrone, and estriol, have a higher affinity for estrogen receptors compared to tamoxifen. Consequently, some side effects observed in male patients with elevated estrogen levels may not be directly attributable to tamoxifen but rather to the estrogen itself, particularly in prostate cancer patients treated with antiandrogens, where breast-related events like gynecomastia and breast pain are often caused by increased estradiol levels. Another factor influencing the appearance of adverse effects is hepatic metabolism and individual genetic variability. In fact, polymorphisms in the cytochrome P450 genes can determine the capacity to metabolize tamoxifen, influencing the production of active metabolites and systemic drug exposure, leading to variability in response and tolerability, even at the same dose. Tamoxifen may have different effects in females compared to males, significantly impacting liver and kidney function, as well as sensitivity to side effects. In females, common side effects include:

• Elevated liver enzymes such as ALT (alanine aminotransferase) and AST (aspartate aminotransferase), which are indicators of potential hepatic toxicity. These increases may signal liver damage and require regular monitoring of liver function during treatment.

• Reduced plasma proteins, such as albumin and α1-acid glycoprotein (ACP), which may indicate liver involvement in drug metabolism and altered protein profiles.

• Increased creatinine levels, which signal potential renal involvement, indicating that the kidneys could also be affected by tamoxifen treatment.
  
  

Studies in female rats treated with high doses of tamoxifen suggest that the loss of estrogen’s protective effect is a crucial factor. Normally, estrogens exert an antioxidant effect, protecting cells from oxidative damage. However, when estrogenic action is blocked by tamoxifen, this protective effect is lost, exposing the liver to greater oxidative stress. Oxidative damage to DNA and liver proteins observed in these studies appears to be a primary mechanism of cell damage caused by tamoxifen. Additionally, there is increased activation of hepatic biotransformation enzymes involved in drug metabolism. This activation may increase the formation of reactive and toxic products, further contributing to hepatocellular damage and hepatic toxicity. The key role of oxidative stress and lipid peroxidation appears to be particularly relevant in females. These processes may lead to the formation of free radicals and other harmful molecules that damage liver cells, causing inflammation and liver fibrosis over time. In summary, females appear to be more vulnerable to the negative effects of tamoxifen, especially at the hepatic and renal levels. The loss of estrogen’s protective effect and increased oxidative stress significantly contribute to the drug's hepatotoxicity. This requires careful management and continuous monitoring to prevent long-term damage, with particular attention to liver enzymes and creatinine levels.

Bibliography

Chemical formula

C13H10N2O4

Usage

Sedative and antiemetic (in the past). 

Nowadays, it is used for the treatment of multiple myeloma and leprosy.

Gender Differences

History → Synthesized and commercialized in the 1950s as a sedative with antiemetic effects for pregnant women. Due to the lack of testing in pregnant animals, it caused abortions, malformations, and severe congenital effects, especially affecting limbs, as an inhibitor of angiogenesis. Following these findings, it was subsequently withdrawn from the market. The case of thalidomide is considered one of the greatest disasters in the history of pharmacology.

Due to its teratogenic effect, thalidomide can only be prescribed after informing the patient about the potential risks, especially related to possible conception during therapy. Therefore, both women and men are advised to use effective contraceptive methods if undergoing thalidomide treatment.

Chemical formula

C₁₂H₂₁NO₈S

Information about the compound

A substituted sulfamate monosaccharide.

Usage

• It is used as an anticonvulsant and antiepileptic drug.

• Indicated in adults for migraine prophylaxis.

• Monotherapy in adults, adolescents, and children over 6 years of age with partial-onset seizures with or without secondary generalization and primary generalized tonic-clonic seizures (grand mal).

• It is also used off-label for weight management, mood disorders, and bipolar disorder.

Gender Differences

• In women taking oral contraceptives in combination with TPM, there may be a reduction in contraceptive effectiveness and an increase in spotting.

• Not recommended during pregnancy, as it has been found to be teratogenic in preclinical studies in mice, rats, and rabbits.

• Not recommended during breastfeeding.

Compound Information
An immunosuppressive drug composed of monoclonal antibodies. The drug blocks the migration of cytokines and consequently acts indirectly on inflammation by reducing the immune response.

Uses
It is used for autoimmune diseases, specifically for Crohn's disease and multiple sclerosis.

Gender Differences

• The elimination of the drug is reduced in females, which makes women more susceptible to side effects.

• Thrombocytopenia and anemia have been reported in neonates born to women exposed to the drug during pregnancy.

Chemical formula

C10H13N5O4

Information on the compound

Zidovudine is an antiviral drug, an inhibitor of HIV replication.

Usage

Used for the treatment of HIV infection and for reducing viral load to lower the risk of sexual transmission of the virus.

Gender Differences

• Women are more susceptible to HIV infection than men.

• HIV-positive women require more support compared to the male population.

• Antiretrovirals are less effective and more toxic in women.

• Overweight women are at higher risk of side effects compared to men.

Chemical formula

C19H21N3O

Information about the compound

Zolpidem is a sedative drug belonging to the imidazopyridine family, acting to reduce brain activity and promote sleep.

Usage

Used for the short-term treatment of insomnia.

Gender differences

After being used for decades, in 2011 the FDA reduced the dose of Zolpidem from 10 mg to 5 mg for women following reports of side effects, especially driving problems the day after use, and a study highlighting the differences between men and women in absorption rates and extent. Specifically, the immediate-release zolpidem has an absorption rate that is 45% higher in women compared to men, while for the extended-release formulation, the difference is between 50% and 70%. In fact, zolpidem clearance in women is, on average, 35% lower than in men. This means that women tend to eliminate zolpidem more slowly than men. In general, women tend to be more sensitive to the effects of sedative drugs.

Additionally, not only female hormones but also testosterone can modify the drug’s activity. When testosterone is present in higher amounts, the activity of zolpidem may be stimulated, while lower levels, as seen in women, can cause a decrease in enzyme activity. This was confirmed by a study in which castrated male rats showed pharmacokinetics similar to that of females, providing further evidence suggesting that zolpidem pharmacokinetics are driven by androgens.

During pregnancy, zolpidem may cause withdrawal symptoms in the newborn. Moreover, the female population is more prone to daytime sedation, risking impairment of driving ability.

Other relevant points:

• Women metabolize zolpidem more slowly than men due to differences in liver enzyme activity, leading to higher drug levels in the blood and a longer duration of effect.

• Higher zolpidem levels in the blood increase the risk of side effects such as:

  • Drowsiness or sedation the next day, which can impair activities like driving.

  • Dizziness and confusion.

  • Increased sensitivity to cognitive and psychomotor damage.

Other specific effects that may occur in the female population:

• Zolpidem can cross the placenta, and maternal use during the third trimester or labor may cause respiratory depression and sedation in newborns.

• Zolpidem is excreted in breast milk. Some reports highlight excessive sedation in breastfed newborns.

• Fluctuations in estrogen and progesterone can affect the pharmacodynamics and pharmacokinetics of zolpidem in women, making its biological response variable depending on the phases of the hormonal cycle.