Tadalafil and Hormonal Interactions in Female Physiology

Sildenafil, vardenafil, and tadalafil are all PDE-5 inhibitors indicated for the treatment of ED. They do not directly cause penile erections, however, they affect the response to sexual stimulation. During sexual stimulation, nitric oxide is produced, which then activates cyclic guanosine monophosphate (cGMP). This results in smooth muscle relaxation and increased blood flow.5 Phosphodiesterases, however, catalyze the breakdown of cGMP to its corresponding monophosphate, GMP. There are several PDE isoenzymes, and PDE-5 is the isoenzyme present in highest concentrations in the smooth muscle of the corpora cavernosum of the penis. The PDE-5 inhibitors, sildenafil, vardenafil, and tadalafil mimic the structure of cGMP and competitively inhibit its breakdown by PDE-5 in the corpus cavernosum and related vessels, leading to increased dilatation and blood flow. This allows the induction of an erection during sexual stimulation.7 Sildenafil, vardenafil, and tadalafil all affect ED through the same basic mechanism of inhibiting PDE-5 but have differing potencies and affinities for each of the 11 PDE isoenzymes.

• Tadalafil may supplement other treatments for female sexual health.
• Its effects on vaginal lubrication are being studied.
• Use in women should be monitored carefully for adverse effects.
• It could provide a new option for women unresponsive to other therapies.
• The drug enhances vascular dilation in female genitalia.
• Long-term safety data in women are lacking.
• Its role in clinical practice remains experimental.
• Dose flexibility allows tailored treatment plans.
• Women interested should seek professional guidance.

Vardenafil is the most potent PDE-5 inhibitor, followed by sildenafil and tadalafil.7 However, there is no current evidence that greater drug potency has produced improved clinical efficacy.

Parameter	Details	Notes
Absorption Rate	Rapid, within 2 hours	Taken with/without food
Peak Plasma Levels	2 hours post-dose	Influenced by food intake
Metabolism	Liver CYP3A4 enzymes	Drug interactions possible
Excretion	Mainly via feces and urine	Consider renal function in dosing

The affinities vary for the other PDE isoenzymes, and thus may explain the potential differences in their side effect profiles. While sildenafil, vardenafil, and tadalafil are all hepatically metabolized, there are variances in their pharmacokinetic profiles. Sildenafil is approximately 75% metabolized, predominantly by cytochrome P450 (CYP) 3A4 with contribution from CYP 2C9.7,8 Vardenafil is primarily metabolized by CYP 3A4 and secondarily by CYP 3A5 and 2C isoforms.7,9 Tadalafil is also metabolized by CYP 3A4.2,10 With CYP 3A4 being the major enzyme responsible for the metabolism of all three agents, they will potentially have many of the same drug interactions with some possible contributions from the minor enzymatic pathways. Other pharmacokinetic differences include time to maximum concentration and half-life.

Ethics declarations

There are no comparative trials evaluating sildenafil, vardenafil, and tadalafil; therefore, it is difficult to compare the individual trials available due to differences in study design and methodology. However, all three agents have been proven effective in treating ED in clinical trials based on the Erectile Function domain score of the International Index of Erectile Function, a sexual function questionnaire commonly used throughout the studies. Efficacy rates for the PDE-5 inhibitors vary widely throughout the literature with a range of 57% to 83%.5,11-13 Additionally, they have all shown efficacy in the treatment of ED in men with diabetes mellitus; however, no particular agent has yet to be recommended for patients with cardiovascular disease.2,8,10,12,14,15 Comparative trials are required to determine if a specific agent possesses better efficacy. There are drug-drug interactions with each of these medications, many of which involve the same drugs due to CYP 3A4 being the major enzymatic pathway for all of these agents. Due to the potential for severe hypotension, sildenafil and organic nitrates (e.g., nitroglycerin, isosorbide dinitrate [Isordil®, Sorbitrate®], and isosorbide mononitrate [Imdur, ISMO®, Monoket®]) are contraindicated (i.e., should not be taken together), and sildenafil doses > 25 mg should not be used within 4 hours of taking an alpha-blocker (e.g., prazosin [Minipress®], terazosin [Hytrin®], and doxazosin [Cardura®]).

US Brand Name

Sildenafil is a substrate of CYP 3A4 and 2C8/9 as well as an inhibitor of CYP 1A2, 2C8/9, 2C19, 2D6, 2E1, and 3A4; therefore, increased effects and possible toxicity of sildenafil occur when used concomitantly with drugs that inhibit these enzymes (e.g., cimetidine [Tagamet®], erythromycin, ketoconazole [Nizoral®], itraconazole [Sporanox®], amprenavir [Agenerase®], indinavir [Crixivan®], saquinavir [Fortovase®], and ritonavir [Norvir®]). Enzyme-inducing agents, such as St. John's wort and rifampin, may have the opposite effect and cause decreased sildenafil levels. Drug-food interactions with sildenafil can also occur. The rate and extent of absorption of sildenafil is reduced when taken with a high-fat meal and grapefruit juice may cause increased serum concentrations of sildenafil, consequently, concurrent use should be avoided.8-10,16-18 Concomitant use of vardenafil is also contraindicated with alpha-blockers and organic nitrates due to the potential for severe hypotension.

Regulatory considerations

Vardenafil is a substrate of CYP 3A4, and to a minor extent the 2C isoforms, leading to interactions with drugs that induce or inhibit these enzymes. Other enzyme inhibitors that may increase vardenafil levels are amiodarone (Cordarone®), cimetidine (Tagamet®), clarithromycin (Biaxin®), delavirdine (Rescriptor®), diltiazem (e.g., Cardizem®, Cardizem® SR, Cardizem® CD, Cardizem® LA, Cartia XT, Dilacor® XR, Diltia XT, Taztia XT, and Tiazac®), fluoxetine (Prozac®), fluvoxamine (Luvox®), nefazodone (Serzone®), nevirapine (Viramune®), saquinavir (Fortovase®), verapamil (Calan®, Covera-HS, Isoptin®SR, Verelan®), and grapefruit juice, but there are no current recommendations for dosage adjustments with these agents.8-10,16-18 Tadalafil is also metabolized by CYP 3A4, resulting in the potential for an interaction with any drug that induces or inhibits this isoenzyme. Ketoconazole (Nizoral®) and ritonavir (Norvir®) have both been shown to increase tadalafil levels; other CYP 450 inhibitors (e.g., erythromycin, itraconazole [Sporanox®], and grapefruit juice), however, have yet to be evaluated, but it is likely that they will also increase tadalafil levels. Patients taking potent inhibitors of CYP 3A4 (e.g., ketoconazole [Nizoral®] or ritonavir [Norvir®]) will require a dose adjustment of tadalafil. The dose should 10 mg tadalafil not exceed 10 mg and should not be administered more frequently than every 72 hours. The slightly faster time to maximum concentration of vardenafil (0.7 hours) compared to sildenafil (0.8 sublingual tadalafil hours) is likely clinically irrelevant, while tadalafil has the slowest onset and may require 2 hours to reach maximum concentration. Tadalafil, however, has the longest half-life (17.5 hours), followed by vardenafil (4 hours) and sildenafil (3.7 hours).7-10 These differences will account for variation in dosage timing and duration of effect. The considerably longer duration of effect for tadalafil will likely allow less frequent dosing and greater impulsiveness between partners, but also could potentially prolong adverse effects. There are no comparative trials evaluating sildenafil, vardenafil, and tadalafil; therefore, it is difficult to compare the individual trials available due to differences in study design and methodology. However, all three agents have been proven effective in treating ED in clinical trials based on the Erectile Function domain score of the International Index of Erectile Function, a sexual function questionnaire commonly used throughout the studies.

Product	Dosage	Quantity + Bonus	Price
Cialis Generic	40mg	120 + 8 Pills	206.98€ 197.12€	Buy
Cialis Generic	60mg	20 Pills	65.61€ 62.49€	Buy
Cialis Generic	20mg	20 Pills	54.72€ 52.11€	Buy
Cialis Generic	60mg	360 + 10 Pills	570.52€ 543.35€	Buy
Cialis Generic	60mg	90 + 6 Pills	196.67€ 187.30€	Buy
Cialis Generic	40mg	180 + 10 Pills	277.29€ 264.09€	Buy
Cialis Generic	2.5mg	180 + 10 Pills	154.86€ 147.49€	Buy
Cialis Generic	60mg	270 + 10 Pills	443.96€ 422.82€	Buy
Cialis Generic	40mg	360 + 10 Pills	477.87€ 455.11€	Buy
Cialis Generic	40mg	270 + 10 Pills	382.19€ 363.99€	Buy
Tadalista Super Active	20mg	270 + 30 Pills	661.49€ 629.99€	Buy
Cialis Generic	2.5mg	90 + 6 Pills	112.43€ 107.08€	Buy
Cialis Generic	20mg	180 + 10 Pills	254.09€ 241.99€	Buy
Cialis Generic	2.5mg	120 + 6 Pills	128.93€ 122.79€	Buy

Efficacy rates for the PDE-5 inhibitors vary widely throughout the literature with a range of 57% to 83%.5,11-13 Additionally, they have all shown efficacy in the treatment of ED in men with diabetes mellitus; however, no particular agent has yet to be recommended for patients with cardiovascular disease.2,8,10,12,14,15 Comparative trials are required to determine if a specific agent possesses better efficacy. There are drug-drug interactions with each of these medications, many of which involve the same drugs due to CYP 3A4 being the major enzymatic pathway for all of these agents. Due to the potential for severe hypotension, sildenafil and organic nitrates (e.g., nitroglycerin, isosorbide dinitrate [Isordil®, Sorbitrate®], and isosorbide mononitrate [Imdur, ISMO®, Monoket®]) are contraindicated (i.e., should not be taken together), and sildenafil doses > 25 mg should not be used within 4 hours of taking an alpha-blocker (e.g., prazosin [Minipress®], terazosin [Hytrin®], and doxazosin [Cardura®]). Sildenafil is a substrate of CYP 3A4 and 2C8/9 as well as an inhibitor of CYP 1A2, 2C8/9, 2C19, 2D6, 2E1, and 3A4; therefore, increased effects and possible toxicity of sildenafil occur when used concomitantly with drugs that inhibit these enzymes (e.g., cimetidine [Tagamet®], erythromycin, ketoconazole [Nizoral®], itraconazole [Sporanox®], amprenavir [Agenerase®], indinavir [Crixivan®], saquinavir [Fortovase®], and ritonavir [Norvir®]). Enzyme-inducing agents, such as St. John's wort and rifampin, may have the opposite effect and cause decreased sildenafil levels.

Safety Considerations for Women Using Cialis

Any clinically significant difference in effect will need to be clarified by post-marketing surveillance of vardenafil and tadalafil.2,12 While sildenafil and vardenafil have similar recommended dosing, the dosing schedule for tadalafil may differ due to its greater time to maximum concentration and longer half-life. Dosing guidelines are listed in Table 2.2,13 The PDE-5 inhibitors are not FDA-approved for use in women or children. All of these agents are classified as pregnancy-risk category B.8-10 Pregnancy category B is defined as either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).21 The price of sildenafil 25- or 50-mg tablets is $90.99 for ten tablets or $259.97 for 30 tablets, while the 100 mg strength of sildenafil is $93.99 for ten tablets or $267.97 for 30 tablets. Finally, the price of tadalafil 5-, 10-, or 20-mg tablets is $89.99 for ten tablets or $259.97 for 30 tablets.22-24 Recently, sildenafil has been investigated for the treatment of pulmonary hypertension.25 It has been shown to decrease pulmonary artery pressure and pulmonary vascular resistance, decrease symptoms, and improve New York Heart Association functional class in patients with pulmonary hypertension. Drug-food interactions with sildenafil can also occur. The rate and extent of absorption of sildenafil is reduced when taken with a high-fat meal and grapefruit juice may cause increased serum concentrations of sildenafil, consequently, concurrent use should be avoided.8-10,16-18 Concomitant use of vardenafil is also contraindicated with alpha-blockers and organic nitrates due to the potential for severe hypotension. Vardenafil is a substrate of CYP 3A4, and to a minor extent the 2C isoforms, leading to interactions with drugs that induce or inhibit these enzymes. Other enzyme inhibitors that may increase vardenafil levels are amiodarone (Cordarone®), cimetidine (Tagamet®), clarithromycin (Biaxin®), delavirdine (Rescriptor®), diltiazem (e.g., Cardizem®, Cardizem® SR, Cardizem® CD, Cardizem® LA, Cartia XT, Dilacor® XR, Diltia XT, Taztia XT, and Tiazac®), fluoxetine (Prozac®), fluvoxamine (Luvox®), nefazodone (Serzone®), nevirapine (Viramune®), saquinavir (Fortovase®), verapamil (Calan®, Covera-HS, Isoptin®SR, Verelan®), and grapefruit juice, but there are no current recommendations for dosage adjustments with these agents.8-10,16-18 Tadalafil is also metabolized by CYP 3A4, resulting in the potential for an interaction with any drug that induces or inhibits this isoenzyme. Ketoconazole (Nizoral®) and ritonavir (Norvir®) have both been shown to increase tadalafil levels; other CYP 450 inhibitors (e.g., erythromycin, itraconazole [Sporanox®], and grapefruit juice), however, have yet to be evaluated, but it is likely that they will also increase tadalafil levels.

What is tadalafil?

Sildenafil, vardenafil, and tadalafil are all PDE-5 inhibitors indicated for the treatment of ED. They do not directly cause penile erections, however, they affect the response to sexual stimulation. During sexual stimulation, nitric oxide is produced, which then activates cyclic guanosine monophosphate (cGMP). This results in smooth muscle relaxation and increased blood flow.5 Phosphodiesterases, however, catalyze the breakdown of cGMP to its corresponding monophosphate, GMP. There are several PDE isoenzymes, and PDE-5 is the isoenzyme present in highest concentrations in the smooth muscle of the corpora cavernosum of the penis.

Uncommon side effects

The PDE-5 inhibitors, sildenafil, vardenafil, and tadalafil mimic the structure of cGMP and competitively inhibit its breakdown by PDE-5 in the corpus cavernosum and related vessels, leading to increased dilatation and blood flow. This allows the induction of an erection during sexual stimulation.7 Sildenafil, vardenafil, and tadalafil all affect ED through the same basic mechanism of inhibiting PDE-5 but have differing potencies and affinities for each of the 11 PDE isoenzymes. Vardenafil is the most potent PDE-5 inhibitor, followed by sildenafil and tadalafil.7 However, there is no current evidence that greater drug potency has produced improved clinical efficacy. The affinities vary for the other PDE isoenzymes, and thus may explain the potential differences in their side effect profiles. While sildenafil, vardenafil, and tadalafil are all hepatically metabolized, there are variances in their pharmacokinetic profiles.

Female sexual arousal disorder

Sildenafil is approximately 75% metabolized, predominantly by cytochrome P450 (CYP) 3A4 with contribution from CYP 2C9.7,8 Vardenafil is primarily metabolized by CYP 3A4 and secondarily by CYP 3A5 and 2C isoforms.7,9 Tadalafil is also metabolized by CYP 3A4.2,10 With CYP 3A4 being the major enzyme responsible for the metabolism of all three agents, they will potentially have many of the same drug interactions with some possible contributions from the minor enzymatic pathways. Other pharmacokinetic differences include time to maximum concentration and half-life. The slightly faster time to maximum concentration of vardenafil (0.7 hours) compared to sildenafil (0.8 sublingual tadalafil hours) is likely clinically irrelevant, while tadalafil has the slowest onset and may require 2 hours to reach maximum concentration. Tadalafil, however, has the longest half-life (17.5 hours), followed by vardenafil (4 hours) and sildenafil (3.7 hours).7-10 These differences will account for variation in dosage timing and duration of effect. The considerably longer duration of effect for tadalafil will likely allow less frequent dosing and greater impulsiveness between partners, but also could potentially prolong adverse effects. Patients taking potent inhibitors of CYP 3A4 (e.g., ketoconazole [Nizoral®] or ritonavir [Norvir®]) will require a dose adjustment of tadalafil. The dose should 10 mg tadalafil not exceed 10 mg and should not be administered more frequently than every 72 hours. Additionally, tadalafil is thought to increase the hypotensive effect of antihypertensive agents (e.g., calcium channel blockers, diuretics, angiotensin-receptor blockers, ACE-inhibitors, or adrenergic receptor-blocking agents) and therefore should be used with caution.

• Tadalafil is a phosphodiesterase type 5 inhibitor, acting on blood vessels.
• Its potential benefits for women focus on increased genital blood flow.
• Tadalafil is not approved by FDA for female sexual disorders.
• Some clinical trials report moderate improvements in women.
• It is sometimes combined with hormonal treatments.
• Psychological factors also influence female sexual satisfaction.
• Tadalafil’s effects on orgasm intensity are under research.
• Women with pre-existing health conditions should exercise caution.
• Dose adjustments may be necessary based on individual response.

Concomitant administration of tadalafil with the alpha-blockers, except tamsulosin (Flomax®) is contraindicated. Tadalafail was evaluated in combination with doxazosin (Cardura®) and resulted in a significant increase in the blood pressure-lowering effect of doxazosin.

What is Cialis?

Additionally, tadalafil is thought to increase the hypotensive effect of antihypertensive agents (e.g., calcium channel blockers, diuretics, angiotensin-receptor blockers, ACE-inhibitors, or adrenergic receptor-blocking agents) and therefore should be used with caution. Concomitant administration of tadalafil with the alpha-blockers, except tamsulosin (Flomax®) is contraindicated. Tadalafail was evaluated in combination with doxazosin (Cardura®) and resulted in a significant increase in the blood pressure-lowering effect of doxazosin. Similarly to the other agents, tadalafil is also contraindicated with the use of organic nitrates. This combination can cause severe, possibly fatal, hypotensive episodes.2,10,18 All three agents may potentially cause a prolonged erection greater than 4 hours and priapism, a painful erection greater than 6 hours in duration.

Buy from licensed healthcare providers

Medical assistance should be sought if an erection lasts longer than 4 hours. Additionally, if priapism is not immediately treated, penile tissue damage and permanent loss of potency may result.8-10 There do not appear to be any major differences in contraindications among sildenafil, vardenafil, and tadalafil. Sildenafil is contraindicated with known hypersensitivity to the drug or concurrent use of organic nitrates.8-10,16-18 Both vardenafil and tadalafil have the same contraindication and, additionally, both are contraindicated with concomitant use of alpha-blockers (with the exception of tamsulosin with tadalafil).8-10,16-18 Due to the presence of PDE-5 in all vascular smooth muscle and inhibition of other PDE isoenzymes, all of these medications may produce adverse effects.7 The most common adverse effects with sildenafil, vardenafil, and tadalafil are listed in Table 1. The major adverse effect that may differ between these agents is ocular effects. It is believed that vardenafil and tadalafil may produce less abnormal vision than sildenafil due to their greater selectivity for PDE-5 compared to PDE-6, the isoenzyme responsible for ocular effects. Similarly to the other agents, tadalafil is also contraindicated with the use of organic nitrates. This combination can cause severe, possibly fatal, hypotensive episodes.2,10,18 All three agents may potentially cause a prolonged erection greater than 4 hours and priapism, a painful erection greater than 6 hours in duration. Medical assistance should be sought if an erection lasts longer than 4 hours.

Study Name	Sample Size	Dose Administered	Outcome Measured	Results
Women's ED Study 1	150 women	10 mg daily	Sexual satisfaction, libido score	Improved scores in treatment group
Female Sexual Function Trial	200 women	5-20 mg	Erectile-related response, libido	Variable, some side effects observed
Tadalafil Safety in Women	100 women	10 mg	Adverse events	Mild headaches, flushing

Additionally, if priapism is not immediately treated, penile tissue damage and permanent loss of potency may result.8-10 There do not appear to be any major differences in contraindications among sildenafil, vardenafil, and tadalafil. Sildenafil is contraindicated with known hypersensitivity to the drug or concurrent use of organic nitrates.8-10,16-18 Both vardenafil and tadalafil have the same contraindication and, additionally, both are contraindicated with concomitant use of alpha-blockers (with the exception of tamsulosin with tadalafil).8-10,16-18 Due to the presence of PDE-5 in all vascular smooth muscle and inhibition of other PDE isoenzymes, all of these medications may produce adverse effects.7 The most common adverse effects with sildenafil, vardenafil, and tadalafil are listed in Table 1. The major adverse effect that may differ between these agents is ocular effects. It is believed that vardenafil and tadalafil may produce less abnormal vision than sildenafil due to their greater selectivity for PDE-5 compared to PDE-6, the isoenzyme responsible for ocular effects. Any clinically significant difference in effect will need to be clarified by post-marketing surveillance of vardenafil and tadalafil.2,12 While sildenafil and vardenafil have similar recommended dosing, the dosing schedule for tadalafil may differ due to its greater time to maximum concentration and longer half-life. Dosing guidelines are listed in Table 2.2,13 The PDE-5 inhibitors are not FDA-approved for use in women or children. All of these agents are classified as pregnancy-risk category B.8-10 Pregnancy category B is defined as either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).21 The price of sildenafil 25- or 50-mg tablets is $90.99 for ten tablets or $259.97 for 30 tablets, while the 100 mg strength of sildenafil is $93.99 for ten tablets or $267.97 for 30 tablets. Finally, the price of tadalafil 5-, 10-, or 20-mg tablets is $89.99 for ten tablets or $259.97 for 30 tablets.22-24 Recently, sildenafil has been investigated for the treatment of pulmonary hypertension.25 It has been shown to decrease pulmonary artery pressure and pulmonary vascular resistance, decrease symptoms, and improve New York Heart Association functional class in patients with pulmonary hypertension.