Tadalafil is a drug used to treat male erectile dysfunction (impotence). It was developed by the biotechnology firm ICOS and marketed worldwide by Eli Lilly and Company under the brand name Cialis.
In the United States, tadalafil has Food and Drug Administration approval and became available in December, 2003 as the third impotence pill after sildenafil (Viagra) and vardenafil (Levitra). Due to its 36-hour effect it is also known as the weekend pill. It should be noted that the drug has not been formally studied in regard to multiple sexual attempts during a 36 hour period.

History

The history of Cialis cannot be discussed without mentioning Pfizer’s drug, Viagra. The FDA’s approval on March 27, 1998, led this prescription drug, Viagra, to a ground breaking success in just the first year of introduction as Pfizer sold drugs worth over a billion dollars. However, things changed considerably for the giant of erectile dysfunction drugs when the FDA also approved Levitra on August 19, 2003, and Cialis on November 21, 2003. In 1993 the drug company Icos began studying IC351, which is a PDE5 enzyme inhibitor, and this is basically the process through which the erectile dysfunction drugs work. In 1994, Pfizer scientists discovered that sildenafil citrate, which is a white crystalline powder that temporarily normalizes erectile function of the penis by blocking an enzyme known to inhibit the production of a chemical that causes erections, caused the heart patients that were participating in a clinical study of a heart medicine to have erections. Although the scientists were not testing the chemical compound IC351 for erectile dysfunction, the compound seemed to have a side effect which could potentially be worth millions, if not billions of dollars. Soon Icos received its very first patent in 1994 on IC351, and the clinical trials of phase 1 took place in 1995. In 1997, phase 2 clinical studies began and Icos performed its first study on patients with erectile dysfunction. Phase 2 lasted about two years, and after that phase 3 began.
In 1998, ICOS Corporation, and Eli Lilly and Company, commercialized the drug for erectile dysfunction, and two years later they filed a new drug application with the U.S. Food and Drug Administration for IC351; the only difference was that this time they decided to call the drug, Cialis. In May of 2002, Icos and Eli Lilly and Company reported to the American Urological Association that the phase 3 tests show that Cialis works for up to 36 hours, and one year later Icos and Eli Lilly and Company received the U.S. FDA’s approval for Cialis.
Eli Lilly purchased ICOS corporation for $2.1 billion dollars in 2006.

Chemistry of Tdalafil (cialis)

The structural formula is:

The chemical designation is: pyrazino[1,2:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.
CIALIS is available as film-coated, almond-shaped tablets for oral administration. Each tablet contains 5, 10, or 20 mg of tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.

References

Mechanism of Action

Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation. Other drugs that operate by the same mechanism include sildenafil (Viagra®) and vardenafil (Levitra®).
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.
In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro, tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.

Pharmacokinetics

Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once-daily dosing, and exposure is approximately 1.6-fold greater than after a single dose. Tadalafil is eliminated predominantly by hepatic metabolism, mainly by cytochrome P450 3A4 (CYP3A4). The concomitant use of potent CYP3A4 inhibitors such as ritonavir or ketoconazole resulted in significant increases in tadalafil AUC values.

Absorption

After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food; thus CIALIS may be taken with or without food.

Distribution

The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.

Metabolism

Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

Elimination

The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).

Pharmacodynamics

Effects on Blood Pressure

Tadalafil 20 mg administered to healthy male subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (difference in the mean maximal decrease of 1.6/0.8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 mm Hg, respectively). In addition, there was no significant effect on heart rate.

Effects on Blood Pressure when CIALIS is Administered with Nitrates

In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Therefore, the use of CIALIS in patients taking any form of nitrates is contraindicated.

Effects on Exercise Stress Testing

The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates.

Effects on Vision

Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with CIALIS, reports of changes in color vision were rare (Effects on Sperm Characteristics

Three studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6 month study) and 20 mg (one 6 month and one 9 month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.

Effects on Cardiac Electrophysiology

The effect of a single 100-mg dose of tadalafil on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two-sided 90% CI=1.2, 4.4). A 100-mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to placebo was 3.1 beats per minute.

Side effects

The most common side effects when using tadalafil are headache, indigestion, back pain, muscle aches, flushing, and stuffy or runny nose. These side effects usually go away after a few hours. Back pain and muscle aches can occur 12 to 24 hours after taking the drug, and the symptom usually disappears after 48 hours.
In May 2005, the U.S. Food and Drug Administration found that tadalafil (along with other PDE5 inhibitors) could lead to vision impairment in certain patient groups, including diabetics. An investigation is currently ongoing.

Drug interactions

Since PDE5 inhibitors such as tadalafil may cause transiently low blood pressure (hypotension), organic nitrates should not be taken for at least 48 hours after taking the last dose of tadalafil. Using organic nitrates (such as the sex drug amyl nitrite) within this timeframe may increase the risk of life-threatening hypotension.
Since people who have taken tadalafil within the past 48 hours cannot take organic nitrates to relieve angina (such as glyceryl trinitrate spray), these patients should seek immediate medical attention if they experience anginal chest pain. In the event of a medical emergency, paramedics and medical personnel should be notified of any recent doses of tadalafil.

FDA ALERT [07/2005]

A small number of men have lost eyesight in one eye some time after taking Cialis, Viagra, or Levitra. This type of vision loss is called non-arteritic anterior ischemic optic neuropathy (NAION). NAION causes a sudden loss of eyesight because blood flow is blocked to the optic nerve.
We do not know at this time if Cialis, Viagra or Levitra causes NAION. NAION also happens in men who do not take these medicines. People who have a higher chance for NAION include those who:

  • have heart disease
  • are over 50 years old
  • have diabetes
  • have high blood pressure
  • have high cholesterol
  • smoke
  • have certain eye problems

FDA has approved new labels for Cialis, Viagra, and Levitra to include information on possible eyesight loss (NAION).
Stop using Cialis, Viagra, or Levitra if you have a loss in your eyesight. Get medical help right away.

Advantages of cialis

One advantage that Cialis has over Viagra is that tadalafil has an half-life of 17.5 hours (and thus Cialis is advertised to work for up to 36 hours) as compared to 4 hours half-life for sildenafil (Viagra). Plus, it works in just 30 minutes and it isn’t affected by food, so you don’t have to plan around meals.

Sources: lilly (pdf), wikipedia, fda, cialis

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