The introduction of Tadalafil in the market has brought a great change in the way Erectile Dysfunction is treated, and has able many suffering from Impotence, to have the freedom of choosing the best time for their sexual performance. The action of Tadalafil, better known as the ”Weekend pill”, and marketed under the name of “Cialis”, has a prolonged inhibitory power of up to 36 hours, making it the Erectile Dysfunction tablet with the longest lasting power on the market today.
Tadalafil goes to work in approximately thirty minutes, and is not affected by food digestion, therefore meals are not required to be planned according with the assumption of the drug. Once it is absorbed in the organism, the action of Tadalafil precludes the enzyme PDE5 from its preventive action on the cyclic GMP, which is triggered by sexual desire.
Tadalafil is a PDE5 inhibitor. It is current marketed in pill form for treating erectile dysfunction (ED) but has been used for other conditions. It initially was developed by the biotechnology company ICOS, and then again developed and marketed world-wide as Cialis, by Lilly ICOS, LLC, the joint venture of ICOS Corporation and Eli Lilly and Company. Cialis tablets, in 5 mg, 10 mg, and 20 mg doses, are yellow, film-coated, and almond-shaped.
In December 2003, the Food and Drug Administration approved tadalafil (as Cialis) for sale in the U.S. as the third ED prescription drug pill after sildenafil (Viagra) and vardenafil (Levitra). Cialis’s 36-hour effectiveness earned it the nickname, “The Weekend Pill”; like sildenafil and vardenafil, tadalafil is recommended as an ‘as needed’ medication. Cialis is the only one of the three that is also offered as a once daily medication.
Moreover, besides ED, tadalafil for the treatment of pulmonary arterial hypertension is currently under regulatory review in multiple regions. In late November 2008, Eli Lilly sold the exclusive rights to commercialize tadalafil for pulmonary arterial hypertension in the United States to United Therapeutics for an upfront payment of $150 million.
During the process of the erection, sexual stimulations produce the forming of cyclic GMP responsible for the increase of blood flow in the corpus cavernous of the smooth muscle, flooding the smooth muscle and resulting in the erection and harden of the penis. The action of Tadalafil focuses on the inhibition of the enzyme PDE5, which would other ways stop the cyclic GMP from performing the enlargement of the blood vessels. By focusing its action only on the specific enzyme PDE5, Tadalafil don’t interfere with the way a natural erection occurs, in fact, during the inhibitory action of Tadalafil on the enzyme PDE5, erections are only taking place when generate by sexual desire.
Although sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) all work by inhibiting PDE5, tadalafil’s pharmacologic distinction is its longer half-life (17.50 hours) — compared to Viagra (4.0–5.0 hours) and Levitra (4.0–5.0 hours) — resulting in longer duration of action, and so partly responsible for “The Weekend Pill” sobriquet. Furthermore, the longer half-life is the basis for current investigation of tadalafil’s daily therapeutic use in relieving pulmonary arterial hypertension. Currently, sildenafil (trade name Revatio) is approved in several world regions as a thrice-daily therapy for pulmonary arterial hypertension.
Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and the smooth muscle of the corpus cavernosum. 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 relaxes smooth muscle and increases blood flow to the corpus cavernosum.
The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil (and sildenafil and vardenafil) inhibits PDE5, however, because sexual stimulation is required to initiate the local penile release of nitric oxide, tadalafil’s inhibition of PDE5 will have no effect without direct sexual stimulation of the penis. The recommended Cialis starting dose for most men is 10 mg, taken as needed before sexual activity (but not more than once daily). The dose may be increased to 20 mg or decreased to 5mg, per its efficacy and the man’s personal tolerance of the drug. To avoid the inconvenience of a man having to program and plan using Cialis around the time of his anticipated sexual activity, Lilly ICOS began a clinical development program to evaluate the risks and benefits of chronic, once-daily use of the drug. In June 2007, the European Commission approved low-dose (2.5 mg and 5 mg) Cialis to be used as single-daily ED therapy.
Moreover, Lilly has completed their pivotal clinical trials of tadalafil for treating pulmonary arterial hypertension, and submission of data to regulatory agencies for marketing approval in the United States, Canada, Mexico, Japan and the European Union began in late 2008. In some patients, there exists an imbalance of the PDE5/NO system in the pulmonary vasculature that favours selective vasoconstriction of the pulmonary arteries. Investigation of tadalafil in this disease presumes that inhibiting PDE5 will effect pulmonary artery vasodilation, thus lowering pulmonary arterial pressure and pulmonary vascular resistance. These physiologic changes may then reduce the workload of the heart’s right ventricle. Right heart failure and pulmonary oedema are the principal consequences of pulmonary arterial hypertension. Data presented at scientific conferences in October 2008 suggest that tadalafil 40 mg once daily is the most effective dose from the Phase 3 tadalafil clinical trial of patients with pulmonary arterial hypertension.
Tadalafil, sildenafil, and vardenafil all act by inhibiting the PDE5 enzyme. These drugs also inhibit other PDE enzymes. Sildenafil and vardenafil inhibit PDE6, an enzyme found in the eye, more than tadalafil. Some sildenafil users see a bluish tinge and have a heightened sensitivity to light because of PDE6 inhibition.Sildenafil and vardenafil also inhibit PDE1 more than tadalafil. PDE1 is found in the brain, heart, and vascular smooth muscle. It is thought that the inhibition of PDE1 by sildenafil and vardenafil leads to vasodilation, flushing, and tachycardia. Tadalafil inhibits PDE11 more than sildenafil or vardenafil. PDE11 is expressed in skeletal muscle, the prostate, the liver, the kidney, the pituitary gland, and the testes. The effects on the body of inhibiting PDE11 are not known.
Side effects
Tadalafil has been used in approximately 15,000 men participating in clinical trials, and over 8 million men worldwide (primarily in the post-approval/post-marketing setting). The most common side effects when using tadalafil are headache, indigestion, back pain, muscle aches, flushing, and stuffy or runny nose. These side effects reflect the ability of PDE5 inhibition to vasodilate (cause blood vessels to widen) and 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) was associated with vision impairment related to NAION (non-arteritic anterior ischemic optic neuropathy) in certain patients taking these drugs in the post-marketing (outside of clinical trials) setting. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION unrelated to PDE5 use, including: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Given the small number of NAION events with PDE5 use (less than 1 in 1 million), the large number of users of PDE5 inhibitors (millions) and the fact that this event occurs in a similar population to those who do not take these medicines, the FDA concluded that they were not able to draw a cause and effect relationship, given these patients underlying vascular risk factors or anatomical defects. However, the label of all three PDE5 inhibitors was changed to alert clinicians to a possible association.
In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including tadalafil, requires a more prominent warning of the potential risk of sudden hearing loss as the result of post marketing reports of deafness associated with use of PDE5 inhibitors.
