Tadalafil
Encyclopedia
Tadalafil is a PDE5 inhibitor
, currently marketed in pill form for treating erectile dysfunction
(ED) under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension. It initially was developed by the biotechnology
company ICOS
, and then again developed and marketed world-wide 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. The approved dose for pulmonary arterial hypertension is 40 mg (two 20-mg tablets) once daily.
Tadalafil is also manufactured and sold under the name of Tadacip by the Indian Pharmaceutical company Cipla
in doses of 10 mg and 20 mg.
On November 21, 2003 the Food and Drug Administration
approved tadalafil (as Cialis) for sale in the United States as the third ED prescription drug pill (after sildenafil citrate (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, tadalafil was approved in May 2009 in the United States for the treatment of pulmonary arterial hypertension and is currently under regulatory review in other regions for this condition. 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.
) on 27 March 1998 was a ground-breaking commercial event for the treatment of ED, with sales exceeding one billion dollars. Subsequently, the FDA approved Levitra (vardenafil
) on 19 August 2003, and Cialis (tadalafil) on 21 November 2003.
Cialis was discovered by Glaxo Wellcome (now GlaxoSmithKline
) under a partnership between Glaxo and ICOS to develop new drugs that began in August 1991. In 1993, the Bothell, Washington, biotechnology company ICOS Corporation began studying compound IC351, a phosphodiesterase type 5
(PDE5) enzyme inhibitor
. In 1994, Pfizer scientists discovered that sildenafil, which also inhibits the PDE5 enzyme, caused penile erection in men participating in a clinical study of a heart medicine. Although ICOS scientists were not testing compound IC351 for treating ED, they recognized its potential usefulness for treating that disorder. Soon, in 1994, ICOS received a patent for compound IC351 (structurally unlike sildenafil and vardenafil), and Phase 1 clinical trials began in 1995. In 1997, the Phase 2 clinical studies were initiated for men experiencing ED, then progressed to the Phase 3 trials that supported the drug's FDA approval. Although Glaxo had an agreement with ICOS to share profits 50/50 for drugs resulting from the partnership, Glaxo let the agreement lapse in 1996 as the drugs developed were not in the company's core markets.
In 1998, ICOS Corporation and Eli Lilly and Company formed the Lilly ICOS, LLC, joint venture company to further develop and commercialize tadalafil as a treatment for ED. Two years later, Lilly ICOS, LLC, filed a New Drug Application with the FDA for compound IC351 (under the tadalafil generic name, and the Cialis brand name). In May 2002, Lilly ICOS reported to the American Urological Association
that clinical trial testing demonstrated that tadalafil was effective for up to 36 hours, and one year later, the FDA approved tadalafil. One advantage Cialis has over Viagra and Levitra is its 17.5-hour half-life
(thus Cialis is advertised to work for up to 36 hours, after which time there remains approximately 25 percent of the absorbed dose in the body) when compared to the four-hour half–life of sildenafil (Viagra).
In 2007, Eli Lilly and Company bought the ICOS Corporation for 2.3 billion dollars. As a result, Eli Lilly owned Cialis and then closed the ICOS operations, ending the joint venture and firing most of ICOS's approximately 500 employees, except for 127 employees of the ICOS biologics facility, which subsequently was bought by CMC Biopharmaceuticals A/S(CMC).
Persons surnamed "Cialis" objected to Eli Lilly and Company's so naming the drug, but the company has maintained that the drug's trade name is unrelated to the surname.
On Oct. 6th, 2011; The U.S. FDA has approved tadalafil to treat the signs and symptoms of benign prostatic hyperplasia (BPH). BPH is a condition in male, where the prostate gland becomes enlarged causing obstruction to free flow of urine. Symptoms may include sudden urges to urinate (Urgency), difficulty in starting urination (Hesitancy), a weak urine stream and more frequent urination especially at night. FDA also has approved it for treatment of BPH and erectile dysfunction (ED); if co-exist,
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 5 mg, 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, tadalafil (Adcirca) 40 mg was approved in 2009 in the United States and Europe (and 2010 in Canada and Japan) as a once-daily therapy to improve exercise ability in patients with pulmonary arterial hypertension. In patients with pulmonary arterial hypertension, the pulmonary vascular lumen is decreased as a result of vasoconstriction and vascular remodeling, resulting in increased pulmonary artery pressure and pulmonary vascular resistance. Tadalafil is believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance. Right heart failure is the principal consequence of pulmonary arterial hypertension.
s 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 (nonarteritic 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 postmarketing reports of deafness associated with use of PDE5 inhibitors.
), organic nitrates should not be taken for at least 48 hours after taking the last dose of tadalafil. Using organic nitrites (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, paramedic
s and medical personnel should be notified of any recent doses of tadalafil.
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.
In the United States, the FDA relaxed rules on prescription drug marketing in 1997, allowing advertisements targeted directly to consumers. Lilly-ICOS hired the Grey Worldwide Agency in New York, part of the Grey Global Group
, to run the Cialis advertising campaign. Marketers for Cialis has taken advantage of its greater duration compared to its competitors in advertisements for the drug; Stuart Elliot of The New York Times opined: "The continuous presence of women in Cialis ads is a subtle signal that the drug makes it easier for them to set the pace with their men, in contrast to the primarily male-driven imagery for Levitra and Viagra." Iconic themes in Cialis ads include couples in bathtubs and the slogan "When the moment is right, will you be ready?" Cialis ads were unique among the ED drugs in mentioning specifics of the drug. As a result, Cialis ads were also the first to describe the side effects in an advertisement, as the FDA requires advertisements with specifics to mention side effects. One of the first Cialis ads aired at the 2004 Super Bowl
. Just weeks before the Super Bowl, the FDA required more possible side effects to be listed in the advertisement, including priapism
. Although many parents objected to the Cialis ad being aired during the Super Bowl, Janet Jackson
's halftime "wardrobe malfunction
" overshadowed Cialis. In January 2006, the Cialis ads were tweaked, adding a doctor on screen to describe side effects and only running ads where more than 90 percent of the audience are adults, effectively ending Super Bowl ads. In 2004, Lilly-ICOS, Pfizer, and GlaxoSmithKline spent a combined $373.1 million to advertise Cialis, Viagra, and Levitra respectively. Cialis has sponsored many golf
events, including the America's Cup
and the PGA Tour
, once being title sponsor of the PGA Tour Western Open
tournament.
PDE5 inhibitor
A phosphodiesterase type 5 inhibitor, often shortened to PDE5 inhibitor, is a drug used to block the degradative action of phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis...
, currently marketed in pill form for treating erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
(ED) under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension. It initially was developed by the biotechnology
Biotechnology
Biotechnology is a field of applied biology that involves the use of living organisms and bioprocesses in engineering, technology, medicine and other fields requiring bioproducts. Biotechnology also utilizes these products for manufacturing purpose...
company ICOS
ICOS
Icos Corporation was the largest biotechnology company in the U.S. state of Washington before it was sold to Eli Lilly and Company in 2007. Co-founded in 1989 by George B. Rathmann, a pioneer in the industry and Chief Executive Officer and co-founder of Amgen, Icos focused on the development of...
, and then again developed and marketed world-wide by Lilly ICOS, LLC, the joint venture of ICOS Corporation and Eli Lilly and Company
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
. Cialis tablets, in 5 mg, 10 mg, and 20 mg doses, are yellow, film-coated, and almond-shaped. The approved dose for pulmonary arterial hypertension is 40 mg (two 20-mg tablets) once daily.
Tadalafil is also manufactured and sold under the name of Tadacip by the Indian Pharmaceutical company Cipla
Cipla
Cipla Limited is a prominent Indian pharmaceutical company, best-known outside its home country for manufacturing low-cost anti-AIDS drugs for HIV-positive patients in developing countries...
in doses of 10 mg and 20 mg.
On November 21, 2003 the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approved tadalafil (as Cialis) for sale in the United States as the third ED prescription drug pill (after sildenafil citrate (Viagra) and vardenafil
Vardenafil
Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...
(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, tadalafil was approved in May 2009 in the United States for the treatment of pulmonary arterial hypertension and is currently under regulatory review in other regions for this condition. 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.
History
The FDA's approval of Viagra (SildenafilSildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
) on 27 March 1998 was a ground-breaking commercial event for the treatment of ED, with sales exceeding one billion dollars. Subsequently, the FDA approved Levitra (vardenafil
Vardenafil
Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...
) on 19 August 2003, and Cialis (tadalafil) on 21 November 2003.
Cialis was discovered by Glaxo Wellcome (now GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
) under a partnership between Glaxo and ICOS to develop new drugs that began in August 1991. In 1993, the Bothell, Washington, biotechnology company ICOS Corporation began studying compound IC351, a phosphodiesterase type 5
CGMP specific phosphodiesterase type 5
cGMP-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina....
(PDE5) enzyme inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
. In 1994, Pfizer scientists discovered that sildenafil, which also inhibits the PDE5 enzyme, caused penile erection in men participating in a clinical study of a heart medicine. Although ICOS scientists were not testing compound IC351 for treating ED, they recognized its potential usefulness for treating that disorder. Soon, in 1994, ICOS received a patent for compound IC351 (structurally unlike sildenafil and vardenafil), and Phase 1 clinical trials began in 1995. In 1997, the Phase 2 clinical studies were initiated for men experiencing ED, then progressed to the Phase 3 trials that supported the drug's FDA approval. Although Glaxo had an agreement with ICOS to share profits 50/50 for drugs resulting from the partnership, Glaxo let the agreement lapse in 1996 as the drugs developed were not in the company's core markets.
In 1998, ICOS Corporation and Eli Lilly and Company formed the Lilly ICOS, LLC, joint venture company to further develop and commercialize tadalafil as a treatment for ED. Two years later, Lilly ICOS, LLC, filed a New Drug Application with the FDA for compound IC351 (under the tadalafil generic name, and the Cialis brand name). In May 2002, Lilly ICOS reported to the American Urological Association
American Urological Association
The American Urological Association is a professional association in the United States for urology professionals.-Awards:*Hugh Hampton Young Award. Presented annually to an individual for outstanding contributions to the study of genitourinary tract disease. This award is sponsored by Karl Storz...
that clinical trial testing demonstrated that tadalafil was effective for up to 36 hours, and one year later, the FDA approved tadalafil. One advantage Cialis has over Viagra and Levitra is its 17.5-hour half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
(thus Cialis is advertised to work for up to 36 hours, after which time there remains approximately 25 percent of the absorbed dose in the body) when compared to the four-hour half–life of sildenafil (Viagra).
In 2007, Eli Lilly and Company bought the ICOS Corporation for 2.3 billion dollars. As a result, Eli Lilly owned Cialis and then closed the ICOS operations, ending the joint venture and firing most of ICOS's approximately 500 employees, except for 127 employees of the ICOS biologics facility, which subsequently was bought by CMC Biopharmaceuticals A/S(CMC).
Persons surnamed "Cialis" objected to Eli Lilly and Company's so naming the drug, but the company has maintained that the drug's trade name is unrelated to the surname.
On Oct. 6th, 2011; The U.S. FDA has approved tadalafil to treat the signs and symptoms of benign prostatic hyperplasia (BPH). BPH is a condition in male, where the prostate gland becomes enlarged causing obstruction to free flow of urine. Symptoms may include sudden urges to urinate (Urgency), difficulty in starting urination (Hesitancy), a weak urine stream and more frequent urination especially at night. FDA also has approved it for treatment of BPH and erectile dysfunction (ED); if co-exist,
Mechanism of action
Although sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) all work by inhibiting PDE5, tadalafils 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 5 mg, 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, tadalafil (Adcirca) 40 mg was approved in 2009 in the United States and Europe (and 2010 in Canada and Japan) as a once-daily therapy to improve exercise ability in patients with pulmonary arterial hypertension. In patients with pulmonary arterial hypertension, the pulmonary vascular lumen is decreased as a result of vasoconstriction and vascular remodeling, resulting in increased pulmonary artery pressure and pulmonary vascular resistance. Tadalafil is believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance. Right heart failure is the principal consequence of pulmonary arterial hypertension.
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 effectAdverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s when using tadalafil are headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, indigestion, back pain, muscle aches, flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
, 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
found that tadalafil (along with other PDE5 inhibitors) was associated with vision impairment related to NAION (nonarteritic anterior ischemic optic neuropathy
Anterior ischemic optic neuropathy
Anterior ischemic optic neuropathy is a medical condition involving loss of vision due to damage to the optic nerve from insufficient blood supply. AION is generally divided into two types: arteritic AION and non-arteritic AION...
) 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
Hearing impairment
-Definition:Deafness is the inability for the ear to interpret certain or all frequencies of sound.-Environmental Situations:Deafness can be caused by environmental situations such as noise, trauma, or other ear defections...
as the result of postmarketing reports of deafness associated with use of PDE5 inhibitors.
Drug interactions
Since PDE5 inhibitors such as tadalafil may cause transiently low blood pressure (hypotensionHypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
), organic nitrates should not be taken for at least 48 hours after taking the last dose of tadalafil. Using organic nitrites (such as the sex drug amyl nitrite
Amyl nitrite
Amyl nitrite is the chemical compound with the formula C5H11ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrito functional group. The alkyl group is unreactive and the chemical and biological properties are mainly due to the nitrite group...
) 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, paramedic
Paramedic
A paramedic is a healthcare professional that works in emergency medical situations. Paramedics provide advanced levels of care for medical emergencies and trauma. The majority of paramedics are based in the field in ambulances, emergency response vehicles, or in specialist mobile units such as...
s and medical personnel should be notified of any recent doses of tadalafil.
Selectivity compared with other PDE5 inhibitors
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 PDE1PDE1
PDE1 is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase . PDE1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms...
more than tadalafil. PDE1 is found in the brain, heart, and vascular smooth muscle
Vascular smooth muscle
Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood vessels.Vascular smooth muscle contracts or relaxes to both change the volume of blood vessels and the local blood pressure, a mechanism that is responsible for the...
. It is thought that the inhibition of PDE1 by sildenafil and vardenafil leads to vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
, flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
, and tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
. Tadalafil inhibits PDE11 more than sildenafil or vardenafil. PDE11 is expressed in skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
, the prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
, the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
, and the testes. The effects on the body of inhibiting PDE11 are not known.
Marketing
Grey Global Group
Grey Group is a global advertising and marketing agency, whose slogan is providing solutions - with headquarters in New York City, and 432 offices in 96 countries, operating in 154 cities — organized into four geographical units: North America; Europe, Middle East & Africa, Asia-Pacific and Latin...
, to run the Cialis advertising campaign. Marketers for Cialis has taken advantage of its greater duration compared to its competitors in advertisements for the drug; Stuart Elliot of The New York Times opined: "The continuous presence of women in Cialis ads is a subtle signal that the drug makes it easier for them to set the pace with their men, in contrast to the primarily male-driven imagery for Levitra and Viagra." Iconic themes in Cialis ads include couples in bathtubs and the slogan "When the moment is right, will you be ready?" Cialis ads were unique among the ED drugs in mentioning specifics of the drug. As a result, Cialis ads were also the first to describe the side effects in an advertisement, as the FDA requires advertisements with specifics to mention side effects. One of the first Cialis ads aired at the 2004 Super Bowl
Super Bowl
The Super Bowl is the championship game of the National Football League , the highest level of professional American football in the United States, culminating a season that begins in the late summer of the previous calendar year. The Super Bowl uses Roman numerals to identify each game, rather...
. Just weeks before the Super Bowl, the FDA required more possible side effects to be listed in the advertisement, including priapism
Priapism
Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
. Although many parents objected to the Cialis ad being aired during the Super Bowl, Janet Jackson
Janet Jackson
Janet Damita Jo Jackson is an American recording artist and actress. Known for a series of sonically innovative, socially conscious and sexually provocative records, as well as elaborate stage shows, television and film roles, she has been a prominent figure in popular culture for over 25 years...
's halftime "wardrobe malfunction
Super Bowl XXXVIII halftime show controversy
Super Bowl XXXVIII, which was broadcast live on February 1, 2004 from Houston, Texas on the CBS television network in the United States, was noted for a controversial halftime show in which Janet Jackson's breast, adorned with a nipple shield, was exposed by Justin Timberlake for about half a...
" overshadowed Cialis. In January 2006, the Cialis ads were tweaked, adding a doctor on screen to describe side effects and only running ads where more than 90 percent of the audience are adults, effectively ending Super Bowl ads. In 2004, Lilly-ICOS, Pfizer, and GlaxoSmithKline spent a combined $373.1 million to advertise Cialis, Viagra, and Levitra respectively. Cialis has sponsored many golf
Golf
Golf is a precision club and ball sport, in which competing players use many types of clubs to hit balls into a series of holes on a golf course using the fewest number of strokes....
events, including the America's Cup
America's Cup
The America’s Cup is a trophy awarded to the winner of the America's Cup match races between two yachts. One yacht, known as the defender, represents the yacht club that currently holds the America's Cup and the second yacht, known as the challenger, represents the yacht club that is challenging...
and the PGA Tour
PGA Tour
The PGA Tour is the organizer of the main men's professional golf tours in the United States and North America...
, once being title sponsor of the PGA Tour Western Open
Western Open
The Western Open, a professional golf tournament, was first played in 1899. At the time of its 2006 playing, the Western Open was the 3rd oldest active PGA Tour tournament, after the British Open and U.S. Open...
tournament.