A phosphodiesterase type 5 inhibitor, often shortened to PDE5 inhibitor, is a drug

Medication

A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 used to block the degradative action of phosphodiesterase

Phosphodiesterase

A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...

 type 5 on cyclic GMP in the smooth muscle

Smooth muscle

Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

 cells lining the blood vessels supplying the corpus cavernosum

Corpus cavernosum

Corpus cavernosum may refer to:* corpus cavernosum clitoridis* corpus cavernosum penis* "corpus cavernosum urethrae" was used for corpus spongiosum in older texts* corpus cavernosum conchae...

 of the penis

Penis

The penis is a biological feature of male animals including both vertebrates and invertebrates...

. These drugs are used in the treatment of 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....

, and were the first effective oral treatment available for the condition. Because PDE5 is also present in the arterial wall smooth muscle

Smooth muscle

Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

 within the lung

Lung

The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...

s, PDE5 inhibitors have also been explored for the treatment of pulmonary hypertension

Pulmonary hypertension

In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...

, a disease in which blood vessels in the lungs become abnormally narrow.

Indications

PDE5 inhibitors are clinically indicated for the treatment of erectile dysfunction. Sildenafil

Sildenafil

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...

 citrate, one of the PDE5 inhibitors, is also indicated for the treatment of pulmonary hypertension. Other PDE5 inhibitors such as tadalafil

Tadalafil

Tadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension...

 and vardenafil

Vardenafil

Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...

 have been studied as other possible treatments for this disease.

Sildenafil, the prototypical PDE5 inhibitor, was originally discovered during the search of a novel treatment for angina. Studies in 2002 explored its potential for increasing neurogenesis

Neurogenesis

Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...

 after stroke

Stroke

A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

.

Contraindications

PDE5 inhibitors are contraindicated in those taking nitrate

Nitrate

The nitrate ion is a polyatomic ion with the molecular formula NO and a molecular mass of 62.0049 g/mol. It is the conjugate base of nitric acid, consisting of one central nitrogen atom surrounded by three identically-bonded oxygen atoms in a trigonal planar arrangement. The nitrate ion carries a...

 medication. They are also contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors.

Adverse reactions

The occurrence of adverse drug reaction

Adverse drug reaction

An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s (ADRs) with PDE5 inhibitors appears to be dose related. 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...

 is a very common ADR, occurring in >10% of patients. Other common ADRs include: dizziness, flushing, dyspepsia

Dyspepsia

Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...

, nasal congestion or rhinitis.

On October 18, 2007, the U.S. Food and Drug Administration (FDA) announced that a warning about possible sudden hearing loss would be added to drug labels of PDE5 inhibitors.

Since 2007 there is evidence that 5-phosphodiesterase inhibitors can cause an anterior optic neuropathy

Other ADRs and their incidence vary with the agent and are listed in their individual pages.

Drug interactions

PDE5 inhibitors are primarily metabolised by the cytochrome P450

Cytochrome P450 oxidase

The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...

 enzyme CYP3A4

CYP3A4

Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...

. The potential exists for adverse drug interactions with other drugs which inhibit or induce CYP3A4, including HIV protease inhibitor

Protease inhibitor (pharmacology)

Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...

s, ketoconazole

Ketoconazole

Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...

, itraconazole

Itraconazole

Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...

, and other anti-hypertensive drugs such as Nitro-spray (due to its capacity to diminish blood pressure).

Examples

Sildenafil was the prototypical member of the PDE5 inhibitors. Two other agents, with their own advantages/disadvantages, are also available, and several others are in development.

• avanafil
  Avanafil
  Avanafil is a PDE5 inhibitor being developed for erectile dysfunction. Avanafil currently has no trademarked term associated with it but it is being developed by Vivus Inc. It acts by inhibiting a specific phosphodiesterase type 5 enzyme which is found in various body tissues, but primarily in the...
  
  
• lodenafil
  Lodenafil
  Lodenafil is a drug belonging to a class of drugs called PDE5 inhibitor, which many other erectile dysfunction drugs such as sildenafil, tadalafil, and vardenafil also belong to...
  
  
• mirodenafil
  Mirodenafil
  Mirodenafil is an experimental drug belonging to a class of drugs called PDE5 inhibitors, which many other erectile dysfunction drugs such as sildenafil, tadalafil, and vardenafil also belong to. Like udenafil, lodenafil and avanafil it belongs to a new generation of PDE5 inhibitors.It is not...
  
  
• sildenafil citrate
• tadalafil
  Tadalafil
  Tadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension...
  
  
• vardenafil
  Vardenafil
  Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...
  
  
• udenafil
  Udenafil
  Udenafil is a drug used in urology to treat erectile dysfunction. It belongs to a class of drugs called PDE5 inhibitor, which many other erectile dysfunction drugs such as sildenafil, tadalafil, and vardenafil also belong to. It was developed by Dong-A Pharmaceutical and is marketed under the trade...
  
  

Note that while these drugs preferentially inhibit PDE5, none of them is truly selective, especially at high doses. Sildenafil also inhibits PDE6 and PDE9, with inhibition of PDE6 in the retina thought to be responsible for the vision changes which can be a side effect of the drug. Similarly tadalafil inhibits both PDE5 and PDE11. However the selectivity of the existing drugs is high enough that inhibition of additional PDE subtypes is not generally a problem in clinical use, and while newer "super-selective" PDE5 inhibitors have been developed for research purposes, it is unlikely any of these will be marketed given the saturation of the erectile dysfunction market at present.

Claimed newer inhibitors are icariin

Icariin

Icariin is a flavonol, a type of flavonoid. It is the prenyl acetylation of kaempferide 3,7-O-diglucoside. The compound is derived from several species of plants in the Epimedium family, which are commonly known as Horny Goat Weed or Yin Yang Huo...

, an active component of Epimedium grandiflorum

Epimedium grandiflorum

Epimedium grandiflorum is a species of flowering plant in the barberry family, Berberidaceae, that is native to China, Japan, and Korea. It may have aphrodisiac characteristics due to the presence of icariin and is believed to cause increased sexual activity in goats. It commonly is packed in a...

and possibly 4-Methylpiperazine and Pyrazolo Pyrimidin-7-1, said to be components of the lichen Xanthoparmelia

Xanthoparmelia

Xanthoparmelia is a genus of lichen belonging to the family Parmeliaceae. Xanthoparmelia is synonymous with Almbornia, Neofuscelia, Chondropsis, Namakwa, Paraparmelia, and Xanthomaculina.This family of lichen is commonly found on the mid-east coast of the United States.The name means 'golden...

 scabrosa.

Mechanism of action

Part of the physiological process of erection involves the release of nitric oxide

Nitric oxide

Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

 (NO) in vasculature of the corpus cavernosum

Corpus cavernosum

Corpus cavernosum may refer to:* corpus cavernosum clitoridis* corpus cavernosum penis* "corpus cavernosum urethrae" was used for corpus spongiosum in older texts* corpus cavernosum conchae...

 as a result of sexual stimulation. NO activates the enzyme guanylate cyclase

Guanylate cyclase

-Reaction:Guanylate cyclase catalyzes the reaction of guanosine triphosphate to 3',5'-cyclic guanosine monophosphate and pyrophosphate:-Types:...

 which results in increased levels of cyclic guanosine monophosphate

Cyclic guanosine monophosphate

Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...

 (cGMP), leading to smooth muscle

Smooth muscle

Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

 relaxation in blood vessels supplying the corpus cavernosum, resulting in increased blood flow and an erection.

PDE5 inhibitors inhibit the degradation of cGMP by phosphodiesterase

Phosphodiesterase

A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...

type 5 (PDE5), increasing bloodflow to the penis during sexual stimulation.

This mode of action means that PDE5 inhibitors are ineffective without sexual stimulation.