PDE5 inhibitor

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Chemical structure of sildenafil (Viagra), the prototypical PDE5 inhibitor Sildenafil.svg
Chemical structure of sildenafil (Viagra), the prototypical PDE5 inhibitor

A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated. [1]

Contents

Medical uses

Phosphodiesterase-5 (PDE5) inhibitors such as sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra) are clinically indicated for the treatment of erectile dysfunction. [2] Sildenafil and tadalafil are also indicated for the treatment of some subtypes of pulmonary hypertension, while tadalafil is also licensed for the treatment of benign prostatic hyperplasia. [1]

PDE5 inhibitors have been used as a second line therapy in severe cases of Raynaud phenomenon when it is related to systemic sclerosis per The European Society for Vascular Medicine guidelines. [3]

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 after stroke, [4] but clinical evidence for benefit in cerebrovascular diseases is currently lacking. [1]

Contraindications

PDE5 inhibitors are contraindicated within 24 hours (or 48 hours with tadalafil) of taking alpha-blockers, soluble guanylate cyclase stimulators, or nitrate medications such as isosorbide mononitrate or isosorbide dinitrate. [1] Concurrent use of these medications can lead to life-threatening low blood pressure. [5] PDE5 inhibitors are also contraindicated in patients with previous nonarteritic anterior ischaemic optic neuropathy and hereditary eye diseases. [1]

Despite initial concerns of adverse cardiovascular events in patients prescribed PDE5 inhibitors, several long-term studies have established the safety of the drugs in both healthy patients and patients with cardiovascular risk factors. [1]

Adverse effects

All PDE5 inhibitors are generally well tolerated. [1] The occurrence of side effects, or adverse drug reactions (ADRs), with PDE5 inhibitors depends on the dose and type of agent. [1] Headache is a very common ADR, occurring in >10% of patients. Other common ADRs include: dizziness, flushing, dyspepsia, nasal congestion or rhinitis. [6] Back pain and muscle aches are also more common in patients taking tadalafil. [1]

In 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. [7]

Since 2007 there has been evidence to suggest that PDE5 inhibitors can cause an anterior optic neuropathy, [8] although the absolute risk increase is small. [1]

Finally, there are concerns that PDE5 inhibitors may increase the risk of neonatal mortality in pregnant women, and trials investigating use of the drugs for fetal growth restriction have been suspended. [1]

Drug interactions

PDE5 inhibitors are primarily metabolized by the cytochrome P450 enzyme system, particularly CYP3A4. The potential exists for adverse drug interactions with other drugs which inhibit or induce CYP3A4, including HIV protease inhibitors, ketoconazole, and itraconazole, [6] although coadministration has not been linked to changes in the safety or efficacy of either agent. [1] Combination with nitrovasodilators such as nitroglycerin and PETN is contraindicated because potentially life-threatening hypotension may occur. [9] PDE5 inhibitors do not interact synergistically with other antihypertensive drugs. [1]

Examples

Tadalafil STADA Pharma - T20 - 20 mg Tadalafil von STADA - T20 - 20 Milligramm - Potenzmittel - Bild 005.jpg
Tadalafil STADA Pharma - T20 - 20 mg

The PDE5 inhibitor story begins with the work of the British physician and physiologist Henry Hyde Salter who, in 1886, noticed that his asthma symptoms eased after drinking a strong cup of coffee. We now know that this was due to the bronchodilator properties of caffeine, a non-selective, albeit weak, PDE5 inhibitor. [10] In 1986, Pfizer scientists at Sandwich, UK, started preclinical work on the development of a PDE5 inhibitor (later known as sildenafil citrate) for the treatment of angina.

Sildenafil, tadalafil, vardenafil and avanafil are the main agents marketed globally, although mirodenafil, udenafil, gisadenafil, yonkenafil (tunodafil) and lodenafil are available in some countries. [1] Other agents with weak PDE5 inhibitory properties include fenspiride, MBCQ, zaprinast and icariin. [11]

Although all PDE5 inhibitors share the same mechanism of action, each agent has different pharmacokinetics and pharmacodynamics which affect how quickly it acts, how long its effects last, and its side effects. [1] Notably, although all PDE5 inhibitors preferentially inhibit PDE5, the degree to which they also inhibit other phosphodiesterases influences their side effect profile. [1] For example, sildenafil also inhibits PDE6 which is present in the retina of the eye; this reaction is thought to be responsible for the temporary visual changes which some patients using sildenafil experience. Similarly tadalafil also inhibits PDE11 which is present in the prostate, although no effects on fertility have been reported. [1] Although agents more selective for PDE5 were in development, these trials have been suspended, likely due to the saturation of the market with the introduction of agents with broad cardiovascular benefits, such as SGLT2 inhibitors and endothelin receptor antagonists. [1]

Nevertheless, PDE5 inhibitors already marketed for erectile dysfunction and pulmonary arterial hypertension are undergoing research in several conditions such as resistant hypertension, myocardial infarction, heart failure, intermittent claudication, Raynaud's phenomenon, chronic kidney disease, and diabetes mellitus due to our greater appreciation of their broad physiological properties. [1]

There are some PDE5 inhibitors, generally not approved by any health regulatory agency, that have been found as undeclared ingredients or adulterants in a variety of supplements which are sold as "natural" or "herbal" sexual enhancement products. Examples are acetildenafil, aildenafil, homosildenafil, nitrosoprodenafil, and sulfoaildenafil, thioquinapiperifil.[ citation needed ]

Mechanism of action

Part of the physiological process of vasodilatation involves the release of nitric oxide (NO) by vascular endothelial cells which then diffuses to nearby vascular smooth muscle cells. There, NO activates soluble guanylate cyclase which converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), the main effector of the system. For example, in the penis, NO release at high levels from endothelial cells and penile nerves during sexual stimulation leads to relaxation of the smooth vasculature of the corpus cavernosum, causing vasocongestion and a sustained erection. [1]

PDE5 inhibitors prolong the action of cGMP by inhibiting its degradation by the enzyme PDE5, which is found throughout the body. In the penis, PDE5 inhibitors potentiate the effects of cGMP to prolong erections and increase sexual satisfaction. [12] However, PDE5 inhibitors do not cause erections without sexual stimulation.

As well as their haemodynamic effects, PDE5 inhibitors have also been shown to have anti-inflammatory, antioxidant, antiproliferative, and metabolic properties in several experiments. [1] However, larger and longer-term studies are needed to establish their effectiveness and safety compared to other medications in other diseases.

See also

Related Research Articles

Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a penile erection with sufficient rigidity and duration for satisfactory sexual activity. It is the most common sexual problem in males and can cause psychological distress due to its impact on self-image and sexual relationships.

<span class="mw-page-title-main">Phosphodiesterase inhibitor</span> Drug

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

<span class="mw-page-title-main">Sildenafil</span> Drug for erectile dysfunction and hypertension

Sildenafil, sold under the brand name Viagra among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is also sometimes used off-label for the treatment of certain symptoms in secondary Raynaud's phenomenon. It is unclear if it is effective for treating sexual dysfunction in females. It can be taken orally, intravenously, or through the sublingual route. Onset when taken orally is typically within twenty minutes and lasts for about two hours.

<span class="mw-page-title-main">Phosphodiesterase</span> Class of enzymes

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.

<span class="mw-page-title-main">Tadalafil</span> Medication used to treat erectile dysfunction

Tadalafil, sold under the brand name Cialis among others, is a medication used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension. It is taken by mouth. Onset is typically within half an hour and the duration is up to 36 hours.

<span class="mw-page-title-main">Cyclic guanosine monophosphate</span> Chemical compound

Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface. Through protein kinases activation, cGMP can relax smooth muscle. cGMP concentration in urine can be measured for kidney function and diabetes detection.

<span class="mw-page-title-main">Vardenafil</span> Chemical compound

Vardenafil, sold under the brand name Levitra among others, is a medication that is used for treating erectile dysfunction. It is a PDE5 inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Pulmonary hypertension</span> Increased blood pressure in lung arteries

Pulmonary hypertension is a condition of increased blood pressure in the arteries of the lungs. Symptoms include shortness of breath, fainting, tiredness, chest pain, swelling of the legs, and a fast heartbeat. The condition may make it difficult to exercise. Onset is typically gradual. According to the definition at the 6th World Symposium of Pulmonary Hypertension in 2018, a patient is deemed to have pulmonary hypertension if the pulmonary mean arterial pressure is greater than 20mmHg at rest, revised down from a purely arbitrary 25mmHg, and pulmonary vascular resistance (PVR) greater than 3 Wood units.

Icos Corporation was an American biotechnology company and the largest biotechnology company in the U.S. state of Washington, before it was sold to Eli Lilly and Company in 2007. It was founded in 1989 by David Blech, Isaac Blech, Robert Nowinski, and George Rathmann, a pioneer in the industry and chief executive officer (CEO) and co-founder of Amgen. Icos focused on the development of drugs to treat inflammatory disorders. During its 17-year history, the company conducted clinical trials of twelve drugs, three of which reached the last phase of clinical trials. Icos also manufactured antibodies for other biotechnology companies.

cGMP-specific phosphodiesterase type 5 Mammalian protein found in humans

Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum of the clitoris and of the penis as well as the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

Sex and drugs refers to the influence of substances on sexual function and experience. Sex and drugs date back to ancient humans and have been interlocked throughout human history. Sexual performance is known as the execution of the act of sex and the quality of sexual activity. This includes elements such as libido, sexual function, sensation. Drugs are termed as any chemical substance that produces a physiological and or psychological change in an organism. Drugs categorized as psychoactive drugs, antihypertensive drugs, antihistamines, cancer treatment, and hormone medication have a significant impact on sexual performance. Various drugs result in different effects, both positive and negative. Negative effects may include low libido, erection issues, vaginal dryness and anorgasmia. Positive effects usually address these issues, overall enhancing sexual performance and contributing to a more enjoyable sexual experience. It is crucial to know that the impact of drugs on sexual performance varies among individuals, especially among different genders.

<span class="mw-page-title-main">Avanafil</span> Chemical compound

Avanafil is a PDE5 inhibitor approved for erectile dysfunction by the FDA on April 27, 2012 and by EMA on June 21, 2013. Avanafil is sold under the brand names Stendra and Spedra. It was invented at Mitsubishi Tanabe Pharma, formerly known as Tanabe Seiyaku Co., and licensed to Vivus Inc., which partnered with Menarini Group to commercialise Spedra in over forty European countries, Australia, and New Zealand. Metuchen Pharmaceuticals obtained exclusive rights within the United States.

<span class="mw-page-title-main">Acetildenafil</span> Chemical compound

Acetildenafil (hongdenafil) is a synthetic drug which acts as a phosphodiesterase inhibitor. It is an analog of sildenafil (Viagra) which has been detected in numerous different brands of "herbal aphrodisiac" products sold in convenience stores that claim to boost libido and alleviate erectile dysfunction.

<span class="mw-page-title-main">Nitrovasodilator</span> Drug that causes vasodilation by releasing nitric oxide

A nitrovasodilator is a pharmaceutical agent that causes vasodilation by donation of nitric oxide (NO), and is mostly used for the treatment and prevention of angina pectoris.

<span class="mw-page-title-main">Lodenafil</span> Chemical compound

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. Like udenafil and avanafil it belongs to a new generation of PDE5 inhibitors.

<span class="mw-page-title-main">Mirodenafil</span> Chemical compound

Mirodenafil belongs to the drug class PDE5 inhibitors, which includes avanafil, sildenafil, tadalafil, udenafil, and vardenafil, and is the first-line treatment for erectile dysfunction. Developed by SK Chemicals Life Science, mirodenafil is marketed in Korea under the trade name Mvix, offered both as tablets and as orally dissolving films.

<span class="mw-page-title-main">Sulfoaildenafil</span> Chemical compound

Sulfoaildenafil (thioaildenafil) is a synthetic drug that is a structural analog of sildenafil (Viagra). It was first reported in 2005, and it is not approved by any health regulation agency. Like sildenafil, sulfoaildenafil is a phosphodiesterase type 5 inhibitor.

<span class="mw-page-title-main">Zaprinast</span> Chemical compound

Zaprinast was an unsuccessful clinical drug candidate that was a precursor to the chemically related PDE5 inhibitors, such as sildenafil (Viagra), which successfully reached the market. It is a phosphodiesterase inhibitor, selective for the subtypes PDE5, PDE6, PDE9 and PDE11. IC50 values are 0.76, 0.15, 29.0, and 12.0 μM, respectively.

Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.

<span class="mw-page-title-main">Homosildenafil</span> Chemical compound

Homosildenafil is a synthetic drug which acts as a phosphodiesterase inhibitor. It is an analog of sildenafil and vardenafil. Homosildenafil was first identified as an adulterant in sex enhancement products in 2003 and was more recently detected in dietary supplements.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Tzoumas N, Farrah TE, Dhaun N, Webb DJ (November 2019). "Established and emerging therapeutic uses of phosphodiesterase type 5 inhibitors in cardiovascular disease". British Journal of Pharmacology. 177 (24): 5467–5488. doi: 10.1111/bph.14920 . PMC   7707100 . PMID   31721165.
  2. ↑ Kandeel FR. "Treatment of Erectile Dsyfunction in Men with Heart Disease". Male Sexual Dysfunction: Pathophysiology and Treatment. CRC Press, 2013. p. 453.
  3. ↑ Belch, Jill; Carlizza, Anita; Carpentier, Patrick H.; Constans, Joel; Khan, Faisel; Wautrecht, Jean-Claude; Visona, Adriana; Heiss, Christian; Brodeman, Marianne; Pécsvárady, Zsolt; Roztocil, Karel (2017-10-01). "ESVM guidelines – the diagnosis and management of Raynaud's phenomenon". VASA. Zeitschrift für Gefässkrankheiten. 46 (6): 413–423. doi: 10.1024/0301-1526/a000661 . ISSN   0301-1526. PMID   28895508.
  4. ↑ Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, et al. (November 2002). "Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats". Stroke. 33 (11): 2675–80. doi:10.1161/01.STR.0000034399.95249.59. PMID   12411660.
  5. ↑ Webb DJ, Freestone S, Allen MJ, Muirhead GJ (March 1999). "Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist". The American Journal of Cardiology. 83 (5A): 21C–28C. doi:10.1016/S0002-9149(99)00044-2. PMID   10078539.
  6. 1 2 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.[ page needed ]
  7. ↑ "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". Food and Drug Administration. 2007-10-18. Retrieved 2011-10-30.
  8. ↑ Rao AR, Thwaini A, Ahmed HU, Shergill IS, Minhas S (July 2007). "The phosphodiesterase inhibitors and non-arteritic anterior ischaemic optic neuropathy: increased vigilance is necessary". BJU International. 100 (1): 3–4. doi:10.1111/j.1464-410X.2007.06839.x. PMID   17488310. S2CID   43862884.
  9. ↑ Haberfeld H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN   978-3-85200-196-8.
  10. ↑ Boswell-Smith V, Spina D, Page CP (January 2006). "Phosphodiesterase inhibitors". British Journal of Pharmacology. 147 Suppl 1 (S1): S252-7. doi:10.1038/sj.bjp.0706495. PMC   1760738 . PMID   16402111.
  11. ↑ Dell'Agli M, Galli GV, Dal Cero E, Belluti F, Matera R, Zironi E, et al. (September 2008). "Potent inhibition of human phosphodiesterase-5 by icariin derivatives". Journal of Natural Products. 71 (9): 1513–7. doi: 10.1021/np800049y . PMID   18778098. S2CID   86637628.
  12. ↑ Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA (May 1998). "Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group". The New England Journal of Medicine. 338 (20): 1397–404. doi: 10.1056/NEJM199805143382001 . PMID   9580646.

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