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PDE5 inhibitor
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A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating drug which works by
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blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic
Contribute GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs
Help dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are
Learn to edit used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment
Community portal available for ED. Because PDE5 is also present in the smooth muscle of the walls of the
Recent changes
Chemical structure of sildenafil
arterioles within the lungs, sildenafil and tadalafil are FDA-approved for the treatment of (Viagra), the prototypical PDE5
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pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are inhibitor

Tools being appreciated.[1]

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Contents [hide]
Related changes
Special pages 1 Medical uses
Permanent link 2 Contraindications
Page information 3 Adverse effects
Cite this page
4 Drug interactions
Wikidata item
5 Examples
Print/export 6 Mechanism of action
Download as PDF 7 See also

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 Printable version 8 References
9 Further reading
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Medical uses [ edit ]

Català Phosphodiesterase-5 (PDE5) inhibitors such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) are clinically indicated for the
Deutsch treatment of erectile dysfunction.[2] Sildenafil and tadalafil are also indicated for the treatment of some subtypes of pulmonary
Français hypertension, while tadalafil is also licensed for the treatment of benign prostatic hyperplasia.[1]
한국어
Bahasa Indonesia PDE5 inhibitors have been used as a second line therapy in severe cases of Raynaud phenomenon when it is related to systemic
Svenska sclerosis per The European Society for Vascular Medicine guidelines.[3]
中 Sildenafil, the prototypical PDE5 inhibitor, was originally discovered during the search of a novel treatment for angina. Studies in 2002
5 more explored its potential for increasing neurogenesis after stroke,[4] but clinical evidence for benefit in cerebrovascular diseases is currently
lacking.[1]
Edit links

Contraindications [ edit ]

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 [ edit ]

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]

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 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 [ edit ]

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 [ edit ]

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 and lodenafil are
available in some countries.[1] Other agents with weak PDE5 inhibitory properties include 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

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 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]

Mechanism of action [ edit ]

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]
Tadalafil STADA Pharma - T20 - 20
PDE5 inhibitors prolong the action of cGMP by inhibiting its degradation by the enzyme PDE5, mg

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 [ edit ]

Discovery and development of phosphodiesterase 5 inhibitors

References [ edit ]

1. ^ a b c d e f g h i j k l m n o p q r s t u Tzoumas N, Farrah TE, Dhaun N, Webb DJ (November 2019). "Established and emerging

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

Further reading [ edit ]

Uzunov P, Weiss B (September 1972). "Separation of multiple electrophoresis". Biochimica et Biophysica Acta. 284 (1): 220–6.
molecular forms of cyclic adenosine-3',5'-monophosphate doi:10.1016/0005-2744(72)90060-5 . PMID 4342220 .
phosphodiesterase in rat cerebellum by polyacrylamide gel

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 Weiss, Benjamin (1975). Differential Activation and Inhibition of the Kanthapillai P, Lasserson T, Walters E (October 2004). "Sildenafil for
Multiple Forms of Cyclic Nucleotide Phosphodiesterase. Advances in pulmonary hypertension" . The Cochrane Database of Systematic
Cyclic Nucleotide Research. 5. pp. 195–211. ISBN 978-0-89004-021-8. Reviews (4): CD003562. doi:10.1002/14651858.CD003562.pub2 .
PMID 165666 . PMC 6396057 . PMID 15495058 .
Fertel R, Weiss B (July 1976). "Properties and drug responsiveness of Rao AR, Thwaini A, Ahmed HU, Shergill IS, Minhas S (July 2007). "The
cyclic nucleotide phosphodiesterases of rat lung" . Molecular phosphodiesterase inhibitors and non-arteritic anterior ischaemic optic
Pharmacology. 12 (4): 678–87. PMID 183099 . neuropathy: increased vigilance is necessary" . BJU International.
Weiss B, Hait WN (1977). "Selective cyclic nucleotide 100 (1): 3–4. doi:10.1111/j.1464-410X.2007.06839.x .
phosphodiesterase inhibitors as potential therapeutic agents". Annual PMID 17488310 . S2CID 43862884 .
Review of Pharmacology and Toxicology. 17: 441–77.
doi:10.1146/annurev.pa.17.040177.002301 . PMID 17360 .

V·T·E Phosphodiesterase inhibitors [show]

V·T·E Urologicals, including antispasmodics (G04B) [show]

V·T·E Nitric oxide signaling modulators [show]

Categories: PDE5 inhibitors

This page was last edited on 2 July 2021, at 18:41 (UTC).

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