INTRODUCTION:

Erectile dysfunction (impotence) is the inability to get and keep an erection firm enough for sex. Having erection trouble from time to time isn't necessarily a cause for concern. If erectile dysfunction is an ongoing issue, however, it can cause stress, affect your self-confidence and contribute to relationship problems. Problems getting or keeping an erection can also be a sign of an underlying health condition that needs treatment and a risk factor for heart disease. Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme (EC 3.1.4.17) from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

The phosphodiesterase (PDE) isozymes, found in several tissues including the rod and cone photoreceptor cells of the retina, belong to a large family of cyclic nucleotide PDEs that catalyze cAMP and cGMP hydrolysis.^1,2

The interest in PDEs as molecular targets of drug action has grown with the development of isozyme-selective PDE inhibitors that offer potent inhibition of selected isozymes without the side-effects attributed to nonselective inhibitors such as theophylline. Sildenafil, vardenafil, tadalafil, and avanafil are PDE5 inhibitors that are significantly more potent and selective than zaprinast and other early PDE5 inhibitors.

PDE5 is an enzyme that accepts cGMP and breaks it down. Sildenafil, vardenafil and tadalafil are inhibitors of this enzyme, which bind to the catalytic site of PDE5. Both inhibitors bind with high affinity and specificity, and cGMP-binding to the allosteric sites stimulates binding of PDE5 inhibitors at the catalytic site. The kinetics of inhibitor binding and inhibition of catalysis imply the existence of two PDE5 conformers, and results of native gel electrophoresis reveal that PDE5 exists in two apparently distinct conformations, i.e., an extended conformer and a more compact conformer.

PDE5 activity is modulated by a rapidly reversible redox switch. Chemical reduction of PDE5 relieves autoinhibition of enzyme functions; allosteric cGMP-binding activity is increased 10-fold, and catalytic activity is increased ~3-fold. The redox effect on allosteric cGMP-binding occurs in the isolated regulatory domain. A change in the state of reduction of PDE5 or the isolated regulatory domain is associated with an apparent conformational change similar to that caused by phosphorylation.

PDE5 is expressed in human colonic cells and in intestinal tissue and its activity is regulated by intracellular cGMP levels in these cells that increase on GCC activation. This presumably occurs through binding of cGMP to the GAF domains in the N-terminus of PDE5, resulting in allosteric activation of the enzyme.

The mechanism of action of E4021 on both the nonactivated and activated forms of rod PDE6 because both states are relevant to understanding how PDE5-selective inhibitors may alter signal transduction pathways in photoreceptor cells. PDE5-selective inhibitors may show good discrimination of PDE5 from most other PDE isoforms.

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.

Immunohistology has shown that PDE5 localizes in heart cells at the sarcomere z-disk, but can also be found in diffuse amounts in the cytosol. Increased expression of PDE5 has also been measured in hypertrophic disease and has been linked to oxidative stress, and PDE5 inhibition has shown beneficial effects in the failing heart. In an experiment, PDE5 overexpression was found to contribute to worsened pathological remodeling after mouse cardiomyocytes experienced myocardial infarction. The role of PDE5 in heart failure and cardiac treatment involving PDE5 inhibitors have been major areas of focus for both lab and clinical studies.^1,2,4

PDE5 inhibitor:

A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating drug which 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.

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. Concurrent use of these medications can lead to life-threatening low blood pressure. PDE5 inhibitors are also contraindicated in patients with previous nonarteritic anterior ischaemic optic neuropathy and hereditary eye diseases.

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.

Medical uses:

Phosphodiesterase-5 (PDE5) inhibitors such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) are clinically indicated for the treatment of erectile dysfunction. 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. 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. 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, but clinical evidence for benefit in cerebrovascular diseases is currently lacking.^1,2,4

Adverse effects:

All PDE5 inhibitors are generally well tolerated. The occurrence of side effects, or adverse drug reactions (ADRs), with PDE5 inhibitors depends on the dose and type of agent. 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. 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. Since 2007 there has been evidence to suggest that PDE5 inhibitors can cause an anterior optic neuropathy, although the absolute risk increase is small. 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.

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, although coadministration has not been linked to changes in the safety or efficacy of either agent. Combination with nitrovasodilators such as nitroglycerin and PETN is contraindicated because potentially life-threatening hypotension may occur. PDE5 inhibitors do not interact synergistically with other antihypertensive drugs.

Examples:

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.^3,5

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. Notably, although all PDE5 inhibitors preferentially inhibit PDE5, the degree to which they also inhibit other phosphodiesterases influences their side effect profile. 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. 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.

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.

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^3,5.

Erectile dysfunction:

Symptoms:

Erectile dysfunction symptoms might include persistent:

· Trouble getting an erection

· Trouble keeping an erection

· Reduced sexual desire

Causes:

Male sexual arousal is a complex process that involves the brain, hormones, emotions, nerves, muscles and blood vessels. Erectile dysfunction can result from a problem with any of these. Likewise, stress and mental health concerns can cause or worsen erectile dysfunction.Sometimes a combination of physical and psychological issues causes erectile dysfunction. For instance, a minor physical condition that slows your sexual response might cause anxiety about maintaining an erection. The resulting anxiety can lead to or worsen erectile dysfunction.

Risk factors:

As you get older, erections might take longer to develop and might not be as firm. You might need more direct touch to your penis to get and keep an erection.

Various risk factors can contribute to erectile dysfunction, including:

· Medical conditions, particularly diabetes or heart conditions

· Tobacco use, which restricts blood flow to veins and arteries, can — over time — cause chronic health conditions that lead to erectile dysfunction

· Being overweight, especially if you're obese

· Certain medical treatments, such as prostate surgery or radiation treatment for cancer

· Injuries, particularly if they damage the nerves or arteries that control erections

· Medications, including antidepressants, antihistamines and medications to treat high blood pressure, pain or prostate conditions

· Psychological conditions, such as stress, anxiety or depression

Complications:

Complications resulting from erectile dysfunction can include:

· An unsatisfactory sex life

· Stress or anxiety

· Embarrassment or low self-esteem

· Relationship problems

· The inability to get your partner pregnant

Prevention:

The best way to prevent erectile dysfunction is to make healthy lifestyle choices and to manage any existing health conditions. For example:

· Work with your doctor to manage diabetes, heart disease or other chronic health conditions.

· See your doctor for regular checkups and medical screening tests.

· Stop smoking, limit or avoid alcohol, and don't use illegal drugs.

· Exercise regularly.

· Take steps to reduce stress.

· Get help for anxiety, depression or other mental health concerns.

Treatment:

The first thing your doctor will do is to make sure you're getting the right treatment for any health conditions that could be causing or worsening your erectile dysfunction.

Depending on the cause and severity of your erectile dysfunction and any underlying health conditions, you might have various treatment options. Your doctor can explain the risks and benefits of each treatment and will consider your preferences. Your partner's preferences also might play a role in your treatment choices.^6,7,8,9

Oral medications:

Oral medications are a successful erectile dysfunction treatment for many men. They include:

· Sildenafil (Viagra)

· Tadalafil (Adcirca, Cialis)

· Vardenafil (Levitra, Staxyn)

· Avanafil (Stendra)

All four medications enhance the effects of nitric oxide — a natural chemical your body produces that relaxes muscles in the penis. This increases blood flow and allows you to get an erection in response to sexual stimulation.

Other medications:

Other medications for erectile dysfunction include:

Alprostadil self-injection. With this method, you use a fine needle to inject alprostadil (Caverject, Edex) into the base or side of your penis. In some cases, medications generally used for other conditions are used for penile injections on their own or in combination. Examples include alprostadil and phentolamine. Often these combination medications are known as bimix (if two medications are included) or trimix (if three are included).

Each injection is dosed to create an erection lasting no longer than an hour. Because the needle used is very fine, pain from the injection site is usually minor.

Side effects can include mild bleeding from the injection, prolonged erection (priapism) and, rarely, formation of fibrous tissue at the injection site.

Alprostadil urethral suppository: Alprostadil (Muse) intraurethral therapy involves placing a tiny alprostadil suppository inside your penis in the penile urethra. You use a special applicator to insert the suppository into your penile urethra.^8,9

The erection usually starts within 10 minutes and, when effective, lasts between 30 and 60 minutes. Side effects can include a burning feeling in the penis, minor bleeding in the urethra and formation of fibrous tissue inside your penis.

Testosterone replacement: Some people have erectile dysfunction that might be complicated by low levels of the hormone testosterone. In this case, testosterone replacement therapy might be recommended as the first step or given in combination with other therapies.

Exercise:

Recent studies have found that exercise, especially moderate to vigorous aerobic activity, can improve erectile dysfunction.

Even less strenuous, regular exercise might reduce the risk of erectile dysfunction. Increasing your level of activity might also further reduce your risk.

CONCLUSION:

REFERENCES:

1. 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. 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. "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". Food and Drug Administration. 2007-10-18. Retrieved 2011-10-30.

7. 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.

8. FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". Food and Drug Administration. 2007-10-18. Retrieved 2011-10-30.

9. 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.

Received on 12.09.2022 Modified on 06.10.2022

Asian J. Pharm. Res. 2023; 13(1):63-67.

DOI: 10.52711/2231-5691.2023.00012