Drugs for Erectile Dysfunction

DRUGS FOR ERECTILE DYSFUNCTION

Erectile dysfunction (ED) refers to the inability of men to attain and maintain an erect penis with sufficient rigidity to allow sexual intercourse. It occurs mainly past middle age and is common after the age of 65 years. A variety of vascular, neurogenic, hormonal, pharmacologic or psychogenic causes may under lie the disorder.

Sexual arousal increases blood flow to the penis and relaxes the cavernosal sinusoids so that they fill up with blood, making the penis rigid, elongated and erect. Nitric oxide (NO) released from parasympathetic non-adrenergic noncholinergic (NANC) nerves and vascular endothelium is the major transmitter causing relaxation of smooth muscle in corpus cavernosum and blood vessels supplying it; ACh and PGs also play a role. A variety of mechanical/prosthetic devices and surgery have been used for ED, but drug therapy has made a big impact recently.

1. Androgens

Parenteral testosterone esters or transdermal testosterone therapy is effective only when androgen deficiency is demonstrated to be responsible for the loss of libido and ED.

2. Phosphodiesterase5 (PDE5) Inhibitors

Nitric oxide causes smooth muscle relaxation by generating cGMP intracellularly which then promotes dephosphorylation of myosin light chain kinase (MLCK) so that myosin fails to interact with action (see Fig. 39.3). Inhibition of PDE5, the cGMP degrading isoenzyme in cavernosal and vascular smooth muscle, results in accumulation of cGMP and marked potentiation of NO action. Sildenafil, Tadalafil and vardenafil are selective PDE5 inhibitors developed in the past decade and found effective in a majority of patients with ED.

Sildenafil:

It is an orally active drug, marketed in the USA in 1998 and 2 years later in India, for treatment of ED. It became an instant hit, but the enthusiasm has passed off now. Sildenafil acts by selectively inhibiting PDE5 and enhancing NO action in corpus cavernosum. Penile tumescence during sexual arousal is improved, but it has no effect on penile tumescence in the absence of sexual activity. It does not cause priapism in most recipients.

Oral bioavailability of sildenafil is ~40%, peak blood levels are attained in 1–2 hr; it is metabolized largely by CYP3A4 and an active metabolite is produced; t½ in men <65 years averages 4 hours. It is recommended in a dose of 50 mg (for men > 65 years 25 mg), if not effective then 100 mg 1 hour before intercourse. Duration and degree of penile erection is increased in 74–82% men with ED including diabetic neuropathy cases. Over 20 controlled trials involving >3000 men have demonstrated improved erection with sildenafil compared to placebo. However, sildenafil is ineffective in men who have lost libido or when ED is due to cord injury or damaged nervi eregantis.

Since NO is an important regulator of pulmonary vascular resistance, PDE5 inhibitiors lower pulmonary arterial pressure. Sildenafil is more selective for pulmonary circulation than vardenafil, and is the only PDE5 inhibitor shown to improve arterial oxygenation in pulmonary hypertension. It has now become the drug of choice for this condition.

Adverse Effects

Side effects are mainly due to PDE5 inhibition related vasodilatation— headache, nasal congestion, dizziness, flushing and fall in BP, loose motions. Sildenafil, in addition, weakly inhibits the isoenzyme PDE6 which is involved in photoreceptor transduction in the retina. As such, impairment of colour vision, especially bluegreen discrimination, occurs in some recipients. Few cases of sudden loss of vision due to nonarteritic ischaemic optic neuropathy (NAION) among users of PDE5 inhibitors have been reported, but no causal relationship has been established.

Sildenafil markedly potentiates the vasodilator action of nitrates; precipitous fall in BP and MI can occur. After >6 million prescriptions dispensed in USA, the FDA received reports of 130 deaths related to sildenafil use by the year 2002. Most deaths occurred in patients with known risk factors, drug interactions or contraindications, and were timed either during or within 4–5 hours of sex. Sildenafil is contraindicated in patients of coronary heart disease and those taking nitrates. Though sildenafil remains effective for <8 hours, it is advised that nitrates be avoided for 24 hours. Caution is advised in presence of liver or kidney disease, peptic ulcer, bleeding disorders. Inhibitors of CYP3A4 like erythromycin, ketoconazole, verapamil, cimetidine potentiate its action. Caution is required also in patients of leukaemia, sickle cell anaemia, myeloma which predispose to priapism.

Sildenafil is erroneously perceived as an aphrodisiac. Men even without ED are going for it to enhance sexual satisfaction.

PENEGRA, CAVERTA, EDEGRA 25, 50, 100 mg tabs.

Tadalafil

It is a more potent and longer acting congener of sildenafil; t½ 18 hours and duration of action 24–36 hours. It is claimed to act faster, though peak plasma levels are attained between 30–120 min. Side effects, risks, contraindications and drug interactions are similar to sildenafil.

Because of its longer lasting action, nitrates are contraindicated for 36–48 hours after tadalafil. Due to its lower affinity for PDE6, visual disturbances occur less frequently.

Dose: 10 mg at least 30 min before intercourse (max. 20 mg) MEGALIS, TADARICH 10, 20 mg tabs, MANFORCE 10 mg tab.

Vardenafil

Another congener of sildenafil with similar timecourse of action; peak levels in 30–120 min and t½ 4–5 hours. Side effects, contraindications and interactions are also the same. A weaker inhibition of PDE6 is claimed, but photosensitivity is reported. It prolongs QT interval; should be avoided in hyperkalaemia and in patients with long QT or those receiving class IA and class III antiarrhythmics.

Dose: 10 mg (elderly 5 mg), max 20 mg.

3. Papaverine/Phentolamine Induced Penile Erection (PIPE) Therapy

Injection of papaverine (3–20 mg) with or without phentolamine (0.5–1 mg) in the corpus cavernosum produces penile tumescence to permit intercourse. However, the procedure requires skill and training. Priapism occurs in 2–15% cases, which if not promptly treated leads to permanent damage. This is reversed by aspirating blood from the corpus cavernosum or by injecting phenylephrine locally. Repeated injections can cause penile fibrosis. Other complications are—local haematoma, infection, paresthesia and penile deviation. In view of the availability of PDE5 inhibitors, it is rarely used now; only in cases not responding to sildenafil and alprostadil.

4. Prostaglandin E₁

Alprostadil (PGE₁) injected directly into the corpus cavernosum using a fine needle, or introduced into the urethra as a small pellet, produces erection lasting 1–2 hours to permit intercourse. Alprostadil injections are less painful than papaverine, but local tenderness may occur. Penile fibrosis and priapism are rare. It is now the most commonly used drug in patients not responding to PDE5 inhibitors.