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This combination must be avoided as it can produce significant hypotension and is potentially fatal. The guidance from the Committee on Safety of Medicines (CSM) regarding nitrates and sildenafil states (1): sildenafil and nitrates - it is stated that these should not be used concurrently.

Nitrates are stated as those used for cardiovascular disease, e.g.

amyl nitrate sildenafil should not be used in men for whom sexual activity is inadvisable e.g. patients with severe cardiovascular disorders such as severe heart failure or unstable angina. The British Heart Foundation have addressed the use of GTN spray and nitrate tablets and phosphodiesterase (PDE5) inhibitors (sildenafil, tadalafil, verdenafil) (2): nitrate therapy is an absolute contraindication to PDE5 inhibitors (1,2,3) combination of nitrates with PDE5 inhibitors can produce unpredictable excess vasodilation, leading to profound hypotension - same risk also applies with nicorandil if hypotension does occur then the patient should be placed in the Trendelenburg position and emergency help sought.

Resuscitation with intravenous fluids should be initiated as soon as possible. GTN spray should not be used within 24 hours of taking sildenafil or vardenafil and within 48 hours of taking tadalafil note though that coital angina is not common and nitrates can often be safely discontinued or substituted in stable patients if a patient has stable angina and erectile dysfunction then a reassessment of the need for nitrates should be undertaken before denying treatment with a PDE5 inhibitor if a patient with CHD (and also taking a PDE5 inhibitor) develops angina during sexual activity, he must discontinue immediately and relax for 5-10 minutes. If he stands up then this will reduce the preload and may relieve symptoms. if the angina pain does not resolve after 20-30 minutes the emergency services should be called informing them of the PDE5 inhibitor use - also sex should not be attempted again before the patient has undergone a thorough reassessment (2) The concurrent use of nicorandil and PDE5 inhibitors is also contraindicated (2,3) - this is due to the nitrate component of nicorandil.

although PDE5Is are safe with most antihypertensive agents, coadministration with nitrates or alpha-blockers poses a risk of severe hypotension (4,5) all alpha-blockers can cause vasodilation and orthostatic hypotension, and coadministration with PDE5Is increases the risk of a clinically significant decrease in BP (5) only after patients are on stable alpha-blocker therapy should PDE5Is be initiated, starting with a low dose (5) Referral to specialist is appropriate if severe CVD which makes sexual activity unsafe or a situation when PDE5 inhibitor use contra- indicated (6) from a therapeutical point of view, intracavernous injections of PGE1 (alprostadil) are efficient and safe second line in the treatment of erectile dysfunction in the cardiac population, whatever the origin. No drug interactions with the various treatment used in cardiology, notably derived nitrates, has been reported other treatment options include vacuum devices, insertion of transurethral alprostadil (MUSE), intracavernosal alprostadil (Caverjet) nitrates are contraindicated within 24 hours of sildenafil and vardenafil and within 48 hours of tadalafil.

Only after patients are on stable alph-blocker therapy should PDE5Is be initiated, starting with a low dose potent cytochrome P450 3A4 inhibitors, including erythromycin, clarithromycin, ketoconazole, itraconazole, and HIV protease inhibitors, increase PDE5I plasma concentrations. PDE5I drug interactions have the potential to cause life-threatening hypotension in patients with coexisting cardiac disease requiring nitrates or alpha blockers (5) "uroselective" alpha-blockers (tamsulosin, alfuzosin) preferentially inhibit alpha 1A and alpha 1D receptors found primarily in the prostate and benefit patients with benign prostatic hypertrophy.

Other alpha-blockers (terazosin) are less selective, and some (doxazosin) are used as third-line agents for hypertension because of their higher affinity for alpha -1B receptors, which are abundant in the peripheral vasculature (5) Viagra and health: Beyond ED. When the history of men's health is written, 1998 will go down as a banner year. That's when sildenafil (Viagra) was approved by the FDA to treat erectile dysfunction (ED). But when the history of sildenafil is written, 2005 will also be special. That's when the FDA approved the medication that revolutionized male sexuality for a nonsexual condition.

The illness is pulmonary hypertension, and

sildenafil

Sildenafil was the first effective oral medication for ED.

In 2003 it was joined by vardenafil (Levitra) and tadalafil (Cialis).

Although there are some differences between these drugs (vardenafil starts working sooner and tadalafil works longer), they all act in exactly the same way to combat ED.

The three drugs are so similar because they share a common target, an enzyme called phosphodiesterase-5 (PDE-5).

To understand why blocking PDE-5 improves sexual function, however, you have to know how erections develop. Normal erections require a receptive state of mind, adequate levels of testosterone, and healthy arteries, veins, and nerves. But they also require a tiny chemical messenger called nitric oxide (NO). It serves two crucial functions: transmitting the impulses of arousal between nerves and relaxing the smooth muscle cells in the arteries, allowing them to widen and admit more blood to the penis. Nitric oxide is essential because it signals the arterial cells to produce cyclic guanosine monophosphate (cGMP), the chemical that increases the flow of blood to the penis. But the tissues of the penis also produce PDE-5, the enzyme that breaks down cGMP. In normal circumstances, the penis generates enough cGMP to produce a rigid erection and enough PDE-5 to end the erection when ejaculation is complete. In many men with ED, this intricate system is out of balance, but one of the three oral medications can often make it right.

By inhibiting PDE-5, they increase the supply of cGMP, which for many men will allow erections to develop.

In test tubes, vardenafil and tadalafil inhibit PDE-5 a bit more effectively than sildenafil does.

But laboratory potency doesn't necessarily predict clinical activity.

In this case, it means that lower doses of the newer drugs will achieve comparable results to the older drug's success rate.

Vardenafil is marketed in 2.5-, 5-, 10-, and 20-milligram (mg) tablets; tadalafil in doses of 5, 10, and 20 mg; and sildenafil, 25, 50, and 100 mg.

Each produces better results at higher doses, but the top doses are also more likely to cause side effects. And all the drugs are more effective in men with mild ED than in those who are severely impaired.

Doctors have had more clinical experience with sildenafil than its newer rivals.

Still, all three drugs seem to achieve similar results. The response is best in men with no identifiable organic cause of ED (about 90%), but it's less favorable for diabetics (about 50%), and it's hard to predict for men who have been treated for prostate cancer. If PDE-5 were found exclusively in the penis, the side effects of these drugs would be limited to that obdurate organ; in fact, a rare side effect is priapism, painful prolonged erections that require urgent treatment.

But small amounts of PDE-5 are found in blood vessels in other parts of the body.

In addition, PDE-5 is just one of 11 enzymes in the phosphodiesterase family. The others are concentrated in different parts of the body.

While the ED pills have a much greater affinity for PDE-5 than the other PDEs, they have some ability to inhibit those closely related enzymes.

Both factors explain why the ED pills sometimes produce side effects in many parts of the body.

The most common side effects are headaches and facial flushing, which occur in about 15% of men. Other reactions include nasal congestion, indigestion, and back pain; blue-tinged vision is even less common. In almost every case, these side effects are mild and transient.

But new information has added a rare eye disease to the list.

Nonarteritic anterior ischemic optic neuropathy (NAION) is a poorly understood disorder that can cause blindness.

In March 2005, doctors reported that seven men experienced visual impairment within hours of using sildenafil. Since then, additional cases have been reported to the FDA related to sildenafil, tadalafil, and vardenafil.