Nitrates and phosphodiesterase inhibitors

The combination of nitrates (and drugs such as nicorandil) with sildenafil is contraindicated. 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. This is because of the risk of severe hypotension. Nitrates are stated as those used for cardiovascular disease, e.g. GTN spray, and also recreational compounds 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.
  • sublingual nitrates e.g. 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.

alpha blockers

• 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)

Notes:

• 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)

Reference:

1. CSM/MCA. Current Problems in Pharmacovigilance 1999; 25:16.
   
2. British Heart Foundation (factfile 6/2005).Drugs and Erectile Dysfunction.
3. Prescriber (2003), 14 (20), 28-31.
4. Schwartz BG, Kloner RA. Clinical cardiology: physician update: erectile dysfunction and cardiovascular disease. Circulation. 2011 Jan 4;123(1):98-101.
5. Scheartz BG, Kloner RA.. Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation. 2010 Jul 6;122(1):88-95
6. NHS Camden (Accessed 25/9/12). Patient Pathway: Erectile Dysfunction.