The phosphodiesterase type-5 inhibitors potentiate hypotensive effects of nitrates in a proportion of patients, which might result in potentially serious hypotension or even precipitatemyocardial infarction. Therefore, concurrent use of sildenafil,tadalafil or vardenafil with organic nitrates (glyceryl trinitrate(nitroglycerin), isosorbide dinitrate, isosorbide mononitrate, etc.)is contraindicated. The concurrent use of nicorandil and all phosphodiesterase type-5 inhibitors is also contraindicated.
Erectile dysfunction. Two double-blind, placebo-controlled studies in groups of 15 or 16 men with angina found that fall in blood pressure seen when taking nitrates and a single 50mg dose of sildenafil was about doubled. Those given sildenafil and isosorbide dinitrate 20mg twice daily had a mean blood pressure fall of 44/26 mmHg compared with 22/13 mmHg with placebo. Those who used 500 micrograms of sublingual glyceryl trinitrate one hour before sildenafil had a mean blood pressure fall of 36/21 mmHg compared with 26/11 mmHg with glyceryl trinitrate and placebo. Individual blood pressure falls as great as 84/52 mmHg were seen (See reference number 1). A postmarketing report from FDA in US for period late March to July 1998 briefly lists 69 fatalities after taking sildenafil. These were mostly in middle-aged and elderly men (average age 64), 12 of whom had also taken glyceryl trinitrate (nitroglycerin) or a nitrate medication, but it is not clear what part (if any) nitrates played in deaths (See reference number 2). In a limited and preliminary study it was reported that no blood pressure alteration was seen when a small dose of glyceryl trinitrate (amount not specified) was given as a dermal patch while subjects were taking 50mg of sildenafil. In addition, beneficial effects of glyceryl trinitrate on radial artery pressure waveform were approximately doubled, and persisted for up to 8 hrs (See reference number 3).
Pulmonary hypertension. In a study of combined use of intravenous sildenafil and inhaled nitric oxide in management of pulmonary hypertension in 15 infants, significant hypotension occurred, which, along with a decrease in oxygenation, was considered sufficiently detrimental for study to be stopped early (See reference number 4). Conversely,beneficial combined use has been described in one adult patient with severe hypoxemia caused by pulmonary hypotension (See reference number 5). Note that nitric oxide is not to be confused with anaesthetic nitrous oxide, which is not a nitric oxide donor and therefore poses no risk,(See reference number 6)see Mechanism below.
In a double-blind,randomised, placebo-controlled study, 51 patients with chronic stable angina were given tadalafil 5 mg, 10mg or a placebo, followed 2 hrs later by a single 400-microgram dose of sublingual glyceryl trinitrate. Although tadalafil caused little additional decrease in blood pressure to that seen with glyceryl trinitrate, a potentially clinically significant blood pressure reduction (standing systolic BP less than 85 mmHg) was seen in 13 and 11 of patients when given tadalafil 5 and 10 mg, respectively, compared with one patient in placebo group (See reference number 7,8). In a similar study in 45 patients taking long-term oral isosorbide mononitrate, tadalafil 5 or 10mg had minimal effects on decrease in blood pressure caused by this nitrate, but again, more patients had a standing systolic BP of less than 85 mmHg when receiving tadalafil 10mg than placebo (6 versus 0) (See reference number 7,8). Another similar study in 48 healthy subjects compared effects of tadalafil 10 mg, sildenafil 50 mg, and placebo, in combination with sublingual glyceryl trinitrate 400 micrograms. Again, it was found that presence of tadalafil had minimal effects on mean maximum decreases in blood pressure, but it was noted that 23 patients given tadalafil and 23 given sildenafil had a standing systolic blood pressure of 85 mmHg or less following use of nitrate, compared with 12 in placebo group (See reference number 8,9). In a further study, a haemodynamic interaction between tadalafil 20mg and sublingual glyceryl trinitrate was seen when glyceryl trinitrate was given 4, 8 and 24 hrs after tadalafil, and was not seen at 48 hrs and beyond. Note that no time points between 24 and 48 hrs were examined (See reference number 10).
An analysis of rates of serious cardiovascular adverse events (mortality, myocardial infarction, thrombotic strokes) in clinical studies involving tadalafil indicated that adverse events were no more frequent than in general population of men with erectile dysfunction (See reference number 8).
A single 400-microgram dose of sublingual glyceryl trinitrate (nitroglycerin) given to 18 healthy subjects 1 to 24 hrs after a single 10mg dose of vardenafil was found to be no different to placebo in causing changes in seated heart rate and blood pressure (See reference number 11,12). However, a single 20mg dose of vardenafil did potentiate blood pressure-lowering effects and increases in heart rate (about an 8 mmHg additional drop in systolic BP compared with placebo) seen with sublingual nitrates (400 micrograms) taken 1 and 4 hrs after vardenafil. These effects were not seen when nitrate was taken 24 hrs after vardenafil dose (See reference number 11,13).
Sexual stimulation causes endothelium of penis to release nitric oxide (NO), which in turn activates guanylate cyclase to increase production of cyclic guanosine monophosphate (cGMP). This relaxes blood vessel musculature of corpus cavernosum thus allowing it to fill with blood and cause an erection. The erection ends when guanosine mono-phosphate is removed by an enzyme (type 5 cGMP phosphodiesterase, or PDE5). Sildenafil, tadalafil and vardenafil inhibit this enzyme thereby increasing and prolonging effects of guanosine monophosphate. Because this vasodilation is usually fairly localised (these drugs are highly selective for PDE5) it normally only causes mild to moderate falls in blood pressure (on average about 10 mmHg) with mild headache or flushing. However,if other nitrates (e.g. glyceryl trinitrate) are taken concurrently, high levels of nitric oxide enter circulation, and this markedly increases systemic vasodilation and hence hypotensive effect.
The interaction between phosphodiesterase type-5 inhibitors and nitrates is established,clinically important, potentially serious and even possibly fatal. Sildenafil and organic nitrates of any form are contraindicated both for erectile dysfunction(See reference number 14,15) (within 24 hrs of each other(See reference number 6)) and for pulmonary hypertension(See reference number 16,17)because of risk of precipitating serious hypotension, or even myocardial infarction (See reference number 18). The ACC/AHA Expert consensus document provides a useful list of many of organic nitrates available, which include glyceryl trinitrate (nitroglycerin), isosorbide mononitrate, isosorbide dinitrate and illicit substances such as amyl ni
Similarly, manufacturers of vardenafil(See reference number 11,13) and tadalafil(See reference number 19,20) say that their combination with nitrates (taken either regularly and/or intermittently) is contraindicated. Nitrates should not be given for at least 48 hrs after last dose of tadalafil (See reference number 19,20).
It is not yet known whether nicorandil interacts with phosphodiesterase inhibitors to a clinically relevant extent or not,(See reference number 21)but because part of its vasodilatory actions are mediated by release of nitric oxide (like conventional nitrates), manufacturers of nicorandil contraindicate its use with all phosphodiesterase inhibitors (See reference number 22).
Webb DJ,Muirhead G, Wulff M, Sutton A, Levi R, Dinsmore WW. Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina.J Am Coll Cardiol (2000) 36, 25–31.
FDA (US Food and Drug Administration) postmarketing information sildenafil citrate (Viagra): Postmarketing safety of sildenafil citrate (Viagra). Reports of death in Viagra users received from marketing (late March) through July 1998. August 27th 1998.
O’Rourke M,Jiang X-J. Sildenafil/nitrate interaction. Circulation (2000) 101, e90.
Stocker C,Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS. Intravenoussildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery. Intensive Care Med (2003) 29, 1996–2003.
Bigatello LM,Hess D, Dennehy KC, Medoff BD, Hurford WE. Sildenafil can increase theresponse to inhaled nitric oxide. Anesthesiology (2000) 92, 1827–9.
ACC/AHA Expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. J Am Coll Cardiol (1999) 33,273–82.
Kloner RA,Emmick J, Bedding A, Humen D. Pharmacodynamic interactions betweentadalafil and nitrates. Int J Impot Res (2002) 14 (Suppl 3) S29.
Kloner RA,Mitchell M, Emmick J. Cardiovascular effect of tadalafil. Am J Cardiol (2003) 92 (Suppl) 37M–46M.
Kloner RA,Mitchell MI, Bedding A, Emmick J. Pharmacodynamic interactions betweentadalafil and nitrates compared with sildenafil. J Urol (Baltimore) (2002) 167 (Suppl) 176–7.
Kloner RA,Hutter AM, Emmick JT, Mitchell MI, Denne J, Jackson G. Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol (2003) 42, 1855–60.
Levitra (Vardenafil hydrochloride trihydrate). Bayer plc. UK Summary of product characteristics,November 2006.
Mazzu AL,Nicholls AJ, Zinny M. Vardenafil, a new selective PDE-5 inhibitor, interacts minimally with nitroglycerin in healthy middle-aged male subjects. Int J Impot Res (2001) 13 (Suppl 5) S64.
Levitra (Vardenafil hydrochloride). Bayer Pharmaceuticals Corporation. US prescribing information,March 2007.
Viagra (Sildenafil citrate). Pfizer Ltd. UK Summary of product characteristics,June 2006.
Viagra (Sildenafil citrate). Pfizer Inc. US Prescribing information,October 2006.
Revatio (Sildenafil citrate). Pfizer Ltd. UK Summary of product characteristics,March 2007.
Revatio (Sildenafil citrate). Pfizer Inc. US Prescribing information,July 2006.
Viagra (Sildenafil). Pfizer Inc. Dear Doctor letter,May 1998.
Cialis (Tadalafil). Eli Lilly and Company Ltd. UK Summary of product characteristics,July2006.
Cialis (Tadalafil). Eli Lilly and Company Ltd. US Prescribing information,January 2007.
Aventis Pharma,Personnal communication, February 2000.
Ikorel (Nicorandil). Sanofi-Aventis. UK Summary of product characteristics,June 2004.