Why nitrate should not be used with sildenafil?

Published: May 2001

Prescriber Update 21: 8-9 May 2001

Medsafe Editorial Team

Sildenafil (Viagra™) plus nitrates may result in a precipitous fall in blood pressure. Do not use nitrates to relieve an angina attack if the patient has recently taken sildenafil - use other angina treatments instead. Doctors and nurses must ask about Viagra use before administering glyceryl trinitrate (GTN) spray or any other nitrate preparation.

Sildenafil should not be prescribed if there is regular or intermittent nitrate use

Sildenafil is contraindicated in patients taking nitrates for cardiovascular disease. This includes all dose forms such as oral (e.g. GTN spray, sublingual tablets, slow release preparations), injectable (e.g. sodium nitroprusside) and topical (e.g. transdermal patches) nitrates. Remember to ask patients about nitrates used recreationally, e.g. amyl nitrate. Also remind patients who are using nitrates, that they must not take sildenafil.

Sildenafil, through inhibition of phosphodiesterase type 5, enhances the effect of local nitric oxide release in the corpus cavernosum during sexual stimulation. This results in arterial and venous dilation and inflow of blood. If exogenous nitrates are given, there will be a systemic rise in nitric oxide concentrations, which in combination with sildenafil, potentiates the vasodilatory effect of nitrates. This can cause a significant drop in blood pressure (BP) and may be life threatening.

Doctors, nurses and paramedics must ask patients (men and women2) about recent Viagra™ use before administering GTN spray or any other nitrate.

If the patient has taken sildenafil, give analgesia - NOT nitrates - to relieve angina pain

When a patient who has taken sildenafil develops acute angina, other anti-angina treatments must be used instead of nitrates, for example: aspirin, morphine, oxygen, β-adrenergic blockers (note: the potentiating effect on BP reduction is not observed with sildenafil when used in combination with non-nitrate vasodilators), and heparin. In serious or complicated cases of angina or chest pain, advice should be sought from a cardiologist, and transfer of the patient to hospital in an ambulance is recommended.

It is unknown when nitrates can be safely administered to patients who have taken sildenafil.1 The risk of an exaggerated BP response with nitrates decreases with time from the dose of sildenafil. Based on pharmacokinetics, plasma levels of sildenafil are low at 24 hours1 and some authors suggest that after 24 hours the administration of a nitrate may be considered2. However some conditions such as age over 65 years, hepatic impairment, severe renal impairment or use of cytochrome P450 3A4 inhibitors (including erythromycin, ketoconazole, diltiazem and HIV protease inhibitors) can result in reduced clearance of sildenafil. In such patients, the time frame for withholding nitrates will be longer.1 The advice of a cardiologist or emergency physician should be sought in situations of doubt. If the decision is made to administer nitrates, close monitoring must be provided with proper facilities available for fluid and vasopressor support2, and emergency resuscitation.

In the event of inadvertent co-administration of nitrates and sildenafil, close monitoring must be undertaken in an environment where fluid replacement, vasopressor support and emergency resuscitation can be provided (usually in hospital). With significant hypotension, place the patient in the Trendelenburg position, administer intravenous fluid and consider using alpha-agonists in severe cases (bearing in mind that these may exacerbate any coronary ischaemia present).

Please refer to the full data sheet1 (available on the Medsafe website: www.medsafe.govt.nz) before prescribing Viagra™.

a Sildenafil is approved only for use in men, but unapproved use by women may occur.

References

Sildenafil (Viagra) is the most effective oral therapy currently available for erectile dysfunction. Patients should be given clear instructions regarding the use of sildenafil. The most common side effects include flushing, headaches, dyspepsia, and transient visual changes. In combination with nitrates, it can and has caused fatal hypotension. It should not be prescribed to patients on nitrates. Additionally, nitrates should not be administered to anyone who has recently ingested sildenafil. Synergetic blood pressure lowering has not been observed when sildenafil was used with other classes of antihypertensives. Sildenafil is not offered to patients with low cardiac output states, those on intensive regimens to prevent heart failure or those with acute coronary ischemia.

Keywords: Sildenafil, erectile dysfunction, heart failure

Impotence – the preferred term is now erectile dysfunction is a common problem affecting between 10 to 30 million men in the United States.1 Worldwide, more than 100 million men are estimated to have some degree of erectile dysfunction.2,3 The introduction of sildenafil (Viagra) has been a valuable contribution to many patients suffering from erectile dysfunction, and the drug, has now been approved by the Ministry of Health in Saudi Arabia. There have been >20 million prescriptions written for sildenafil. A total of 69 death has been reported to the FDA as of August 26, 1998, in patients who have used sildenafil.4 Recently, the American College of Cardiology/American Heart Association (ACC/AHA) published their “Expert Consensus Document” on the use of sildenafil in patients with cardiovascular disease.4 This article is based primarily on the recommendations made in that “document”.

Sildenafil acts as a selective inhibitor of cycle GMP-specific phosphodiesterase type 5, resulting in smooth muscle relaxation, vasodilation, and enhanced penile erection. The vasodilating action of sildenafil affects both the arteries and the veins.5

Reported side effects in the normal healthy population are usually associated with vasodilation. These include headaches (16%), flushing (10%), rhinitis (4%), dizziness (2%), hypotension (<2%), and postural hypotension (<2%). Other side effects include dyspepsia (7%), blue-green color-tinged vision and blurred vision (3%), and an unexplained myalgia.3,4

Although their incidence is small, serious cardiovascular events including significant hypotension can occur in certain population at risk. Most at risk are individuals who are concurrently taking organic nitrates.4

Sexual dysfunction in men after the diagnosis of coronary artery disease or a myocardial infarction is common.7 Most is due to the fear that the exertion of sexual activity will precipitate another myocardial infarction, but 10 to 15% of erectile dysfunction is due to organic causes.8 In USA, approximately 5.5 million men take nitrates on a regular basis for angina pectoris,9 and another half million will experience a heart attack annually and are potential candidates for nitrate therapy. Sildenafil is potentially contraindicated in these 6 million patients. All patients taking either sildenafil or nitrates must be warned of the contraindications and potential consequences of taking sildenafil within 24-hour interval after taking a nitrate preparation, including sublingual nitroglycerin.

Sildenafil is predominantly metabolized by both the P 450 2C9 and the P450 3A4 pathways. Thus, potent inhibitors of the P450 3A4 pathway may increase the plasma concentrations of sildenafil and its pharmacological effects. Cimetidine and erythromycin are commonly prescribed drugs that inhibit the P450 3A4 pathway. The simultaneous administration of either of these agents significantly increases the plasma concentration of sildenafil; a lower initial dose (25 mg) rather than the recommended 50 mg should be considered in the coadministration of sildenafil to patients receiving either of these agents.4

Many drugs are metabolized by the P450 3A4 pathway but are not inhibitors of the pathway. The coadministration of one of these drugs may lead to competitive inhibition of the metabolism of sildenafil. Physicians should be aware of the potential interaction of such agents. This list of commonly prescribed drugs metabolized via the P450 3A4 pathway includes: amiodarone, digoxin, diltiazem, losartan, nifedipine, atorvastatin, cerivastatin, lovastatin, simvastatin, and cisapride.4 Patients with severe renal impairment (creatinine clearance <30 ml/min) have a reduced clearance of sildenafil. Thus, the duration of the effect of sildenafil in these patients will be prolonged and particular care should be taken in the administration of concomitant medications that may lower blood pressure.

Plasma concentrations of sildenafil and of its metabolites may be significantly increased in patients with hepatic dysfunction. Thus, the duration of activity of sildenafil may be prolonged and the extent of its effect enhanced. As in patients with renal dysfunction, the initiation of therapy at 25 mg rather than 50 mg may be appropriate in patients with hepatic dysfunction. Because the effects of sildenafil have not been evaluated in patients with bleeding disorders or in patients taking non-aspirin antiplatelet agents (e.g. ticlopidine, clopidogrel or dipyridamole), caution should be exercised when the drug is administered in these clinical settings.4

What are the current recommendations for prescribing sildenafil to patients at risks? Sildenafil is absolutely contraindicated in patients taking any long-acting nitrates or using short-acting nitrates because of the risk of developing potentially life-threatening hypotension. All patients taking organic nitrates, even if they have not asked for Viagra, should be informed about the nitrate-sildenafil hypotensive interaction. Similarly, patients must be warned of the contraindication of taking sildenafil in the 24-hour time interval after taking a nitrate preparation, including sublingual nitroglycerin.

Other patients in whom the use of sildenafil is potentially hazardous include those with active coronary ischemia, those with congestive heart failure and borderline low blood volume and low blood pressure status; those with complicated, multidrug, antihypertensive therapy regimens; and those taking medications that may effect the metabolic clearance of sildenafil. If patients are taking a combination of antihypertensive medications, they should be cautioned about the possibility of sildenafil-induced hypotension. Although firm data are lacking, pre-Viagra treadmill test to assess for the presence of stress-induced ischemia can be helpful. If the patient can achieve ≥ 5 to 6 METS on an exercise tolerance test without demonstrating ischemia, the risk of ischemia during coitus without the added stress of a heavy meal or alchohol ingestion, is probably low.4

In patients with recurring mild angina after sildenafil use, other nonnitrate antianginal agents, such as β-blockers, should be considered. Patients taking sildenafil who have an acute myocardial infarction should be treated in the usual manner including, where appropriate, primary angioplasty or thrombolysis. The only difference is that nitrates are contraindicated for these patients.

In patients with unstable angina, therapy should include only non-nitrate antianginal medications. To date, there is no evidence of significant interactions between sildenafil and heparin, β-blockers, calcium channel blockers, narcotics or aspirin. These drugs can be used as appropriate. After 24 hours, nitrates may be administered if close monitoring is provided. In patients who inadvertently received nitrates while taking sildenafil and who manifest a severe hypotensive response, it is essential to have the capability to support the patient with fluid resuscitation and alpha-adrenergic agonists.4

A number of unresolved issues remain to be answered. One of such issues is assessing the risks of sildenafil use in patients with heart failure, patients with myocardial infarction or stroke within 6 months, or patients with uncontrolled hypertension. Such patients were not included in the published studies. Thus, there are possible problems in the use of Viagra in these patients. Other unresolved issues include central nervous system, effects of sildenafil, hypotensive effects with sildenafil alone in high-risk cardiac patients (severe heart failure) and its musculo-skeletal effects.

Finally, whether the promise of sildenafil will be realized after many more men have been treated and the drug has been taken repeatedly for prolonged period of time remains to be seen.

1. Cohan P, Korenamn SG. Erectile dysfunction. J Clin Endocrinol Metab. 2001;86:2391–4. [PubMed] [Google Scholar]

2. Jackson G. Viagra: a three-year sexual revolution and the need to recognize its role within the NHS. Int J Clin Pract. 2001;55:75–6. [PubMed] [Google Scholar]

3. Goldstein I, Lue TF, Padua-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338:1397–404. [PubMed] [Google Scholar]

4. Cheitlin MD, Hutter AM, Jr, Brindis RG, et al. The ACC/AHA “Expert Consensus Department”. Use of sildenafil (Viagra) in patients with cardiovascular disease. J Am Coll Cardiol. 1999;33:273–82. [PubMed] [Google Scholar]

5. Utiger RD. A pill for impotence (editorial) N Engl J Med. 1998;338:1458–9. [PubMed] [Google Scholar]

6. Riley AJ, Athanasiadis L. Impotence and its non-surgical management. Br J Clin Pract. 1997;51:99–105. [PubMed] [Google Scholar]

7. Muller JE, Mittleman A, Maclure M, Sherwood JB, Toffler GH. Triggering myocardial infarction by sexual activity. JAMA. 1996;275:1405–9. [PubMed] [Google Scholar]

8. Tardif GS. Sexual activity after a myocardial infarction. Arch Phys Med Rehab. 1989;70:763–6. [PubMed] [Google Scholar]

9. Mitka M. Viagra leads as rivals are moving up. JAMA. 1998;280:119–20. [PubMed] [Google Scholar]