PDE5-Inhibitors and Nitrates: How Firm is the Contraindication?

Everybody has seen the subtle ads on television about erectile dysfunction (ED) which you might have mistakenly thought it was advertising an impossibly effective antidepressant. Or maybe something about not washing vintage cars? Anyway, more men are in or approaching their golden years and this trend increases the co-prevalence of two common medical conditions: heart disease and ED. The latter is a serious sexual problem which not only contributes to psychological and interpersonal problems, but also is an important predictor of mortality, cardiovascular death, myocardial infarction (MI) and congestive heart failure (CHF) in men with coronary artery disease (CAD).

Erectile dysfunction is easily treated with a handful of very effective drugs called phosphodiesterase-5 inhibitors (PDE5I): Viagra (sildenafil), Cialis (tadalafil) and Levitra/Staxyn (vardenafil). One absolute contraindication of PDE5Is is using nitroglycerin products. I learned in pharmacy school that this combination is a definite no-go and a call to the physician was in order. However, I have recently noticed that despite the contraindication, I have seen more than one physician waive this contraindication for CAD patients who have rescue sublingual nitroglycerin. So I decided to do an in-depth review of the evidence supporting the interaction while also trying to find evidence-based recommendations to guide the safe use of PDE5-inhibitors in CAD patients.

Prime Suspects: Blockbuster PDE5-Inhibitors and Nitrates

Clinicians were initially cautious when using PDE5-I in certain patients with heart disease. Now we know we can generally use them safely in certain patients who are considered low-risk of cardiovascular event due to resumption of sexual activity (1,2). It is important to note that anyone with cardiovascular disease (e.g.: CAD, CHF) should first consult their physician for an evaluation as to whether one can resume sexual activity because this level of exertion increases the chance of suffering a cardiac or vascular event (e.g..: heart attack or stroke). Of course it is important to rekindle your love life, but make sure to get the green light from your doctor first.

PDE5-inhibitors are effective and generally safe to use as indicated and they are very frequently prescribed to patients with little tolerability issues. Common side effects (rate: 1 out of 100: dyspepsia, nasal congestion or rhinitis, dizziness, visual disturbances, flushing,headaches or myalgia) are minor and reversible. There are, however, post-marketing reports of hearing loss and non-arteritic anterior ischaemic optic neuropathy (NAION) causing sudden loss of vision in patients taking PDE5 inhibitors, but there’s little evidence as of yet that they conclusively cause either hearing or vision (3,4) loss. There are also a few reports of priapism related to the use of sildenafil in overdoses but also in patients who took normal doses (5). Sudden loss of vision or hearing, and having an erection of more than 4 hours following any PDE5-inhibitors are medical emergencies and should be treated as soon as possible.

Nitrates typically are indicated for acute symptomatic relief of chest pain (due to angina or MI) or for long-term management of stable CAD (e.g: daily use). These includes nitroglycerin or glyceryl trinitrate in the form of patches, ointments, sublingual tablets/spray or injections; isosorbide dinitrate and isosorbide-5 mononitrate as regular or sublingual tablets. Nitrates are life-saving drugs and everyone who is prescribed these products should never go without them. Also important: rescue type formulations should be regularly checked to see if they are expired (due to loss of effectiveness) because they are only occasionally used and thus tend to outlast their expiry date.

Headaches are common side effect, and although they can appear in at least 50% of all patients who start taking nitrates, it is usually a minor problem and disappear within days to a week or so. Nitrate-related headaches can be treated with acetaminophen until resolved (6).

Mechanism of PDE5-Inhibitors – Nitrates Interaction

Physiologically, erections are initiated by a sexual stimuli which triggers endothelium-mediated vasodilation mediated by cGMP, which promotes trabecular and vascular smooth muscle relaxation. Sildenafil and it’s ilk distribute not just in the intended target, but also to platelets, veins, systemic arteries, lung and cardiac vasculature. Specifically, PDE5Is inhibit the breakdown of cGMP while nitrates increase the supply of cGMP; if taken together, they result in an excessive accumulation of cGMP which can cause severe vasodilation and hypotension (2,3,7).

Other important parameters to remember is that PDE5Is aren’t all hepatically metabolized the same way: tadalafil is the different one here in that it takes about 2 hours to act, is unaffected by fatty foods and lasts a full 36 hours due to CYP3A4 (100%) inactivation (T1/2=17.5h); sildenafil’s and vardenafil’s onsets of actions are both around 30 to 60 minutes, but longer if taken with a fatty meal ( yet act about 12 hours with metabolism shared by CYP3A4 (80%) and 2C9 (20%) (T1/2= 4-5h)). This is important clinically in terms of recommendations of PDE5I-Nitrate interactions. Other drug-PDE5I interactions are not addressed directly in this review (alpha-blockers, etc) and readers are to revise references 10 and 11 for an extensive overview of PDE5-inhibitor interactions.

CAD and it’s risk factors such as diabetes, hypertension and hyperlipidemia are all prevalent in patients suffering from erectile dysfunction (8). Fortunately, co-prescription of Nitrates and PDE5Is seems relatively low (3.3% in one study) but potentially could be lower because it may be that multiple prescribers are an important driver in a potentially dangerous PDE5I interaction (9). This provides a unique opportunity for community pharmacists to monitor this dangerous interaction, comprehensively inform the patient of the risks of nitrate-PDE5Is co-prescription and to resolve potential drug-related problems.

Recommendations

The American Heart Association and the American College of Cardiology have offered guidance on this clinical problem (10,11,12):

  • Nitrates can be administered only 24 hours (6 half-lives) after sildenafil intake to allow full clearance of the drug; Additionally, nitrates should be withheld for at least 48 hours after tadalafil intake; a low dose of PDE5Is should be initiated in patients with a stable dose of an non-selective (cardioselective; doxazosin) alpha-blocker.
  • It may be prudent to allow additional time to elapse in patients with conditions that increase plasma levels of PDE5Is
  • Use extra caution when using moderate to strong CYP3A4 inhibitors or inducers, dose adjustments may be required
  • Patients prescribed PDE5Is should be counseled to inform emergency workers and physicians about their most recent PDE5I intake so that nitrates can be avoided.
  • If a patient has taken a PDE5I, receives a nitrate, and becomes hypotensive from pronounced vasodilation, it is suggested to place the patient in the Trendelenburg position; treat with aggressive fluid resuscitation, and if necessary an beta-agonist (phenylephrine), alpha-agonist (norepinephrine), and intra-aortic balloon counterpulsation; there is no antidote to PDE5Is.
  • All other medications should be given if appropriate to the clinical condition, including the antianginal agents beta-blockers, calcium channel blockers, and morphine, as well as aspirin, statins, oxygen, thrombolytics, and antiplatelet agents as indicated.

Conclusion

Appropriate patient counselling of PDE5-inhibitors include discussion on life-threatening interaction with nitrates (and alpha-blockers) causing severe hypotension (less than 85 systolic mmHg) and also on the initial signs and symptoms; for example: severe headache, dizziness, or syncope. They should also be warned to avoid recreational inhaled poppers and nitroglycerin from friends and family, or black market or “natural” health products (e.g.: PDE5I-laced “traditional remedies”).

Only after documenting your communication with the prescriber(s) and patient that both clearly consent to the co-prescription of PDE5-inhibitors and nitrates should a pharmacist waive such interaction. Make sure the primary care provider is aware of the co-prescription and that the patient clearly understands the risks: if one takes a PDE5I and uses a rescue nitrate, one also needs to know that if they are suffering from anginal symptoms they may have to forgo one medication which is part of life-saving protocols (12). For a more detailed reading on these contraindications and other dangerous nitrate interactions refer to references 10 and 11.

One last point for pharmacists: given there is an estimated 3% co-prescription rate of PDE5I and nitrates – which means 1 out of every 33 patients taking a PDEI may also be taking a nitrate – a pro-active systematic search of pharmacy patient profile databases could easily investigate this potentially dangerous drug-related problem, especially in moderate to high-volume pharmacies.

References
1) Kostis JB, Jackson G, Rosen R et al., Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference), Am J Cardiol. 2005 Dec 26;96(12B):85M-93M. Epub 2005 Dec 27 (free full text) : http://www.ajconline.org/article/S0002-9149(05)00671-5/fulltext

2) Viagra Drug Monograph, Drug Product Database, (free full text, updated 08/13 and accessed 02/15)
3) P. J. Wright, Comparison of Phosphodiesterase Type 5 (PDE5) Inhibitors, Int J Clin Pract. 2006;60(8):967-975 (Subscription required at : http://www.medscape.com/viewarticle/542736_4 )
4) R Basson, Sexual Health: Male Sexual Dysfunction, Therapeutic Choices, Canadian Pharmacists Association, (Paid Subscription, updated 09/14 and accessed 02/15)
5) Sharma S, Panda S, Sharma S, Singh SK, Seth A, Gupta N. Prolonged priapism following single dose administration of sildenafil: A rare case report. Urol Ann [serial online] 2009 [cited 2015 Feb 5];1:67-8 (free full text) : http://www.urologyannals.com/text.asp?2009/1/2/67/56041

6)Nitrates Monograph, CPhA, e-Therapeutics (Paid subscription, updated 02/10 and accessed 02/15)

7)Emmick JT, Stuewe SR, Mitchell M. Overview of the cardiovascular effects of tadalafil.Eur Heart J Suppl. 2002;4 (free full text)

8) Seftel AD, Sun P, Swindle R. The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction.J Urol 2004;171:2341 (abstract only)

9) LL Chang, M Ma, H Allmen, SC. Henderson, K Harper, and K Hornbuckle, Co-possession of phosphodiesterase type-5 inhibitors (PDE5-I) with nitrates,Current Medical Research & Opinion, June 2010, Vol. 26, No. 6 : Pages 1451-1459 (abstract only)

10) Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr,Zusman RM. Use of sildenafil (Viagra) in patients with cardiovascular disease: Technology and Practice Executive Committee. Circulation. 1999;99:168 –177 (free full text) : http://circ.ahajournals.org/content/99/1/168.full

11) BG. Schwartz, RA. Kloner, Drug Interactions With Phosphodiesterase-5 Inhibitors Used for the Treatment of Erectile Dysfunction or Pulmonary Hypertension, Circulation, 2010;122:88-95 (free full text) : http://circ.ahajournals.org/content/122/1/88.full.pdf+html

12) 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes: Executive Summary, Circulation. 2014;130:2354-2394 (free full text, accessed 23/02/15) : http://circ.ahajournals.org/content/130/25/2354

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