A 59 y/o male patient is in for his semi-annual check up and prescription refill. His medical history is significant for mild HTN and angina. His meds include atenolol, HCTZ, and PRN SL nitroglycerin. In conversation with the patient he relays to you some 'problems' with his wife. Upon further exploration, he confides that he has had some 'trouble performing' recently. He asks you to prescribe that blue pill they advertise on the TV.

Do you agree or not? Why or why not?

I hope this is an easy one for you and everyone knows the interaction and contraindication of using sildenafil and organic nitrates, including SL nitroglycerin. Nitrates can potentiate the hypotensive effects of sildenafil. Depending on the patient, this can cause a serious effects putting excess strain on the diseased heart.

Some options to consider:

1.  Change the patient antihypertensive medications. Beta blockers and most HTN meds have been reported to cause erectile dysfunction. Providers and patients must balance the benefits of the meds vs. other drug options vs. the side effects. There are other phosphodiesterase 5 (PDE5) inhibitors in the pipeline. They are vardenafil  (brand name? GSK) and tadafil (Cialis® Lilly). Final FDA approval dates are unknown. They are expected to have the same class-type contraindications as sildenafil.

2.  Change the erectile dysfunction meds. Other options may include second line therapies to include alprostadil injections, alprostadil urethral inserts, vacuum assist devices, etc. Uprima® (apomorphine) was also being trialed for erectile dysfunction but was withdrawn by the manufacturer in June 2000.

3.  Penile implants are generally considered third line therapy, esp for men in whom oral or injectable medical therapies do not work or are undesirable.

Information from MICROmedex:

1. Summary: Sildenafil inhibits phosphodiesterase type 5 (PDE5) which is responsible for the metabolic degradation of cyclic guanosine monophosphate (cGMP). Organic nitrates exert their action by activation of guanylate cyclase, which increases cGMP. Because of the potential for excessive hypotensive effects as a result of increased cGMP, the concomitant use of sildenafil and organic nitrates is contraindicated. It is unknown when nitrates can again be safely administered following sildenafil administration (Prod Info Viagra(R), 2000). A randomized, double-blind, placebo-controlled, 2-way crossover study of 12 healthy men demonstrated that sildenafil potentiates the hypotensive effects of organic nitrates (Webb et al, 1999).

2. Adverse Effect: potentiation of hypotensive effects

3. Clinical Management: The concomitant administration of sildenafil and organic nitrates in any form is contraindicated. It is unknown when nitrates can again be safely administered following sildenafil administration.

4. Severity: major

5. Onset: rapid

6. Documentation: good

7. Probable Mechanism: increased levels of cyclic guanosine monophosphate (cGMP) from sildenafil and nitrates

8. Literature Reports:

    a. A randomized, double-blind, placebo-controlled, two-way crossover study of 12 healthy men demonstrated that sildenafil potentiates the hypotensive effects of organic nitrates. The men received either 25 mg sildenafil three times daily or placebo for four days, followed by a single morning dose on day 5. Nitroglycerin was given intravenously on day 4 as a stepwise infusion one hour after the sildenafil morning dose. On day 5, nitroglycerin 500 mcg was given sublingually one hour after the morning dose of sildenafil or placebo. In both cases, the nitroglycerin was discontinued when the subject's systolic blood pressure was decreased by more than 25 mm Hg. For the intravenous infusion, two of the 12 subjects in the placebo group completed the 25-minute infusion, while none completed the infusion in the sildenafil group. Similarly, with sublingual nitroglycerin, four of the 12 subjects in the placebo group removed the sublingual tablet after three to four minutes, versus 11 of 12 subjects who removed the tablet after two to seven minutes in the sildenafil group. The most frequently occurring adverse events reported by the 12 subjects were headache and dizziness (Webb et al, 1999).

    b. Two studies demonstrated the effects of a single oral dose of sildenafil citrate on blood pressure in men taking nitric oxide donor drugs, isosorbide mononitrate and glyceryl trinitrate, for stable angina. Two double-blind, placebo-controlled, randomized, two-way crossover trials were completed. Sixteen subjects received oral isosorbide mononitrate beginning five to seven days before receiving a single dose of sildenafil or placebo. Administration of isosorbide mononitrate with sildenafil resulted in substantially greater decreases in blood pressure from baseline (-52/-29 mm Hg) as compared with those subjects receiving isosorbide mononitrate plus placebo (-25/-15 mm Hg). The second study involved fifteen male subjects who were receiving sublingual nitroglycerin as needed for stable angina. A single dose of sildenafil or placebo followed by nitroglycerin sublingual one hour later was administered to patients. At least seven days later, subjects received the alternate study drug (sildenafil or placebo) and nitroglycerin sublingual one hour later. Sildenafil plus nitroglycerin resulted in an increase in mean reductions from baseline in systolic/diastolic blood pressure (-36/-21 mm Hg) compared with placebo plus nitroglycerin (-26/-12 mm Hg). Substantially greater decreases in blood pressure occur from baseline with administration of isosorbide mononitrate plus sildenafil compared to patients receiving isosorbide mononitrate plus placebo. A clinically significant reduction in blood pressure occurs with concomitant use of sildenafil and nitrates, such as isosorbide mononitrate and nitroglycerin (Webb et al, 2000).

REFERENCES:

-Webb DJ, Freestone S, Allen MJ et al: Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 1999; 83(suppl a):21C-28C. 

- Product Information: Viagra(R), sildenafil citrate. Pfizer Labs, New York, NY, (PI revised 1/2000, reviewed 8/2000).

- Webb D, Muirhead G, Wulff M et al: Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina. J Am Coll Cardiol 2000; 36(1):25-31.