SILDENAFIL (VIAGRA) AND THE HEART
DR. HASSAN CHAMSI-PASHA,
Published in Egyptian Heart
Journal in September 1999
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. There have now been >3.6 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 ACC/AHA published their “Expert Consensus Document” on the
use of sildenafil in patients with cardiovascular disease.(4) This editorial is based primarily
on the recommendations made in that “document”.
Sildenafil acts
as a selective inhibitor of cyclic 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% is due
to organic causes of erectile dysfunction(8). In U.S.A., 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 pathway and the P450 3A4
pathway. 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 P 450 3A4
pathway. The simultaneous
administration of either of these agents significantly increases the plasma
concentration of sildenafil; a lower initial dose (25 mg) should be considered
in the coadministration of sildenafil to patients receiving either of these
agents. (4)
Many drugs are
metabolized by the P 450 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. The list of a commonly prescribed drugs metabolized via the
P 450 3A4 pathway include: 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 effects enhanced. As in patients in 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 experienced 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 therapy 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 affect 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 alcohol ingestion, is probably low. (4)
In patients
with recurring mild angina after sildenafil use, other nonnitrate antianginal
agents, such as ß-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 thrombolytics.
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,
ß-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 in patients with uncontrolled hypertension. Such patients were not included in the
publishes studies. Thus, there are
possible problems in the use of Viagra in these patients. Other unresolved issues include:
sildenafil interaction with non aspirin antiplatelet agents (e.g. ticlopidine,
clopidogrel and dipyridamole), central nervous systems 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 periods
remains to be seen.
References:
1. Furlow WL. Prevalence of impotence in United
States. Med Aspects Hum Sex 1985;
10:13-6.
2. Morley JE. Impotence. Am J Med 1986; 80:897-905.
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.
4. Cheitlin MD,
Hutter Jr AM, Brindis RG, et al. The ACC/AHA “Expert Consensus Document”. Use of
Sildenafil (Viagra) in patients with cardiovascular disease. J Am Coll Cardiol 1999; 33:273-82.
5. Utiger RD. A
pill for impotence (editorial). N Engl J Med 1998; 338:1458-9.
6. Riley AJ,
Athanasiadis L. Impotence and its
non-surgical management. Br J Clin
Pract 1997, 51:99-105.
7.
Muller JE, Mittleman A, Maclure M, Sherwood JB, toffler
GH. Triggering myocardial
infarction by sexual activity. JAMA 1996; 275:1405-9.
8. Tardif GS. Sexual activity
after a myocardial infarction.
Arch Phys Med Rehab 1989; 70:763-6.
9. Mitka M. Viagra leads as rivals are moving
up. JAMA 1998; 280: 119-20. News.