ACC/AHA Expert Consensus Document
`
`Use of Sildenafil (Viagra) in Patients With
`Cardiovascular Disease
`Writing Group Members
`
`Melvin D. Cheitlin, MD, FACC, Cochair; Adolph M. Hutter, Jr, MD, MACC, Cochair;
`Ralph G. Brindis, MD, MPH, FACC; Peter Ganz, MD, FACC; Sanjay Kaul, MD;
`Richard O. Russell, Jr, MD, FACC; Randall M. Zusman, MD, FACC*
`
`Technology and Practice Executive Committee
`
`James S. Forrester, MD, FACC, Chair; Pamela S. Douglas, MD, FACC; David P. Faxon, MD, FACC;
`John D. Fisher, MD, FACC; Raymond J. Gibbons, MD, FACC; Jonathan L. Halperin, MD, FACC;
`Adolph M. Hutter, Jr, MD, MACC; Judith S. Hochman, MD, FACC; Sanjiv Kaul, MD, FACC*;
`William S. Weintraub, MD, FACC; William L. Winters, Jr, MD, MACC; Michael J. Wolk, MD, FACC
`
`Executive Summary
`The pharmaceutical preparation sildenafil citrate (Viagra) is
`being widely prescribed as a treatment for male erectile
`dysfunction, a common problem that in the United States
`affects between 10 and 30 million men. The introduction of
`sildenafil has been a valuable contribution to the treatment of
`erectile dysfunction, which is a relatively common occur-
`rence in patients with cardiovascular disease. This article is
`written to appropriately caution and not to unduly alarm
`physicians in their use of sildenafil in patients with heart
`disease.
`Reported cardiovascular side effects in the normal healthy
`population are typically minor and associated with vasodila-
`tation (ie, headache, flushing, and small decreases in systolic
`and diastolic blood pressures). However, although their inci-
`dence is small, serious cardiovascular events, including sig-
`nificant hypotension, can occur in certain populations at risk.
`Most at risk are individuals who are concurrently taking
`organic nitrates. Organic nitrate preparations are commonly
`prescribed to manage the symptoms of angina pectoris. The
`coadministration of nitrates and Viagra significantly in-
`creases the risk of potentially life-threatening hypotension.
`Therefore, Viagra should not be prescribed to patients receiv-
`ing any form of nitrate therapy.
`Although definitive evidence is currently lacking, it is
`possible that a precipitous reduction in blood pressure with
`nitrate use may occur over the initial 24 hours after a dose of
`
`Viagra. Thus, for patients who experience an acute cardiac
`ischemic event and who have taken Viagra within the past
`24 h, administration of nitrates should be avoided. In the
`event that nitrates are given, especially within this critical
`time interval, it is essential to have the capability to support
`the patient with fluid resuscitation and a-adrenergic agonists
`if needed. In patients with recurring angina after Viagra use,
`other nonnitrate antianginal agents, such as b-blockers,
`should be considered.
`Other patients in whom the use of Viagra is potentially
`hazardous include those with active coronary ischemia; those
`with congestive heart failure and borderline low blood vol-
`ume and low blood pressure status; those with complicated,
`multidrug, antihypertensive therapy regimens; and those tak-
`ing medications that may affect the metabolic clearance of
`Viagra. With respect to patients following complicated mul-
`tidrug, antihypertensive programs, the randomized studies
`included a large number of hypertensive patients. However,
`most patients were controlled with 1 antihypertensive agent,
`and only a small number were controlled with 3 antihyper-
`tensive agents. Until adequate studies are done in these
`subgroups of patients, sildenafil should be prescribed with
`caution.
`Viagra acts as a selective inhibitor of cyclic GMP
`(cGMP)–specific phosphodiesterase type 5,
`resulting in
`smooth muscle relaxation, vasodilatation, and enhanced pe-
`nile erection. Although the cardiovascular effects of sildenafil
`
`The ACC/AHA Expert Consensus Document “Use of Sildenafil (Viagra) in Patients With Cardiovascular Disease” was approved by the Board of
`Trustees of the American College of Cardiology in September 1998 and the American Heart Association Science Advisory and Coordinating Committee
`in September 1998. Reprints of this document are available by calling 800-253-4636 (US only) or writing American College of Cardiology, Educational
`Services, 9111 Old Georgetown Road, Bethesda, MD 20814-1699. To make photocopies for personal or educational use, call the Copyright Clearance
`Center at 978-750-8400.
`*Those authors designated with an asterisk have indicated a potential conflict of interest with respect to the topic of this document. They have excused
`themselves from discussions or the preparation of the text whence this potential conflict would apply.
`January 1999
`(J Am Coll Cardiol 1999;33:273– 82)
`© 1998 American College of Cardiology and American Heart Association, Inc.
`PII S0735-1097(98)006561-1
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`reported in available randomized, controlled clinical trials
`were relatively minor, heart disease patients represented only
`a small fraction of studied patients and patients with heart
`failure, patients with myocardial infarction or stroke within 6
`months or patients with uncontrolled hypertension were not
`included in these studies. Thus, there are possible problems in
`the use of Viagra in these patients that have not been
`adequately studied.
`Given the increasing reports of deaths in which the use of
`Viagra may be implicated, clinicians need to exercise caution
`when advising their patients with heart disease about taking
`this medication. Specific recommendations regarding silde-
`nafil (Viagra) and the cardiac patient are summarized in the
`following Table.
`
`Summary Table of Clinical Recommendations
`
`A. Use of Viagra clearly contraindicated
`1. Concurrent use of nitrates (see Appendix A)
`B. Cardiovascular effects of Viagra may be potentially hazardous (use
`dependent on individual clinical assessment)
`1. Patients with active coronary ischemia who are not taking nitrates (eg,
`positive exercise test for ischemia)
`2. Patients with congestive heart failure and borderline low blood
`pressure and borderline low volume status
`3. Patients on a complicated, multidrug, antihypertensive program
`4. Patients taking drugs that can prolong the half-life of Viagra (see
`Appendix B)
`
`I. Preamble
`The present document is an expert consensus. This type of
`document is intended to inform practitioners, payers and
`other interested parties of the opinion of the American
`College of Cardiology (ACC) concerning evolving areas of
`clinical practice and/or technologies that are widely available
`or are new to the practice community. Topics chosen for
`coverage by Expert Consensus Documents are so designated
`because the evidence base and experience with the technol-
`ogy or clinical practice are not sufficiently well developed to
`be evaluated by the formal ACC/American Heart Association
`(AHA) Practice Guidelines process. Thus, the reader should
`view the Expert Consensus Documents as the best attempt of
`the ACC to inform and guide clinical practice in areas in
`which rigorous evidence is not yet available. Where feasible,
`Expert Consensus Documents will include indications and
`contraindications. Some topics covered by Expert Consensus
`Documents will be addressed subsequently by the ACC/AHA
`Practice Guideline process.
`
`A. Sildenafil (Viagra) Use for Erectile Dysfunction
`Male erectile dysfunction defined as “the inability to attain
`and/or maintain penile erection sufficient for satisfactory
`sexual performance (1)” is a common problem in the United
`States affecting between 10 and 30 million men (2,3). Sexual
`dysfunction in men after the diagnosis of coronary artery
`disease or a myocardial infarction is common. Most is due to
`fear that
`the exertion of sexual activity will precipitate
`another myocardial infarction, but 10% to 15% is due to
`organic causes of impotence (4). Approximately 5.5 million
`
`men take nitrates on a regular basis for angina pectoris (5),
`and another half a million will experience a heart attack
`annually and are potential candidates for nitrate therapy (6).
`Sildenafil
`is potentially contraindicated in as many as 6
`million patients.
`The introduction of sildenafil citrate (Viagra), a drug that
`acts as a selective inhibitor of cGMP–specific phosphodies-
`terase type 5 (PDE5), which results in smooth muscle
`relaxation, vasodilatation, and enhanced penile erection, has
`been a major advancement
`in the treatment of erectile
`dysfunction (7). The vasodilating action of sildenafil affects
`both the arteries and the veins, so the most frequent side effects
`of sildenafil are headache and facial flushing (8). Sildenafil
`causes small decreases in systolic and diastolic blood pressures,
`but clinically significant hypotension is rare. Studies of sildenafil
`and nitrates taken together show much greater drops in blood
`pressure. For that reason, it is contraindicated to use sildenafil in
`patients who take long-acting nitrates or who use short-acting,
`nitrate-containing medications.
`In the phase II/III studies completed before Food and Drug
`Administration (FDA) approval, .3700 patients received
`sildenafil and almost 2000 received placebo in double-blind
`and open-label studies. None were taking long-acting nitrates,
`although patients with coronary artery disease were not
`excluded. Approximately 25% of the patients had hyperten-
`sion and were taking antihypertensive medications, and 17%
`were diabetic. In these studies,
`the incidence of serious
`cardiovascular adverse effects was similar in the double-blind
`sildenafil group, the double-blind placebo group, and the
`open-label group. There were 28 patients who had a myocar-
`dial infarction. When adjusted for patient-years of exposure,
`there were no differences in myocardial
`infarction rate
`between the sildenafil group and the placebo group, and no
`deaths were attributed to treatment. The incidence of myo-
`cardial infarction was 1.7/100 patient-years (95% CI, 0.8 to
`2.6) in the sildenafil group and 1.4/100 patient-years (95%
`CI, 0.2 to 2.6) in the placebo group (9). In the subsequent
`analysis done in May 1998, sildenafil exposure had increased
`to 4913 patient-years (693 double-blind sildenafil; 4220
`open-label extensions), and 26 deaths had been reported, for
`an incidence rate of 0.53/100 patient-years. The incidence for
`placebo remained the same (ie, 2 deaths or 0.57/100 patient-
`years) (5).
`There have now been .3.6 million prescriptions (10)
`written for sildenafil, and 4500 patients taking sildenafil have
`been followed up without any change in the above conclu-
`sions. A total of 69 deaths have been reported to the FDA as
`of August 26, 1998,
`in patients who have used Viagra
`(10,11). Twenty-one were due to unknown causes, 2 due to
`stroke, and 46 related to probable cardiac events (10,11).
`Twelve deaths involved a possible interaction between Vi-
`agra and nitrates (10,11).
`Patients with erectile dysfunction are mostly over age 45
`and are in general more likely to have risk factors predispos-
`ing them to cardiovascular disease, including myocardial
`infarction and stroke. The vast majority of patients in the
`clinical development program did not have known coronary
`disease or congestive heart failure, nor were hypertensive
`patients taking complicated, multidrug, antihypertensive
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`medical regimens included in the program. Furthermore, 62%
`of the patients taking Viagra were within the 45- to 64-year-
`old age category, and only 23% were aged $65 years (Pfizer
`Inc, unpublished data). Although sildenafil is not presently
`indicated in women, the cautions referred to in this document
`should probably apply to both men and women, pending
`studies performed specifically in women.
`
`B. Development of an ACC Expert
`Consensus Document
`In July 1998, responding to inquiries from both concerned
`physicians and the press, ACC president Spencer King asked
`the ACC Technology and Practice Executive Committee
`(TPEC) to supervise the writing of a press release, summary
`statement and Expert Consensus Document on sildenafil
`(Viagra). This article was written to appropriately caution and
`not to unduly alarm physicians in their use of sildenafil in
`patients with heart disease.
`Dr. King and TPEC chair Dr James Forrester selected a
`group of physicians with specific expertise to prepare the
`document. Drs. Melvin Cheitlin and Adolph Hutter, Jr, were
`chosen as cochairs of the Writing Group, on the basis of their
`status as well-recognized senior clinical cardiologists and
`their experience in producing clinical practice guidelines.
`Other members were selected for specific expertise: Dr
`Brindis (managed care), Dr Ganz (vascular reactivity), Dr
`Kaul (nitric oxide donors), and Dr Zusman (pharmacology of
`antihypertensive agents). Dr King also invited the AHA to
`jointly author the document. Dr Richard Russell (critical care
`cardiology) was appointed to the Writing Group by AHA
`president Dr Valentin Fuster. All members of the Writing
`Group were asked to carefully review any potential conflicts
`of interest they might have regarding their industry relation-
`ships. Those writers who indicated conflicts are identified in
`the byline.
`The Writing Group reviewed both the limited published
`data on Viagra and unpublished data provided by the manu-
`facturer of Viagra, Pfizer Inc. With respect to the unpublished
`data, all members of the Writing Group who had access to
`these documents signed statements that
`they would not
`distribute this information outside of the Writing Group until
`such time as it became public information. Members of the
`Writing Group were instructed to channel all communications
`with Pfizer through ACC professional staff to eliminate the
`appearance of bias.
`After completion of the document, 10 external referees
`reviewed the text. A copy of the draft was also provided to
`Pfizer and to the FDA for comment. The comments from
`external review, which were kept anonymous, were provided
`to the Writing Group, which made revisions as they deemed
`appropriate. The Expert Consensus Document was approved
`by vote of the TPEC for presentation to the ACC Board of
`Trustees, which voted to approve its publication in the
`Journal of the American College of Cardiology. The AHA
`Scientific Advisory Committee also reviewed and approved
`this document for publication in Circulation.
`
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`II. Background
`A. Physiology of Erection
`Penile erection is accomplished by engorgement of cavernous
`spaces within the corpora cavernosa under near-arterial pres-
`sures and involves dilation of arterial inflow, relaxation of
`corpora cavernosa smooth muscle, and constriction of venous
`outflow (12). The blood flow to the penis is supplied by the
`cavernosal arteries and their branches, the helicine arteries,
`which empty directly into the cavernous spaces (12). Erection
`is initiated by dilation of helicine arteries, resulting in marked
`augmentation of blood inflow and transmission of arterial
`pressures to the cavernosal spaces. Relaxation of smooth
`muscle trabeculae surrounding cavernosal spaces facilitates
`blood pooling and engorgement. Restriction of venous out-
`flow is also essential to entrapment of blood in the corpora
`cavernosa and is caused by compression of venules by the
`expanding smooth muscle trabeculae against the thick tunica
`albuginea (12).
`
`B. Role of Nitric Oxide and cGMP
`the
`The relaxation of the penile arterial smooth muscle,
`corporal smooth muscle, and therefore erection is under the
`control of the autonomic nervous system (13). The principal
`neural mediator of penile smooth muscle relaxation is nitric
`oxide (NO) (13,14). NO and its derivatives have received
`much attention because they also account for the biological
`activity of the endothelium-derived relaxation factor and of
`organic and inorganic nitrate vasodilators. Three isoforms of
`NO synthase (NOS) that convert L-arginine to NO have been
`identified: neuronal (nNOS; type I NOS), inducible (iNOS;
`type II NOS), and endothelial (eNOS; type III NOS). Termi-
`nals containing nNOS densely innervate the corpus caverno-
`sum and its arterial supply (13,14). NO derived from the
`endothelium lining penile arteries and cavernosal sinuses also
`participates in the erectile response. The arterial dilator
`actions of NO and its relaxant effect on the smooth muscle of
`the corpus cavernosum are mediated by the activation of
`soluble guanylate cyclase and production of cGMP, which
`acts as a second messenger (13,14). Accumulation of cGMP
`leads to a reduction in intracellular calcium and smooth
`muscle relaxation. The degradation of cGMP into its inactive
`form, GMP, is catalyzed by cyclic nucleotide phosphodies-
`terase enzymes (15,16). The predominant isoform of this
`enzyme in the corpus cavernosum is PDE5 (12,15). Inhibitors
`of the activity of this enzyme prevent the breakdown of
`cGMP, resulting in enhanced penile erection.
`
`III. Sildenafil
`A. Introduction and Mechanism of Action
`Sildenafil belongs to a class of compounds called PDE
`inhibitors. PDEs comprise a diverse family of enzymes that
`hydrolyze cyclic nucleotides (cAMP and cGMP) and there-
`fore play a critical role in the modulation of second-
`messenger signaling pathways (15).
`Sildenafil is a potent and selective inhibitor of cGMP-
`specific PDE5 (Pfizer, unpublished data), the predominant
`isozyme that metabolizes cGMP in the corpus cavernosum of
`the penis. cGMP is the second messenger of NO and, a
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`principal mediator of smooth muscle relaxation and vasodi-
`latation in the penis. By inhibiting the hydrolytic breakdown
`of cGMP, sildenafil prolongs the action of cGMP. This
`results in augmented smooth muscle relaxation and hence,
`prolongation of the erection. Prior production of cGMP by
`NO, released primarily from the nonadrenergic, noncholin-
`ergic (nitroxidergic) cavernosal nerves in response to sexual
`stimulation, is required for sildenafil to be effective (13,14).
`Relatively high levels of PDE5 are found in the human
`corpus cavernosum; in vascular, visceral and tracheal smooth
`muscle; and in platelets (15). Sildenafil is a potent inhibitor of
`PDE5, with favorable selectivity (.1000-fold) for human
`PDE5 over human PDE2 (isozyme found predominantly in
`the adrenal cortex) (15), PDE3 (found predominantly in
`smooth muscles, platelets, and cardiac tissue) (15), and PDE4
`(found predominantly in the brain and lung lymphocytes)
`(15) and moderate selectivity (.80-fold) over PDE1 (a
`cGMP-hydrolyzing isozyme found predominantly in the
`brain, kidney, and smooth muscle) (15). Sildenafil is only
`’10-fold as potent for PDE5 as for PDE6 (an enzyme found
`in the photoreceptors of the human retina); this lower selec-
`tivity is presumed to be the basis for abnormalities related to
`color vision observed with higher doses or plasma levels of
`sildenafil (Pfizer, unpublished data). The ’4000-fold greater
`selectivity for PDE5 over PDE3 is important because inhib-
`itors of PDE3 (the isozyme involved in regulation of cardiac
`contractility), such as milrinone, vesnarinone and enoximone,
`that have been used in patients with heart failure, are
`generally associated with increased incidence of cardiac
`arrhythmias and other serious side effects (17).
`
`B. Pharmacokinetics and Metabolism
`Sildenafil is rapidly absorbed after oral administration, with
`absolute bioavailability of ’40%. Plasma concentrations
`peak within 30 to 120 minutes (median, 60 minutes) of oral
`dosing in the fasted state. Sildenafil is primarily metabolized
`by the cytochrome P450 3A4 (major route) and 2C9 (minor
`route) hepatic microsomal isoenzymes, which convert it to an
`active N-desmethyl metabolite that has been shown to possess
`50% of the parent drug’s potency for inhibiting PDE5.
`Plasma concentrations of this metabolite are ’40% of those
`seen for sildenafil, so that the metabolite accounts for ’20%
`of the pharmacological effects of sildenafil. Sildenafil and its
`active metabolite are both highly bound to plasma proteins
`(’96%), and their terminal half-lives are ’4 hours each. The
`mean steady-state volume of distribution for sildenafil is 105
`L, indicating distribution into the tissues. Sildenafil is ex-
`creted as metabolites predominantly in the feces (’80% of
`administered oral dose) and to a lesser extent in the urine
`(’13% of the administered oral dose). Less than 0.001% of
`the administered dose appears in the semen; this dose is very
`unlikely to have any effects in the partners of patients taking
`sildenafil. Plasma levels of sildenafil are increased in patients
`aged .65 years (40% increase) and in patients with hepatic
`impairment (eg, cirrhosis; 80% increase), severe renal impair-
`ment (creatinine clearance ,30 mL/min; 100% increase), and
`concomitant use of potent cytochrome P450 3A4 inhibitors
`(eg, macrolide antibiotics such as erythromycin [200% in-
`crease] and clarithromycin; cimetidine; and antifungal agents
`
`such as ketoconazole and itraconazole) (18). Protease inhib-
`itors such as indinavir, ritonavir, nelfinavir, and saquinavir
`have not been formally studied but, being potent 3A4 inhib-
`itors, are anticipated to have similar effects on sildenafil
`metabolism (Pfizer, unpublished data).
`
`C. Pharmacodynamics
`The pharmacodynamic end points that have been investigated
`with sildenafil reflect the distribution of PDE5 in different
`tissues, ie, human corpus cavernosum (penile tumescence),
`vascular smooth muscle (vasodilatation), and platelets (anti-
`platelet function).
`
`1. Effects on Penile Tumescence
`The efficacy of sildenafil in enabling patients with erectile
`dysfunction due to a broad spectrum of causes, including
`vasculogenic (diabetes), neuroreflexogenic (spinal cord inju-
`ry), and psychogenic (nonorganic), to achieve and maintain
`erection sufficient for satisfactory sexual intercourse has been
`demonstrated in all 21 double-blind, randomized, placebo-
`controlled, multicenter studies (Pfizer, unpublished data).
`
`2. Cardiovascular Effects
`
`a. Effects on Cardiac Contractility
`Unlike cAMP-specific PDE3 inhibitors (milrinone, vesnari-
`none, and enoximone) that increase long-term mortality in
`patients with heart failure (17,19), sildenafil is highly selec-
`tive (.4000-fold) for human PDE5 over human PDE3 and
`has not been found to elevate cAMP (Pfizer, unpublished
`data). The cardiotoxic effects of PDE3 inhibitors are thought
`to be related to increases in intracellular cAMP in the
`myocardium (15,19,20). Furthermore, PDE5 is not present in
`cardiac myocytes, and sildenafil has been shown to have no
`direct inotropic effects on dog trabeculae muscle (Pfizer,
`unpublished data). However, sildenafil has not been investi-
`gated extensively in heart failure patients.
`
`b. Effects on Blood Pressure and Heart Rate
`Sildenafil produces a transient modest reduction in systolic (8
`to 10 mm Hg) and diastolic (5 to 6 mm Hg) blood pressures,
`with peak effects evident at 1 hour after the dose (coincident
`with peak plasma concentrations) and returning to baseline
`values by 4 hours after the dose (Pfizer, unpublished data).
`No significant effects are observed on heart rate. The hypo-
`tensive effects of sildenafil are neither age dependent (similar
`reductions in blood pressure in patients aged ,65 years
`compared with those .65 years) nor dose related (over the
`range of 25 to 100 mg) and rarely result
`in reports of
`orthostatic effects. Doses as high as 800 mg have been well
`tolerated in some healthy volunteers (13).
`
`c. Effects on Central Hemodynamics and Peripheral
`Vasculature
`In normal volunteers, no significant changes in cardiac index
`were evident up to 12 h after the dose for oral sildenafil (100
`to 200 mg) or intravenous sildenafil (20 to 80 mg) (Pfizer,
`unpublished data). Significant decreases in systemic vascular
`resistance index were reported at the end of intravenous
`sildenafil infusion (20 to 80 mg), when plasma concentrations
`were highest (Pfizer, unpublished data). Sildenafil has both
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`arteriodilator and venodilator effects on the peripheral vas-
`culature (Pfizer, unpublished data). In 8 patients with stable
`angina, intravenous sildenafil reduced systemic and pulmo-
`nary arterial pressures and cardiac output by 8%, 25%, and
`7%, respectively, consistent with its mixed arterial (systemic
`and pulmonary hypotension) and venous (drop in stroke
`volume secondary to decreased preload) vasodilator effects
`(14).
`In conclusion, consistent with the anticipated effects re-
`sulting from an increase in cGMP levels in vascular smooth
`muscle, sildenafil possesses vasodilatory properties, which
`result in mild, generally clinically insignificant decreases in
`blood pressure when taken alone.
`
`d. Platelet Effects
`Sildenafil has no direct effects on platelet function but will
`modestly potentiate the inhibitory effect of the NO donor
`sodium nitroprusside on ADP-induced platelet aggregation ex
`vivo, consistent with the requirement for an NO drive for
`sildenafil
`to produce its pharmacological effects (Pfizer,
`unpublished data). No effects on bleeding or prothrombin
`times were seen in healthy subjects receiving sildenafil alone
`or concurrently with aspirin or warfarin. In addition, no
`adverse bleeding episodes have been reported with the use of
`sildenafil (Pfizer, unpublished data). However, because the
`effects of sildenafil have not been evaluated in patients with
`bleeding disorders or in patients taking nonaspirin antiplatelet
`agents (eg, ticlopidine, clopidogrel or dipyridamole), caution
`should be exercised when the drug is administered in these
`clinical settings.
`
`3. Effects on Visual Function
`Transient visual abnormalities (mostly color-tinged [blue-
`green] vision,
`increased perception of light, and blurred
`vision) have been reported in patients taking sildenafil,
`especially at high oral doses (.100 mg) (Pfizer, unpublished
`data). These visual effects appear to be related to the weaker
`inhibiting action of sildenafil on PDE6, which regulates
`signal transduction pathways in the retinal photoreceptors.
`Sildenafil is 10-fold selective for PDE5 over PDE6 (Pfizer,
`unpublished data). In patients with inherited disorders of
`retinal PDE6, such as retinitis pigmentosa, sildenafil should
`be administered with extreme caution (Pfizer, unpublished
`data).
`
`4. Adverse Effects
`The adverse effects of sildenafil reflect its pharmacological
`activity of inhibition of PDE5 in various tissues and can be
`broadly classified into 4 major adverse reactions:
`
`1. Vasodilatory effects resulting in headache (16%), flush-
`ing (10%), and rhinitis (4%) (the latter presumably as a
`result of hyperemia of nasal mucosa where PDE5 is
`present). Dizziness (2%), hypotension (,2%), and pos-
`tural hypotension (,2%) have been reported rarely and
`occur at a similar rate in sildenafil- and placebo-treated
`patients (Pfizer, unpublished data).
`2. Gastrointestinal effects resulting in dyspepsia and burn-
`ing sensation from reflux due to relaxation of lower
`esophageal sphincter (7%) (Pfizer, unpublished data).
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`3. Visual abnormalities resulting in blue-green color-
`tinged vision, increased perception of light, and blurred
`vision (3%), especially at higher doses (Pfizer, unpub-
`lished data).
`4. Musculoskeletal effects resulting in myalgias, especially
`with multiple daily doses. No treatment-related changes
`in serum creatine kinase or electromyogram have been
`observed, however (Pfizer, unpublished data). There is
`no obvious pharmacological explanation for this effect.
`
`IV. Drug-Drug Interactions and Concomitant
`Disease States
`A. Interaction With Nitrates
`The vasodilator actions of nitrates are profoundly amplified
`with concomitant use of sildenafil, resulting in major hemo-
`dynamic compromise and potentially fatal events (Pfizer,
`unpublished data). This interaction likely applies to all
`nitrates and NO donors, irrespective of their predominant
`hemodynamic site of action (see Appendix A for a list of
`commonly used nitrates). Sildenafil may also potentiate the
`hypotensive effects of an inhaled form of nitrate, such as
`amyl nitrate or nitrite, also known as “poppers,” and therefore
`is contraindicated. Poppers act by dilating blood vessels, and
`the concurrent recreational use of poppers and sildenafil
`could result in sudden and marked lowering of blood pres-
`sure, which can be potentially serious or even fatal. This
`interaction may be even more pronounced in patients taking
`protease inhibitors concurrently (eg,
`indinavir [Crixivan],
`ritonavir
`[Norvir], nelfinavir
`[Viracept], or saquinavir
`[Invirase]).
`Dietary sources of nitrites, nitrates, and L-arginine (the
`substrate from which NO is synthesized) do not contribute to
`the circulating levels of NO in humans and therefore are
`unlikely to interact with sildenafil. The anesthetic agent
`nitrous oxide does not undergo any detectable biotransforma-
`tion and is eliminated unchanged from the body, mostly via
`the lungs, usually within minutes of its administration.
`Because it does not form NO in the human body and does not
`itself activate guanylate cyclase, there is no contraindication
`to its use after administration of sildenafil.
`It is not known how much time must elapse from the time
`at which a patient takes sildenafil before a nitrate-containing
`medication might be given without the marked hypotensive
`effect being produced. On the basis of the pharmacokinetic
`profile of sildenafil, it can be assumed that the coadministra-
`tion of a nitrate within the first 24 hours is likely to produce
`an exaggerated hypotensive response and is therefore contra-
`indicated unless the benefits are determined to far outweigh
`the risks. After 24 h, the administration of a nitrate may be
`considered, but once again, the response to initial dosages
`must be monitored carefully. In patients in whom the half-life
`of sildenafil may be prolonged (see below), a more extended
`period of time from sildenafil administration to nitrate ad-
`ministration may be required. The preferred form of nitrate
`therapy in this setting would be short-acting intravenous
`nitroglycerin infusion under close hemodynamic monitoring.
`Similarly, all patients taking either sildenafil or nitrates
`must be warned of the contraindications and the potential
`consequences of taking sildenafil in the 24-hour interval after
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`taking a nitrate preparation, including sublingual nitroglycer-
`in. Although sublingual nitroglycerin is very short-acting, its
`need in the previous 24 hours suggests that it may be needed
`again after sildenafil-enhanced sexual relations. Furthermore,
`the presence of even trace amounts of nitrates may have
`unknown effects in combination with sildenafil. The admin-
`istration of sildenafil to a patient who has taken a nitrate in the
`preceding 24 hours is contraindicated.
`Appendix A is a listing of nitrate preparations available in
`the United States. Other preparations may be available in
`other countries. A careful history of the medications taken by
`a patient who has taken sildenafil is essential before treatment
`of the patient for presumed myocardial ischemia or infarction
`is initiated.
`
`B. Interaction With Antiplatelet Agents
`A clinical trial combining sildenafil with aspirin showed no
`pharmacokinetic interaction between the 2 medications and
`no additional effect of sildenafil on bleeding time. Dipyri-
`damole is believed to exert antiplatelet effects by at least two
`mechanisms. Its nonspecific PDE action increases platelet
`cAMP, and it increases plasma adenosine by blocking its
`reuptake by erythrocytes (21). Ticlopidine and clopidogrel
`produce antiplatelet aggregatory activity by inhibiting ADP-
`mediated platelet activation (22). No specific interaction
`studies have been conducted between sildenafil and dipyri-
`damole, ticlopidine, or clopidogrel.
`
`C. Interaction With Other PDE Inhibitors
`PDEs are considered to be major mediators of cross talk
`between different second-messenger signaling pathways (15),
`eg, cGMP is known to inhibit PDE3, which hydrolyzes
`cAMP, thereby resulting in enhanced cAMP levels (15,20).
`This increase in cAMP levels can potentially augment cAMP-
`mediated effects in various tissues where PDE3 is localized,
`ie, Ca21 current (ICa) and inotropy in cardiac myocytes (23),
`vascular smooth muscle relaxation (24), and platelet inhibi-
`tion (25). The risk of precipitating a cardiotoxic, hypotensive
`or hemorrhagic event secondary to combining sildenafil with
`specific PDE3 inhibitors (such as milrinone, vesnarinone or
`enoximone) or with nonspecific PDE inhibitors (such as
`theophylline, dipyridamole, papaverine, and pentoxifylline) is
`currently unknown, but such effects are unlikely (17).
`
`D. Drug-Drug Interactions Affecting Metabolic
`Clearance of Sildenafil
`Sildenafil
`is an inhibitor of the cytochrome P450 2C9
`metabolic pathway.