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These included 219 cardiovascular events (MI, arrhythmia, cardiac arrest, collapse), 140 sudden deaths, and 18 cerebrovascular accidents.

The reporting period represented about 4 million to 5 million men and approximately 9 million prescriptions, which translates to approximately 8.5 deaths per million men per month (4).

However, it was determined from an analysis of adverse events reported to the FDA between March 1998 and August 1999 that important data were missing from these reports, such as medical histories, cause of death and sildenafil citrate dosing (42).

As of September 30, 2001, Pfizer's clinical safety database contained information on the extent of exposure to sildenafil citrate from 124 completed and ongoing double-blind and open-label clinical trials involving 5054 placebo-treated and 6896 sildenafil citrate-treated patients, representing 2593 PY of observation (43).

Analysis of these data revealed that the overall MI incidence rate was similar in marley drugs viagra placebo-treated (0.95/100 PY) and sildenafil citrate-treated patients (0.85/100 PY; P = 0.801).

For the open-label studies, analysis of data from patients representing 10,859 PY of sildenafil citrate exposure demonstrated an MI incidence rate of 0.53/100 PY.

The overall MI rate for double-blind and open-label sildenafil citrate-treated patients was 0.58/100 PY.

Similar rates have been reported in a number of epidemiologic studies (44).

The database also contains (as of September 30, 2001) reports of 5 deaths (from all causes) among double-blind placebo-treated patients and 9 deaths among sildenafil citrate-treated patients.

This corresponds to all-cause mortality rates of 0.53/100 PY and 0.55/100 PY, respectively (P = 0.945). The overall (double-blind and open-label) mortality rate among sildenafil citrate-treated patients was 0.37/100 PY, which is lower than that (0.66/100 PY) calculated for men aged 40 to 64 years in the US for 1999. These results clearly show that the incidences of MI and all-cause mortality among patients who received double-blind and/or open-label sildenafil citrate treatment are similar to those observed among patients who received placebo, or in men in the same age cohort of the general population (43).

Carson III (45) reported that the incidence of adverse cardiovascular events in patients taking sildenafil does not differ from that for the general population. Cardiac electrophysiological effects of sildenafil citrate.

In the past few years, the cardiac electrophysiological effects of sildenafil citrate have been investigated extensively (46).

Geelen and colleagues (46) demonstrated that sildenafil citrate induces a dose-dependent block of the rapid component of the delayed rectifier potassium current ( I Kr ).

They also reported that sildenafil citrate can have an action similar to that of class III antiarrhythmic drugs (46).

These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during co-administration of another CYP3A4 inhibitor, or after drug overdose (11).

Prolonged cardiac repolarization caused by sildenafil citrate could result in malignant ventricular arrhythmias and lead to sudden cardiac death in some of these patients (11). Swissa and colleagues (47) demonstrated that a combination of sildenafil citrate and a nitric oxide donor increases ventricular tachyarrhythmia/VF vulnerability in the normal right ventricle of swine. Although many reports have demonstrated the arrhythmogenic effects of sildenafil citrate, some studies have reported otherwise.

Vardi and colleagues (48) showed that sildenafil citrate does not alter the hemodynamic responses to exercise or change the incidence of ventricular arrhythmias in men with cardiovascular disease and ED. Chiang and colleagues (49) found that sildenafil citrate at concentrations up to 30 µM has no significant effect on either the rapid ( I Kr ) or the slow ( I Ks ) components of the

delayed

Recent studies have also demonstrated that oral administration of 50 mg sildenafil citrate does not

affect

Furthermore, Nagy and colleagues (51) recently reported that sildenafil citrate reduces arrhythmia severity during ischemia 24 h after oral administration in dogs.

Ischemic preconditioning results in powerful cardioprotective effects (52). Repeated brief episodes of ischemia initiate a cascade of intracellular signaling events which help prevent future myocardial infraction and stunning (52). After initial observation, this phenomenon, termed "myocardial preconditioning", was studied intensively to try to understand its cellular mechanisms and apply this knowledge towards protection of the human heart from ischemic heart disease. Current data suggest that sildenafil citrate has a preconditioning-like cardioprotective effect in

the

They observed an improved post-ischemic recovery of ventricular function, a reduction in the incidence of VF, and a decrease in MI. At higher doses, sildenafil caused a significant increase in the incidence of VF, while at very low doses it had no effect on cardiac function (54). However, a study by Reffelmann and Kloner (55) demonstrated otherwise.

In their report, they did not find a decrease in myocardial necrosis following ischemia-reperfusion in a rabbit model.

The reason for these negative results was not clear.

The only noticeable difference in the experimental procedure was a considerably longer drug infusion time ( 5 min) in the study by Reffelmann and Kloner (55) as compared to that used by Ockaili and colleagues (56) ( 1 min), which could potentially affect the hemodynamic response prior to ischemia. Signaling mechanisms in sildenafil-induced cardioprotection. Although sildenafil citrate has been shown to have a powerful preconditioning-like cardioprotective effects in animal models of ischemia-reperfusion injury,

the

ATP

Mitochondria are known to play an essential role in cell survival via ATP synthesis and maintenance of Ca 2+ homeostasis (59). Opening mitoK ATP channels partially compensates the membrane potential, which enables additional protons to be pumped out to form an H + electrochemical gradient to drive both ATP synthesis and Ca 2+ transport. Recently, Das and colleagues (60) reported that protein kinase C also plays an essential role in sildenafil-induced cardioprotection in rabbits. We conclude that, in view of the increasing incidence of sudden cardiac death in ED patients treated with sildenafil citrate, it is essential to understand how this drug affects the entire cardiovascular system, especially the heart. According to extensive data available to date, sildenafil citrate has been shown to pose minimal cardiovascular risks to healthy people taking this drug. Some precautions, however, are needed for patients with cardiovascular disease. Further clinical and basic investigation on the cardiovascular effects of sildenafil citrate is needed to assure proper treatment of ED in patients with cardiovascular disease.

Chew KK, Earle CM, Stuckey BG, Jamrozik K & Keogh EJ (2000). Erectile dysfunction in general medicine practice: prevalence and clinical correlates. International Journal of Impotence Research viagra pills generic brand , 12: 41-45. Sexual dysfunction in the United States: prevalence and predictors. Journal of the American Medical Association , 281: 537-544. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ & McKinlay JB (1994).

Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.

Greenstein A, Chen J, Miller H, Matzkin H, Villa Y & Braf Z (1997). Does severity of ischemic coronary disease correlate with erectile function? International Journal of Impotence Research , 9: 123-126. Israilov S, Baniel J, Shmueli J, Niv E, Engelstein D, Segenreich E & Livne PM (2004). Treatment program for erectile dysfunction in patients with cardiovascular diseases.

Khan MA, Ledda A, Mikhailidis DP, Rosano G, Vale J, Vickers M & Consensus Writing Committee (2002). Second Consensus Conference on Cardiovascular Risk Factors and Erectile Dysfunction.

Erectile dysfunction and sildenafil citrate and cardiologists.

Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD & Wicker PA (

1998

Oral sildenafil in the treatment of erectile dysfunction. Shakir SA, Wilton LV, Boshier A, Layton D & Heeley E (2001). Cardiovascular events in users of sildenafil: results from first phase of prescription event monitoring in England.

Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms.

Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Acute myocardial infarction after the use of sildenafil.

Clinical trials of sildenafil citrate (Viagra) demonstrate no increase in risk of myocardial infarction and cardiovascular death compared with placebo.

International Journal of Clinical Practice , 57: 597-600.

Manfroi WC, Caramori PR, Zago AJ, Melchior R, Zen V, Accordi M, Gutierres D & Noer C (2003).

Hemodynamic effects of sildenafil in patients with stable ischemic heart disease.

Cheitlin MD, Hutter Jr AM, Brindis RG, Ganz P, Kaul S, Russell Jr RO & Zusman RM (1999).

Use of sildenafil (Viagra) in patients with cardiovascular disease. Cheitlin MD, Hutter Jr AM, Brindis RG, Ganz P, Kaul S, Russell Jr RO & Zusman RM (1999). Use of

sildenafil

Effect of oral milrinone on mortality in severe chronic heart failure.

Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3). Nony P, Boissel JP, Lievre M, Leizorovicz A, Haugh MC, Fareh S & de Breyne B (1994). Evaluation of the effect of

phosphodiesterase

European Journal of Clinical Pharmacology , 46: 191-196. Corbin J, Rannels S, Neal D, Chang P,

Grimes

Herrmann HC, Chang G, Klugherz BD & Mahoney PD (2000). Hemodynamic effects of sildenafil in men with severe coronary artery disease.

Rajfer J, Aronson WJ, Bush PA, Dorey FJ & Ignarro LJ (1992).

Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission.

Sebkhi A, Strange JW, Phillips SC, Wharton J & Wilkins MR (2003). Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. Stiebellehner L, Petkov V, Vonbank K, Funk G, Schenk P, Ziesche R & Block LH (2003).

Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension.

Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, Bohm M & Sybrecht GW (2001). Effect of inhaled iloprost plus generic viagra hims oral sildenafil in patients with primary pulmonary hypertension. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Chattipakorn N, Fotuhi PC, Zheng X & Ideker RE (2000).

Left ventricular apex ablation decreases the upper limit of vulnerability. Chattipakorn N, Fotuhi PC, Sreenan CM, White JB & Ideker RE (2000).

Pacing after shocks stronger than the upper limit of vulnerability: impact on fibrillation induction. Influence of postshock epicardial activation patterns on initiation of ventricular fibrillation by upper limit of vulnerability shocks.

Chattipakorn N, Banville I, Gray RA & Ideker RE (2001).

Mechanism of ventricular defibrillation for near-defibrillation threshold shocks: a whole-heart optical mapping study in swine. Chattipakorn N, Fotuhi PC, Chattipakorn SC & Ideker RE (2003).

Three-dimensional mapping of earliest activation after near-threshold ventricular defibrillation shocks.

Journal of Cardiovascular Electrophysiology , 14: 65-69. Pediatric Clinics of North America , 51: 1211-1221. Pacing following shocks stronger than the defibrillation threshold: impact on defibrillation outcome. Journal of Cardiovascular Electrophysiology , 11: 1022-1028. Prediction of defibrillation outcome by epicardial activation patterns following shocks near the defibrillation threshold. Journal of Cardiovascular Electrophysiology , 11: 1014-1021.

Chattipakorn N, Banville I, Gray RA & Ideker RE (2004). Effects of shock strengths on ventricular defibrillation failure.

Sildenafil in patients with cardiovascular disease. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Alloggiamento get viagra without prescription T, Zipp C, Raxwal VK, Ashley E, Dey S, Levine S & Froelicher VF (2001). Padma-Nathan H, Eardley I, Kloner RA, Laties AM & Montorsi F (2002).

A 4-year update on the safety of sildenafil citrate (Viagra).

McGovern PG, Jacobs Jr DR, Shahar E, Arnett DK, Folsom AR, Blackburn H & Luepker RV (2001). Trends in acute coronary heart disease mortality, morbidity, and medical care from 1985 through 1997: the Minnesota heart survey.

Sildenafil: a 4-year update in the treatment of 20 million erectile dysfunction patients.

Geelen P, Drolet B, Rail J, Berube J, Daleau P, Rousseau G, Cardinal R, O'Hara GE & Turgeon J (2000).

Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. Swissa M, Ohara T, Lee MH, Kaul S, Shah PK, Hayashi H, Chen PS & Karagueuzian HS (2002).

Sildenafil-nitric oxide donor combination promotes ventricular tachyarrhythmias in the swine right ventricle. Vardi Y, Bulus M, Reisner S, Nassar S, Aboud L, Sprecher E & Gruenwald I (2003). Effects of sildenafil citrate (Viagra) on hemodynamic parameters during exercise testing and occurrence of ventricular arrhythmias in patients with erectile dysfunction and cardiovascular disease. Kaya D, Guler C, Esen AM, Barutcu I & Dincel C (2004). Sildenafil citrate does not alter ventricular repolarization properties: novel evidence from dynamic QT analysis. Annals of Noninvasive Electrocardiology , 9: 228-233.

Sildenafil (Viagra) reduces arrhythmia severity during ischaemia 24 h after oral administration in dogs.

Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse get viagra without prescription heart. Das S, Maulik N, Das DK, Kadowitz PJ & Bivalacqua TJ (2002).

Cardioprotection with sildenafil, a selective inhibitor of cyclic 3',5'-monophosphate-specific phosphodiesterase 5. Drugs under Experimental and Clinical Research , 28: 213-219.

Effects of sildenafil on myocardial infarct size, microvascular function, and acute ischemic left ventricular dilation. Ockaili R, Salloum F, Hawkins J & Kukreja RC (2002). Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits. The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5.

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The role of mitochondrial KATP channels in cardioprotection. Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits.

Chattipakorn, Cardiac Electrophysiology Unit, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Research supported in part by the Thailand Research Fund (TRF) grant RSA4680010 (N. Chattipakorn) and the funding from the China Medical Board, Faculty of Medicine, Chiang Mai University (N. All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License.

Bandeirantes, 3900 14049-900 Ribeirao Preto SP Brazil Tel. Use of Sildenafil in Patients with Cardiovascular Disease.

Armenio Costa Guimaraes, Marcus Vinicius Bolivar Malachias, Otavio Rizzi Coelho, Emilio Cesar Zilli, Rafael Leite

Luna

It is common among patients with cardiovascular diseases or their risk factors.

This dysfunction occurs mainly among individuals with coronary artery disease, after episodes of acute ischemic syndrome, hypertensive patients underpharmacologic treatment, and among patients with heart get viagra without prescription failure.

In approximately 85% of these cases, the fear of a cardiac event during coitus constitutes an important factor for erectile dysfunction 2-4 .

Discovery of sildenafil citrate has represented a great development in the treatment of erectile dysfunction; it may benefit, among many others, those patients with cardiovascular diseases or with their risk factors 5 .

Even though clinical trials including more than 3,700 patients with erectile dysfunction, 2,000 of them in controlled studies with placebo, have shown a good tolerance for the medication, more intense circulatory side effects may occur in individuals with cardiovascular disease, mainly those patients using medications with organic nitrates 6 . These circumstances require recommendations by specialists so that sildenafil can be safely used. In the Massachusetts Male Aging Study (MMAS), erectile dysfunction significantly correlated with 3 groups of diseases: atherosclerosis, hypertension, and diabetes mellitus 7 . The most important organic factor involved in this dysfunction is impairment of penile blood flow, common in men above 50 years of age with atherosclerosis or diabetes. It is estimated that 50% (ranging from 28% to 59%) of diabetic patients have erectile dysfunction. Mechanism of action ? Sildenafil belongs to the class of phosphodiesterase inhibitors.

The erectile action of sildenafil combines increase in arterial flow with reduction in the venous flow of cavernous body of penis. Sildenafil leads to relaxation of smooth muscle of penile arteries and trabeculae surrounding the sinusoidal spaces, resulting in a greater engorgement of cavernous body. The trabeculae of engorged sinusoidal spaces compress the penile venules against the tunica albuginea, reducing venous flow, contributing to maintenance of engorgement of cavernous body 8 .

Relaxation of this smooth muscle results from a decrease in intracellular calcium mediated by accumulation of the second messenger, the cyclic guanosine monophosphate (cGMP), whose production results from activation of guanyl cyclase by nitric oxide produced by the stimulus of endothelial cells generated by sexual desire. The limiting factor in this process is degradation of cGMP by the enzyme 5 phosphodiesterase (PDE5) present in high concentrations in the penile structures.

Sildenafil facilitates erection due to its high specificity and potency as an inhibitor of this phosphodiesterase 9,10 .

Acting in the final phase of the biochemical cycle of erection, the action of sildenafil depends on sexual desire and, therefore, it is not an aphrodisiac.

Lower concentrations of PDE5 may also be found in the smooth muscle of arteries in general, of viscera and trachea, and in platelets. Seven types of phosphodiesterases have already been identified.

Sildenafil has a lower inhibiting power upon other isoenzymes of phosphodiesterase as compared with PDE5. It has a weak selectivity (1,000 times smaller) for PDE2 (predominates in the adrenal cortex), PDE3 (smooth muscle, platelets and myocardium), and PDE4 (lymphocytes of the brain and lungs).

It has a moderate selectivity viagra pills shoppers (80 or more times smaller) for PDE1 (predominates in the brain, kidneys and smooth muscle) and an only 10-times smaller selectivity for PDE6 (photoreceptors of the retina), the probable cause of visual disorders that may occur with the use of sildenafil. The 4,000-times lower selectivity for PDE3 (involved in myocardial contractility) is important because the inhibitors of this isoenzyme (milrinone, vesnarinone, and enoximone) used for treating heart failure cause cardiac arrhythmia and have other noxious effects 8,10 .

The peak of plasma concentration of sildenafil occurs 30 to 120 minutes (mean of 60 minutes) after oral ingestion, during fasting.

In the liver, sildenafil is partially converted into a metabolite that accounts for approximately 20% of its pharmacological action, and both circulate almost completely bound to plasma proteins (96%).

The major hepatic metabolic pathways are the cytochrome P450 3A4 (main) and P450 2C9 (secondary) 8,11 . Excretion is predominantly fecal (80%); only 13% are urinary.

For a given oral dose of sildenafil, plasma concentrations of the drug may be 40% higher in individuals above 65 years of age,

80%