1 Division of Nephrology Department of Internal Medicine Shin-Kong Wu Ho-Su Memorial Hospital Department of Pathology Veteran General Hospital-Taipei Taipei Taiwan ROC
Sir,
Since its approval by the US Food and Drug Administration as the first safe and effective oral agent for the treatment of erectile dysfunction in late March 1998, sildenafil citrate (ViagraTM) has been widely used in USA [1] and the rest of the world, even in the black market in Taiwan. Sildenafil (ViagraTM) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphadiesterase type 5 (PDE 5), the predominant isoenzyme which metabolises cGMP in human corpus cavernosum. Cyclic GMP is the second messenger of nitric oxide (NO) and the principal mediator of smooth-muscle relaxation and vasodilatation in the penis. In general, sildenafil is safe with only mild adverse reactions of headache, flushing, nasal congestion, dyspepsia, and mild visual disturbances reported by less than 20% of over 3700 patients who were evaluated [23]. Here we report a case of acute renal failure following the use of sildenafil.
Case.
An otherwise healthy 39-year-old man without drug using history was referred to our hospital on August 6, 1998 because of epigastric fullness, bilateral flank soreness for 5 days and dysuria, tenesmus, and anorexia for 1 day. Nine days before admission, he took one tablet of ViagraTM (100 mg) for 2 consecutive days, and his erection persisted for 45 h after the last dose. During hospitalization, he was shown to be a physically well nourished man without hypertension, oedema, hypovolaemia or anaemia, his blood pressure was 140/90 mmHg, pulse rate was 82/min, serum creatinine and BUN were 9.9 mg/dl and 53 mg/dl, respectively. Urinalysis revealed nothing particular. During the third day of admission he developed oliguria (300 ml/day), serum Na was 142 mEq/l, K 6.5 mEq/l, iCa 4.10 mg/dl, P 4.7 mg/dl. Arterial pH was 7.385, pCO2 32.1 mmHg and [HCO3]
19.3 mmol/l. Haematological evaluation revealed a Hct 45%, Hb 14.9 gm/dl and leukocyte count of 9800/mm3 with normal classification. Serological studies i.e. C3, C4, ANA were within normal limits. Virological screening for anti-HAV IgM, HbsAg, anti-HCV and anti-HIV were negative. On the fourth day of admission, he developed diuresis (4050 ml/day), serum creatinine was 4.9 mg/dl, K 5.2 mEq/l, and creatinine clearance was 36 ml/min. Renal sonogram showed bilaterally normal renal size (~10 cm in length), shape and cortical echogenecity. A percutaneous renal biopsy was performed 5 days after admission, the specimen revealed 14 glomeruli with prominent capillary dilatation and congestion. There was prominent dilatation of cortical tubules and flattening of tubular epithelial cells, segmental regeneration of tubular epithelial cells and moderate interstitial oedema (Figure 1). A diagnosis of acute tubular necrosis was made. His renal function progressively improved after supportive treatment. Serum creatinine decreased to 2.7 mg/dl 7 days after admission and he was discharged. On August 17, his serum creatinine was 1.9 mg/dl. On September 21, his serum BUN was 16 mg/dl, creatinine was 1.3 mg/dl, potassium 4.2 mEq/l and he is doing well.
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Recent studies about the mechanism of penile erection have indicated that the relaxation of the corpus cavernosal smooth muscle cells, which is mediated by both non-adrenergic, non-cholinergic neurons and by cholinergic mechanisms, is caused by NO and its second messager, cGMP [4,5]. Sildenafil (ViagraTM) is a potent and competitive inhibitor of the PDE5 [6,7], the predominant isoenzyme in the human corpus cavernosum which is responsible for degradation of cGMP. As such, sildenafil will enhance relaxation of the corpus cavernosal smooth muscle, which in turn increases blood flow into the cavernosal spaces, thus leading to increased intracavernosal pressure, a key factor for penile erection [8].
Studies in vitro have shown that sildenafil is selective for PDE5 (>80-fold for PDE1, >1000-fold for PDE2, PDE3 and PDE4) [9]. The approximately 4000-fold selectivity for PDE5 versus PDE3 is important, because PDE3 is involved in control of cardiac contractility and renal vascular tone [10]. Sildenafil is only 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina [9], this is thought to be the basis for colour vision abnormalities observed with higher doses of sildenafil. Pharmacokinetically, sildenafil is rapidly absorbed after oral administration with bioavailability of about 40%, the time for maximum plasma concentration is 30 to 120 min (median 60 min). It is 96% bound to plasma protein and eliminated predominantly by hepatic metabolism with a half-life about 35 h [9].
For most patients, the recommended dosing regimen is 50 mg taken 1 h before sexual activity with maximum dosing frequency once per day. In general, sildenafil citrate is well tolerated with the adverse reactions like headache, flushing, dyspepsia, nasal congestion, abnormal colour vision, etc. all less than 20% [2,3], and doses up to 800 mg/day in healthy volunteers show no other side effect. However, 100 mg sildenafil produced an average decrease of less than 10 mmHg of systemic blood pressure in normal subjects, and there is a contraindication for combined use of sildenafil and organic nitrates, because sildenafil was shown to potentiate the hypotensive effects of nitrates. Our patient took 200 mg ViagraTM in 2 consecutive days, and his erection persisted for 45 h after the last dose. This sign indicated that his vasodilatation was maintaining for hours. Because there are sporadic cases shown priapism following the use of sildenafil (personal communication), the haemodynamics and optimal dosage of sildenafil in Orientals need further investigation.
References
Medical Director and Nephrologist, Pfizer Inc
Sir,
I refer to the letter by Chang et al. [I] in which they report a temporal association between the ingestion of two consecutive doses of sildenafil 1 00 mg by a healthy subject and his presentation several days later with symptoms of acute renal failure which resolved without treatment.
There are several important pieces of information that are unknown about this case and other features that are puzzling. Firstly the authors do not state why this patient was prescribed sildenafil (erectile dysfunction at his age without a predisposing factor is unusual), nor whether during the period he took sildenafil he took any other pharmacological agents, either medicinal or non-prescribed agents such as alcohol or other recreational drugs. Secondly, the subject apparently had no symptoms coincident with the ingestion of Viagra other than a 4-5 h erection. If the authors are postulating that the acute tubular necrosis occurred secondary to low systemic blood pressure it would be very unusual for this not to be associated with symptoms of dizziness, fatigue or syncope at the same time. The occurrence of bilateral flank pain and dysuria several days after ingestion of sildenafil also seems inconsistent with an acute event of hypotension. The authors imply that the duration of a systemic haemodynamic effect is likely to be similar to the duration of erection. This is not correct as haemodynamic and erectile effects may be dissociated and an erection is only likely to occur and be maintained if there is sexual stimulation leading to neural release of NO in the corpus cavernosum. The authors imply that phosphodiesterases, especially type 111, might affect 'renal vascular tone' (which is not found in their cited reference [3]) but, as they note, Viagra inhibits type V with 4000-fold greater specificity than type 111. Actually, phosphosdiesterase inhibitors have been shown in rats to accelerate recovery from acute tubular necrosis [2].
With respect to experience in the Asian population, doubleblind, placebo-controlled clinical trials have thus far included close to 400 patients receiving Viagra, many of them receiving 100 mg doses daily for seven consecutive days. It is important to note that there were no instances of acute renal failure or priapism.
Inevitably, with several million prescriptions for sildenafil citrate having been written in the USA alone since launch, there are bound to be reports of rare medical events that occur in temporal association with sildenafil by chance alone. With individual reports it is almost impossible to exclude or confirm the role a particular agent (in this case sildenafil) in the genesis of the event. Before nephrologists link sildenafil with acute renal failure, we will need to have both more information about this particular case and further evidence from continued monitoring of spontaneous adverse events over time.
References