Sildenafil-Associated Hepatoxicity: a Review of the Literature

European Review for Medical and Pharmacological Sciences 2017; 21 (1 Suppl): 17-22 Sildenafil-associated hepatoxicity: a review of the literature

S. GRAZIANO1, A. MONTANA2, S. ZAAMI3, M.C. ROTOLO1, A. MINUTILLO1, F.P. BUSARDÒ3, E. MARINELLI3

1Drug Abuse and Doping Unit, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy 2Laboratory of Forensic Toxicology, Department “G.F. Ingrassia”, University of Catania, Catania, Italy 3Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy

Abstract. – Sildenafil citrate (Viagra®) is a Introduction vasoactive agent available worldwide since 1998 for the treatment of male erectile dysfunction. It Sildenafil citrate (Viagra®) is a vasoactive is a selective phosphodiesterase type 5-enzyme agent, which became available worldwide in 1998 inhibitor able to potentiate the downstream ef- for the treatment of male erectile dysfunction. fects of nitric oxide on smooth muscle relaxation and vasodilation through its effects on the The drug acts by inhibiting the phosphodiester- cyclic guanosine monophosphate (c-GMP) path- ase type 5 (PDE5) enzymes that specifically way in the erectile tissue of the penis. When degrade the cyclic guanosine monophosphate sildenafil is orally administered, it is rapidly ab- (cGMP), responsible for the nitric oxide induced sorbed with a maximum plasma concentration smooth muscle relaxation and vasodilatation1. achieved within 1 h and has a terminal half-life PDE5 is found in particularly high concentration of between 3 to 6 h. The drug is extensively and in the corpus cavernosum, the erectile tissue rapidly metabolized by the liver, primarily by of the penis; it is also found in the retina and the CYP3A4 enzyme. Although the drug is well tolerated, specific adverse events have been vascular endothelium. Increased cGMP concen- observed, like flushing, headaches, dyspepsia, tration results in vasodilation and an increased and visual disturbances. Liver toxicity related inflow of blood in penis tissue which facilitates to sildenafil consumption has been considered the generation and maintenance of an erection2,3. a very rare event. However, in the last decade, Recently, it has been found that the vasodilatory some cases of sildenafil-associated hepatotox- effects of sildenafil also help to reduce symp- icity have been reported. Furthermore, some he- toms of pulmonary arterial hypertension and it patic intoxications have been reported after the 4-6 intake of “natural” or “herbal” aphrodisiac sup- is thus also applied for this medical indication . plements sold through Internet, sex shops, so- Sildenafil is available as film-coated tablets, oro- cial media, and by word-of-mouth found to con- dispersible tablets, powder for oral suspension, tain sildenafil and other phosphodiesterase type and in solutions for injection. Its therapeutic 5 (PDE-5) inhibitors. Studies investigating a pos- dosage ranges from 10 to 100 mg/day and is well sible link between sildenafil use and liver dam- tolerated7. Common side effects include head- age are limited, and the underlying mechanism aches, flushing, back pain, visual disturbances, responsible for hepatotoxicity is still missing. nasal congestion, and tachycardia. Sildenafil is Studies in animals evidence that the hematopoietic function of the liver may have severely been contraindicated in patients using nitrates and, to affected as a result of a probable toxic effect of a lesser extent, alpha-blockers since it improves sildenafil. Here, the studies reporting liver toxic- the hypotensive effects of these drugs, leading to ity by sildenafil in humans and in animals are re- serious cardiovascular effects, like myocardial is- ported and discussed. chemia and stroke8,9. Sildenafil results to be completely metabolized in the liver by cytochrome Key Words: Sildenafil, Hepatotoxicity, Liver toxicity. P450 microsomal isozymes 3A4 (major route) and 2C9 (minor route)10,11. It has been shown that

Corresponding Author: Francesco Paolo Busardò, MD; e-mail: [email protected] 17 S. Graziano, A. Montana, S. Zaami, M.C. Rotolo, A. Minutillo, F.P. Busardò, E. Marinelli some hepatic conditions (i.e. hepatic congestion, the cyclic guanosine monophosphate (c-GMP) hepatic cirrhosis, elevated hepatic pressure) can pathway in the corpora cavernosa, as well as the affect sildenafil clearance leading to an increased pulmonary vasculature and the retina22,23. When drug concentration inside the body12. Liver tox- sildenafil is orally administered to healthy - vol icity related to sildenafil consumption has been unteers, it is rapidly absorbed and metabolized, considered a very rare event. However, in the with a maximum plasma concentration achieved last 10 years, some cases of sildenafil-associated within 1 h and a terminal half-life of between 3 hepatotoxicity have been reported13-18. It is well to 6 h10,11. Its absolute oral bioavailability is about known that sildenafil can also be easily purchased 40%. Sildenafil is cleared almost exclusively by from illegal dealers (e.g. medicines and drugs hepatic metabolism. The primary metabolite is of abuse pushers) or through Internet websites the N-desmethyl sildenafil, UK-103, 320, which without medical prescription, mandatory for this has a similar PDE-5 specificity profile, but with drug. Moreover, it has been identified in counter- about half the potency on the parent drug. More- feit medications and/or herbal supplements sold over, its plasma concentrations reach about 40- as a “natural” aid in erectile dysfunction19 and 50% of those of the parent drug, following oral can be used for recreational purposes in the be- administration. lief that the drug increases libido and improves sexual performance also in healthy individuals. Sildenafil-Associated It is possible to speculate that cases of unexpect- Hepatotoxicity Reports ed intoxications hepatic dysfunctions due to the International literature concerning sildena- illicit, not declared, and/or unaware sildenafil fil-associated liver toxicity in humans is scarce: consumption have been completely missed20,21. In up to now only five studies exist reporting cases this paper, we give an overview of the reported of hepatotoxicity secondary to sildenafil con- cases of sildenafil-associated hepatotoxicity and sumption. of the studies that have investigated the effects of The first case of sildenafil-associated hepatic sildenafil use and liver damage. toxicity was described in 2003 in a 65-year-old man, who assumed sildenafil (50 mg Viagra® 1-2 times/month) under medical supervision17. Materials and Methods Although the subject had taken the medication for about 1 year, he had never shown any The identification of scientific articles was sildenafil-associated side effects, when sud- performed in main databases as Pubmed, Biosis denly 24 h after the intake of a Viagra pill, he Medline, Cochrane Central, Scopus, Web of Sci- presented constipation followed by epigastric ence, Science Direct, EMBASE, up to November pain, 38.5°C body temperature, and 2 days later 2016 using the following keywords: “sildenafil”, brown urine. Physical examination showed an “Viagra”, “liver”, “hepatotoxicity”, “liver dam- enlarged tender liver together with increased age”, “hepatic dysfunction”, “liver harm”, “liver levels of serum aspartate aminotransferase toxicity”, “liver failure”, “liver injury”. The main and alanine aminotransferase (AST and ALT keywords “sildenafil” and “Viagra” were indi- respectively), gamma-glutamyl transferase vidually searched and then again in association (GGT), and alkaline phosphatase (ALP) liver to each of the others. The papers not suitable for functionality enzymes. These values normal- the purpose of the review were excluded. Papers ized in the following 2 (GGT) and 4 (AST, were screened independently by three co-authors ALT, and ALP) months, respectively. Accord- and included if selected at least by two of them. ing to the criteria for drug-induced liver dis- orders24, a sildenafil-associated hepatotoxicity was suggested as being probably related to an Results ischemic mechanism, since the patient was also under medical treatment for cardiac insuffi- Sildenafil Mechanism of Action ciency with a calcium antagonist. Immediately and Metabolism after this first case, a sildenafil-associated hep- As above reported, sildenafil is a selective atitis was described18 in a 56-year-old man with PDE-5 inhibitor able to potentiate the down- no liver disease risk factors, who took sildenafil stream effects of nitric oxide on smooth muscle (Viagra®, 25 mg) in two different occasions at relaxation and vasodilation through its effects on 48 h of delay, between the first and the sec-

18 Sildenafil-associated hepatoxicity: a review of the literature ond. After about one month, he presented dark fronted with the analytical findings, the patient urine, jaundice, increased levels of serum AST, finally admitted he used sildenafil (50 mg, tab- ALT, GGT, ALP and total bilirubin. A liver bi- lets) a few times in the previous three months. opsy showed anomalies associated with choles- Clinical conditions and hepatic functions were tatic hepatitis. Tests for anti-hepatitis C virus found to be normal within 3 months of the ad- antibodies, IgM anti-hepatitis A virus, IgM and mission. On the basis of the liver enzyme and IgG anti-hepatitis E, and tests for Epstein-Barr histological patterns, the case was classified as and Cytomegalovirus, were all negative. An- a hepatocanalicular injury, linked to a probable ti-mitochondrial, anti-nuclear, anti-reticulum immune-mediated mechanism. Another case of endoplasmatic, and anti-smooth-muscle anti- liver damage was described in 2009, involving a bodies were also absent in serum. Doppler healthy 58-year-old man with jaundice, pruritus, echocardiography showed no alterations. The and malaise14. The laboratory values showed patient clinically normalized within about one increased levels of liver enzymes and the lapa- month after the first onset of clinical signs, ex- roscopic examination revealed a green, enlarged cept for the total bilirubin that decreased slowly liver, with a smooth surface without nodularity. falling by 50% within 180 days. It was hypoth- Liver biopsy revealed features of intrahepatic esized that the sildenafil-associated hepatitis cholestasis, with marked bile stasis in canaliculi was due to an immune-allergic mechanism, around the pericentral area and a minimal cel- since the liver biopsy showed a high number of lular necroinflammation in the portal area. All eosinophils. In 2005, a case of acute liver tox- the possible causes of hepatitis, such as viral icity was observed in a 49-year-old man with infection, metabolic diseases, and autoimmune no risk factors other than medical treatment etiology, were excluded. The patient initially de- for diabetes (glibenclamide), prescribed with clared no history of recent drug use or excessive Viagra® (50 mg/day) for erectile dysfunction16. alcohol intake. However, he finally confessed to After 4 weeks he showed a right hypochondrial having taken sildenafil 50 mg one month before pain without fever, jaundice, palpable hepato- symptom onset. The drug was obtained from a megaly and with no signs of encephalopathy. friend and used, as self-declared, for “recrea- Blood analysis was characterized by normal tional” purposes. Clinical conditions improved GGT, ALP and total bilirubin values, but with rapidly without any medical treatment and were increased AST and ALT. Clinical condition and found to be normal four months after symptom liver enzyme values returned to normality in onset. A diagnosis of probable sildenafil-in- 20 days after sildenafil withdrawal, suggesting duced cholestatic hepatotoxicity was formulat- a diagnosis of sildenafil-associated hepatotox- ed, but the causal relationship between sildenafil icity from unknown mechanisms. The antidia- use and liver damage remained uncertain. betic drug (glibenclamide) was excluded from the hepatitis genesis, since the altered hepatic Hepatotoxicity Induced By a Herbal condition improved without withdrawing that Supplement Containing Sildenafil drug. A 59-year-old healthy man was admitted In the past years, sildenafil and other phos- to the hospital in 2008 because of jaundice, phodiesterase Type 5 (PDE-5) inhibitors have pruritus, anorexia, nausea, fatigue, weight loss been detected in the majority of “natural” or and a tender, palpable liver15. He did not declare “herbal” aphrodisiac supplements sold through any medication, dietary supplement or xenobi- Internet, sex shops, social media, and by word- otic administration in the previous days. Serum of-mouth. A Dutch study showed that more analysis showed increased total bilirubin, ALP, than three-quarters of herbal supplements used AST, and ALT values. Liver biopsy showed to enhance sexual potency contain therapeutic a severe cholestasis in the sinusoids and a doses of sildenafil or its analogues19. However, large number of eosinophilic granulocytes in up to now, only one report has been published the portal field and sinusoids. Renal function, about liver toxicity caused by the consumption electrolytes, hematologic parameters, serum al- of an adulterated “Chinese herbal” supplement, bumin, and prothrombin time were all normal. called “Tiger King” commercialized for sexual Serology for hepatitis A, B, and C, cytomegal- enhancement13. A 65-year-old male was admit- ovirus and Epstein-Barr virus and auto-anti- ted to hospital after a week of malaise and bodies (antinuclear, antimitochondrial, and anti weakness. He had a history of cirrhosis and smoot-muscle antibodies) were negative. Con- acute hepatitis, and referred occasional mild

19 S. Graziano, A. Montana, S. Zaami, M.C. Rotolo, A. Minutillo, F.P. Busardò, E. Marinelli alcohol consumption. One month before admis- impairment treated with sildenafil experienced sion, he was treated for community-acquired a worsening of their alkaline phosphatase, AST, pneumonia. He denied the use of other drugs or ALT, or total bilirubin values; however, none of herbal and dietary products. Physical examina- these alterations was attributed to sildenafil. A 77 tion revealed chronic signs of cirrhosis and acute % of men with hepatic impairment experienced hepatitis. Laboratory analysis showed increased sildenafil-related adverse effects (mild to severe) AST and ALT values, and a slight elevated level compared with 37% of placebo patients with he- of total bilirubin. During hospitalization, the pa- patic impairment. tient finally admitted the use of a “natural herbal A study30 published in 2011 investigated the medicine” for sexual enhancement called “Tiger histological effects of sildenafil citrate on the King” purchased from a local dealer and taken liver of adult Wistar rats treated daily with 3 two and half weeks before symptoms onset (half different sildenafil dose concentrations for 6 tablet/time, 2-3 times/week). Chemical analy- weeks. Histological results showed a dilatation sis of the product evidenced the presence of of the central vein of the liver with lysed red sildenafil, and it was calculated that the patient blood cells and a cytoarchitectural distortion assumed a dose of about 20-35 mg each time. of the organ; increased levels of liver enzymes Within three days after hospital admission, the were also observed. The authors suggest that the patient’s clinical status and liver function im- hematopoietic function of the liver may have proved without any specific treatment. His liver been highly affected as a result of the probable function tests normalized thirty days post dis- toxic effect of sildenafil. Another study by Nna charge. According to the Naranjo adverse drug et al31 reported that chronic administration of reaction scale25 and the Roussel Uclaf Causality sildenafil in adult Wistar rats could cause sig- Assessment Method (RUCAM)26 the probability nificant alteration in liver functions as revealed of association of hepatotoxicity with sildena- in the increased serum concentration of liv- fil was “possible” and “probable” respectively er enzymes and bilirubin; moreover, following (Naranjo score of 4, RUCAM score of 7). Al- sildenafil withdrawal, only a poor reversal of though the mechanism underlying liver toxicity hepatotoxicity was observed. Jarrar et al32 found remained unknown, the authors proposed that in that subchronic exposure to sildenafil overdoses the patient the pre-existing liver damage had led reveals significant biochemical and structural to a major susceptibility to sildenafil-associated (i.e. hepatocytes nuclear alterations, necrosis, hepatotoxicity. bile duct hyperplasia, inflammatory cells infil- tration, hepatic vessels congestion) alterations Sildenafil and Liver Damage in the hepatic tissues that might affect liver The use of sildenafil citrate as a treatment for functions. erectile dysfunction was approved in March 1998 by the United States Food and Drug Adminis- tration, and in September 1998 by the European Conclusions Medicines Agency. The safety profile of sildenafil has been investigated in over 120 manufactur- Although the published literature suggests a er-sponsored clinical trials and other independent possible link between hepatotoxicity and the use studies; moreover, some comprehensive reviews of sildenafil, the mechanism underlying liver tox- have also been published27,28. Common silde- icity is still unknown. The few cases reported to nafil-related adverse effects include headaches, date suggest that sildenafil-associated liver dam- facial flushing, nasal congestion, and dyspepsia, age is a rare but not impossible event. However, and are mild to moderate. As previously de- it should be considered that the manifestations scribed10,11 sildenafil is extensively and rapidly of drug-induced hepatotoxicity are highly var- metabolized by the liver, primarily by CYP3A4 iable, ranging from asymptomatic elevation of enzymes. A recent review involving 67 dou- liver enzymes to fulminant hepatic failure, and ble-blind placebo-controlled trials and post-mar- so it could be possible that some sildenafil-asso- keting safety database29 showed that in males with ciated hepatotoxicity cases may have been totally moderate hepatic impairment the sildenafil safety missed, especially when sildenafil consumption profiles are similar to those in males with erectile is not declared, illicit, and/or unaware (i.e. in dysfunction and no impairment of hepatic func- case of counterfeit herbal products for erectile tion. Specifically, only 23% of men with hepatic dysfunction)20,21,33.

20 Sildenafil-associated hepatoxicity: a review of the literature

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