OVERVIEW

CASE REPORT

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Nifedipine	21829-25-4	C17-H18-N2-O6

ANNOTATED BIBLIOGRAPHY

References updated: 11 January 2017

• Zimmerman HJ. Calcium channel blockers. Drugs used in cardiovascular disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 646-7.

  (Expert review of hepatotoxicity published in 1999; among calcium channel blockers, diltiazem, nifedipine, bepridil and verapamil have been incriminated in instances of hepatic injury).
• De Marzio DH, Navarro VJ. Calcium channel blockers. Hepatotoxicity of cardiovascular and antidiabetic drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 524.

  (Review of hepatotoxicity of calcium channel blockers mentions that diliazem, nefidipine and verapamil have been implicated in causing cholestatic liver injury in a small number of patients).
• Michel T, Hoffman BB. Calcium channel antagonists. Treatment of myocardial ischemia. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 755-60.

  (Textbook of pharmacology and therapeutics).
• Rotmensch HH, Roth A, Liron M, Rubinstein A, Gefel A, Livni E. Lymphocyte sensitization in nifedipine-induced hepatitis. Br Med J 1980; 281; 976-7. [PMC free article: PMC1714362] [PubMed: 7000285]

  (69 year old man developed fever and jaundice 10 days after starting nifedipine [bilirubin 3.0 mg/dL, AST 56 U/L, Alk P 420 U/L, ESR 95 mm/hr], with rapid resolution and recurrence of fever and Alk P elevations after rechallenge with a single dose).
• Davidson AR. Lymphocyte sensitization to nifedipine-induced hepatitis. Br Med J 1980; 281: 1354. [PMC free article: PMC1714796] [PubMed: 7437797]

  (Letter in response to Rotmensch [1980] with a similar case: 59 year old man developed fatigue 2 weeks after starting nifedipine [bilirubin 3.0 mg/dL, ALT 49 U/L, Alk P 1.5 times ULN], resolving rapidly upon stopping).
• Abramson M, Littlejohn GO. Hepatic reactions to nifedipine. Med J Aust 1985; 142: 47-8. [PubMed: 3965874]

  (Two cases: 65 year old man developed jaundice 6 weeks after starting nifedipine [bilirubin 1.8 mg/dL, ALT 1220 U/L, Alk P 1094 U/L], resolving within 1 month and later tolerating verapamil; 72 year old man developed fever and arthralgias 6 weeks after starting verapamil [bilirubin normal; ALT 100 U.L, Alk P 457 U/L], resolving in a few weeks).
• Welch HG, Lazar B, Gresser J, McMahon BJ. Nifedipine-induced hepatitis. Alaska Med 1986; 28:11-2. [PubMed: 3717520]

  (50 year old woman with myocardial ischemia developed AST elevations [31 rising to 361 U/L] within 4 days of starting nefidipine, with no change in bilirubin [1.0 mg/dL] and rapid resolution when it was stopped).
• Kiire CF, Rutherford D. Nifedipine-associated jaundice: a second case. East Afr Med J 1986; 63: 560-1. [PubMed: 3792245]

  (75 year old man developed jaundice and abdominal pain 2 weeks after starting nifedipine [bilirubin 3.5 mg/dL, AST 53 U/L, Alk P 139 U/L], resolving within 2 months of stopping).
• Richter WO, Schwandt P. Serious side effects of nifedipine. Arch Intern Med 1987; 147: 1852. [PubMed: 3662717]

  (69 year old woman developed marked Alk P elevations [943 U/L] with normal bilirubin [1.5 mg/dL], with no change after stopping prazosin and allopurinol, but prompt decrease after stopping nifedipine and recurrence on inadvertent rechallenge [Alk P 529 U/L]).
• Shaw DR, Misan GM, Johnson RD. Nifedipine hepatitis. Aust N Z J Med 1987; 17: 447-8. [PubMed: 3435325]

  (80 year old woman developed nausea and abdominal pain 4 days after starting nifedipine and having an episode of shock [bilirubin 2.0 mg/dL, AST 1065 U/L, LDH 1190 U/L, Alk P 352 U/L], resolving within 8 weeks).
• Biour M, Grange JD, Barbare JC, et al. [Hepatic involvement due to nifedipine. Description of a case and review of the literature] Therapie 1987; 42: 301-3 [French]. [PubMed: 3660324]

  (60 year old man developed jaundice 10 days after starting nifedipine [bilirubin 16.1 mg/dL, ALT 36 times ULN, Alk P 2.3 times ULN], resolving within one month of stopping).
• Babany G, Uzzan F, Larrey D, et al. Alcohol-like liver lesions induced by nifedipine. J Hepatol 1989; 9: 252-5. [PubMed: 2809167]

  (78 year old woman taking nifedipine developed mild elevations of Alk P [1.5 times ULN] and GGT [5.3 times ULN] and underwent liver biopsy that showed steatohepatitis and Mallory bodies, and had ascites 6 months later despite normal enzymes; repeat biopsy showed fibrosis and fat without Mallory bodies; no follow up after stopping nefidine was given).
• Sawaya GF, Robertson PA. Hepatotoxicity with the administration of nifedipine for treatment of preterm labor. Am J Obstet Gynecol 1992; 167: 512-3. [PubMed: 1497061]

  (25 year old pregnant woman developed early uterine contractions and was treated with terbutaline and nifedipine whereupon ALT rose to as high as 845 U/L with no symptoms or jaundice, falling to normal 2 weeks after delivery and stopping nifedipine).
• Basile C, Mascia E. Dihydropyridine calcium channel blockers: a rare and reversible cause of hepatotoxicity with cholestasis in a CAPD patient. Nephrol Dial Transplant 1999; 14: 2776-7. [PubMed: 10534534]

  (76 year old man developed jaundice 3 years after starting nifedipine [bilirubin 6.2 mg/dL, ALT 79 U/L, Alk P 955 U/L], resolving within 1 month of stopping and recurring within 6 weeks of starting amlodipine [bilirubin 6.3 mg/dL, ALT 74 U/L, Alk P 398 U/L] resolving in 3 weeks: Case 1).
• Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366-72. [PubMed: 10972368]

  (Randomized clinical trial of nifedipine versus diuretics for an average of 3 years in 6321 patients reported similar outcomes and no differences in adverse events; liver toxicity not mentioned).
• Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. [PubMed: 15390328]

  (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, but none were attributed to calcium channel blockers).
• Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. [PubMed: 16165719]

  (Summary of 25 years of adverse drug reaction reporting in Sweden identified 103 cases of drug induced acute liver failure; only one case was possibly linked to a calcium channel blocker: felodipine).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, calcium channel blockers were implicated as a sole agent in 2 cases [1 amlodipine, 1 verapamil] and as one of several agents in 2 cases [both amlodipine]).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were linked to calcium channel blockers).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 114: 1419-25. PubMed Citation (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but no cases were attributed to calcium channel blockers).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases; one case was attributed to verapamil, but none were linked to diltiazem or other calcium channel blockers).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 39 [4%] were due to antihypertensive agents including 4 due to calcium channel blockers [amlodipine in 1 and verapamil in 3 instances], but none to diltiazem).