Hepatitis atorvastatin

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lactones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A), Atorvastatin has the longest duration of action. 

Contraindications Concurrent use of a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin) in patients with active hepatic disease or unexplained persistent elevations in serum transaminase levels, moderate or severe hepatic insufficiency... 

The answer is d. (Hardman, pp 885-886. Katzung, pp 591-592.) Atorvastatin is a structural analogue of an intermediate formed from the action of HMG-CoA reductase. This could result in a modest decrease in plasma cholesterol. Hepatic cholesterol synthesis may decrease significantly however, nonhepatic tissues increase their rate of synthesis as a compensatory mechanism. The other and perhaps more important effect of the HMG-CoA inhibitors is to increase high-affinity LDL receptors. The plasma LDL is lowered by this action because of an increase in the catabolic rate of LDL and hepatic extraction of LDL precursors. 

Atorvastatin, simvastatin, rosuvastatin Inhibit HMG-CoA reductase Reduce cholesterol synthesis and up-regulate low-density lipoprotein (LDL) receptors on hepatocytes modest reduction in triglycerides Atherosclerotic vascular disease (primary and secondary prevention) t acute coronary syndromes Oral duration 12-24 h Toxicity Myopathy, hepatic dysfunction Interactions CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors... 

A 49-year-old man with pre-existing hepatic pathology took rosiglitazone 4 mg/day for 2 months and 8 mg/day for 5 months (114). He developed a bull face and then edema of the eyelids and neck. He had anorexia and nausea. His serum sodium was 110 mmol/1, potassium 3.3 mmol/1, chloride 81 mmol/1, cholesterol 21 mmol/1, triglycerides 33 mmol/1, and his liver enzymes were raised. Rosiglitazone was withdrawn and he was given saline and potassium, acarbose for his diabetes, spironolactone 200 mg/day for edema, and atorvastatin 10 mg/ day for hyperlipidemia. He improved over 3 weeks. 

A 65-year-old woman developed fatigue, jaundice, and altered liver function tests while taking atorvastatin (20 mg/day for some weeks) (14). On the basis of clinical, serological, and histological findings, a diagnosis of autoimmune hepatitis was made. 

The authors suggested that atorvastatin may have unmasked an underlying autoimmune hepatitis. 

A patient developed atorvastatin-induced severe autoimmune hepatitis and a lupus-like syndrome. Although the drug was immediately withdrawn, the disease persisted and deteriorated to a fulminant form with acute hepatic failure. There was no response to conventional immunosuppression with glucocorticoids and azathioprine. Only the introduction of intense immunosuppressive therapy, as used in solid organ transplantation, led to a complete and sustained recovery. The patient had the HLA haplotypcs DR3 and DR4, which are well-known genetic factors associated with autoimmune diseases. 

Rhabdomyolysis and acute hepatitis have been reported in association with the co-administration of diltiazem and atorvastatin (28). 

Pelli N. Autoimmune hepatitis revealed by atorvastatin. Eur J Gastroenterol Hepatol 2003 15 921 i. 

A 50-year-old woman with previous autoimmune thyroid disease taking atorvastatin developed acute hepatitis when she also was given ezetimibe (4). Further investigations, including liver biopsy, showed a probable drug-induced autoimmune hepatitis. 

Heyningen CV. Drug-induced acute autoimmune hepatitis during combination therapy with atorvastatin and ezetimibe. Ann Clin Biochem 2005 42 402-4. 

HMG CoA reductase inhibitors can be associated with small rises in alanine transaminase activity, but have not been definitely associated with severe morbidity involving altered hepatic function. The results of randomized trials do not suggest that statins in standard doses are hepato-toxic. In none of the large randomized studies in which standard doses were assessed (atorvastatin 10 mg/day, fluvastatin 40-80 mg/day, pravastatin 40 mg/day, simvastatin 20-40 mg/day) was there any clear excess risk of hepatitis or any other serious liver-related adverse events. Long-term large randomized trials have confirmed an excess of persistent rises in transaminases with atorvastatin 80 mg/day compared with lower doses or placebo, and similarly some excess with simvastatin 80 mg/day, but hepatitis and liver failure were not reported (4). 

In a comparison of atorvastatin with pravastatin, of 224 patients taking atorvastatin, two had clinically significant increases in alanine transaminase activity (32). They recovered during the next 4 months, one after withdrawal of atorvastatin and the other after a dosage reduction. Withdrawals due to adverse effects were similar in the two groups. One patient developed hepatitis while taking atorvastatin, but was able to tolerate simvastatin (33). The authors concluded that this adverse effect was not a class effect. Eosinophils in a liver-biopsy specimen pointed to an immunological mechanism. 

Jimenez-Alonso J, Osorio JM, Gutierrez-Cabello F, Lopez de la Osa A, Leon L, Mediavilla Garcia JD. Atorvastatin-induced cholestatic hepatitis in a young woman with systemic lupus erythematosus. Grupo Lupus Virgen de las Nieves. Arch Intern Med 1999 159(15) 1811-2. 

Nakad A, Bataille L, Hamoir V, Sempoux C, Horsmans Y. Atorvastatin-induced acute hepatitis with absence of crosstoxicity with simvastatin. Lancet 1999 353(9166) 1763 1. 

Atorvastatin is readily absorbed after the oral administration. Multiple daily dosages in the form of 2.5-80 mg capsules produce a maximum steady state concentration (Cmax) of 1.95-252 /ig/ml within 1-2 h. The AUC increases in proportion to the dose of atorvastatin, but the increase in Cmax is greater than for the proportional dose. The low systemic availability is attributed to the presystemic clearance in gastrointestinal mucosa and/or hepatic first pass metabolism. Food significantly... 

Hepatic dysfunction due to atorvastatin administration is characterized by a raised serum aspartate (AST) or alanine (ALT) level. The overall frequency of hepatotoxicity with atorvastatin has been estimated at... 

The UK Medicines and Healthcare Products Regulatory Agency (MHRA) data show that several deaths have occurred from hepatotoxicity. Most reports of hepatic adverse drug reactions (ADRs) relate to atorvastatin and simvastatin [36]. There are relatively fewer for pravastatin and fluvastatin. However, this may reflect their ... 

Pelli N, Setti M, Ceppa P, Toncini C, Indiveri F (2003) Autoimmune hepatitis revealed by atorvastatin. Eur J Gastroenterol Hepatol 15 921-924. Sniderman AD (2004) Is there value in liver function test and creatine phosphokinase monitoring with statin use Am J Cardiol 94 30F-4F. Dujovne CA (2002) Side effects of statins hepatitis versus ransaminitis myositis versus CPKitis . Am J Cardiol 89 1411-1413. 

Child-Pugh clinical classification scheme (Table 7.5). Serum albumin concentrations were of greatest predictive value for two of the drugs shown in the table. However, this marker was not correlated with the hepatic clearance of lansoprazole, and a combination of all three laboratory tests was better correlated with hepatic clearance of atorvastatin than was serum albumin alone. Serum concentrations of aspartate aminotransferase (AST) or alanine transaminase (ALT) were not correlated with hepatic drug clearance, as might be expected from the fact that these enzymes reflect hepatocellular damage rather than hepatocellular function. 

Figure 11.9 Different effects of itraconazole and obtained from the previous literature. The details cyclosporin A on the plasma AUC of pravastatin, are described in the Section 11.7.1. BA simvastatin, and atorvastatin [210, 221-224], bioavailability, Fa Fg fraction of dose absorbed The fold-increase in the plasma AUC of statins from the small intestine to the portal vein, Fh was expressed after coadministration of hepatic availability,...

---