Statins adverse effects

Over the last decade, several studies in tens of thousands of patients have revealed that lowering cholesterol, specifically lowering LDL cholesterol with statins, is effective for both primary and secondary prevention of IHD-related events. Statins shown to decrease morbidity and mortality associated with IHD include lovastatin, simvastatin, pravastatin, and atorvas-tatin.22,23 A recent meta-analysis showed that the risk of major adverse cardiac events is reduced by 21% with the use of statins in patients at high risk for IHD-related events.23... 

Once absorbed, ezetimibe undergoes extensive glucuronida-tion in the intestinal wall to the active metabolite (ezetimibe glucuronide). Ezetimibe and the active metabolite are entero-hepatically recirculated back to the site of action, which limits systemic exposure and may explain the low incidence of adverse effects (Table 9-9). Ezetimibe alone or with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in LFTs. Currently, clinical trials designed to determine ezetimibe s effects on CHD morbidity and mortality have not been completed. The time until maximum effect on lipids for ezetemibe is generally 2 weeks. 

Resins are moderately effective in lowering LDL cholesterol but do not lower triglycerides (Table 9-8). Moreover, in patients with elevated triglycerides, the use of a resin may worsen the condition. This may be due to a compensatory increase in HMG-CoA reductase activity and results in an increase in assembly and secretion of VLDL. The increase in HMG-CoA reductase activity can be blocked with a statin, resulting in enhanced reductions in serum lipids (see section on combination therapy). Resins reduce LDL cholesterol from 15% to 30%, with a modest increase in HDL cholesterol (3% to 5%) (Table 9-8). Resins are most often used as adjuncts to statins in patients who require additional lowering of LDL cholesterol. Since these drugs are not absorbed, adverse effects are limited to the gastrointestinal tract (Table 9-9). About 20%... 

Oral colchicine causes dose-dependent GI adverse effects (nausea, vomiting, and diarrhea) in 50% to 80% of patients before relief of the attack. Non-GI adverse effects include neutropenia and axonal neuromyopathy, which may be worsened in patients taking other myopathic drugs (e.g., statins) or in those with renal insufficiency. Colchicine should not be used concurrently with macrolide antibiotics (especially clarithromycin) because reduced biliary excretion may lead to increased plasma colchicine levels and agranulocytosis. 

Constipation occurs in fewer than 10% of patients taking statins. Other adverse effects include elevated serum aminotransferase levels (primarily alanine aminotransferase), elevated creatine kinase levels, myopathy, and rarely rhabdomyolysis. 

Like all drugs, the statins have their adverse effects. Hepatotoxicity is occasionally seen and potentially serious muscle problems arise rarely. See your doctor. 

Action HMG-CoA reductase inhibitor Dose 5-40 mg PO daily max 5 mg/d w/cyclosporine, 10 mg/d w/gemfibrozil or CrCl <30 mL/rain (avoid Al-/Mg-based antacids for 2 h after) Caution [X, /-] Contra Active liver Dz, unexplained T LFT Disp Tabs SE Myalgia, constipation, asthenia, abd pain, N, myopathy, rarely rhabdomyolysis Interactions T Effects OF warfarin T risk of myopathy W/ cyclosporine, fibrates, niacin, statins EMS T Effects of warfarin concurrent EtOH use can T risk of liver tox Asian pts have an T risk of adverse effects OD Unlikely to cause life-threatening Sxs... 

With growing interest in the use of statins in women, the question naturally arises whether hormonal replacement could have any effect on their efficacy or safety. Data from the HERS (conducted in women with cardiac disorders) seem to have shown that there is no interaction (37). Estrogen replacement itself resulted in a significant increase in the early risk of primary events in women who did not use statins but not in statin users. Adjustment for statin use after randomization showed no adverse effect of estrogen on the efficacy of statins, in terms of either cardiovascular events or mortality. 

In other respects, the adverse effects of cerivastatin are similar to those of other statins (3), and a pooled analysis of studies of cerivastatin 100-400 micrograms/day taken for at least 8 weeks showed no differences in drug-related adverse events between cerivastatin and placebo (4). There was no association between plasma transaminase or creatine kinase activities and cerivastatin dosages. 

The adverse effects of the statins are mostly limited to slight increases in liver and muscle cnzym cs in the blood. Hypersensitivity reactions are very rare. There is no evidence of tumor-inducing effects. Second-generation effects are suspected, and statins should not be used during pregnancy. 

The adverse effects of statins have been reviewed in the light of the ever increasing dosages that are being used to lower LDL cholesterol to a minimum (2). In another review high doses of atorvastatin and simvastatin were specially emphasized (3). 

In a series of seven cases of neuropathy, all were axonal peripheral neuropathies and both thick and thin nerve fibers were affected (10). No cause of peripheral neuropathy other than statin treatment could be identified. In this series at least four of the cases were irreversible, probably due to long exposure to statins (4—7 years versus 1-2 years in previous reports). Besides an effect on ubiquinone, interference with cholesterol synthesis may alter nerve membrane function, since cholesterol is a ubiquitous component of human cell membranes. Neuropathy has not been observed in extensive long-term trials of lipid-lowering drugs. It could be due to patient selection, a low frequency of the adverse effect, or lack of attention to symptoms of peripheral neuropathy. The observed association may also not be causal. 

This case suggests that acute polyradiculoneuropathy may represent a rare but serious adverse effect of statin treatment. The pathophysiology of acute neuropathy on statin exposure is unknown a hypersensitivity reaction resulting in an immune-mediated process has been suggested. It is possible that this patient had relapsing Guillain-Barre syndrome unrelated to the use of statins. 

Emerging data associate statins with a reduced risk of Alzheimer s disease however, two women had significant cognitive impairment temporally related to statin therapy (18). One took atorvastatin, and the other first took atorvastatin then simvastatin. Cognitive impairment and dementia as potential adverse effects associated with statins has been reviewed (17). 

Adverse effects of statins on the skin are rare, although statins can affect cutaneous lipid content. A series of skin reactions have been described in patients using statins (35). 

Rhabdomyolysis is a problem with several lipid-lowering drugs (SEDA-13, 1325 SEDA-13, 1328 SEDA-13, 1330 SEDA-19, 409), especially when they are used in combination (37). In individuals with pre-existing renal insufficiency this can lead to an earlier need for chronic dialysis (38). All statins can cause myopathy and rhabdomyolysis, but not all statins are alike. For example, the evidence to date, based on almost 2 decades of experience, points to an extremely low risk of myopathy and rhabdomyolysis with lovastatin, and lovastatin 20 mg tablets are being considered for non-prescription availability in several countries (39). Furthermore, muscle adverse effects do not necessarily occur after a change from one statin to another (40). Interactions between various hypolipidemic drugs and other drugs also sometimes cause rhabdomyolysis (SEDA-18, 426). For instance, itraconazole markedly increases plasma concentrations of lovastatin, and in one subject plasma creatine kinase was increased 10-fold within 24 hours of administration of this combination (41). 

In 2006 the National Lipid Association s Statin Safety Assessment Task Force concluded that chronic liver disease and compensated liver disease are not contraindications to the use of statins, but that they are contraindicated in decompensated disease or liver failure [2, 3] see Hepatic Adverse Effects. 

All the statins have been variously implicated in muscle-related adverse drug reactions such as myalgia, myopathy and rhabdomyolysis, which are thought to occur as a direct effect of HMG GoA-reductase inhibition in a dose-dependent marmer [30]. There have been fatalities. If patients have increased exposure to a drug due to a reduction in first-pass or subsequent metabolism by hepatocytes, these adverse effects are more likely to occur. 

STATINS GRAPEFRUIT JUICE t levels with simvastatin slight rise with atorvastatin. t risk of adverse effects such as myopathy Constituent of grapefruit juice inhibits CYP3A4-mediated metabolism of simvastatin Patients taking simvastatin and atorvastatin should avoid grapefruit juice... 

STATINS PROTON PUMP INHIBITORS Possible T efficacy and adverse effects of atorvastatin Inhibition of P-gp, reducing first-pass clearance Monitor closely... 

PROTEASE INHIBITORS LOVASTATIN, SIMVASTATIN T risk of adverse effects Inhibition of CYP3A4-mediated metabolism of these statins Avoid co-administration... 

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