2005;85(suppl 5) – ABC CARDIOL

Artigo de Pesquisa

Pharmacokinetics of statins

Statins are lipid lowering agents that promote their effects on plasma lipids through the inhibition of HMG-CoA reductase, a crucial enzyme in the cascade of cholesterol synthesis, leading to reduction of tissue cholesterol pool and consequently, to an upregulation of the LDL receptor expression. There are considerable differences among statins regarding some pharmacokinetic properties, such as the coefficient of hydrophilicity, via liver metabolism (especially regarding P450 cytochrome and isoenzymes), plasma half-life and efficacy of serum lipid changes. They may also differ regarding interactions with other drugs that share the same pathway of metabolism. Recently, many pleiotropic effects have been reported with these drugs, such as anti-inflammatory properties, improvement in endothelial function and benefits on hemostasis.

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Statins in chronic renal disease

Soraia R. C. Ferreira et al. Aloísio M. Rocha José Francisco K. Saraiva

Hypertriglyceridemia and low HDL-c are common features in patients with chronic renal failure. Cardiovascular mortality is substantially increased in the presence of chronic renal disease (10-20 times higher). There is evidence from clinical trials with statins suggesting their protective role in the progression of renal disease. In addition, reduced rates of non-fatal myocardial infarction and cardiac mortality were seen after renal transplant in patients receiving fluvastatin. However, a recent study with atorvastatin failed to demonstrate reduction in cardiovascular morbidity and mortality among diabetic patients on hemodyalisis therapy. Ongoing trials will define the precise role of statins in this subset of patients.

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Combination of drugs: statins and niacin

Jairo Lins Borges

Combination of statins with niacin appears to be an attractive association, in the presence of mixed dyslipidemia with low HDL-c levels, when monotherapy is insufficient to achieve target lipid levels. Clinical benefits were observed by the combination of statins with niacin in the FATS, HATS and ARBITER 2 trials, showing attenuation of atherosclerosis development and/or reduction in coronary events following favorable lipid changes. In general, this combination can be well-tolerated. Recommendations for appropriate monitoring of liver and muscle enzymes are important to reduce the rate of side effects. In addition, careful titration of each drug is recommended.

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Hypolipidemic therapy under special conditions: acquired immune deficiency syndrome

Pai Ching Yu et al. Daniela Calderaro Enéas M. O. Lima Bruno Caramelli

Lipid alterations can be observed early among patients with AIDS disease. Commonly, these lipid abnormalities include low HDL-C and modest increase in triglyceride plasma levels. Highly Active Anti-Retroviral Therapy (HAART) in these patients may aggravate the dyslipidemia, with notable increases in triglycerides as well as in LDL-C. There are several mechanisms proposed to explain the mixed hyperlipidemia observed in these subjects, including different steps in lipid metabolism. The importance of the treatment of dyslipidemia became evident with the increased life expectancy and reports of cardiovascular complications in these individuals. There is an insulin resistance state in patients with AIDS disease under treatment with HAART, who present with lypodistrophy, hypertriglyceridemia, low levels of HDL-C. Antiretroviral drugs are metabolized by CYP P450 3A4 and interactions with some statins, especially with simvastatin are expected to occur. Treatment with lipid-lowering agents should be based on lipid profile and coronary risk. For hypertriglyceridemias, fibrates (mainly fenofibrate or bezafibrate) should be the drugs of choice, as well as statins (mainly pravastatin). Combined treatment using fibrates plus statins are recommended for severe mixed hyperlipidemias under very close monitoring for adverse effects.

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Mechanisms of rhabdomyolysis with statins

Maria Eliane Campos Magalhães

Rhabdomyolysis is uncommon, but is a serious side-effect observed following statin use. The occurrence of fatal rhabdomyolysis reported in the USA since the introduction of statins in the market in the late eighties was very rare (0,15 cases per million patients treated per year). However, myopathy, defined as muscle symptoms associated with CK elevation is much more common (1-5%). Mechanism of statin-induced myopathy is not fully understood. Several hypotheses have been proposed: decreased cellular levels of isoprenoids and ubiquinone, increased rates of apoptosis, changes in chloride channels impairing cell-membrane hyperpolarization, and changes in the cell-membrane permeability. Interactions with other drugs, and preexisting metabolic alterations may predispose to myopathy.

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Ezetimibe: pharmacokinetics and therapeutics

Renata G. Araújo et al. Antonio Casella Filho Antonio Carlos P. Chagas

Ezetimibe is an inhibitor of cholesterol absorption that is liver glucuronized after its rapid absorption, and is mobilized to the enterocytes, where together with its metabolites it exerts hypolipidemic effects, avoiding the absorption of cholesterol, through the reduction of specific cholesterol-transporter enzymes in the gut. This drug can be given once daily due to its prolonged plasma half-life, and is usually very well-tolerated. Elimination of ezetimibe and its metabolites is mainly via fecal excretion. In general, the use of ezetimibe alone promotes modest effects on plasma LDL-c, however, when combined with statins, a remarkable change in the lipid profile can be observed.

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Special recommendations for lipid-lowering treatment: efficacy and safety

Tania Leme da Rocha Martinez et al. Helena Maria do Nascimento

Pharmacologic lipid-lowering interventions should be monitored periodically to assess efficacy and safety parameters. Statins are usually well-tolerated drugs and major side effects include increased serum liver and muscle enzymes (AST, ALT, CK). Treatment should be stopped or diminished in case of significant increase of AST or ALT (> 3x ULN), or CK (> 10x ULN). Other lipid lowering agents may also produce hepatotoxicity or myositis, especially in association with statins (fibrates and nicotinic acid) or in presence of metabolic abnormalities (thyroid, liver or renal disorders). Nicotinic acid can also increase glucose and uric acid plasma levels. Laboratory tests might be performed prior to hypolipidemic drug treatment and should be repeated every three months during the first year and then at 6-mo intervals. Shorter intervals should be recommended in individual cases.

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Mechanisms of hepatotoxicity

Marcelo Chiara Bertolami

Liver disease following the use of hypolipidemic drugs has been reported as a cellular damage (increases in AST or ALT enzymes) without cholestatic alterations (bilirubin and or alkaline phosphatase increases). Six mechanisms were proposed for hepatotoxicity : 1. High energy reactions on P450 cytochrome impairing calcium homestasis with rupture of intracellular fibrils and hepatocyte lysis. 2. Impairment of transporter proteins related to the bile acids flux (mechanism proposed for fibrate liver toxicity). 3. Immune reactions due to the formation of metabolites linked to enzymes following liver metabolism of hypolipidemic drugs. 4. Hepatotoxicity by T cells with additional inflammation mediated by neutrophils. 5. Apoptosis mediated by TNF and Fas (immune mediated). 6. Oxidative stress due to damage of intracellular organelles. In addition, advanced age, alcohol in excess, high doses of hypolipidemic drugs, interaction with other drugs, and previous active liver disease might increase liver toxicity.

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Combination of drugs: statins and fibrates

Hermes Toros Xavier

Monotherapy for the treatment of dyslipidemias is commonly insufficient to achieve all lipid targets recommended by current guidelines. Therefore, the use of combined treatment has emerged as a new option in many cases in the last few years. A review of 36 studies in which the combination of statins with fibrates was used revealed 29 cases of rhabdomyolysis with a prevalence of 0,12% in the risk of myopathy. Combination of a statin with genfibrozil appeared to cause more rhabdomyolysis than with newest fibrates (especially when compared with fenofibrate or bezafibrate). Advanced age, diabetes, females, concomitant medications, renal insufficiency, excess in alcohol intake, exercises, trauma and surgery were all associated with higher rates of adverse effects.

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Pharmacology of fibrates

Hermes Toros Xavier

Fibrates are drugs commonly used in hypertriglyceridemias. After their absorption, fibrates are metabolized by the liver, using P450 isoenzymes not shared by statins. However, for some fibrates, such as genfibrozil, an interaction with statins can occur during their liver glucuronidation, or by displacement of free fraction of statins linked to proteins in plasma. Plasma half-life is variable among fibrates (2-80 h). Recently it has been shown that fibrates produce plasma lipid changes mainly by stimulating peroxisome-proliferation activation receptors alpha. Through this action, there is an increase in the transcription of some genes related to lipid metabolism, such as LLP, APOAI, APOAII, ABCA-1, as well as decrease in the expression of APOCIII, and many other actions.

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Pharmacology of niacin or nicotinic acid

Raul D. Santos

Niacin or nicotinic acid is a soluble vitamin with hypolipidemic properties. Niacin reduces triglycerides (20 50%), LDL-c (5-25%), and raises HDL c (15-35%). The Coronary Drug Project study showed that the use of niacin was associated with reduction on coronary events and total mortality, and more recently it has been demonstrated that niacin combined with other hypolipidemic drugs can attenuate the progression of coronary atherosclerosis. Niacin appears to reduce the mobilization of free fatty acids from the adipocytes, acting on specific receptors, diminishing the liver formation of triglyceride-rich lipoproteins. There are two forms of niacin, one of rapid absorption (crystalline), more commonly associated with flushing, and another of extended release, recently reported to be better tolerated. The use of niacin can be associated with dyspepsia, increased plasma levels of liver enzymes and also with a modest elevation in glucose and uric acid plasma levels, at least using the extended-release preparation up to 2g/d.

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Hypolipidemic therapy in special situations: hypothyroidism and liver disease

Fernando H. Y. Cesena et al. Hermes Toros Xavier Protásio L. da Luz

Hypothiroidism is common in the elderly, especially among women. It should be suspected in the presence of classic signals and symptoms, and can be detected by an elevation of serum thyroid stimulating hormone (TSH). Lipid abnormalities in the presence of subclinical hypothiroidsm are of minor importance. However, the importance of specific treatment (hormone replacement) increases with the magnitude of thyroid disturbance. Some hypolipidemic agents can aggravate prior liver disease, however, recent studies have shown that statins might be useful in the presence of steatohepatitis. Some associations of hypolipidemic drugs can increase liver enzymes, and careful monitoring is recommended.

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