Hyperlipidemias: Tiwari A

Tiwari A, Bansal V, Chugh A, Mookhtiar K. · Ranbaxy Research Laboratories, Metabolic & Urology Group, New Drug Discovery Research, Gurgaon-122001, Haryana, India. · Expert Opin Drug Saf. · Pubmed #16907655 No free full text.

Abstract: Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors represent the most successful class of drugs for the treatment of hypercholesterolaemia and dyslipidaemia implicated in the pathogenesis of coronary heart disease and atherosclerosis. However, the popular profile of statins in terms of efficacy has been maligned by its adverse events. The myotoxicity, ranging from mild myopathy to serious rhabdomyolysis, associated with HMG-CoA reductase inhibitors, during treatment of hypercholesterolaemia is of paramount importance. Rhabdomyolysis is a rare but idiosyncratic muscle wasting disorder of different etiologies. Statin-associated rhabdomyolysis causes skeletal muscle injury by self-perpetuating events leading to fatal irreversible renal damage through a series of biochemical reactions. Preferential distribution and action of statins in liver could be the key to minimise myotoxicity concerns. Hepato-specific distribution of statins is governed by various factors such as physicochemical properties, pharmacokinetic properties and selective transporter-mediated uptake in liver rather in extrahepatic cells. The interactions of statins with concomitant drugs of different classes merit attention for their safety profile. Although pharmacokinetic as well as pharmacodynamic interactions have been implicated in pathophysiology of statin-induced muscle wasting, the underlying mechanism is not clearly understood. Besides, pharmacokinetic and phramcodynamic factors, statin-associated myotoxcity may also implicate pharmacogenomic factors. The pharmacogenomics characterised by CYP polymorphism and other genetic factors is responsible for inter-individual variations to efficacy and tolerability of statins. The pathophysiological mechanisms may include statin-induced differences in cholesterol:phospholipid ratio, isoprenoid levels, small GTP binding proteins and apoptosis. However, the present understanding of pathophysiological mechanisms, does not offer a reliable approach to address the same at preclinical level. Although statin-associated myotoxicity affects compliance, quality of life of patient and discontinuation rate, yet the low incidence of myotoxicty including rhabdomyolysis and less severity of commonly occurring myopathy and myalgia do not raise doubts about the clinical efficacy and tolerability of statins. Medical management of myotoxicity seems to be pivotal for the proper compliance of patients with statin treatment. The appropriate and judicious use of drugs would substantially reduce the likelihood of developing clinically important myopathy.

Tiwari A. · Metabolic and Urology Group, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon-122001, Haryana, India. · Drug Discov Today. · Pubmed #16635810 No free full text.

Abstract: Statins are an established therapeutic modality for the treatment of hypercholesterolemia. Although they generally exhibit a good efficacy and tolerability profile, their reputation has been tarnished as a result of reports of myotoxicity and, more recently, observations of proteinuria. The increased incidence of proteinuria with rosuvastatin was of particular concern, and raised questions about the renoprotective actions of statins. Different hypotheses have been put forward to explain the mechanisms of statin-induced proteinuria. The multifarious effects of statins, independent of their effects on cholesterol-lowering, form the basis of such hypotheses. However, rosuvastatin-associated proteinuria is transient and reversible and even at the highest dose did not affect renal function after prolonged treatment. It would appear that clinically relevant proteinuria is not associated solely with rosuvastatin and might represent a minor class effect of statins with a fairly low incidence. However, definitive proof of this assertion will need to be provided by rigorous testing.