Antihyperlipidemic Agents PDF

 PK Absorption of the ingested doses of the reductase inhibitors varies from 40% to 75% with the exception of fluvastatin, which is almost completely absorbed. All have high first-pass extraction by the liver. Most of the absorbed dose...

 PK Absorption of the ingested doses of the reductase inhibitors varies from 40% to 75% with the exception of fluvastatin, which is almost completely absorbed. All have high first-pass extraction by the liver. Most of the absorbed dose is excreted in the bile; 5–20% is excreted in the urine. Plasma halflives of these drugs range from 1 to 3 hours except for atorvastatin (14 hours), pitavastatin (12 hours), and rosuvastatin (19 hours  PK……. Atorvastatin, fluvastatin, and rosuvastatin are fluorine- containing congeners Short-acting statins are given by mouth at night to reduce peak cholesterol synthesis in the early morning. They are well absorbed and extracted by the liver, their site of action, and are subject to extensive presystemic metabolism via cytochrome P450 and glucuronidation pathways. Lovastatin and simvastatin are inactive lactone prodrugs that are hydrolyzed in the gastrointestinal tract to the active β-hydroxyl derivatives, whereas pravastatin has an open, active lactone ring.  Clinical uses of Statins Secondary prevention of myocardial infarction and stroke in patients who have symptomatic atherosclerotic disease (e.g. angina, transient ischaemic attacks, or following myocardial infarction or stroke). Primary prevention of arterial disease in patients who are at high risk because of elevated serum cholesterol concentration In severe drug-resistant dyslipidaemia (e.g. heterozygous familial hypercholesterolaemia), ezetimibe is combined with statin treatment. Contraindicated in pregnancy.  Other actions of Statins…. improved endothelial function reduced vascular inflammation reduced platelet aggregability increased neovascularisation of ischaemic tissue increased circulating endothelial progenitor cells stabilisation of atherosclerotic plaque antithrombotic actions enhanced fibrinolysis inhibition of germ cell migration during development immune suppression protection against sepsis  Adverse Effects of Statins Statins are well tolerated; Have mild unwanted effects including – muscle pain (myalgia), – gastrointestinal disturbance, – raised concentrations of liver enzymes in plasma, – insomnia and rash. More serious adverse effects are rare but include severe myositis (rhabdomyolysis) and angio-oedema. – Myositis is a class effect of statins, occurs also with other lipid-lowering drugs (especially fibrates) and is dose related.3 It is commoner in patients with low lean body mass or uncorrected hypothyroidism.  PK Several fibric acid derivatives (fibrates) are available, including bezafibrate, ciprofibrate, gemfibrozil, fenofibrate and clofibrate. These markedly reduce circulating VLDL, and hence triglyceride, with a modest (approximately 10%) reduction in LDL and an approximately 10% increase in HDL.  PK…. Gemfibrozil is absorbed quantitatively from the intestine and is tightly bound to plasma proteins. – It undergoes enterohepatic circulation and readily passes the placenta. – The plasma half-life is 1.5 hours. – Seventy percent is eliminated through the kidneys, mostly unmodified. – The liver modifies some of the drug to hydroxymethyl, carboxyl, or quinol derivatives. Fenofibrate is an isopropyl ester that is hydrolyzed completely in the intestine. – Its plasma half-life is 20 hours. – Sixty percent is excreted in the urine as the glucuronide, and about 25% in feces.  Therapeutic Uses Mixed dyslipidaemia (i.e. raised serum triglyceride as well as cholesterol), provided this is not caused by excessive alcohol consumption. Fenofibrate is uricosuric, which may be useful where hyperuricaemia coexists with mixed dyslipidaemia. In patients with low high-density lipoprotein and high risk of atheromatous disease (often type 2 diabetic patients;. Combined with other lipid-lowering drugs in patients with severe treatment-resistant dyslipidaemia. – This may, however, increase the risk of rhabdomyolysis.  PK Colestipol, cholestyramine, and colesevelam are useful only for isolated increases in LDL. In patients who also have hypertriglyceridemia, VLDL levels may be further increased during treatment with resins The bile acid-binding agents are large polymeric cationic exchange resins that are insoluble in water. They bind bile acids in the intestinal lumen and prevent their reabsorption. The resin itself is not absorbed  Adverse Effects Ezetimibe does not appear to be a substrate for cytochrome P450 enzymes. Has low incidence of reversible impaired hepatic function with a small increase in incidence when given with a reductase inhibitor. Myositis has been reported rarely