Drugs in dyslipidaemias Dr Sanjeewani Fonseka Department of Pharmacolgy

Atheroma Focal disease of intima Deposition of C in arterial wall

Atheromatous disease myocardial infarction Cerebo vascular accidents

Lipids chy remnant chy Cleared by liver TAG Exo FFA FFA Skeletal, cardiac and adipose tissue Endo Liver - bile (+ cholesterol) Synthesized by liver VLDL LDL Cell membrane HDL

Dyslipidaemias Hypercholesterolaemia Hypertriglyceridaemia Mixed dyslipidaemia

Dyslipidaemias Primary Genetically Cassify according to lipoprotein particle Secondary DM Alcohol Nephrotic CRF Hypothyroidism Liver disease Drugs

Drugs in dyslipidaemias Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids

Drugs in dyslipidaemias Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids

Statins Competitive inhibition of HMG CoA reductase HMG Co A HMG Co A mevalonic acid reductase Reduced C in the liver ↑ Expression of LDL receptor Increased LDL clearance

Activation of sterol regulatory element binding protein 2 (SREBP2) ↑ Expression of gene encoding LDL receptor

Other effects of statins statin cont; Other effects of statins Improve endothelial function Decreased coagulation Decreased inflammation Improved stability of atherosclerotic plaques

Extensive pre- systemic metabolism statin cont; Well absorbed Metabolized in liver Extensive pre- systemic metabolism

Statins ↓ LDL-cholesterol by 25-55% ↑ HDL-cholesterol by 5% statin cont; Statins ↓ LDL-cholesterol by 25-55% ↑ HDL-cholesterol by 5% ↓ triglycerides by 10-35% Given once daily (nocte)

Statins Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin statin cont; Statins Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin

statin cont; Clinical use Primary prevention Secondary prevention

Statins: adverse effects statin cont; Statins: adverse effects Hepatotoxicity Myotoxicity Dyspepsia, abdominal pain, diarrhoea Angioedema

Statins: hepatotoxicity statin cont; Statins: hepatotoxicity Asymptomatic ↑ ALT, AST First 6 months Discontinued if ALT / AST > 3 times the upper limit of normal range

Statins: myotoxicity Pain / tenderness, weakness statin cont; Statins: myotoxicity Pain / tenderness, weakness ↑ CK > 10 times upper limit of normal Reversible ↑ risk with concurrent fibrate therapy, hypothyroidism, renal insufficiency

Drugs in dyslipidaemias Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids

Fibrates Activate peroxisome proliferator-activated receptor-α (PPARα) Heterodimer binds to peroxisome proliferator response elements (PPREs) in the promoter regions of specific genes

Fibrates cont

Gemfibrozil, fenofibrate ↓ LDL-cholesterol by 5-20% Fibrates cont: Gemfibrozil, fenofibrate ↓ LDL-cholesterol by 5-20% ↑ HDL-cholesterol by 10-35% ↓ triglycerides by 20-50%

Fibrates cont Clinical use Mixed dyslipidaemia Low HDL

Fibrates cont Well absorbed Elimination renal

Fibrates: adverse effects Fibrates cont Fibrates: adverse effects Gastrointestinal discomfort Myopathy ↑ liver transaminases Gallstone formation (Gemfibrozil) Displace warfarin from albumin binding sites

Drugs in dyslipidaemias Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids

Bile acid binding resins Cationic polymer resins that bind non-covalently to negatively-charged bile acids in small intestine Enterohepatic circulation of bile acids interrupted causing up-regulation of 7α-hydroxylase in hepatocytes

Bile acid binding resins cont;

Bile acid binding resins cont Increased expression of the LDL receptor Concurrent up-regulation of hepatic cholesterol and triglyceride synthesis

Bile acid binding resins cont Cholestyramine, colestipol ↓ LDL-cholesterol by 15-30% ↑ HDL-cholesterol by 3-5% Triglycerides: no effect or ↑

Decreased absorption of digoxin, warfarin, fat-soluble vitamins Bile acid binding resins cont Not absorbed from GIT Bloating & dyspepsia Decreased absorption of digoxin, warfarin, fat-soluble vitamins Take one hour before or 4 h after colestyramine

Drugs in dyslipidaemias Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids

Niacin Also known as nicotinic acid ↓ LDL-cholesterol by 5 – 25% ↑ HDL-cholesterol 15 – 35% ↓ Triglycerides by 20 – 50%

↓ adipocyte hormone-sensitive lipase activity Niacin cont; ↓ adipocyte hormone-sensitive lipase activity ↓ availability of FFA to liver for TG (VLDL) synthesis ↑ half-life of apoA-I (major apolipoprotein in HDL)

adverse effects Cutaneous flushing & pruritus Niacin cont; adverse effects Cutaneous flushing & pruritus Release of prostaglandins D2 & E2 Prevented by aspirin Extended-release formulations associated with less flushing hyperuricaemia, impaired insulin sensitivity, myopathy

Drugs in dyslipidaemias Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids

Inhibitors of cholesterol absorption Ezetimibe Decreases cholesterol transport from micelles into enterocytes by inhibiting brush border protein NPC1L1 Reduces cholesterol incorporation into VLDL in liver

Inhibitors of cholesterol absorption rapidly absorbed by enterocytes Eliminated in bile Undergoes enterohepatic circulation Clinical benefit uncertain

Drugs in dyslipidaemias Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids

Omega-3 fatty acids Eicosapentaenoic acid (EPA) Docosahexaenoic acid (DHA)

Reduce triglycerides Increase C Benefit - uncertain

Summary Most important hyperlipidaemia is hypercholesterolaemia Most effective drug – statin Drugs reduce risk of MI