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

Synthesizedby liver

LipidsExo

Endo

TAG

FFA FFA

chy remnant Cleared

byliver

VLDL LDL

(+ cholesterol)Liver - bile

Cell membrane

HDL

chy

Skeletal, cardiac and adipose tissue

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

• Improve endothelial function

• Decreased coagulation

• Decreased inflammation

• Improved stability of atherosclerotic plaques

statin cont;

statin cont;

• Well absorbed

• Metabolized in liver

• Extensive pre- systemic metabolism

Statins

• ↓ LDL-cholesterol by 25-55%

• ↑ HDL-cholesterol by 5%

• ↓ triglycerides by 10-35%

• Given once daily (nocte)

statin cont;

Statins

• Lovastatin

• Pravastatin

• Simvastatin

• Fluvastatin

• Atorvastatin

• Rosuvastatin

statin cont;

statin cont;

Clinical use

• Primary prevention

• Secondary prevention

Statins: adverse effects

• Hepatotoxicity

• Myotoxicity

• Dyspepsia, abdominal pain, diarrhoea

• Angioedema

statin cont;

Statins: hepatotoxicity

• Asymptomatic

• ↑ ALT, AST

• First 6 months

• Discontinued if ALT / AST > 3 times the upper limit of normal range

statin cont;

Statins: myotoxicity

• Pain / tenderness, weakness

• ↑ CK > 10 times upper limit of normal

• Reversible

• ↑ risk with concurrent fibrate therapy, hypothyroidism, renal insufficiency

statin cont;

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

Fibrates cont:

• Gemfibrozil, fenofibrate

• ↓ LDL-cholesterol by 5-20%

• ↑ HDL-cholesterol by 10-35%

• ↓ triglycerides by 20-50%

Clinical use

• Mixed dyslipidaemia

• Low HDL

Fibrates cont

• Well absorbed

• Elimination renal

Fibrates cont

Fibrates: adverse effects

• Gastrointestinal discomfort

• Myopathy

• ↑ liver transaminases

• Gallstone formation (Gemfibrozil)

• Displace warfarin from albumin binding sites

Fibrates cont

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 ↑

• Not absorbed from GIT

• Bloating & dyspepsia

• Decreased absorption of digoxin, warfarin, fat-soluble vitamins

• Take one hour before or 4 h after colestyramine

Bile acid binding resins cont

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

• ↓ availability of FFA to liver for TG (VLDL) synthesis

• ↑ half-life of apoA-I (major apolipoprotein in HDL)

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

Niacin cont;

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