Dr Heethal Jaiprakash

Introduction
Hyperlipidemia can be due to single inherited gene defect in lipoprotein metabolism or more commonly a combination of genetic and life style modifications Drugs which lower the levels of lipids and lipoproteins in blood The primary goal of cholesterol lowering agents is to decrease the LDL level
Dr Heethal Jaiprakash 2

Metabolism of Chylomicron
Intestine
Intestinal cell B48 Extra hepatic tissue

B48

Adipose tissue

Liver

Dr Heethal Jaiprakash

Functions of VLDL, LDL & HDL

LDL
LDL B100

Extra hepatic v tissue

VLDL E, C, Liver B100

HDL LACT

IDL

HDL A1
LCAT

Adipose tissue

HDL

Muscle

Dr Heethal Jaiprakash

Type I ( Familial Hyperchylomicronemia) Deficiency of lipoprotein lipase or of normal apolipoprotein CII Low fat diet. No drug therapy Type IIA(Familial Hypercholesterolemia) Defects in synthesis or processing of LDL receptor Diet , cholestyramine, niacin or statins Type IIB( Familial combined Hyperlipidemia) over production of VLDL by the liver Diet , drugs similar to that for Type II A Type III( Familial dysbetalipoproteinemia) Due to over production or underutilisation of IDL Diet , drugs like niacin, fenofibrate or statins Type IV(Familial Hypertriglyceridemia) Over production and/or decreased removal of VDL and TG Diet , drugs like niacin and fenofibrate Type V( Familial mixed Hypertriglyceridemia) Increased production or decreased clearance of VLDL and chylo Diet , drugs like niacin, fenofibrate or statins
Dr Heethal Jaiprakash

chylo micro

LDL

VLDL

LDL

IDL

VLDL

VLDL

chylo micro
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Classification of Hyperlipoproteinaemias

Primary

Single gene defect- monogenic or genetic Mutliple genetic, dietary , physical activity- polygenic or multifactorial

Secondary

Diabetes, myxodema, nephrotic syndrome, chronic alcoholism, drugs

Dr Heethal Jaiprakash

Classification of Hypolipidemic drugs

HMG- Co A Reductase inhibitors Fibrates
Atorvastatin, Simvastatin, Levostatin

Fenofibrate, Gemfibrozil

Nicotinic acid ( Niacin)

Dr Heethal Jaiprakash 8

Classification of Hypolipidemic drugsContd

Cholestyramine, Colestipol Bile acid Sequestrants

Cholestrol absorption inhibitors

Ezetimibe

Dr Heethal Jaiprakash

HMG-CoA Reductase inhibitors

They primarily reduce the LDL levels Most efficacious and best tolerated Mechanism: 1. Inhibition of HMG Co A reductase 2. Increase in LDL receptors Pharmacokinetics: Administered orally Biotransformed Excreted primarily through bile and faeces
Dr Heethal Jaiprakash 10

HMG CoA Reductase

Dr Heethal Jaiprakash

Statins
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Adverse effects: Liver- abnormality in liver functions Muscle- Myopathy, Rhabdomyolysis Contraindications Pregnancy and lactation Uses: All types of hyperlipidemias- less with familial hypercholesterolemia

Dr Heethal Jaiprakash

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Fibrates(fibric acid derivatives) Mechanism Activates PPAR

Lipoprotein lipase synthesis Degradation of Triglycerides
Lowering of circulating TGs
Dr Heethal Jaiprakash 14

They primarily decrease the triglyceride levels Also increase HDL levels Pharmacokinetics: Absorbed orally Biotransformed Excreted in urine Adverse effects: Gastrointestinal Lithiasis Myositis Contraindications- severe liver or renal dysfunction Uses: Treatment of Type III, Type IV, V
Dr Heethal Jaiprakash 16

Niacin
It is a B group vitamin Higher doses reduces plasma lipids Most effective drug in increasing HDL-CH Pharmacokinetics: Administered orally Excreted in urine

Dr Heethal Jaiprakash

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Mechanism of action of niacin

Triacylglycerol Niacin Fatty Acids Niacin Adipose tissue is the storage site of fats Fats in the form of triacylglycerol is converted to Fatty acids by Lipolytic enzymes These fatty acids are transported to the liver in the blood stream where they are converted back to triacylglycerol These TGs are packed in VLDL lipoproteins and are released into to the circulation becoming a potential threat Niacin inhibits the process of lipolysis in the adipose tissue. This eventually reduces the amount of Fatty acids entering the circulation.

Fatty Acids Triacylglycerol VLDL

Dr Heethal Jaiprakash

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Adverse effects: Intense cutaneous pruritis- due to prostaglandin release Nausea, abdominal pain Hyperuricemia Impaired glucose tolerance Hepatotoxicity Uses : Type III,IV,V
Dr Heethal Jaiprakash 19

Bile acid binding resins

Bind to negatively charged bile acids and bile salts in the Small intestine Decreased total plasma cholesterol

Resin+ bile acid complex

Activates Increased hepatic uptake of cholesterol containing LDL particles- fall in plasma LDL

Excreted in feaces

Decreased intracellular cholesterol concentration

Prevent enterohepatic circulation

Dr Heethal Jaiprakash

Increased conversion of cholesterol to bile acids

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Pharmacokinetics : Taken orally Totally excreted in faeces Adverse effects: GITImpaired absorption- Vitamin A,D,E,K Uses: Type IIa and IIb hyperlipidemias
Dr Heethal Jaiprakash 22

Cholesterol absorption inhibitors:

Inhibits intestinal absorption of dietary and biliary cholesterol in small intestine

Decreased delivery of intestinal cholesterol to the liver

Decreased hepatic cholesterol stores and increased clearance from the blood
Dr Heethal Jaiprakash 23

Ezetimibe is generally Combined with statins Pharmacokinetics : Biotransformed Undergoes enterohepatic circulation Excreted in faeces Adverse effects: Reversible hepatic dysfunction
Dr Heethal Jaiprakash 24