Hypolipidemic Drugs

Hypolipaedimic drugs

Be bold-Be different!

Hypolipaedimic drugs

• Importance or why to study? • Lipoproteins • The diseases • Drugs • How to use?

Atherosclerosis and hyperlipioprotenimia What is the significance?

• Narrow –arterial lumen • Thrombosis of artery • Embolization • Distal ischemia • Ulceration • Weaken arterial wall • Aneurisms

Importance or why to study? • CHD –Cause half of all deaths • CHD correlated LDL, Cholesterol , Triglycerides and low levels of HDL • Cholesterol levels elevated because of • Lifestyle-Genetic OR Genetic + Lifestyle factors • Lowering CHE levels reduces the risk of CHD-30-40% • Life style modifications and hypolipedemics • Life long treatment

Lipoproteins

Hydrophobic lipids are carried by lipoproteins in aqueous envn. Of plasma

Lipoproteins

Classified on the basis of density, • Triglyceride (which makes them less dense) • Apoproteins (which makes them more dense). •

Metabolism of plasma lipoproteins and related genetic diseases

Liver expresses LDL receptors Removes ~75% of LDL from plasma.

Excreted in Bile

Manipulation of hepatic LDL receptor expression most effective way to modulate plasma LDL-C levels

he exogenous and endogenous lipoprotein metabolic pathways

HDL metabolism and

reverse cholesterol transport

Transport of excess cholesterol Liver & intestine →nascent HDLsfrom periphery to liver for excretion in the bile Cholesterol from macrophages and other peripheral cells → esterified by LCAT → mature HDLs HDL cholesteryl ester can be transferred by CETP from HDLs to VLDLs and chylomicrons HDL cholesterol can be selectively taken up by the liver via SR-BI (scavenger receptor class BI) LCAT=lecithin-cholesterol acyltransferase CETP=cholesteryl ester transfer protein

•

LDL Atherogenic

• LDL →modified by oxidation → foam-cell formation → arterial lesions

• HDL Protective • HDL -reverse cholesterol transport - excess cholesterol is acquired from cells and transferred to the liver for excretion • HDL also may protect against atherogenesis by mechanisms not directly related to reverse cholesterol transport. • Antiinflammatory, antioxidative, platelet antiaggregatory, anticoagulant, and profibrinolytic activities

five

Statins Clofibrate

Fibric Acid… Nicotinic Acid Resins

Omega-3

Others: Probucol, Gugulipid, Fibre

Statins • 6 statins • Inhibit rate limiting step in the bio-synthesis of cholesterol [Decreased production] • ↓ • Up regulates LDL receptors [Increased clearance] • Lova. and Sim. –Pro-drugs • LDL[20-25%], T.G.[35-40%] at high doses, If T.G. ↓ by 25%, HDL↑ [5-10%]

↓cholesterol concentration activates Sterol Regulatory Element Binding Protein (SREBP), Transcription factor that up-regulates

Pleiotropic effects of statins • Cholesterol-independent  Improving endothelial function  Enhancing the stability of atherosclerotic plaques  Decreasing oxidative stress and inflammation  Inhibiting the thrombogenic response.  Decrease macrophage infiltration  Extrahepatic effects on the immune system, CNS, and bone  Mediated by  Inhibition of isoprenoids

Statins…..ADE • Myopathy & Hepatotoxicity • Myopathy = CK 10 times normal • If more than 5 times-consider stoppage • More in- ↑ 80 yrs, Renal

dys., Periop. period, Untreated hypothyroid

Statins ADE…. • Myopathy rarely occurs in the absence of combination therapy • Routine CK monitoring is not recommended unless the statins are used with one of the predisposing drugs. • Myopathy can occur months to years after combined therapy is initiated • Myoglobinuria, renal failure, and death have been reported • Pregnancy-safety not established

Statins…..DI • Fibrates, Cyclosporine, Warfarin, Macrolides, Azoles • If combined with above drugsdose of statin=25% • Precaution-Basic ALT→Repeat after 3 months →If normal no further monitoring

Why Statins administered at night? • Hepatic cholesterol synthesis is maximal between midnight and 2:00 A.M. • Statins with half-lives of 4 hours or less (except Atorvastatin and Rosuvastatin) should be taken in the evening.

Bile acid sequestrant s

•Oldest and the safest •Not absorbed from the GIT 1.Cholestyr amine, 2.Colestipol, 3.Colesevelam

Bile acid sequestrants MOA: • Highly positively charged • Bile acids -Negatively charged • Bound bile acids are excreted in the stool • 95% of bile acids are normally reabsorbed • This process depletes the pool of bile acids

Bile acid sequestrants.. • Bile-acid synthesis increases. • Cholesterol content declines • Stimulates the production of LDL receptorseffect similar to that of statins. • Increase in hepatic LDL receptors increases LDL clearance and lowers LDL-C levels

• This effect is partially offset by the enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase • Inhibition of reductase activity by a statin - increases the effectiveness of the resins.

Bile acid sequestrants ADE and DI • Rarely- hyperchloremic acidosis [Chloride salts] • Severe hypertriglyceridemia is a CI • Unpleasant to patients • Bloating and dyspepsia [↓Dissolving several h.before] • Constipation • ↓ Absorption - Thiazides, Furosemide, Propranolol, l-thyroxine, Digoxin, Warfarin, and some of the statins [4 h. before or 1 h. after above drugs] • Colesevelam- ↓ Absorption of Verapamil

Niacin

Adipose tissue • Inhibits lipolysis of triglycerides by lipase • ↓Transport of FFA to the liver- ↓ hepatic TG synthesis Liver • ↓ TG synthesis by inhibiting - synthesis and esterification of FA • ↓ TG → ↓ VLDL production→ ↓ LDL • Raises HDL-C levels • Favorably affects virtually all lipid parameters

Niacin-ADE

• Flushing and dyspepsia – affects compliance • Ceases in most patients after 1 to 2 weeks • Coffee, tea, alcohol –Increase • Minimized by low doses, aspirin • Severe hepato-toxicity- [common with SR prep, Crystalline form preferred]

• Causes insulin resistance

• CI

• Pregnancy, APD

Fibric Acid Derivatives: PPAR Activators • Clofibrate, Gemfibrozil, Fenofibrate, Bezafibrate, and Ciprofibrate MOA: • Bind to PPARα- liver and adipose tissue • Stimulate -Increased LPL synthesis, • Increases in HDL-C • ↑TG clearance and ↓ hepatic triglyceride synthesis • DOC -Severe hypertriglyceridemia • Paroxisome-Proliferator-Activated-Rec.

Fibric Acid Derivatives: ADE & DI • GIT • Rash, urticaria, hair loss, myalgias, fatigue, headache, impotence, and anemia • Increases in liver transaminases • Potentiate the action of oral anticoagulantsdisplacing them from PPB sites • Myopathy [with Statin] • Gemfibrozil inhibits hepatic uptake of statins by OATP2. • Gemfibrozil also competes for the same glucuronosyl transferases that metabolize most statins. • As a consequence, levels of both drugs may be increased when they are co-administered

Fibric Acid Derivatives: ADE & DI • ↑ Gall stones • Renal failure and hepatic dysfunction – relative CI • Statin+Fibrate - avoided in patients with compromised renal function. • Fibrates should not be used by children or pregnant women

Ezetimibe MOA

• Inhibits a specific transport process in jejunal enterocytes-transport protein -NPC1L1 • ↓Cholesterol absorption • Compensatory increase in cholesterol synthesis • Can be inhibited with statin

• • • • •

Ezetimibe…… Dual therapy with Ezetimibe & Statins Statin: “prevents the enhanced cholesterol synthesis induced by ezetimibe” Ezetimibe “Prevents increase in cholesterol absorption induced by statins”

• Ezetimibe-ADE

• Pregnancy-Not established • rashes

Actions of drugs

LDL Goals & treatment cut points:NCEP LDL Goal

Initiate

Consider drug

Risk category mg/dL

Life style change

High risk

<100

≥ 100

≥ 100

Mod.high risk

<130

≥ 130

≥ 130

Moderate risk <130

≥ 130

≥ 160

Low risk

≥ 160

≥ 190

<160

therapy

Be bold-Be different!

k n a Th u yo

Not indifferent!!!!