Hypolipidemic Agents

Hypolipaedimic drugs

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Atherosclerosis and hyperlipidemia What is the significance?

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

The risk

 Hyperlipidemia major cause o Atherosclerosis-associated

conditions o CHD, ischemic cerebrovascular disease, PVD  ↑LDL & ↑ TG ↓(HDL-C), increased atherogenic risk  Reduction plasma cholesterol-lowers the risk of

PLASMA LIPOPROTEIN METABOLISM

 Hydrophobic lipids are

carried by lipoproteins in aqueous envn. Of plasma  Lipoproteins = lipids and proteins  Lipid=cholesterol, triglycerides, and phospholipids

Lipids & Lipoproteins  2 main lipids in

   

blood -cholesterol and triglyceride Carried in lipoproteins Cholesterol is an essential element: Animal cell membranes Backbone of steroid hormones and bile acids;

 Triglycerides are

important in transferring energy from food into cells.  Why lipids are deposited into the walls of large and mediumsized arteries—an event with potentially lethal

Chol-HDL-VLDL-HDL-LDL •Lipoproteins are – classified on the basis of density, •Triglyceride (which makes them less dense) •Apoproteins (which makes them more dense).      

Total Chol = HDL + VLDL + LDL VLDL = TG/5 LDL = Total Chol. – HDL- VLDL

Metabolism of plasma lipoproteins and related genetic diseases

Excreted in Bile

•Liver expresses a large complement of LDL receptors •Removes ~75% of all LDL from the plasma. •Manipulation of hepatic LDL receptor expression most effective way to modulate plasma LDL-C levels

The exogenous and endogenous lipoprotein metabolic pathways

HDL metabolism and reverse

cholesterol transport

•Liver & intestine →nascent HDLs • 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  Atherogenic when they are modified by oxidation  Process leads to foam-cell formation in arterial

lesions  Controlled clinical trials - antioxidant vitamins found ineffective in prevention

 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. 

•ACoA, acetylcoenzyme A • C, cholestero CE, cholesteryl ester •HDL, highdensity Lipoprotein •HMG-CoA reductase •LDL, lowdensity Lipoprotein •MVA, mevalonate •TG, triglyceride •VLDL, very low-density lipoprotein.

Clofibrate

Omega-3

Others: Probucol, Gugulipid, Fibre

Statins

 6 statins  Inhibit rate limiting step in the bio-synthesis

of cholesterol

 ↓  Up regulates LDL receptors[Hepatocytes]  ↓LDL levels by enhancing the removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL production  Lovastatinn 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

Statins…..  Non-lipid lowering cardio-

protective effects Improved endothelial function

↑ Plaque stability-↓

Inflammation Improved circulation ↓ Lipo-Protein oxidation

Statins…..ADE

 Myopathy & Hepatotoxicity  Myopathy = CK 10 times

normal[0.01%]  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…..ADE  DI:  Fibrates, Cyclosporine,

Digoxin, Warfarin, Macrolides, Azoles  If combined with above dose of statin-25%N  Precaution-Basic ALT→Repeat after 3 months →If normal no

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

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

Bile acid sequestrants  Oldest and the safest -

not absorbed from the GIT  Cholestyramine,colestip ol, Colesevelam MOA:  Highly positively charged [large in size]  Bind negatively charged bile acids  Bound bile acids are excreted in the stool  95% of bile acids are normally reabsorbed  This process depletes the pool of bile acids

 Hepatic bile-acid synthesis  







increases. Hepatic cholesterol content declines Stimulates the production of LDL receptors- effect similar to that of statins. The 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]

Niacin: MOA 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

Niacin-MOA

Niacin-ADE  Flushing and dyspepsia – affects compliance  Ceases in most patients after 1 to 2 weeks

of a stable dose  Coffee, tea, alcohol –Increase flushing  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 brown adipose tissue [Kidney, heart, and skeletal muscle].  Stimulate -fatty acid oxidation, increased LPL synthesis,  Increases in HDL-C -due to PPARa stimulation of apoA-I and apoA-II expression  ↑TG clearance and ↓ hepatic triglyceride synthesis  DOC -treating severe hypertriglyceridemia and the chylomicronemia syndrome

Fibric Acid Derivatives: ADE & DI  Gastrointestinal side effects  Rash, urticaria, hair loss,

 

  



myalgias, fatigue, headache, impotence, and anemia Increases in liver transaminases Potentiate the action of oral anticoagulants- displacing 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

 ↑ Lithogenicity of bile  Renal failure and hepatic

dysfunction - relative contraindication  Combined 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  Does not affect intestinal triglyceride absorption  Also inhibits intestinal absorption of plant sterols  Compensatory increase in cholesterol synthesis  Can be inhibited with statin  ↓Cholesterol absorption →↓ Cholesterol in

Ezetimibe….  The diminished remnant cholesterol

content → decreases atherogenesis directly [ chylomicron remnants are very atherogenic lipoproteins]  Reduced delivery of intestinal cholesterol - stimulates expression LDL receptor expression and cholesterol biosynthesis  Enhances LDL-C clearance from the

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

OMEGA-3  EPA + DHA  FDA approved

 ↓ Hepatic TG synthesis,  ↓TG 50%, HDL ↑ by 10%,

VLDL ↓ 40%.  Increased bleeding with anti coagulants

Actions of drugs

Future  Potent statins- ↓LDL 65%  Inhibitors of MTP  ACAT2 inhibitors- alt. to

Ezetimibe  CETP inhibitors [↑ HDL] [JTT 705, Torcetradib][Torcetrapib Torpedoed!]  Antioxidants  Surgical:  Partial ileal bypass, Portacaval

LDL Goals & treatment cut points:NCEP

Risk category

LDL Goal mg/dL

Initiate Life style change

Consider drug therapy

High risk

<100

≥ 100

≥ 100

Mod.high risk

<130

≥ 130

≥ 130

Moderate risk <130

≥ 130

≥ 160

Low risk

≥ 160

≥ 190

<160

Proof of the Pudding!

Chol TG LDL HDL

Befor e 374 300 198 30

After 3 mo. Of tt. 164A+E 160 94 38

Lipoprotein lipase deficiency Rare

Deficiency of LDL receptor Less common

Polygenic, multifactorial Commonest

Apoprotein in IDL, Chy.micro.-abnormal Rare

MF & genetic Common

Genetic Less common

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k n a Th ou y

Not indifferent!!!!