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Lipids & Treatment of Dyslipidaemia

Prof Samir Helmy Assaad Khalil Dpt Internal Medicine Unit of Diabetes, Metabolism & Immunology Alexandria Faculty of Medicine 2006

Fat Digestion
Liver Duodenum Biliary Transport and Storage




Two Sources of Cholesterol: Synthesis and Absorption Liver Synthesis* (~800 mg/day) Dietary cholesterol (~300± (~300±700 mg/day) Biliary cholesterol (~1000 mg/day) Extrahepatic tissues Absorption (~700 mg/day) Intestine Fecal bile acids and neutral sterols (~700 mg/day) .

Secondary Causes of Low HDL      Smoking Obesity (visceral fat) Very-low-fat diet Hypertriglyceridemia Drugs Beta-blockers Androgenic steroids Androgenic progestins .

LDL-C Treatment Goals LDLLDL-C Goal (mg/dl) <100 <130 <160 Risk Category CHD or CHD Risk Equivalents (10-year risk >20%) 2+ Risk Factors (10-year risk e20%) 0 1 Risk Factor .

CHD Risk Equivalents  >20% 10-year risk of CHD (Framingham projections) Diabetes Other forms of clinical atherosclerotic disease: Peripheral arterial disease Abdominal aortic aneurysm Carotid artery disease   .

Lp(a). and VLDL-C2   .Non-HDL Cholesterol   Non-HDL Cholesterol = TC HDL Cholesterol1 Secondary target of therapy when serum TG u 200 mg/dL1 New non-HDL-C goal for patients with elevated TG is LDL-C goal + 30 mg/dL1 Non-HDL-C includes all atherogenic lipoprotein particles including LDL-C. IDL-C.

the least common type. yType IV : Increased endogenous TG and cholesterol. increased TG & cholesterol. increased chylomicrons remnants & VLDL remnants because they carry mutant form of Apo E (Apo E2) which cannot act as a proper ligand for the receptor involved in remnant uptake by the liver. cholesterol and TG. yType II b: Cholesterol moderately increased with mild increased TG. common. uncommon.Freidrikson Classification yType I : Increased exogenous TG. rare yType II a: Very high cholesterol with normal TG. common. yType V : Increased chylomicron and VLDL. most common type. . yType III : Broad beta increased.

retinoids. etc«) Diabetes Mellitus Alcohol Lipid abnormalities TG TG TG Cholesterol Cholesterol Cholesterol Cholesterol TG (±) TG Cholesterol HDL TG TG HDL HDL . oral contraceptives. corticosteroids. anabolic steroids.Causes of 2ry Hyperlipidaemia Causes Chronic renal Failure Bulimia Pregnancy Hypothyroidism Cholestasis Anorexia Nervosa Nephrotic Syndrome Drugs(Diuretics.

Levels at post absorptive 12-16h fast (per 100 ml plasma) yTotal Lipids: 400-800 mg/100ml plasma 50-150 mg 150-200 mg (70-75% esterified) 150-250 mg yTriglycerides (TG): yCholesterol (Total): yPhospholipids (PL) (Total): yFree Fatty Acids (FFA): 5-20 mg .

10Step 5: Determine risk category to establish LDL-C goal. Step 3: Determine the presence of major risk factors. need for LDLTLC & drug therapy. Step 6: Identify metabolic syndrome and treat. Step 7: Treat elevated TG. Step 4: If 2 + risk factors (other than CHD) are present without CHD or CHD risk equivalent. assess 10-y CHD risk. Step 2: Identify presence of clinical CHD or CHD risk equivalents.Management of hyperlipidemias according to NCEP-ATP III Guidelines NCEPStep 1: Determine Lipoprotein levels. Step 8: Treat decreased HDL-C. HDLStep 9: How to estimate (Framingham Risk-Scores) 10-y risk Risk10- .

women >55 years)* . CHD in female first degree relative <65 years) yAge (men >45 years.Major Risk Factors (Exclusive of LDL Cholesterol) that Modify LDL Goals* yCigarette smoking yHypertension (BP ³140/90 mmHg or on antihypertensive medication) yLow HDL cholesterol (<40 mg/dL)‚ yFamily history of premature CHD (CHD in male first degree relative <55 years.

LDL-C Goals and Cut points Risk Category CHD or CHD risk equivalent u2 Risk Factors 10-yr risk 10 20% 10-yr risk <10% <2 Risk Factors LDL-C Goal <100 mg/dL <130 mg/dL <130 mg/dL <160 mg/dL Consider Drug Therapy u130 mg/dL* u130 mg/dL u160 mg/dL u190 mg/dL * 100±129 m /dL = fter LC.Treatment Categories. con ider t tin. or fibr te ther . ni cin.

Treatment of Hyperlipidemia Hi h LDL-C LDLher eutic Life t le Ch n e Dru Ther her her of Choice: Statin Altern tive: Re in or ni cin .

Inhibitors of Cholesterol Synthesis and Absorption .

Inhibitors of Cholesterol Synthesis: Statins Inhibit synthesis of cholesterol by cells Lower LDL cholesterol   Mechanism: Promote LDL Clearance .

The LDL Lowering Efficacy of the Currently Available Statins Daily Dose 10 mg 20 mg 40 mg 80 mg Atorva 39% 43% 50% 60% Fluva Lova Prava 22% Simva 30% 38% 41% 47% 22% 25% 36% 27% 32% 42% 32% 34% .

5% of cases in dose-dependent manner Serious liver problems are exceedingly rare Manage by reducing statin dose or discontinue until levels return to normal Myopathy Occurs in 0.5 to 2.2 to 0.Statin Side Effects   Common Myalgia Fatigue Headache GI intolerance Flu-like symptoms Increase in liver enzymes Occurs in 0.4% of patients Rare cases of rhabdomyolysis Reduce by  Cautiously using statins in patients with impaired renal function  Using the lowest effective dose  Cautiously combining statins with fibrates  Avoiding drug interactions  Careful monitoring of symptoms Presence of muscle toxicity requires the discontinuation of the statin  .

Cholesterol Absorption Inhibitors  Inhibit absorption of dietary cholesterol Inhibit reabsorption of biliary cholesterol Lower LDL cholesterol   Mechanism: Inhibit LDL Formation .

Bile Acid Resins: Mechanism of Action G ll l dder o Chole terol 7-E h drox l e 7o Conver ion of chole terol to A o A ecretion Bile Acid Enterohepatic Recirculation Termin l Ileum Re b or tion of bile cid o Liver o LDL Rece tor o VLDL nd LDL remov l A Excretion Net Effect: q LDL-C LDL- .

Ezetimibe L m h Enteroc te Inte tin l Lumen Ezetimibe Cholesterol ACAT NPC1L1 X Cholestery ABCG5/G8 l Ester .

Nicotinic Acid: Mechanism of Action Mobilization of FFA A o erum VLDL re ult in reduced li ol i to LDL erum LDL LD L VLDL TG synthesi s VLDL secretio n VLDL HDL Liver Hepatocyte Circulation Systemic Circulation Decreases hepatic production of VLDL and of apo B .

1±2 g/d (Niaspan OTC products. headache. Hyperglycemia and reduced insulin sensitivity. release). GIT hepatotoxicity. Adverse effects ±  Flushing. 2±4 g/d ImmediateExtendedExtended-release (Niaspan®). hepatotoxicity. itching. .Clinical Features of Nicotinic Acid  Products available (daily dose) ± ± ± Immediate-release. sustained-release. Peptic ulcer disease. Reduces coronary events (Coronary Drug Project). (sustained(sustained- ± ± Activation of peptic ulcer.  Contraindications ± ± Active liver disease or unexplained LFT elevations. e2 g/d sustained-   Best agent to raise HDL.

abn LFTs Hepatic or renal dysfunction Pre-existing gallbladder disease Mechanism of Action: Efficacy: Side Effects: Contraindications: . or increases Increase HDL-C 15 25% in hypertriglyceridemia GI upset (8%). cholelithiasis. remains the same. myositis.Fibric Acid Derivatives Indications: Adjunctive therapy to diet Hypertriglyceridemia (Type IV and V) Combined hyperlipidemia (Type IIb) with low HDL-C who do not respond to nicotinic acid Increase peripheral lipolysis and decrease hepatic TG production Decrease TG 25 50% LDL-C decreases.

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