Hypolipidemic drugs Dr. Kiran Piparva.pptx

Hypolipidemic drugs Dr. Kiran Piparva.pptx

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  Dr. Kiran G.Piparva. Assistant professor, All India Institute of Medical Science, Rajkot Hypolipidaemic drugs
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  Fat in diet:Cholesterol: • Critical substrate for the body: Essential for  Building cell membranes,  the myelin sheath and the brain  Building block of steroid hormones  Core component of bile salts, which helps in digest dietary fats and fat soluble vitamins
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  What is lipoprotein LIPIDApoprotein Triglyceride Cholesterol Apoprotein • Surface protein • Provide structure stability • Acting like ligand and help for metabolism of lipoprotein lipoprotein
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  Lipoprotein metabolism Lipoprotein =Lipid ( CH CHE TG) + Protein (apolipoprotein) Chylomicron / Chylomicron remnant - B48 (exogenous – contains dietary TG) VLDL / IDL /LDL = B100 (endogenous – contains liver TG) HDL – apoA-I / II apoC-I / II / III
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  Reverse cholesterol pathwayvia HDL Anti-inflammatory, antioxidant, antiplatelet, antiaggregatory action
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  Hypolipidaemic drugs Hyperlipidemia =Major cause of atherosclerosis and atherosclerosis-induced conditions, such as coronary heart disease (CHD) and ischemic cerebrovascular disease Lower the levels of lipids and lipoproteins
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  Type of hyperlipoproteinemia…. Primary: a)Single gene defect- Monogenic/genetic b) Multiple genetic, dietary and physical activity related causes- Polygenic/ multifactorial. • Secondary: Associated with • Diabetes, Myxoedma, Nephrotic syndrome, Chronic alcoholism • Drugs(corticosteroids, oral contraceptives, beta blockers)
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  Type of primaryHyperlipoproteinemias
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  LDL and atherosclerosis ElevatedLDL is a major risk factor for the development of atherosclerosis Monocyte chemotaxis ↑ Formation of foam cell Injury to endothelial cell/dysfunction Foam cell necrosis Oxidized LDL HDL – good cholesterol- facilitates removal CH from tissues
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  Classification of hypolipidemicdrugs….
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  HMG –CO Areductase inhibitors……. Lovastatin Atorvastatin Pravastatin Rosuvastatin Simvastatin Pitavastatin HMG CoA reductase inhibitors = STATINS
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  Mechanism of action ofstatins
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  Acetyl CoA + AcetoacetylCoA HMG CoA Mevalonate Cholesterol HMG CoA reductase Statins ↓Cholesterol SREBP activation Nucleus LDL –R gene ↑expression of LDL receptors ↑Uptake of LDL Protease activation Liver cell Multistep Mechanism of action - STATIN
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  Statins = Pharmacologicalaction M/A: Competitively inhibits HMG CoA reductase (3hydroxyl 3methyl glutaryl) LDL-C - ↓ 30-55% HDL-C - ↑5-10% TG - ↓ Pravastati Simvastatin low potency Lovastatin Rosuvastatin high potency Pitavastatin Atorvastatin HMG CoA reductase activity – MAXIMUM at night(midnight – 2am) Statins are given at bed time Except – Rosuvastatin & Atorvastatin – longer T1/2 Prodrugs
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  Potential Cardioprotective EffectsOther Than LDL Lowering = Pleiotropic effects of statins
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  • Well tolerated:Mild GIT/ Headache ADR of statain • Myopathy: Commonest- muscle weakness, myalgia (serious rhabdomyolysis – rare) when co-prescribed with – nicotinic acid - Gemfibrozil - CYP 3A4 inhibitors (erythromycin, cyclosporine, HIV protease inhibitors Drugs inhibiting metabolism of statins ↑ risk of myopathy Erythromycin Ketoconazole Uncommon: Hepatotoxicity -↑ alanine transaminase [ALT] and aspartate transaminase [AST] To be avoided in pregnancy
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  Clinical status ofStatins: • 1st choice drugs in reducing raised LDL-CH/ (primary /secondary hyperlipidemias)… • Secondary prevention:↓ Mortality & morbidity – Acute coronary Syndrome, Stroke, peripheral artery disease, particularly after MI • Primary prevention: Statins: ↓ mortality even in the absence of cardiovascular disease • Also used in primary hypercholesterolemia
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  Drug Characteristic Potency (dose) Remarkable effect onlipid profile ADR Lovastatin/ Pravastatin Lactone precursor form- Lyophilic Lower efficacy Low potency Extensive FPM short half life (2-4 hrs) 10-40mg Low to moderate (30- 40%) Simvastatin (twice potent) Higher risk of myopathy Atorvastatin High efficacy High potency Longer half life (18- 24hrs) 10-40mg Highest LDL CH lowering -55-60% (10mg Rosu=20mg Ato) Rosuvastatin 5-20mg Pitavastatin 1-4mg No extra benefit Avoid with gemfibrozil
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  2. Lipoprotein lipaseactivator (PPAR activators) /Fibrates: FIBRATES • 1st generation: Gemfibrozil • 2nd generation: Fenofibrate(prodrug ), bezafibrate
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  Fibrates : Pharmacologicalaction Gemfibrozil: Older generation Bezafibrate: 2nd generation same properties Fenofibrate: 2nd generation: Greater HDL and LDL apart from TG lowering effect. Increased risk of myopathy
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  Fibrates - GemfibrozilBezafibrate Fenofibrate ( prodrug ) ADR • Git – Diarrhea epigastric distress • Rash headache fatigue • Myalgia To be avoided in pregnant women Dose reduction is required in the elderly and renal insufficiency • Myalgia Gemfebrozil + statin -- ↑myopathy risk (gemfebrozil inhibits hepatic uptake and glucuronidation of statins)
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  Clinical status offibrate USE - Oral • Useful in hypertriglyceridemias • Particularly useful in type 3 & 4 hyperlipoproteinaemias Don’t use fibrate: 1. If TG level do not lower after 2months of Primary/secondary prevention of CVD 2. Prophylactic use of CKD 3. Diabetes and CKD 4. Don’t combine with statin
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  •Saroglitazar ?? PPAR -αPPAR -y Thiazolidinediones fibrates Diabetes dyslipidaemia Only approved in indai
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  NIACIN (Nicotinic acid) Bindingto niacin receptor (site: adipose tissue/liver) ↓ hormone sensitive lipase activity inhibit intracellular lipolysis ↓ plasma free FA from adipose tissue to liver ↓ TG synthesis in liver - 20-50% ↓ plasma VLDL ↓ plasma LDL ↓apoA-I clearance ↑T1/2 of apoA-I Increase plasma HDL Doses are higher than required for vitamin effects Best agent available for increasing HDL-C 20-35% Lower total CH 15-25 %
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   Skin Cutaneous vasodilator FlushingPruritus-Occur at every dose How to reduces ….. Start with low dose Prior aspirin Laropiprant (Protanoid receptor inhibitors)  GIT: Dyspepsia, vomiting Long term Liver dysfunction Jaunice Hyperglycemia Hyperuricemia Gout Atrial arrhythmias C/I: Pregnancy /Children NIACIN: Adverse drug reaction  Large doses needed for hypolipidemic action – poorly tolerated  50% patient can take full dose
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   Highly efficaciousfor type 3,4,5 hyperlipidemia but use is restricted to high risk group only….  Not recommended alone or combination with statin for prevention of CVD (As per NICE guideline- )  Imp indication is……..  To control pancreatitis associated with hypertriglyceridemaemias  Dose : 2gm /day Clinical use: Current status of niacin…
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  Ezetimibe:  Sterol absorptioninhibitor CH CH NPC1L1 Luminal membrane Basolateral membrane Jejunal enterocyte Niemann pick C1 like 1 protein - transports CH into cell Inhibition of NPC1L1 by Ezetimibe ↓CH delivery to liver ↑LDL receptor expression ↓plasma LDL (15-20%) Ezetimibe Used as adjunctive therapy with statins (synergistic effect)
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  • Ezetimibe inhibitcholesterol absorption by 54%, precipitating a compensatory increase in cholesterol synthesis that can be inhibited with a cholesterol synthesis inhibitor such as a statin. • Ezetimibe reduces LDL-C levels by 15-20% Contraindicated in pregnant and nursing women, women in childbearing years in the absence of contraception Ezetimibe: Pharmacological action
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  • Weak hypocholesterolemiadrug • As adjuvant - Used to supplement statin • Ezetimibe+Statin (low dose)= High dose of statin – LDL reduction (reduces upto 60%) ADR: GI upset, Reversible hepatic dysfunction Myositis (Rare) Clinical status of Ezetimibe
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  Bile acid sequestrants Interruptenterohepatic cycle of bile acids Cholestyramine Colestipol Colesevalam Highly positive charged + large size – not absorbed when given orally Bind with negatively charged bile acids Bile acids excreted in stools ↓hepatic CH and LDL receptor expression ↑ ------- ↓ plasma LDL Dyspepsia , bloating ,constipation Interfere with absorption of other drugs Not used as monotherapy Combined with statins
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  Drug Class AgentsEffects (% change) Side Effects HMG CoA reductase inhibitors Rosuvastatin Atorvastatin  LDL (20-55),  HDL (5-15)  Triglycerides (7-30) Myopathy, increased liver enzymes Fibrates (LPL activators Gemfibrozil Fenofibrate LDL (5-20), HDL (10-20)  Triglyceride (20-50) Dyspepsia, gallstones, myopathy Nicotinic Acid Niacin  LDL (15-30),  HDL (15-40)  Triglyceride (20-50) Flushing, Hyperglycemia, hyperuricemia GI distress, hepatotoxicity Cholesterol absorption inhibitor Ezetimibe  LDL( 14-18),   HDL (1-3) Triglyceride (2) Headache, GI distress
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  Newer hypolipidemic drugs: 1.PCKS19inhibitors: Antibody of PCKS19 (Aerilocumab), Inlciserin 2. ATP Citrate Lyase Inhibitor: Bempedoic acid
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  Guidelines for hypolipidemicdrugs use: 1. Who need to start hypolipidemic drug? 2. Treatment of high plasma LDL-CH: Nonpharmacological measure & Pharmacological therapy 3. Treatment of low HDL-CH level 4. Treatment of Raised TG level
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  Why to treatHigh CH level? • High LDL- High risk for CAD/ Stroke • High TG Independent risk factor • Low HDL for CAD Evidence based medicine Hyperlipidemia: Coronary artery disease (CAD) Hyperlipidemic drugs: • Decrees morbidity and mortality in Coronary artery disease (CAD) • Best hypolipidemic drugs: STATIN: 1st line (effective, well tolerated and safe)
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  1. Who needto start hypolipidemic drug?: Risk factor for coronary artery disease 1. Age: Man > years, Women >55 years 2. Hyperlipidaemia: High LDL- CH (≥160mg/dl) or total CH: ≥ 240mg/dl) 3. Family history of MI/Sudden cardiac death before 55 years (men), Women (65 years) in first degree relatives 4. Hypertension: BP>140/90mm of Hg and antihypertensive Rx 6. Obesity: BMI> 25kg/m2) or Waist >40” (M)/ > 35” (F) 5. Diabetes mellitus 7. Smoking
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  Targe lipid profile
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  Non pharmacological approach: Lifestylemodification: • Diet modification: Low fat, low cholesterol diet, limitation of saturated and trans-fats • Regular exercise • Body weight control • Smoking session • Restricted alcohol
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  • Indication forstatin therapy: 1. Subjects with ASCVD irrespective of plasma CH level 2. All subjects with LDL- CH >190mg/dl 3. All diabetes > 40 years of age 4. Subjects aged 40 years with ASCVD risk > 7.5% irrespective of plasma CH level. Statin therapy:  High intensity (Atorvastatin (80mg)/Rosuvastatin (10-40ng)  Moderate intensity ( Rest all statins & others)  Low intensity 3. Treatment of high plasma LDL-CH
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  INDICATION: CAD patients+low HDL +Metabolic syndrome • Rx of metabolic syndrome - normalize HDL-CH • Primary approach in subject with low HDL-CH: Reduces LDL –CH by Intensive statin therapy • No benefit of adding niacin to statin therapy Statin therapy:  High intensity (Atorvastatin (80mg)/Rosuvastatin (10-40ng)  Moderate intensity ( Rest all statins & others)  Low intensity 2. Treatment of low HDL-CH
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  Drug therapy: Statin+ Fenofibrate + Niacin 3. Treatment of raised TG level Vigilance for myopathy INDICATION: Hypertriglyceridemia: • Rx depends upon severity and cause (Obesity, physical activity, high carbohydrate high calorie diet, saturated and tans fat, alcohol, smoking, diabetes, kidney disease, drugs, genetic disorder) • TG level >500mg/dl: Risk of developing acute pancreatitis