Hypolipidemia, HYPOLIPIDEMIC DRUGS - Vijay.pptx

Hypolipidemia, HYPOLIPIDEMIC DRUGS - Vijay.pptx

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  Hypolipidemic Drugs -By Dr. VijayR Junior Resident King George’s Medical University, Lucknow
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  Content • Introduction • Metabolism •Hypolipidemic drugs • Pharmacotherapy of hyperlipidaemia
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  Introduction Dyslipidaemia • Abnormal amountof lipids in blood • Disorder of lipoprotein metabolism • Lipoprotein overproduction and deficiency • Lipids typically include cholesterol levels, lipoproteins, chylomicrons, VLDL, LDL, apolipoproteins, and HDL
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  • Dyslipidemia isa major cause of • Atherosclerotic cardiovascular disease (ASCVD), • Ischemic cerebrovascular disease • Peripheral vascular disease • Cardiovascular disease is the number one cause of death globally (WHO) • Common causes of dyslipidaemias • Genetic disorders, Lifestyle factors and • Metabolic diseases such as diabetes mellitus.
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  • Hyperlipoproteinemia • Primary: due to a) A single gene defect: is familial and called ‘monogenic’ or genetic b) Multiple genetic, dietary and physical activity related causes : polygenic or multifactorial • Secondary : • Associated with diabetes, myxoedema, nephrotic syndrome, chronic alcoholism, drugs (corticosteroids, oral contraceptives, beta blockers)
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  Lipid metabolism
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  • LIPOPROTEIN • Macromolecule= Lipid + protein (apoproteins) • Lipid – free and esterified cholesterol, TGs, and phospholipids • Divided into 6 classes on the basis of their particle size and density
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  HDL pathways andreverse cholesterol transport
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  Pharmacotherapy of hyperlipidaemia
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  HMG-COA Reductase Inhibitors •Most efficacious, most commonly used and best tolerated • All statins produce peak LDL-CH lowering after 1-2 weeks therapy • Different statins differ in their potency and maximal efficacy in reducing LDL-CH • HMG-COA reductase activity maximum at midnight
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  • MECHANISM OFACTION Inhibit HMG- Co A reductase competitively (HMG-Co A to Mevalonic acid) Inhibit biosynthesis of cholesterol Depletion of cholesterol in hepatocytes Increase LDL receptors expression on hepatocytes Increased hepatic uptake of LDL , IDL & decreased plasma LDL
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  LOVASTATIN • First clinicallyused statin • Oral administration -Absorption incomplete & extensive 1st pass metabolism, T-half – 2-4 hrs. • Dose- 10-40 mg /day , maximum- 80 mg. SIMVASTATIN • Twice as potent & efficacious than lovastatin • Greater rise in HDL-CH , T-half – 2-4 hrs • Dose – 10-40 mg/day, maximum- 80 mg.
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  PRAVASATIN • Efficacy nearlysimilar to lovastatin • Additional decreases plasma fibrinogen level, T-half- 1-3 hrs • Dose – 10-40 mg/day ATORVASTATIN • Most commonly used due to high efficacy • LDL-CH lowering is 55-60 % at 80 mg /day ceiling dose • Anti-oxidant property, Longer plasma T-half – 14-18 hrs • Dose – 10-40 mg/day , maximum -80 mg
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  ROSUVASTATIN • Highly potent& efficacious ( 10 mg rosuvastatin= 20 mg atorvastatin) • Greater LDL-CH reduction in severe hypercholesterolemia • Rises Plasma HDL by 10-15 %, T-half – 18 -24 hrs . • Dose – 5-20 mg once daily , maximum 40 mg /day PITAVASTATIN • Latest most potent statin • LDL-CH lowering is 40 % at 4 mg/ day ceiling dose • Use in combination with gemfibrozil is avoided • Dose – 1-4 mg/day , maximum 4 mg/day
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  Adverse effects • Myopathy It is the only serious reaction  Rare < 1 in 1000  Rhabdomyolysis  Myopathy & liver injury are common when given with nicotinic acid/ gemfibrozil or CYP3A4 inhibitors • GI complaints • Headache & sleep disturbance • Rashes
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  HMG-COA Reductase Inhibitors USES •Primary hyperlipidaemia (1st choice of drugs) • Secondary hypercholesterolemia • All types of atherosclerotic cardiovascular disease -new onset angina - MI - Acute coronary syndrome - Thrombotic stroke - Peripheral arterial disease
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  Pleiotropic Effects ofStatins • Anti- Inflammatory (↓CRP) • Anti- Thrombotic • Anti- Platelets • ↑NO levels • Anticoagulants (↓plasma fibrinogen) • ↓ Uric acid
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  LIPOPROTEIN LIPASE ACTIVATOR( FIBRATES ) • Activators of PPARα- gene transcription regulator ( Expressed mainly in liver & brown adipose tissue) • 1st generation – Gemfibrozil • 2nd generation - Bezafibrate Fenofibrate
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  LIPOPROTEIN LIPASE ACTIVATOR( FIBRATES ) MECHANISM OF ACTION • Increases lipoprotein lipase synthesis – ↑ clearance of triglyceride rich lipoprotein • ↑ clearance of VLDL • ↑ fatty acid oxidation – Lowers triglycerides • ↑ HDL-Cholesterol by activation of apoA-I & apoA-II activation
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  GEMFIBROZIL • ↓ plasmaTG level by ↑ breakdown and ↓ hepatic synthesis of TG • Completely absorbed orally • Metabolised by enterohepatic circulation, Excreted in urine. • T-half is 1 – 2 hours, Dose 300-600 mg per day. USES • Hypertriglyceridaemia • Acute pancreatitis ( for prevention) • Familial hyperlipemia & Endogenous hypertriglyceridemia.
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  LIPOPROTEIN LIPASE ACTIVATOR( FIBRATES )……… SIDE EFFECT • Epigastric distress • Loose motions • Skin rash • Blurred vision and headache CONTRAINDIACTION • Children • Pregnant women • Renal failure
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  LIPOPROTEIN LIPASE ACTIVATOR( FIBRATES )……… BEZAFIBRATE • Greater LDL-CH lowering property than gemfibrozil. • Circulating fibrinogen and glucose level decrease • Absorbed orally • Metabolised by enterohepatic circulation • Dose 200 mg BD or TDS with meal
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  LIPOPROTEIN LIPASE ACTIVATOR( FIBRATES )……… Side effects of Bezafibrate • GI upset • Myalgia • Rashes Contraindications of Bezafibrate • Renal failure • Pregnant female • Children
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  LIPOPROTEIN LIPASE ACTIVATOR( FIBRATES )……… FENOFIBRATE • Greater LDL CH lowering action than others fibrates • Most suitable fibrate for combining with statins • T-half 20 hours • Dose -200 mg per day with milk
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  LIPOPROTEIN LIPASE ACTIVATOR( FIBRATES )……… SIDE EFFECT OF FENOFIBRATE • Myalgia • Hepatitis • Cholelithiasis • Rhabdomyolysis & Rashes. CONTRAINDICATION OF FENOFIBRATE • Chronic kidney disease • Diabetes  Fibrate therapy should be discontinued after 2 months If an adequate lowering of TGs level not obtained
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  LIPOLYSIS AND TRIGLYCERIDESYNTHESIS INHIBITORS NICOTINIC ACID (Niacin): • ↑ HDL-CH up to 25-30%, ↓ TGs and LDL cholesterol. • ↓ lipoprotein levels MECHANISM OF ACTION • ↓ intracellular lipolysis by lipase • Direct inhibition of TGs synthesis in liver • ↓Apo A1 degradation(HDL)
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  LIPOLYSIS AND TRIGLYCERIDESYNTHESIS INHIBITORS………. • USES • Hypertriglyceridaemia • Familial hypertriglyceridemia • Mixed hypertriglyceridaemia • Heterozygous hypercholesteremia
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  LIPOLYSIS AND TRIGLYCERIDESYNTHESIS INHIBITORS………. SIDE EFFECT • Flushing (MC) Contraindication : • Pruritis and rashes Diabetes (cutaneous vasodilation) Pregnancy • Dyspepsia Childrens • Skin dryness • Hyperuricemia • Other long term effects are : liver dysfunction and Jaundice
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  LIPOLYSIS AND TRIGLYCERIDESYNTHESIS INHIBITORS………. • Dose : • Start with 100 mg TDS • gradually increase 2-4 gm daily divided dose • Aspirin taken before niacin substantially attenuate flushing by inhibition of PG synthesis • Laropiprant combining with it to reduce flushing • Use of sustained release (ER/SR) tablet to subdue flushing
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  STEROL ABSORPTION INHIBITOR •EZETIMIBE • MECHANISM OF ACTION • Inhibition of cholesterol absorption by intestinal mucosa (NPC1L1 transport protein) Niemann Pick C1 – like 1 protein • Compensatory hepatic CH production ↑ • LDL – CH lower by 15 – 20%
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  EZETIMIBE……. • Enhance cholesterolsynthesis block by combining with statins • t1/2 = 22 hrs • Low dose statins + ezetimibe effective as high dose of statin alone • 60% decrease LDL –CH • No specific adverse effect • Dose – 10 mg OD
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  BILE ACID SEQUESTERANT(RESINS) • MECHANISM OF ACTION • Highly positively charged molecules that bind negatively charged bile acids. • Safest as not absorbed from intestine. • Due to large size, resins are not absorbed and bound bile acids are excreted in stool • Pool of bile acids depleted
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  BILE ACID SEQUESTERANT……… •Not popular clinically because they SIDE EFFCTS: • Unpalatable Heart burn • Inconvenient Flatulence • Have to be taken in larger dose Dyspepsia • Interfere with absorption of many drugs Malabsorption of Vit K • Poor patient acceptability and folic acid • All the hypolipidemic drugs are absolutely C/I in pregnancy except Resins- DOC in pregnancy.
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  PCSK 9 inhibitors(Proprotein convertase subtilisin/kexin type 9) • Alirocumab • Evolocumab • Inclisiran (mRNA) • 1st two are monoclonal antibodies • Injectable and expensive
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  • PCSK9, aproduct of hepatocytes • Secreted into the plasma • Where it binds to the LDL receptors facilitating lysosomal degradation of LDL receptors • ↓the expression of LDL receptors on the cell membrane • ↓ the clearance of LDL cholesterol.
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  USES • Adults • Reducethe risk of MI, stroke, and unstable angina • Primary hyperlipidemia, • Heterozygous familial hypercholesterolemia • Homozygous familial hypercholesterolemia
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  Newer Drugs • Saroglitazar- PPARα and PPARγ agonist • Icosapent ethyl - Omega -3 Fatty Acid Ethyl Esters • Lomitapide - Inhibitor of Microsomal Triglyceride Transfer • Bempedoic Acid - ATP-Citrate Lyase Inhibitor • Evinacumab- dgnb - Inhibitor of Angiopoietin- Like Protein 3 • Torcetrapib, Anacetrapib- CETP inhibitor. Anacetrapib banned → ↑↑ MI/Stroke, ↑ HDL. • Avasimibe- ACAT 1 inhibitor. Under Clinical trails
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