Drugs acting on Hyperlipoproteinemias PDF

Drugs acting on hyperlipoproteinemias Angelika Jagielska Lipoproteins https://www.shutte rstock.com/pl/searc h/hdl ...

Drugs acting on hyperlipoproteinemias Angelika Jagielska Lipoproteins https://www.shutte rstock.com/pl/searc h/hdl  Apolipoprotein Class Subtypes Associated Lipoproteins Functions Key Roles/Clinical Relevance - Reverse cholesterol transport - ApoA-I: Major HDL protein, cardioprotective. ApoA ApoA-I, ApoA-II, ApoA-IV HDL - Activates LCAT (ApoA-I) - ApoA-II: Stabilizes HDL particles. LDL, VLDL, IDL, - Structural protein for lipoproteins - ApoB-100: Key in LDL cholesterol delivery. ApoB ApoB-100, ApoB-48 Chylomicrons - LDL receptor binding (ApoB-100) - ApoB-48: Dietary lipid transport in intestines. ApoC-I, ApoC-II, ApoC-III, - ApoC-II: Activates LPL (triglyceride breakdown). ApoC VLDL, Chylomicrons - Modulates LPL (lipoprotein lipase) activity ApoC-IV - ApoC-III: Inhibits LPL (modulates metabolism). - Lipid transport - Involved in cholesterol metabolism and immune ApoD - Small HDL particles - Carrier of small hydrophobic molecules (e.g., functions. steroids) - ApoE4: Linked to Alzheimer’s disease and cardiovascular - Lipoprotein clearance ApoE ApoE2, ApoE3, ApoE4 Chylomicrons, VLDL, HDL risk. - Binds LDL receptors - ApoE3: Most common isoform. - Lipid transport ApoL ApoL1, ApoL2, etc. HDL - ApoL1 variants associated with kidney disease. - Role in innate immunity ApoM - HDL - Transports sphingosine-1-phosphate (S1P) - Involved in vascular health and immune regulation. - Structurally similar to ApoB-100 - High Lp(a) levels linked to atherosclerosis and Apo(a) - Lipoprotein(a) [Lp(a)] - Includes kringle domains cardiovascular disease. Lipoprotein Hierarchy  Lipoprotein Hierarchy Diameter Protein Cholesterol & Lipoprotein Phospholipid (%) Triglyceride (%) Primary Source Main Role (nm) (%) Cholesteryl Ester (%) Intestinal cells Transport dietary triglycerides from the intestine to Chylomicrons 75–1200 1–2 2–10 3–9 85–90 (enterocytes) tissues. Deliver triglycerides synthesized by the liver to VLDL 30–80 5–10 15–20 10–20 50–65 Liver peripheral tissues. Derived from VLDL Transitional lipoprotein between VLDL and LDL; IDL 25–35 10–15 25–30 20–25 25–35 during circulation involved in lipid transport during metabolism. Derived from IDL Deliver cholesterol to tissues; elevated levels are LDL 18–28 20–25 45–50 20–25 5–10 during circulation associated with atherosclerosis ("bad cholesterol"). Collect excess cholesterol from tissues and return it HDL 5–15 30–35 15–25 30–35 3–10 Liver to the liver for excretion ("good cholesterol"). Physiology of the lipoproteins  Physiology of the lipoproteins A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition.pdf Production of the cholesterol https://epomedicine.com/medical-students/cholesterol-synthesis-mnemonic/  Cholesterol Normal lipid panel Total cholesterol: Below 200 mg/dL. High-density lipoprotein (HDL) cholesterol: Above 60 mg/dL. Low-density lipoprotein (LDL) cholesterol: Below 100 mg/dL Triglycerides: Below 150 mg/dL.  Dyslipidemia Dyslipidemia: abnormal amounts of lipid in the blood Hyperlipidemia: elevates lipids in the blood (cholesterol, triglycerides, and or lipoproteins) Hyperlipoproteinemia: elevated levels of LDL, VLDL Hypercholesterolemia: elevated total cholesterol >200 mg/dL Hypertriglyceridemia: elevated triglyceride levels >150 mg/dL Frederickson Classification  Frederickson Classification 1. Type I: Familial Hyperchylomicronemia Cause: Deficiency in lipoprotein lipase (LPL) or its cofactor apolipoprotein C-II. Elevated lipid/lipoprotein: Chylomicrons (triglycerides). Associated risk: No increased risk of atherosclerosis but severe pancreatitis and eruptive xanthomas. Treatment: Very low-fat diet, avoiding triglycerides. 2. Type IIa: Familial Hypercholesterolemia Cause: Mutation in the LDL receptor gene or defective ApoB-100. Elevated lipid/lipoprotein: LDL cholesterol. Associated risk: Markedly increased risk of atherosclerosis, early-onset coronary artery disease. Treatment: Statins, PCSK9 inhibitors, and lifestyle changes. 3. Type IIb: Familial Combined Hyperlipidemia Cause: Overproduction of VLDL and LDL. Elevated lipid/lipoprotein: LDL cholesterol and triglycerides. Associated risk: Increased risk of atherosclerosis and cardiovascular disease. Treatment: Statins, fibrates, niacin or combination therapies. Frederickson Classification 4. Type III: Dysbetalipoproteinemia (Remnant Hyperlipidemia) Cause: Mutations in ApoE (e.g., ApoE2/E2 homozygosity). Elevated lipid/lipoprotein: Chylomicron remnants and IDL (intermediate-density lipoproteins). Associated risk: Palmar xanthomas, tuberous xanthomas, and increased risk of peripheral vascular disease. Treatment: Drugs of choice fibrates, then niacin, then statins 5. Type IV: Familial Hypertriglyceridemia Cause: Overproduction or impaired breakdown of VLDL. Elevated lipid/lipoprotein: VLDL (triglycerides). Associated risk: Risk of pancreatitis but minimal atherosclerosis. Treatment: Fibrates, omega-3 fatty acids, and lifestyle modifications. 6. Type V: Mixed Hyperlipidemia Cause: Combination of abnormalities affecting chylomicrons and VLDL metabolism. Elevated lipid/lipoprotein: Chylomicrons and VLDL (triglycerides). Associated risk: High risk of pancreatitis, eruptive xanthomas, and fatty liver. Treatment: Low-fat diet, fibrates, niacin, omega-3 fatty acids. 3.1 Dyslipidemia Primary causes Familial Hypertriglyceridemia: Genetic defects in enzymes like lipoprotein lipase lead to high triglycerides. Familial Combined Hyperlipidemia: A combination of genetic factors resulting in elevated cholesterol and triglycerides. Familial Dysbetalipoproteinemia: ApoE gene mutations lead to elevated triglycerides and cholesterol. Lipoprotein(a) Elevation: Genetic variations in the LPA gene cause high Lp(a) levels, increasing cardiovascular risk. Tangier Disease: ABCA1 gene mutations result in very low HDL cholesterol. Abetalipoproteinemia: MTTP gene mutations impair fat and cholesterol absorption.  Secondary causes A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition.pdf Atherogenesis https://www.sciencedirect.com/topics/pharmacology- toxicology-and-pharmaceutical-science/atherogenesis Pharmacotherapy of the hyperlipoproteinemias Statins (HMG-CoA Reductase Inhibitors)  Statins Mechanism of action: Inhibit HMG-CoA (3-Hydroxy-3-Methylglutaryl-Coenzyme A) reductase, a key enzyme in cholesterol synthesis. Upregulate LDL receptors in the liver, increasing LDL clearance. Pleiotropic effect. Indications: Hyperlipidemia and mixed dyslipidemia Primary dysbetalipoproteinemia (Type III hyperlipoproteinemia) Hypertriglyceridemia Atherosclerosis Primary and secondary prevention of atherosclerotic cardiovascular disease Familial hypercholesterolemia Statins Adverse effects: Myopathy, rhabdomyolysis, liver enzyme elevation, gastrointestinal discomfort. Examples: Atorvastatin, Rosuvastatin, Simvastatin, Pravastatin, Lovastatin.  Fibrates Fibrates Mechanism of action: Activate PPAR-alpha (peroxisome proliferator-activated receptor-alpha), enhancing lipoprotein lipase activity. Reduces VLDL production and triglycerides. Indications: Hypercholesterolemia, mixed dyslipidemias with high triglycerides.  Fibrates Fibrates Fatty acid Synthesis of PPAR-alpha oxydation apolipoprotein CIII TG synthesis Activity of lipoprotein lipase VLDL synthesis VLDL catabolism and chylomicrons TG level in plasma Fibrates Adverse effects: Gallstones, myopathy (especially when combined with statins), GI upset. Examples: Fenofibrate, Gemfibrozil, Bezafibrate.  Bile Acid Sequestrants Bile Acid Sequestrants Mechanism of action: Bind bile acids in the intestine, preventing reabsorption. Forces the liver to convert cholesterol into bile acids, reducing LDL cholesterol. Indications: Isolated high LDL cholesterol  Bile Acid Sequestrants Adverse effects: Constipation, bloating, GI discomfort. Examples: Cholestyramine, Colestipol, Colesevelam. Niacin (Vitamin B3)  Niacin (Vitamin B3) Mechanism of action: In adipose tissue, niacin inhibits the lipolysis of triglycerides by hormone-sensitive lipase, which reduces transport of free fatty acids to the liver and decreases hepatic triglyceride synthesis. Niacin also may inhibit a rate-limiting enzyme of triglyceride synthesis, diacylglycerol acyltransferase-2 Indications: Mixed dyslipidemias (low HDL, high LDL, and triglycerides). Adverse effects: Flushing (reduced with aspirin), hyperglycemia, hepatotoxicity, GI upset, itching. Examples: Niacin (extended-release and immediate-release formulations). Cholesterol Absorption Inhibitors  Ezetimibe Mechanism of action: Inhibits the absorption of cholesterol at the intestinal brush border by targeting the NPC1L1 transporter. Works synergistically with statins. Indications: High LDL cholesterol. Combination therapy with statins for enhanced LDL reduction. Adverse effects: Diarrhea, fatigue, mild liver dysfunction. Omega-3 Fatty Acids  Omega-3 Fatty Acids Mechanism of action: Reduce hepatic triglyceride synthesis and enhance clearance. Indications: Severe hypertriglyceridemia (>500 mg/dL). Adverse effects: GI upset, fishy aftertaste. Examples: Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), Icosapent ethyl. Lomitapide  Lomitapide Mechanism of action: Inhibits microsomal triglyceride transfer protein (MTP), reducing the production of VLDL and LDL. Indications: Homozygous familial hypercholesterolemia. Adverse effects: Liver enzyme elevation, GI distress. PCSK9 Inhibitors  PCSK9 Inhibitors Mechanism of action: Monoclonal antibodies inhibit PCSK9-Proprotein Convertase Subtilisin/Kexin Type 9, which normally degrades LDL receptors. This enhances LDL receptor recycling and increases LDL clearance. Indications: Severe hypercholesterolemia (e.g., familial hypercholesterolemia, statin-resistant cases). High cardiovascular risk patients. Adverse effects: Injection site reactions, flu-like symptoms, nasopharyngitis. Examples: Alirocumab, Evolocumab. Apolipoprotein B Antisense Oligonucleotides Apolipoprotein B Antisense Oligonucleotides Mechanism of action: Inhibits apoB synthesis, reducing LDL production. Indications: Homozygous familial hypercholesterolemia. Adverse effects: Injection site reactions, flu-like symptoms, elevated liver enzymes. Examples: Mipomersen Cholesteryl ester transfer protein inhibitors  CETP Inhibitors Mechanism of action: Inhibit cholesteryl ester transfer protein (CETP), increasing HDL levels and reducing LDL. Indications: Primarily under study for raising HDL in cardiovascular disease. Examples: Anacetrapib, Evacetrapib. Thank you