1. Introduction to Lipoproteins and Lipid Metabolism Hyperlipidemia (or dyslipidemia) is defined as an elevation in plasma lipids, including cholesterol, cholesterol esters, triglycerides (TGs), and phospholipids. These lipids are insoluble in water and must be transported in the blood complexed with specialized proteins known as apoproteins (apolipoproteins). The lipid-protein complex is called a lipoprotein. Figure 1. Structure and classification of lipoproteins. Lipoproteins consist of a hydrophobic core of triglycerides and cholesteryl esters surrounded by a hydrophilic shell of phospholipids, free cholesterol, and apoproteins. They are classified by density and size, from the large, TG-rich chylomicrons to the small, dense, protein-rich HDL. Dyslipidemia is a major risk factor for atherosclerosis and atherosclerosis-associated conditions such as coronary artery disease (CAD), ischemic stroke, and peripheral vascular disease. 1.1 Classification of Lipoproteins Lipoproteins are classified based on their density, size, and composition. The "Good" vs. "Bad" cholesterol dichotomy is central to clinical pharmacology. LipoproteinDensityMajor Lipid ComponentSourceMajor ApoproteinsFunctionChylomicronsLowestTriglycerides (Dietary)IntestineB-48, C-II, ETransport dietary TGs to adipose/muscle tissue.VLDL (Very Low Density)LowTriglycerides (Endogenous)LiverB-100, C-II, ETransport hepatic TGs to peripheral tissues.IDL (Intermediate Density)IntermediateCholesterol & TGsCatabolism of VLDLB-100, EPrecursor to LDL.LDL (Low Density)LowCholesterolCatabolism of IDLB-100"Bad Cholesterol": Transports cholesterol to tissues. Highly atherogenic.HDL (High Density)HighestPhospholipids & CholesterolLiver/IntestineA-I, A-II, C-II, E"Good Cholesterol": Reverse cholesterol transport (tissues to liver). Note for Exams: 2. Classification of Hypolipidemic Drugs Drugs used to treat dyslipidemia can be classified based on their primary mechanism of action, which involves different organs and pathways. Figure 2. Sites of action of major antihyperlipidemic drugs. The diagram illustrates the key organs (liver, intestine, adipose tissue) and the specific molecular targets for statins, fibrates, bile acid sequestrants, ezetimibe, niacin, and PCSK9 inhibitors. 3. HMG-CoA Reductase Inhibitors (Statins) "The cornerstone of modern lipid-lowering therapy." 3.1 Mechanism of Action Statins are structural analogs of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A). Their primary action is in the liver. Figure 3. Mechanism of action of statins. Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. This lowers intracellular cholesterol, activating the SREBP pathway. SREBP enters the nucleus and increases the expression of the LDL receptor gene, leading to more LDL receptors on the cell surface and increased clearance of LDL from the blood. Effect on Lipid Profile: 3.2 Pleiotropic Effects (Non-Lipid Effects) Statins provide cardiovascular benefits beyond lipid lowering (often asked in PG exams): 3.3 Pharmacokinetics (The "Statins Table") DrugLipophilicityProdrug?Metabolism (CYP)Half-life (t1/2)Timing of DoseLovastatinHighYes (Lactone)3A42–4 hrsEvening/MealSimvastatinHighYes (Lactone)3A42–3 hrsEveningPravastatinLow (Hydrophilic)NoSulfation (Not CYP)1–3 hrsBedtimeAtorvastatinHighNo3A414 hrsAnytimeRosuvastatinLow (Hydrophilic)No2C9 (Minor)19 hrsAnytimeFluvastatinHighNo2C91–3 hrsBedtimePitavastatinHighNo2C912 hrsAnytime 3.4 Adverse Effects 3.5 Drug Interactions 4. Fibric Acid Derivatives (Fibrates) Primary Indication: Severe Hypertriglyceridemia. 4.1 Mechanism of Action Fibrates are agonists of PPAR-α (Peroxisome Proliferator-Activated Receptor-alpha), a nuclear transcription factor. Effect on Lipid Profile: 4.2 Adverse Effects 4.3 Contraindications 5. Bile Acid Sequestrants (Resins) Drugs: Cholestyramine, Colestipol, Colesevelam. 5.1 Mechanism of Action 5.2 Clinical Nuance 5.3 Adverse Effects 6. Cholesterol Absorption Inhibitors Drug: Ezetimibe. 6.1 Mechanism of Action 6.2 Clinical Use 7. Nicotinic Acid (Niacin) "The most effective agent for raising HDL." 7.1 Mechanism of Action 7.2 Adverse Effects & Limitations Note: Due to side effects and lack of robust outcomes data in the statin era (AIM-HIGH, HPS2-THRIVE trials), Niacin use has declined significantly. 8. PCSK9 Inhibitors (The New Era) Drugs: Alirocumab, Evolocumab (Injectable monoclonal antibodies). 8.1 Mechanism of Action Figure 4. Mechanism of action of PCSK9 inhibitors. In the normal state, PCSK9 binds to the LDL receptor and promotes its lysosomal degradation. PCSK9 inhibitors (monoclonal antibodies) bind to circulating PCSK9, preventing it from binding to the receptor. This allows the LDL receptor to recycle back to the cell surface, increasing the number of receptors available to clear LDL. 8.2 Efficacy 8.3 Clinical Use 9. Newer and Miscellaneous Agents 9.1 Bempedoic Acid 9.2 Lomitapide 9.3 Omega-3 Fatty Acids (EPA/DHA) 10. Comparative Summary Table for Exam Revision Drug ClassPrimary EffectLDLHDLTGMajor Side EffectsStatins↓ LDL synthesis↓↓↓↑↓Myopathy, ↑ Liver enzymes, Diabetes risk.Fibrates↑ TG clearance↓ or ↔↑↑↓↓↓Dyspepsia, Gallstones, Myopathy.Niacin↓ VLDL secretion↓↓↑↑↑↓↓Flushing, Gout, Hyperglycemia.Resins↑ Bile excretion↓↓↔↑ (bad)GI distress, bloating, constipation.Ezetimibe↓ Chol. absorption↓↓↔↓Diarrhea, rare liver enzyme elevation.PCSK9-i↑ LDL recycling↓↓↓↓↑↓Injection site reactions, Cost. 11. Clinical Management Guidelines (A Brief Overview) Current guidelines (e.g., ACC/AHA 2018, ESC 2019) move away from "target numbers" alone and focus on Risk Stratification. 12. References (Vancouver Style)
