8. Pharmacology of Hypercholesterolemia

Page 1: Introduction to Pharmacology of Hypercholesterolemia

• Presenting: Dr. Declan McKernan

• Course: PM309 Cardiovascular Drugs

• Contact: declan.mckernan@universityofgalway.ie

Page 2: Lipoprotein Metabolism Overview

• Components involved in lipid transport include:

  • Liver and Peripheral Cells: Key metabolic sites

  • LDL (Low-Density Lipoprotein) and HDL (High-Density Lipoprotein): Major lipoproteins involved in cholesterol transport

  • Key Proteins: HMGCR, PCSK9, SRBI, ApoB100, ApoA1, CETP

  • Process includes conversion of chylomicrons from the intestine to VLDL, LDL metabolism, and distribution in the bloodstream.

Page 3: Learning Outcomes

• Key Goals for PM309:

  • Describe types of dyslipidemias and pharmacological targets.

  • Compare mechanisms of action, pharmacokinetics, and side effects of dyslipidemia-targeting drugs.

Page 4: Atherogenesis and Atherosclerosis

• Atherogenesis: Formation of fatty deposits in arteries.

• Atherosclerosis: Hardening of arteries through calcification.

• **Process:

  1. Injury to dysfunctional endothelium leads to increased adhesion molecules and attachment of monocytes.

  2. Oxidation of LDL cholesterol results in foam cell formation.

  3. Foam cell and T cell accumulation leads to fatty streaks.

  4. Cytokine release promotes cell proliferation and collagen deposition.

  5. Plaque rupture poses risk of thrombosis, potentially leading to stroke or myocardial infarction.

Page 5: Dyslipidemia Classification

• Risk Factors: Increased LDL and decreased HDL cholesterol levels linked to higher CV mortality.

• Primary dyslipidemia: Caused by diet and genetics.

• Secondary dyslipidemia: Related to conditions like diabetes or renal failure.

• Frederickson classification: Six classified phenotypes.

Page 6: Hypercholesterolemia

• Definition: Elevated total plasma and LDL cholesterol levels.

• Familial Hypercholesterolemia (FH): Genetic defects impact LDL receptor synthesis, defective ApoB100, and PCSK9 mutations.

• Polygenic Hypercholesterolemia: No specific genetic cause, often due to gene-environment interactions or multiple genetic defects.

Page 7: Hypertriglyceridemia

• Definition: High plasma triglycerides post-overnight fast.

• Major Causes:

  • Familial hypertriglyceridemia.

  • Familial lipoprotein lipase deficiency.

  • ApoCII deficiency.

• Age, weight gain, obesity, and diabetes contribute to development.

Page 8: Management and Pharmacological Agents

• Diet First Approach: Dietary intervention before drugs unless conditions like FH are present.

• Targets: Cholesterol, saturated, and trans fats.

• Lifestyle Changes: Weight reduction and physical activity important.

• Main Drug Classes:

  1. Statins (inhibit cholesterol synthesis)

  2. PCSK9 Inhibitors

  3. Bile Acid Absorption Inhibitors

  4. Cholesterol Absorption Inhibitors

  5. Fibrates

Page 9: Statins

• Mechanism of Action (MoA): Inhibit HMG-CoA reductase, increase LDL receptor expression, decrease plasma LDL by ~60%.

• Clinical Uses: First-line therapy for hypercholesterolemia, secondary prevention of heart attack and stroke, and primary prevention in at-risk patients.

Page 10: Statins Continued

• Additional Actions: Improve endothelial function, reduce inflammation, prevent platelet aggregation.

• Pharmacokinetics (PK):

  • Good oral bioavailability, metabolized by CYP450 enzymes.

  • Common Side Effects: Muscle pain, GI disturbances, rare rhabdomyolysis. Contraindicated in pregnancy.

Page 11: PCSK9 Inhibitors

• MoA: Monoclonal antibodies prevent binding of PCSK9 to LDL receptors, lowering plasma LDL levels.

• Clinical Uses: For primary hypercholesterolemia in statin-resistant patients or as add-ons.

• Side Effects: Common flu-like symptoms, nasopharyngitis.

Page 12: Bile Acid Absorption Inhibitors

• MoA: Resins bind bile acids, decreasing reabsorption and increasing bile acid synthesis.

• Clinical Uses: Adjuvant therapy to statins.

• Side Effects: Generally well-tolerated but may cause bloating and interfere with vitamin absorption.

Page 13: Cholesterol Absorption Inhibitors

• MoA: Inhibits ~50% cholesterol absorption in the intestines.

• Clinical Uses: Adds to statins or used when statins are contraindicated.

• Side Effects: Well-tolerated; potential issues include diarrhea and headache.

Page 14: Fibrates

• MoA: Act on PPARα, increasing HDL and decreasing triglycerides.

• Clinical Uses: Mixed dyslipidemia, particularly where triglycerides are elevated.

Page 15: Fibrates Continued

• PK: High plasma protein binding, variable half-lives.

• Side Effects: May include GI discomfort and severe rhabdomyolysis. Contraindicated for alcoholics.

Page 16: Other Drugs for Hypercholesterolemia

• Mipomersan: Inhibits synthesis of apoB100; used as add-on for FH.

• Lomitapide: Inhibits triglyceride transfer protein assembly of apoB; clinical use for FH.

Page 17: Summary

• Atherogenesis forms fatty deposits in blood vessels leading to atherosclerosis, increasing coronary artery disease risk.

• Dyslipidemias lead to atherosclerosis; causative factors include genetics, disease conditions, diet, and environment.

• Drugs primarily target cholesterol synthesis and transport to reduce circulatory levels and deposition in vessels.