Presenting: Dr. Declan McKernan
Course: PM309 Cardiovascular Drugs
Contact: declan.mckernan@universityofgalway.ie
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.
Key Goals for PM309:
Describe types of dyslipidemias and pharmacological targets.
Compare mechanisms of action, pharmacokinetics, and side effects of dyslipidemia-targeting drugs.
Atherogenesis: Formation of fatty deposits in arteries.
Atherosclerosis: Hardening of arteries through calcification.
**Process:
Injury to dysfunctional endothelium leads to increased adhesion molecules and attachment of monocytes.
Oxidation of LDL cholesterol results in foam cell formation.
Foam cell and T cell accumulation leads to fatty streaks.
Cytokine release promotes cell proliferation and collagen deposition.
Plaque rupture poses risk of thrombosis, potentially leading to stroke or myocardial infarction.
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.
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.
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.
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:
Statins (inhibit cholesterol synthesis)
PCSK9 Inhibitors
Bile Acid Absorption Inhibitors
Cholesterol Absorption Inhibitors
Fibrates
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.
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.
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.
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.
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.
MoA: Act on PPARα, increasing HDL and decreasing triglycerides.
Clinical Uses: Mixed dyslipidemia, particularly where triglycerides are elevated.
PK: High plasma protein binding, variable half-lives.
Side Effects: May include GI discomfort and severe rhabdomyolysis. Contraindicated for alcoholics.
Mipomersan: Inhibits synthesis of apoB100; used as add-on for FH.
Lomitapide: Inhibits triglyceride transfer protein assembly of apoB; clinical use for FH.
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.