DRUG THERAPY OF HYPERLIPIDEMIA 1. Inhibitiоn оf Chоlesterol Synthesis HMG-CoA Reductаse Inhibitors (Stаtins) Atorvаstatin, Rosuvastatin, Simvastatin, Pravastatin, Lovastatin Mechanism Inhibit HMG-CoA reductase → ↓ hepatic cholesterol synthesis ↑ LDL receptors → ↑ LDL uptake from blood ↓ LDL, ↓ VLDL, mild ↑ HDL Lipid effects ↓↓↓ LDL (20–60%) ↓ TG (10–30%) ↑ HDL (5–10%) Pleiotropic (non-lipid) benefits ↓ inflammation & ROS ↓ endothelial dysfunction ↓ platelet aggregation Stabilize atherosclerotic plaques Pharmacokinetics (high yield) Oral CYP3A4 metabolism: atorvastatin, simvastatin, lovastatin → many drug interactions Pravastatin/rosuvastatin → minimal CYP metabolism → safer interactions Biliary excretion (mostly) Dose adjustment in renal disease (except atorvastatin preferred in severe CKD) Uses All dyslipidemias (first-line) ASCVD prevention (CAD, stroke prevention) Combination therapy with ezetimibe or PCSK9 inhibitors Adverse effects Myopathy → myositis → rhabdomyolysis (↑ CK) Worse with: fibrates (esp. gemfibrozil), niacin, colchicine Hepatotoxicity (↑ LFTs) ↑ Risk of type 2 DM Contraindicated in active liver disease Avoid in pregnancy & breastfeeding 2. ↑ Lipoprotein Lipase (LPL) Activation — Fibrates Fenofibrate (preferred), Gemfibrozil Mechanism Activate PPAR-α → ↑ LPL activity ↑ TG breakdown → ↓ VLDL Lipid effects ↓↓↓ TG (35–50%) ↓ LDL (5–15%) ↑ HDL (5–20%) Uses Severe hypertriglyceridemia (pancreatitis prevention) Mixed dyslipidemia with high TG Adverse effects GI upset Myopathy (↑ with statins, especially gemfibrozil) Gallstones (↑ biliary cholesterol) Hepatotoxicity Possible ↑ CV risk (gemfibrozil concern) Key interaction Gemfibrozil ↑ statin toxicity (CYP inhibition) Pregnancy Avoid unless severe TG (>1000 risk pancreatitis) 3. Inhibition of Cholesterol Absorption Ezetimibe Mechanism Blocks NPC1L1 transporter in intestinal brush border ↓ cholesterol absorption → ↓ hepatic cholesterol → ↑ LDL receptors Lipid effects ↓ LDL (~15–20%) Mild ↓ TG Slight ↑ HDL Uses Add-on to statins (very common) Statin intolerance Adverse effects Diarrhea Mild ↑ LFTs Myalgia (rare, ↑ with statins) Contraindications Active liver disease Pregnancy (limited data) 4. PCSK9 Inhibitors (MOST POWERFUL LDL-Lowering Drugs) Alirocumab, Evolocumab Mechanism Inhibit PCSK9 → prevent LDL receptor degradation ↑ LDL receptors → massive LDL clearance Lipid effects ↓↓↓↓↓ LDL (40–70%) ↓ TG ↑ HDL Uses Familial hypercholesterolemia ASCVD patients needing additional LDL lowering Statin-resistant hyperlipidemia Adverse effects Injection site reactions URTI, nasopharyngitis Rare hypersensitivity Route Subcutaneous every 2–4 weeks 5. Omega-3 Fatty Acids Icosapent ethyl (EPA-only) Omega-3 acid ethyl esters (EPA + DHA) Mechanism ↓ hepatic VLDL synthesis ↑ fatty acid oxidation ↑ LPL activity Anti-inflammatory effects Lipid effects ↓↓↓ TG (25–45%) ↑ HDL Minimal LDL effect (EPA-only preferred) Uses Severe hypertriglyceridemia ASCVD risk reduction (especially EPA-only formulation) Adverse effects Fishy taste (compliance issue) GI upset ↑ bleeding time at high doses (platelet inhibition) Question: A 58-year-old man with a history of coronary artery disease is started on a medication that inhibits HMG-CoA reductase. Three weeks later, he reports muscle pain and weakness. Laboratory testing shows: Creatine kinase (CK): 12,300 U/L (normal: 30–200 U/L) AST/ALT: mildly elevated The patient is also taking gemfibrozil for hypertriglyceridemia. Which of the following best explains this patient’s condition?
Rоcket Burn аnd Mаximum Altitude PHY 2048C Cumulаtive Final Examinatiоn Pоints: 10 Suggested Time: 25–30 minutes Instructions: Show all work. Begin each derivation with an appropriate fundamental physics principle. Clearly define any additional symbols you introduce. Unsupported answers may not receive full credit. A research rocket launches vertically from rest. During the powered portion of the flight, fuel is expelled downward at a constant speed u relative to the rocket. Fuel is consumed at a constant rate λ, so the rocket's mass is m(t) = m0 − λt, 0 ≤ t ≤ tb where m0 is the initial mass and tb is the burnout time. Assume m0 > λtb. Neglect air resistance, take upward as positive, and treat g as constant. After burnout, the rocket coasts upward under gravity alone. Tasks Part A. Starting from conservation of momentum for a variable-mass system, derive the rocket's velocity v(t) during the burn. Your final expression must be in terms of u, m0, λ, t, and g. Part B. Determine the rocket's burnout speed vb. Part C. Derive an expression for the vertical distance yb traveled during the powered portion of the flight. You may use the initial conditions y(0) = 0 and v(0) = 0. Part D. Determine the rocket's maximum altitude ymax above the launch point. Part E. State the minimum condition on u, λ, m0, and tb required for the rocket still to be moving upward at burnout.
Pulley System with Rоtаtiоnаl Inertiа PHY 2048C Cumulative Final Examinatiоn Points: 10 Suggested Time: 20–25 minutes Instructions: Show all work. Begin each derivation with an appropriate physics principle. Clearly define any additional symbols you introduce. Block 1 of mass m1 rests on a frictionless incline of angle θ. It is connected by a light cord over a pulley to a hanging block of mass m2. The pulley has radius R and moment of inertia I. The cord does not slip on the pulley. Assume block 2 moves downward and block 1 moves up the incline. Tasks Part A. Write Newton's second-law equation for each block and the rotational equation for the pulley. Part B. Derive the magnitude of the acceleration a of the system. Part C. Determine the two cord tensions T1 and T2. Part D. Starting from rest, determine the speed v of the blocks after block 2 descends a distance s. You may use either Newton's laws or conservation of energy.