Lecture 7: Atherosclerosis & Coagulation

Lecture 7: Atherosclerosis & Coagulation Atherosclerosis · arterial plaque · endothelial cell damage stimulates atherosclerosis and clotting: ↳ mechanical stress (hemodynamic - hypertension) ↳ immune response & inflammation (nicotine, cytokines) ↳ Oxidative stress (reactive oxygen species aka ROS or free radicals) · plaque made of foam cells (macrophages & lipids) and aggregated platelets (clots) · clot maturation causes calcium deposits making it hard and brittle ↳ risk of rupture or dissection (bleeding into tissues) ↳ may obstruct blood flow ↳ risk of thrombus or embolus Warning Sign = Angina ↳ increased PVR = HTN - - Plaque Pathogenesis ① VCAM-1: Begins due to injury or a trigger (eg. cholesterol). Endothelial cells produce VCAM-1, a surface adhesion molecule ② Monocytes: Circulating monocytes adhere to endothelium with VCAM-1 ③ Macrophages: Monocytes differentiate into macrophages and release free radicals → oxidative stress ④ LDLs: oxidative stress makes circulating lipids (LDL) cytotoxic to endothelial cells causing injury and platelet aggregation ⑤ Foam cells: Oxidized LDLs are phagocytosed by macrophage and become foam cells ⑥ Fatty Streak: Apoptosis of foam cells, leaving lipid residue from LDL "fatty streak" Fatty Streak · first signs of atherosclerosis as young as age 20 · first occurrences in aorta and coronary arteries ↳ Angina → MI - Atherosclerosis TX: · Organic Nitrates ↳ drug: nitroglycerin (nitro) ↳ SL tablet q5 min x 3 doses → call EMS · 1st line tx of coronary flow obstruction (angina diagnosis) Risk Factors: · Hypertension · High lipids · Oxidative Stress (nicotine!) · Family Hx - Fats/Lipids · energy source: 9 cal/g · stored as triglycerides (3 fatty acids + glycerol) in adipose tissue ↳ fatty acids: saturated fats, trans fats, unsaturated fats · Structural resources ↳ cholesterol for hormones, Vitamin D, bile (body + diet) ↳ phospholipids for cell membranes (diet only) · As required fats can break down via glycolysis into glucose Not as bad Not as bad Really bad - Really bad - Types of Lipids · lipids combine w/protein carriers for transport (lipoproteins) ① LDL: distributes to cells, cholesterol carrier ② VLDL: distributes to cells, triglyceride carrier ③ HDL: excreted by liver in bile, primarily cholesterol · Health issues from high LDL & VLDL - hyperlipidemia, hypercholesterolemia 4604 * Dyslipidemia · abnormal (high or low) levels of lipoprotein · note: the liver makes cholesterol from Acetyl-Coa, pyruvate, and other enzymes, and excess cholesterol may be excreted via bile · Lifestyle changes!! · 3 drug subclasses: * DA ① Statins* ↳ 1st line tx post MI ② Niacin (increases HDL) Mostly just ↳ decreases liver cholesterol synthesis & increases for synergy clearance (issue W/antihypertensives) ③ Fibrates (decreases VLDL) ↳ increases lipolysis & metabolism(issue w/anticoagulants) ↳ fenofibrate (Lipidil) ① Statins · “HMG-CoA Reductase Inhibitors” · lowers LDL by inhibiting HMG-CoA causing less cholesterol biosynthesis · drugs: Lovastatin (Mevacor), Atorvastatin (Lipitor), Simvastatin (Zocor) ↳ liver dependent, POqd ↳ s/e: myopathy, drug interactions - Oxidative Stress · caused by free radicals ↳ ROS (unpaired oxygen molecules) ↳ cytotoxic substances · Tx: Antioxidants ↳ help balance oxidative stress ↳ foods high in Vitamin C (grapes, oranges, peppers) ↳ reduces reactive molecules, supports normal cellular enzyme function Hemostasis · the formation of clots 1) primary plug w/platelets 2) coagulation cascade Primary Plug Formation: 1. Vasospasm: endothelin is released causing vasospasm (ACE and NO are also released) 2. platelet adhesion: vWF (glycoprotein) binds to collagen fibers 3. Platelet activation: platelets degranulate and release chemical mediators that signal more platelets ↳ ADP, thromboxane A2, thrombin 4. Platelet aggregation: glycoprotein IIb/IIa increases platelet adhesion and crosslinks platelets to form initial clot - Trigger: internal damage · inactive factors are made in the liver · active factors have "a" (eg. Xa) · remember names and factors O gulation as Proactivating O substrates > efactor 10 - O ~ efactor 2a Trigger: external damage more Antiplatelets · interferes with the ability of platelets to adhere, activate, or aggregate ① blocks thromboxane A2 in degranulation drugs: ASA (Aspirin), Dipyridamole ↳ Cox-1 inhibition = decreased platelet aggregation Low Dose ASA "Baby Aspirin" combo drug: Aggrenox (ASA + dipyridamole) ② block ADP in degranulation · dose for pain/inflammation: 325-650 mg, q4h · dose for CV: 81 mg drug: Clopidogrel (Plavix) · pediatrics - Kawasaki disease: 10-15 mg/kg ↳ better for pediatrics b/c ASA not good for kids ③ Glycoprotein IIB/IIA receptor inhibition drug: abciximab (Reopro), Integrillin, Aggrastat ↳ extremely potent, immediate onset, IV bolus ↳ emergency intervention - s/e of antiplatelets: hemorrhage HITT Anticoagulants · heparin induced thrombocytopenia ① Heparins · immune reaction to heparin (& platelet factor 4) · drug: Heparin, IV (Short t1/2) · also low-molecular-weight heparins: ↳ enoxaparin (lovenox), SC ↳ dalteparin (Fragmin) ↳ apixaban (Eliquis), PO → not heparin type, but same MOA · MOA: inhibits factor Xa & IIa → no thrombin ② Dabigatran (Pradaxa), PO · MOA: blocks thrombin receptors & factor IIa ③ Warfarin (Coumadin), PO · MOA: inhibits hepatic synthesis of specific clotting factors (II, VII, IX, X) · long + 1/2, high PPB, narrow TI Thrombolytics · promote fibrinolysis (clot destruction) by converting plasminogen to plasmin, which then digests the clot/clotting factors · drug: tissue plasminogen activator (tPA)(Alteplase, Reteplase) ↳ IV, T 1/2 13-16 min Lab Monitoring · Warfarin = prothrombin time (PT/INR) · Heparin = activated partial thromboplastin time (aPTT) · Low molecular wt heparins = Anti Factor Xa levels in blood · Bleeding Risk = CBC, Hgb, Plt, Hct Reversing the Effects · Protamine sulfate for Heparins · Praxbind for Pradaxa · Vitamin K for Coumadin (Warfarin)