Cardiovascular System Anatomy and Primary Prevention PDF

Anatomy Refresher and Primary Prevention (ASCVD Risk Assessment): Cardiovascular System: 1. Purpose: a. Transport blood (oxygen and nutrients) to tissues in exchange for CO2 and other waste b. System includes heart (cardio) and blood vessels (vascular) 2. Heart: a. Enclosed in fibrous sac i. Two layers that protect and secure heart behind mediastinum b. Epicardium (OUTER layer) c. Myocardium (MUSCLE) d. Endocardium (INNER layer) e. 4 pumping chambers (2 atria and 2 ventricles) Pathway of Blood Flow through Heart and Lungs: 1. Venous return 2. Right side heart 3. Pulmonary 4. Left side of heart 5. Systemic circulation External Heart (Anterior View): Heart Chambers: 1. Atria: a. “Receiving” chambers of the heart b. Thin walled 2. Ventricles: a. “Discharging” chambers of the heart b. Papillary muscles and trabeculae carneae muscles mark ventricular walls c. Right ventricle pumps blood into pulmonary trunk d. Left ventricle pumps blood into aorta (systemic ventricle) Coronary Circulation: 1. Coronary circulation is the functional blood supply to the heart muscle itself 2. Collateral routes ensure blood delivery to heart even if major vessels are occluded Coronary Arteries: Coronary Veins: Heart Valves: 1. Heart valves ensure unidirectional blood flow through the heart 2. Atrioventricular (AV) valves a. Lie between the atria and the ventricles b. AV valves prevent backflow into the atria when ventricles contract 3. Semilunar valves prevent backflow of blood into the ventricles a. Aortic valves lies between the left ventricle and the aorta b. Pulmonary valve lies between the right and pulmonary trunk Heart Sounds: 1. Heart sounds are associated with closing of heart valves a. FIRST SOUND occurs as AV valves close and signifies beginning of systole (contraction) b. SECOND SOUND occurs when SL valves close at the beginning of ventricular diastole (relaxation) Cardiac Conduction: 1. Muscle is stimulated by nerves is “self-excitable” (aka automaticity) 2. Sinoatrial (SA) node generates impulses at 80-90 times/min 3. Atrioventricular (AV) node delays impulse by 0.1 second 4. AV bundle (bundle of His) splits into two pathways a. Right/left bundle branches 5. Impulse carried through Purkinje fibers to heart apex and ventricular walls 6. Ventricular automaticity at 40 times/min a. Back up plan Cardiac Cycle: 1. Cardiac cycle refers to all events associated with blood through the heart a. Systole: contraction of heart muscle b. Diastole: relaxation of heart muscle 2. Ventricular filling a. Mid to late diastole b. Heart blood pressure is low as blood enters atria (passively) and flows into ventricles 3. AV valves are open then atrial systole occurs 4. Ventricular systole (atria relax) Primary Prevention of CVD: Primary versus Secondary: 1. Primary aims to prevent disease a. Reduces hazards (alters unsafe behaviors) b. Ex. Education about health habits, immunization against infection 2. Secondary aims to reduce the impact of disease that has already occurred a. Follow up and screening to detect progression b. Ex. Medications after heart attack, cardiac rehabilitation, disease support groups ABCDE of Primary Prevention: 1. A: Assess risk and Aspirin 2. B: Blood Pressure 3. C: Cholesterol a. Assess ASCVD risk, personalize with risk enhancers, reclassify with CAC as needed 4. C: Cigarettes 5. D: Diet/weight 6. D: Diabetes 7. E: Exercise Foods Known to Harm: 1. Increased availability and affordability of palpable and high calorie foods a. Sugar b. Low calorie sweeteners c. Refined grains d. Trans fat and saturated fat e. Sodium f. Red meat 2. Low fresh food consumption 3. Fad diets a. High carbohydrate diets and low carbohydrate diets b. Processed red meat Dietary Recommendations: 1. Use as many calories as you eat 2. Eat a variety of nutritious foods 3. Eat less nutrient poor foods 4. Consider the following when making choices: a. Consume a plant based or Mediterranean like diet b. Vegetables c. Fruits d. Nuts e. Fiber rich whole grains f. Lean vegetab;e or animal protein g. Vegetable fiber Overweight and Obesity Epidemic: 1. Overweight = BMI 25-29.9 kg.m 2. Obesity = BMI > 30 kg/m2 3. Increase risk of heart failure and atrial fibrillation too HMG CoA Reductase Inhibitors (Statins): Dyslipidemia: 1. Dyslipidemia is a major cause of atherosclerotic cardiovascular disease such as: a. Coronary artery heart disease b. Ischemic cerebrovascular disease c. Peripheral vascular disease 2. Cardiovascular disease a. Number one cause of death among adults 3. Dyslipidemias caused by a. Genetic factors and effects of lifestyle Sources of Cholesterol in Hypercholesterolemia: 1. Daily cholesterol turnover 2. Endogenous synthesis a. Accounts for 80% of body cholesterol b. 75% is made in liver i. Intestines, adrenals, brain and spinal cord, and skin are also sources ii. All cells are capable of synthesizing cholesterol c. Cholesterol in neuronal tissue is synthesized in situ i. Cholesterol does not cross blood brain barrier Sources of Cholesterol: 1. Dietary cholesterol a. Dietary cholesterol is derived from animal products i. Plants and fungi make alternative sterols (sitosterol, ergosterol) 1. Humans cannot use the plant sterols in place of cholesterol b. Meats (beef, poultry, pork), eggs, and high fat dairy products including butter and cheese, are rich sources of cholesterol Hyperlipidemias: 1. Hyperlipidemia results from disorders of lipoprotein metabolism 2. Hyperlipidemia disorders may be characterized as: a. Hypercholesterolemia: i. Elevated levels of total serum cholesterol b. Hypertriglyceridemia: i. Elevated levels of fasting total serum triglycerides >/= 150 mg/dl c. Mixed hyperlipidemia: i. Elevated serum cholesterol and triglycerides d. Atherogenic dyslipidemia: i. Elevated triglycerides, elevated LDL cholesterol, and reduced HDL cholesterol Lipoproteins: 1. Proteins associated with lipoproteins are called apolipoproteins (apo) a. Required for assembly and function of lipoproteins 2. Efficient transport of dietary lipids from the intestine to tissues a. Fatty acids for energy and metabolism b. Cholesterol transport to tissues and excretion by the liver 3. Because lipid is less dense than water a. Density of lipoprotein particle is determined by the amount of lipid per particle i. The MORE lipid rich, the LEAST dense b. HDL has the least lipid, therefore is the most dense lipoprotein 4. Cholesterol transported in the blood by lipoproteins a. Complexes of lipids and proteins 5. Water insoluble lipids are core components a. Cholesteryl esters and triglycerides (TGs) 6. Water soluble components located on the surface a. Apoproteins, phospholipids, and unesterified cholesterol Very Low Density Lipoproteins (VLDL): 1. Lipoproteins important for transport of hepatic lipids from the liver to the periphery a. Provides an energy source during fasting 2. During the fasting state, lipolysis of adipose TGs generates fatty acids that transported to the liver a. The fatty acids esterified by the liver into TGs, which are packaged into VLDL particles i. VLDL is a triglyceride rich lipoprotein b. After secretion by the liver into the plasma i. TGs of VLDL are released into tissues 1. Skeletal muscle, cardiac muscle, and adipose tissue Low-density lipoprotein (LDL): 1. TG depleted VLDL remnants are processed into intermediates, then remodeled to form LDL 2. The majority of plasma cholesterol is found in LDL 3. LDL becomes atherogenic when modified by oxidation a. Required for LDL uptake by vessels wall macrophages i. Process leads to foam cell formation in arterial lesions, development of atherosclerosis 4. Plasma clearance of LDL is mediated primarily by LDL receptors a. LDL is removed from the circulation by receptor mediated endocytosis in the liver apoB-100 serving as the ligand for the LDL receptor High Density Lipoprotein (HDL): 1. All nucleated cells synthesize cholesterol a. Only hepatocytes and enterocytes excrete cholesterol from the body b. In the liver, cholesterol is secreted into bile, either directly or after conversion to bile acids 2. Cholesterol in peripheral cells is transported by HDL to the liver and intestine for excretion 3. Dyslipidemias are not only characterized by increased plasma levels of cholesterol and/or TGs a. Also by reduced levels of HDL cholesterol Genetic Causes of Dyslipidemia: 1. Genetic variation contributes to elevated LDL-C levels in the general population 2. Most patients with elevated LDL-C a. Polygenic hypercholesterolemia from multiple genetic variants all producing LDL raising effects 3. In patients who are genetically predisposed to higher LDL-C levels, diet plays a key role a. Increased cholesterol in the diet i. Significant increases in LDL levels Genotypes Responsible for Phenotypes: 1. Human genome contains two copies (alleles) of most genes a. Paternal and maternal alleles 2. Heterozygous mutation: mutation on one allele 3. Homozygous mutation: identical mutation on both alleles 4. Autosomal recessive trait a. Two copies of mutant gene required for trait to develop 5. Autosomal dominant: a. The phenotype of heterozygotes is intermediate to the phenotype of homozygotes for the common allele (wild-types), and homozygotes for the mutant allele Familial Hypercholesterolemia (FH): 1. Autosomal dominant hypercholesterolemia a. Single gene (Mendelian) cause of elevated LDL-C b. Mutations of the LDL receptor gene (most common) i. One of the most common sing;e gene disorders in humans ii. Reduces function of the LDL receptor c. Reduced LDL receptor activity in the liver i. Reduced rate of clearance of LDL from the circulation 1. High levels of plasma LDL d. Heterozygous FH most common i. CV disease as early as age 30 e. Homozygous FH: severe atherosclerosis in childhood Low-Density Lipoprotein: 1. Liver expresses a large number of LDL receptors a. Removes LDL from the plasma by binding apoB-100 b. Also binds apoE i. Apolipoprotein in VLDL 2. Altering hepatic LDL receptor gene expression a. Effective way to modulate plasma LDL-cholesterol levels b. Inhibiting cholesterol synthesis with statins i. Increases hepatic LDL receptor expression Low-Density Lipoprotein Receptor Expression: 1. HMG-CoA reductase: key enzyme in cholesterol synthesis 2. Statin inhibition of HMG-CoA reductase a. Decrease cholesterol synthesis in the liver b. Reduced cholesterol levels in liver cells activates sterol regulatory element binding protein (SREBPs) i. Translocate to the nucleus 1. INCREASED gene expression of LDL receptors 2. INCREASED LDL receptors on the plasma membrane 3. Accelerated clearance of LDL and VLDL Inhibition of HMG-CoA Reductase: 1. HMG-CoA reductase is the principal regulatory step in cholesterol synthesis a. Catalyzes the rate limiting step in cholesterol synthesis to generate mevalonate 2. Inhibition of HMG-CoA reductase a. Up regulates LDL receptor expression i. Increases LDL removal from blood 1. Principal mechanism by which statins lower blood cholesterol ii. Increased removal of VLDL particles 1. By binding apoE a. Decreases plasma triglycerides Statin Pharmacology: 1. Statins: a. Widely used for lowering LDL cholesterol i. Rosuvastatin (Crestor) and Atorvastatin (lipitor) b. Statins DECREASE triglycerides c. Statins INCREASE HDL-C by 155 i. Inhibit an enzyme that removes cholesterol from HDL Statin Pharmacokinetics: 1. Absorption from intestine is variable 2. Extensive first pass uptake into liver a. Uptake by organic anion transporters 3. Several are CYP3A4 or CYP2C9 substrates a. Some metabolites are also active 4. Low intensity statins have half-lives of 1-4 hr a. Lovastatin, Pravastatin, simvastatin b. Cholesterol synthesis is diurnal and maximal at night i. Short lived statins should be taken in the evening 5. Atorvastain (Lipitor) and rosuvastatin (Crestor) have 20 hour half lives a. Used for high intensity statin therapy 6. Statins should be discontinued in most pregnancies a. Animal studies have shown fetal abnormalities Additional Beneficial Effects of Statins: 1. Produce anti-inflammatory effects a. Decrease levels of C-reactive protein (CRP) i. An independent marker of inflammation and CVD risk 2. Improvement of endothelial function a. Statin therapy increases nitric oxide release b. Statins decrease thrombogenicity 3. Statins may stabilize atheromas a. Inhibit monocyte infiltration b. Inhibit proliferation of smooth muscle cells Adverse Effects of Statins: 1. Muscle pain 2. Headache 3. Dizziness 4. Gastrointestinal: diarrhea, nausea 5. Diabetes mellitus 6. Increased creatinine kinase a. CK not routinely measured Interactions with Statins: 1. Dosage adjustments often required with concomitant medications 2. CYP3A4 substrates (inhibitors//inducers) may interact a. Fibrates, cyclosporine, digoxin, warfarin, macrolide antibiotics, azole antifungals, niacin, protease inhibitors (FCDW MAANP) 3. The fibrate gemfibrozil competes for uptake into liver a. Substrates for organic anion transporters b. May increase systemic serum concentration of statins i. May enhance the myopathic effects c. Avoid concomitant Genetic Risk for Statin Myopathy: 1. Gene variant in a liver organic anion transporter a. Associated with statin myopathy b. Those homozygous for the variant i. 20 fold higher risk for myopathy c. Variant has lower activity, resulting in decreased statin uptake into liver and higher statin blood levels d. Genetic testing is available for the variant i. Incidence of myopathy caused by the variant is low Ezetimibe (Zetia) and PCSK9 Inhibition: Ezetimibe (Zetia): 1. Ezetimibe (Zetia) is a cholesterol uptake blocker a. Prevents cholesterol from being absorbed by enterocytes of the small intestine i. Blocks Niemann-Pick C1-like 1 (NPC1L1) 1. Sterol uptake transporter on brush border of enterocytes 2. Reduces cholesterol absorption 3. Does not affect TG absorption b. Decreases cholesterol content of chylomicrons i. Remnant chylomicrons are highly atherogenic 2. A decrease in cholesterol delivery to the liver a. Activates sterol regulatory element binding protein (SREBP) i. Increased LDL receptor expression 1. Decreased blood LDL cholesterol levels ii. LDL receptor also binds apoE 1. Apolipoprotein in VLDL 2. VLDL contains high levels of triglycerides a. Reduced blood triglycerides (TGs) 3. Activation of SREBP also increases HMG-CoA reductase expression a. Increased cholesterol synthesis i. Limits the effectiveness of ezetimibe 4. Labeled Indications: a. Familial hypercholesterolemia, homozygous or heterozygous: in combination with a high intensity statin b. Primary hyperlipidemia or mixed hyperlipidemia: as adjunctive therapy to diet and an HMG-COA reductase inhibitor c. Indications as monotherapy: If an HMG-CoA reductase inhibitor is not tolerated in patients with hyperlipidemia i. Lowers LDL-C 1. Similar to low dose statins ii. Decreases TG iii. Increases HDL-C Ezetimibe Pharmacokinetics: 1. Dosing, metabolism, and excretion a. 10 mg taken orally once daily b. Undergoes enterohepatic recirculation c. Plasma half life elimination: 22 hours d. Effect last for up to 2 weeks 2. Interactions: a. Bile acid sequestrants bind ezetimibe i. Reduced effectiveness when taken at similar times ii. Administer at different times of the day Ezetimibe (Zetia): 1. Ezetimibe is most effective when paired with a statin a. Ezetimibe reduces intestinal absorption of cholesterol i. Decreases cholesterol delivery to the liver ii. Activates sterol regulatory element binding protein (SREBP) iii. Activation of SREBP increases HMG-CoA reductase expression 1. Stimulates cholesterol synthesis a. Effect that is counteracted by inhibition of cholesterol synthesis by HMG-CoA reductase inhibitors Ezetimibe Statin Combination: 1. Ezetimibe adds a 15-20% further decrease in LDL-C to a statin’s effect 2. Ezetimibie plus statin increased the number of patients demonstrating coronary plaque regression 3. May allow a lower dose of a statin a. Fewer adverse effects 4. Combination products with a. Bempedoic acid b. Atorvastatin c. Rosuvastatin d. Simvastatin Proprotein convertase subtilisin/kexin type 9 (PCSK9): 1. After LDL receptors in the liver bind LDL from the plasma a. LDL receptor and LDL internalized into the hepatocyte b. Traffics to a lysosome to be degraded or recycled back to the hepatocyte surface 2. PCSK9 binding to the LDL receptor a. Targets the receptor for enzymatic degradation b. Not recycled back to the surface of hepatocytes c. Results in reduced LDL receptor expression d. Less LDL-C removed from the plasma PCSK9 Inhibition: 1. In the presence of PCSK9 and antibody to PCSK9, antibody to PCSK9 prevents the binding of PCSK9 to the LDLR-LDL complex, thereby producing an effect similar to the absence of PCSK9 where the complex dissociates within the endosome, the LDL enters the lysosomal pathway of degradation, and the LDLR is recycled to the membrane Combined effects of statin and PCSK9 antibody: 1. Treatment with a statin and an antibody to PCSK9 a. Levels of LDLR are increased by two different mechanisms 2. Statin inhibition of HMG-CoA reductase reduces cell cholesterol a. Activates SREBP i. Upregulates genes for LDLR and PCSK9 1. LDLRs inserted into plasma membrane 2. PCSK9 is exported into blood b. Without AbPCSK9, increased PCSK9 binds to LDLR-LDL i. Causes LDLR lysosomal destruction 1. Counteracts some of statin's effect on LDLR expression c. With AbPCSK9, PCSK9 is inhibited thereby increasing LDLR surface expression to reduce LDL-cholesterol 3. The combination of a statin and AbPCSK9 prevents the reduction of LDLR surface expression induced by the statin PCSK9 Inhibitors: 1. Monoclonal antibodies against PCSK9 a. Evolocumab (Repatha) b. Alirocumab (Praluent) 2. Labeled Indications include: a. Homozygous familial hypercholesterolemia: Adjunct to diet and other LDL lowering therapies b. Hyperlipidemia primary: Adjunct to diet, alone or in combination with other lipid lowering therapies for primary hyperlipidemia, including heterozygous familial hyperlipidemia, to reduce LDL-C 3. Prevention of CV events in patients with established CVD. Use in combination with optimized lipid-lowering therapy (high-intensity statin) 4. SUBQ injections every 2 or 4 weeks Inclisiran Leqvio: 1. Novel inhibitor of PCSK9 mRNA (gene silencing) 2. Small interfering (si) RNA directed against PCSK9 mRNA 3. siRNA conjugated with an unusual amino sugar a. Targets a liver specific glycoprotein receptor on hepatocyte cell surface 4. Endocytosis of the receptor and bound siRNA a. Enables uptake of Inclisiran primarily into hepatocytes 5. Following hepatocyte uptake a. Antisense strand (complementary human PCSK9 mRNA sequence) integrated into the RNA-induced silencing complex b. Directs catalytic breakdown of PSK9 mRNA c. Prevents PCSK9 protein translation 6. Decreased PCSK9 protein translation a. Increases LDL receptor recycling to the cell surface b. Increased LDL-C uptake from circulation 7. Labeled indications: a. Heterozygous familial hypercholesterolemia b. Atherosclerotic CVD, primary prevention c. Adjunct to diet and maximally tolerated statin therapy who require additional LDL-C lowering 8. Elimination half-life from circulation: 9 hours 9. RNA induced silencing complex in hepatocytes a. Long term activity 10.Single injection, repeated at 3 months, then every 6 months Novel Treatment of Hypercholesterolemia: 1. First in class: a. Bempedoic acid (Nexletol) 2. Adenosine triphosphate-citrate lyase (ACL) inhibitor 3. ACL is an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway a. An enzyme present in liver cells, but not muscle cells i. Potential advantage food reduced myalgia 4. Administration: a. Oral 5. Labeled Indications: a. Atherosclerotic CVD, primary or secondary prevention b. Treatment of heterozygous familial hypercholesterolemia c. As an adjunct to diet and statin therapy, in adult patients who require additional lowering of LDL-C Management of Dyslipidemia: Recommending for Screening: 1. Given importance excess LDL-C plays in development of ASCVD a. Lipid panel is recommended in adults > 20 years b. In patients with significant family history, including Familial Hypercholesterolemia (FH), earlier screening recommended 2. Lipid panels do not require fasting in most a. In individuals whom an initial non-fasting lipid profile reveals a triglycerides level of 400 mg/dL or higher measurement should be repeated following fast b. Fasting sample is recommended in patients with premature family history and if FH is suspected Statins as First Line Agents: 1. Statins and role in ASCVD risk reduction a. Meta analysis of statin trials by CTT support lipid therapy b. Statins are FIRST LINE for both primary and secondary prevention What are the 4 Statin Treatment Groups?: 1. Clinical ASCVD (Secondary Prevention) 2. Primary Hypercholesterolemia > 190 3. 40-75 age with Diabetes and LDL-C > 70 4. 40-75 age Primary Prevention What is “clinical ASCVD” for purposes of Cholesterol Management?: 1. Applies to all patients > 18 years of age + with history of ACS (MI, stable or UA, revascularization), stroke/TIA, ot peripheral arterial disease (including aortic aneurysm) 2. Initial high intensity statin with goal > 50% reduction in LDL-C a. If > 75 years moderate or high intensity statin 3. For patients with stable ASCVD either high or moderate intensity pain 4. Evaluation if patients is at VERY high risk for recurrent ASCVD events What are our Goals in Secondary Prevention? 1. Prevent Major Adverse Cardiovascular Endpoints (MACE) a. Recurrent ASCVD events (myocardial infarction, stroke, etc.) 2. Prevent CV death 3. Prevent Death from any cause LPS AR Statin Initiation: 1. Statin intensity selected based on indication and patient specific risk discussion 2. Baseline laboratory information a. Transaminases/LFTs and confirm NOT severe CKD b. Screen for drug interactions c. Lipid panel 3. Repeated Measures a. Lipid panel at 4-12 weeks after initiation b. Lipid panel every 3-12 months c. No routine monitoring of LFTs or CK VERY High Risk Patients: 1. Defined: a. Multiple major ASCVD events OR 1 major + multiple high risk conditions 2. Treats with maximal tolerated statin 3. If LDL-C remains > 70 mg/dL (non-HDL-C > 100 mg/dL) add non-statin therapy to achieve LDL-C target When and What to Add-On? 1. At time of 2018, two additional medications that lower LDL-C had been shown to improve MACE a. PCSK9-inhibitors and ezetimibe 2. Now Bempedoic acid can be added to list a. Inclisiran (siRNA) is in Phase III RCT 3. PCSK9 Inhibitor if need > 25% additional LDL-C lowering (ezetimibe if close) a. Might favor PCSK9 inhibitor either way based on outcome data Diabetes Specific Risk Enhancers: 1. Used to guide risk discussion in diabetic patients 2. To aid in decisions for initiation or intensification of statin therapy a. Particularly in younger diabetic patients 3. Condition: a. Long duration b. Albuminuria c. eGFR 190 mg/dL high-intensity statin +/- add-on therapy to lower LDL-C by < 50% 4. At least moderate intensity statin in diabetic patients with evaluation of risk enhancers to guide intensification 5. For primary prevention a. In adults 40-75 and LDL-C. 70 mg/dL use PCE to estimate 10 year ASCVD risk b. Consider statin if > = 7.5% and risk discussion favors statin 6. In moderate risk and patient with > 7.5% 5isk, risk enhancing factors, CAC, etc. may support initiation or intensification of statin therapy Mixed Dyslipidemia: Bile Acid Sequestrants: Bile Acid Sequestrants Drugs Cholestyramine (Questran) Colestipol (Colestid) Colesevelam (Welchol) Chemistry 1. Highly charged polymers 2. Bind negatively charged bile acids a. Promotes elimination in feces 3. Insoluble and not absorbed from intestine a. Among the safest hypolipidemic drugs 4. Often preferred meds in children and during pregnancy MOA 1. Bile acids are synthesized in the liver a. CYP P450 oxidation of the parent molecule cholesterol 2. Normally 90% of bile acids are recycled a. Efficiently reabsorbed in the lower small intestine b. Enterohepatic circulation allows each bile acid molecule to be reused 20 times 3. Bind bile acids in the intestine to prevent their reabsorption a. Eliminated in the feces 4. Intestinal loss of bile acids a. Requires new bile acids to be synthesized in the liver b. Synthesis requires the parent molecule cholesterol i. Reduces cholesterol levels in liver cells ii. Activates sterol regulatory element binding proteins iii. LDL receptor expression is INCREASED iv. Hepatic cholesterol synthesis is INCREASED 1. Upregulation of HMG-CoA reductase ADRs BAS-induced bile acid synthesis 1. Increases hepatic triglyceride synthesis a. Most important in patients with significant hypertriglyceridemia b. NOT used in patients with high baseline fasting triglyceride levels 2. Common complaints a. Bloating, indigestion, constipation 3. Interfere with absorption of many drugs a. Diuretics, digoxin, beta-blockers, statins Fibrates: Fibrates Drugs Gemfibrozil (Lopid) Fenofibrate (Tricor, Antara, Trilipix) Indications Treatment of hypertriglyceridemia who have no responded to dietary intervention 1. Elevated triglycerides: risk factor for pancreatitis MOA 1. Fibrates are peroxisome proliferator-activated receptor (PPAR) - alpha agonists a. Transcription factor expressed in the liver and skeletal muscle that increases gene expression for the breakdown of fatty acids for energy by fatty acid oxidation 2. Decrease triglycerides by stimulating fatty acid oxidation 3. Increase lipoprotein lipase expression a. Enhances clearance of triglyceride rich lipoproteins: VLDL 4. Modest increase in HDL may occur PK 1. Are rapidly and efficiently absorbed when taken WITH meals 2. Taken once or twice daily 3. Peak plasma concentrations in 1-4 hours 4. 95% bound to plasma proteins (albumin) 5. Half lives of 1 hour to 20 hours 6. Activate forms excreted in urine a. CI: in SEVERE renal impairment ADRs 1. GI effects a. Dyspepsia, abdominal pain 2. Hepatic effects a. Increased serum aminotransferases (hepatotoxicity) i. Primary fenofibrate ii. Usually resolves with D/C 3. Myopathy a. When combined with statins i. Primarily gemfibrozil Icosapent Ethyl: Icosapent Ethyl Brand Name Vascepa Indications CV risk reduction with hypertriglyceridemia, adjunct to diet to reduce triglyceride levels in adults with severe (>500) hypertriglyceridemia Mechanisms 1. After absorption, Icosapent ethyl converted into EPA 2. Fish oil contains two omega-3 fatty acids a. EPA b. DHA 3. EPA more effective than DHA a. Reducing blood triglyceride levels b. Producing antiplatelet aggregation effects 4. Reduces hepatic production of triglyceride rich VLDL a. Increased fatty acid beta oxidation reduces fatty acids available for triglyceride production 5. Anti-inflammatory: increased circulating EPA/arachidonic acid ratio, inhibition of platelet aggregation Mixed Dyslipidemia: Assessment: 1. Fasting versus non-fasting lipid panel a. Variable effect on triglycerides b. Fasting recommended if non-fasting TG > 400 mg/dL 2. Large elevations in triglycerides affect LDL-C calculation a. Consider ordering directly measured LDL-C in such patients Hypertriglyceridemia: 1. Persistent hypertriglyceridemia increased ASCVD risk a. Persistent = continued elevation followed minimum 4-12 weeks of lifestyle intervention 2. Classification: a. Mild to moderate TG > 150 mg/dL up to 499 mg/dL b. Severe (fasting > 500 mg/dL) c. Very severe (fasting > 1000 mg/dL) Management of Triglycerides from ACC/AHA 2021 Expert Consensus Decision Pathway (ECDP): 1. Evaluate and manage secondary causes 2. Optimize diet and lifestyle 3. Implement statin guidelines (4 benefit groups) 4. Optimize glycemic control 5. Monitor response (and adherence) 6. Conduct clinician patient discussion (treatment options, benefits, harms, patient preferences) Hypertriglyceridemia: 1. No targeted level for TG reduction 2. Approach should prioritize weight loss, lifestyle modifications, LDL-C lowering and ASCVD risk reduction per guideline-directed therapies Why Statins? 1. First line for ASCVD risk reduction a. Unlike fibrates, use has been shown to reduce risk of MACE 2. Main target is LDL-C lowering, but also significant TG reductions a. 10-30% dose dependent reduction in TG 4 TG Benefit Groups: 1. Clinical ASCVD: a. After reach LDL-C goal b. Persistent mild-moderate hypertriglyceridemia c. ADD Icosapent ethyl 2. Diabetes + RF a. Maximally tolerated statin b. If age > 50 yo AND 1 or more RF and persistent mild-moderate hypertriglyceridemia c. ADD Icosapent ethyl 3. Severe: a. TG > 500 mg/dL b. If you meet criteria for statin do first! c. Check adherence and/or intensify statin d. ADD fenofibrate or Icosapent ethyl 4. Very Severe: a. TG > 1000 mg/dL b. Add fenofibrate or Icosapent ethyl c. Simultaneously start station if meet criteria 5. Risk factors: a. Men > 55 b. Female > 65 c. Smoking d. HTN e. HDL f. Elevated hs-CRP Omega-3 Fatty Acids: 1. Formulation: a. Omega-3 acid ethyl esters, Icosapent ethyl, Omega-3 carboxylic acids 2. Mechanism: a. DEC. in VLDL-TG synthesis in the liver and INC. TG clearance from circulating VLDL particles 3. ADRs: a. Burping, diarrhea, increase bleeding risk, increased risk of atrial fibrillation 4. Only Icosapent ethyl, which is purified omega-3 ethyl ester, has resulted in outcome benefit Fibrates: Fenofibrate and Gemfibrozil: Fibrates Mechanism Activates lipoprotein lipase and reduces ApoCIII, resulting in increased lipolysis Effects on Lipids 1. Reduces LDL-C5-20% 2. Reduces TG 30-55% 3. Raise HDL-C 18-22% Adverse Drug Effects 1. Dyspepsia, gallstones, myalgia, increased hepatic transaminases 2. Can increase the risk of myalgia or rhabdomyolysis in patients taking statin therapy (worse with gemfibrozil) Monitoring 1. LFTs at baseline; then every 3 months for 12 months; then only when clinically indicated 2. Evaluate renal function before initiating fenofibrate, within 3 months after initiation, and then every 6 months thereafter Niacin: Niacin Mechanism Inhibits mobilization of free fatty acids from peripheral adipose tissue to the liver and reduces VLDL synthesis, resulting in lower LDL and TG concentrations Effects on Lipids 1. Reduces LDL-C 15-20% 2. Reduces TG 20-50% 3. Raises HDL-C 15-26% Adverse Effects 1. Flushing 2. Hyperglycemia, hyperuricemia 3. Upper GI distress, increased hepatic transaminases Contraindications Liver disease, gout, active peptic ulcer disease Pathophysiology of Hypertension: Hypertension: 1. High blood pressure (hypertension): a. Long term force of the blood acting on artery walls i. High enough to produce vascular or tissue damage 1. Contributes to other diseases a. Most often heart and vascular disease 2. Blood pressure: a. Determined by amount of blood the heart pumps and the resistance to blood flow in arteries b. The more blood the heart pumps and the narrower the lumen of the arteries i. The higher the blood pressure 3. Chronically untreated hypertension: a. Contributes to multiple disease in different tissues i. Stroke, aneurysm, myocardial infarction, heart failure 4. Elevation in systolic and/or diastolic blood pressure: a. Normal: less than 120/80 mm Hg b. Elevated: Systolic between 120-129 and diastolic < 80 c. Stage 1 hypertension: Systolic between 130-139 or diastolic between 80-89 i. Measured on multiple occasions d. Stage 2 hypertension: systolic > 140 or diastolic > 90 e. Isolated systolic hypertension (ISH) is most common in those over age 60 i. Only systolic BP is elevated 5. Symptoms associated with hypertension a. Unless hypertension is severe i. Most with hypertension have no readily observable signs or symptoms b. One third of people with hypertension do not know it 6. Hypertensive crisis (malignant hypertension) a. Severe (immediately life threatening) form of hypertension i. Systolic over 180 and/or diastolic over 120 b. Symptoms include i. Severe headache, confusion, agitation or seizures Hypertension may be primary or secondary: 1. Primary Hypertension: a. Accounts for 90% of all hypertensive patients in US b. Idiopathic: Does not have a known secondary cause c. Also caused essential hypertension 2. Factors contributing to development of primary hypertension: a. Genetic Predisposition: i. Dyslipidemia, diabetes, obesity, age >55 men, 65 women, family history of premature CV disease, low GFR or elevated urinary protein b. Environmental factors: i. Stress, smoking inactivity, obstructive sleep apnea, diet: high sodium intake, excessive alcohol consumption Primary Hypertension: 1. Types of Primary Hypertension: a. Moderate of high renin hypertension i. Most common type ii. Most often treated with RAS meds 1. ACE inhibitor 2. Angiotensin II receptor blocker (ARB) b. Low renin hypertension i. Plasma renin activity levels are LESS than 1/10 that of high renin HTN ii. Treated with 1. Diuretics (thiazide), calcium channel blockers c. Resistant hypertension i. Often requires 3 or more medications Prevalence and Morbidity: 1. Prevalence of hypertension in adults in the US a. Nearly ½ have hypertension b. Influenced by age and gender i. Prevalence increases with age, more prevalence in men 2. Effect of Hypertension a. Stroke: increased more than any other disease b. Heart failure c. Coronary artery disease, angina, myocardial infarction d. Renal failure e. Peripheral artery disease f. Aneurysm g. Retinopathy h. Cognitive decline Secondary Hypertension: 1. Hypertension that occurs secondary to another disease a. Accounts for less than 10% of all hypertensive patients in US b. Treat underlying disease to control secondary hypertension 2. Causes of secondary hypertension: a. Renal or vascular i. Renovascular disease ii. Coarctation of the aorta b. Endocrine: i. Aldosteronism ii. Cushing’s Disease iii. Pheochromocytoma iv. Thyroid disease c. Medications (CAM) i. Corticosteroids ii. Amphetamines/appetites suppressants iii. Monoamine oxidase inhibitor antidepressants Activation of the Renin Angiotensin System (RAS) in Hypertension: 1. Renin is released into the blood by juxtaglomerular cells a. Cleaves angiotensinogen to angiotensin I 2. Angiotensin-converting enzyme (ACE) forms angiotensin II (AngII) a. ACE is expressed in endothelial cells of the vasculature b. AngII conserves Na+ and ultimately raises blood pressure i. Stimulates release Na+ and ultimately raises blood pressure 1. Increases sodium/water retention and potassium excretion Causes of Primary Hypertension: 1. The kidney is responsible for long term control of blood pressure by regulating blood volume a. Reduction in blood volume and blood pressure cause by i. Loss of sodium and water to urine production 2. INCREASED renin secretion counteracts reduced blood volume and pressure a. More sodium and water reabsorbed out of the urine i. Restores blood volume and blood pressure b. Renin is released from granular cells of juxtaglomerular apparatus in the kidney i. Angiotensin II causes vasoconstriction, release of antidiuretic hormone, thirst, and release of aldosterone ii. Aldosterone promotes sodium reabsorption from urine to increase blood volume iii. Antidiuretic hormone binds its receptor in late distal tubule and collecting duct 1. Increased expression of aquaporin water channels Impaired Renal Function Contributes to Hypertension: 1. Essential hypertension may be viewed as reno-vascular dysfunction a. For hypertension to persist i. Kidneys fail to recognize and compensate for 1. Elevated blood pressure or volume expansion b. Most medications used to treat hypertension act to alter kidney function i. Diuretics are the traditional first line therapy for hypertension ii. Renin angiotensin system (RAS) meds block angiotensin II, renin and/or aldosterone iii. Sympatholytics decrease renal sympathetic tone to maintain renal blood flow and decreased renin release c. Chronic kidney disease prevalent in prehypertension i. GFR < 60 ml/min or urinary albumin: creatine ratio > 30 mg/g Excessive Sympathetic Activity Contributes to Hypertension: 1. Sympathetic stimulation of juxtaglomerular apparatus cells leads to excessive renin secretion a. Excessive AngII increases aldosterone levels and Na+ recovery, expanding blood and extracellular fluid (ECF) 2. Removal (ablation) of renal efferent or afferent nerves reverses hypertension a. Suggests that afferents from injured kidneys signal increased sympathetic activity i. Central sympathetic outflow decreases after renal artery afferent nerve ablation in resistant hypertension b. Sympathetic efferent to kidneys maintain high renin release Genetic Components of HTN: 1. Genome-wide polymorphism analysis identified the first gene mutation to cause hypertension a. Expression of mutants of a serine/threonine kinase is associated with elevated blood pressure i. Relationship first identified in an Amish population 1. 20% of those with European ancestors a. Carry a copy of the mutant gene ii. Polymorphism results in elevated expression of the kinase 1. Increased blood pressure in both heterozygotes and homozygotes b. The kinase phosphorylates Na/K/2Cl transporter in the thick ascending limb of the loop of Henle (loop diuretic target) and Na/Cl transporter in the distal tubule (thiazide sensitive) i. Both transporter are activated, enhancing Na uptake causing increased blood pressure Thiazide Diuretics: Sites of Action of Diuretics in the Nephron: Thiazide Diuretics: 1. History a. Developed from carbonic anhydrase inhibitors in an effort to find more potent diuretics b. Block the Na/Cl transporter in distal convoluted tubule c. Chlorothiazide, the first benzothiazide diuretic, replaced the mercurial diuretics 2. Therapeutic uses: a. Hypertension: i. Often first line treatment for hypertension b. Edema i. Adjunctive treatment (added to a loop diuretic) 1. Refractory edema associated with heart failure, renal impairment, hepatic cirrhosis Thiazide Diuretics: Therapeutic Use and Actions: 1. Hypertension: a. Most common use of thiazide diuretics 2. Therapeutic effects in hypertension a. Produce a modest increase in NaCl excretion i. Produces mild diuresis b. Increases urinary volume and loss of body water c. Reduces blood volume and extracellular fluid (ECF) d. Well tolerated and safe for most patients e. Inexpensive (generics available) f. Lowers blood pressure up to 15-20 mmHg Mechanism of Action: 1. Thiazides block Na+ Cl- symporter in early distal tubule a. Inhibition of sodium chloride symporter increases sodium and chloride concentration in tubule filtrate increases water excretion b. Increased sodium and chloride concentration in tubule filtrate increases water excretion c. 90% of Na+ is reabsorbed prior to distal tubule i. Diuretic effect is modest 2. Thiazides increase K+ excretion a. As the urine reaches the collecting duct, the increased sodium activates sodium/potassium ATPase on the basolateral membrane, which increases excretion of potassium into the urine i. Reduction in serum K+ Biological Effects of Thiazides: 1. Thiazides reduce Ca++ excretion a. Due to enhanced Ca++ reabsorption in distal tubule b. Less sodium in the cell increases the concentration gradient for sodium to flow into the cell through sodium/calcium exchanger, which pumps more calcium into the interstitium c. Avoid use in patients with hypercalcemia (hyperparathyroidism) 2. Thiazides decrease uric acid excretion a. Thiazides compete with uric acid for organic acid transporters in the proximal tubule i. May worsen gout Adverse Effects of Thiazides: 1. Hypokalemia a. Usually modest, but may be a concern in patients subject to arrhythmias i. K+ depletion may worsen arrhythmias 2. Hyperlipidemia a. Serum triglycerides and cholesterol may increase modestly 3. Hyperuricemia a. Gout attacks may occur more frequently in those already subject to gout 4. In diabetic patients may produce hyperglycemia 5. Hypersensitivity reactions a. Questions about significance of patients with a prior allergic reaction to antibiotic sulfonamides b. Risk of allergic reactions to non-antibiotic sulfur containing meds after allergic reaction to antibiotic sulfonamides is thought to be extremely low Pharmacokinetics: 1. Most are well absorbed orally 2. Onset of action a. Oral preparations within 2 hours 3. Dosages vary depending on potency a. 1-2 mg/day to 1-2 g/day (chlorothiazide) 4. Half lives vary from 2 hr to 2 days 5. Most undergo renal clearance; some of the more recent are metabolized 6. Newer meds are much more potent than the thiazide (chlorothiazide) Thiazide Combination Products: 1. Thiazides (mostly hydrochlorothiazide) are often combined with other antihypertensives a. With K+-sparing diuretic b. With vasodilator c. With B-blocker d. With ACE inhibitor e. With AngII receptor antagonist f. With renin inhibitor Hypertension and the Renin-Angiotensin System: The Juxtaglomerular Apparatus of the Kidney: 1. Juxtaglomerular apparatus: a. Group of cells located between afferent and efferent arterioles and distal tubule 2. Juxtaglomerular apparatus regulates a. Glomerular blood flow and filtration rate b. Renin release 3. High levels of the tubule filtrate flow in the distal tubule from excessive glomerular filtration a. Causes macula Densa cells to release a vasoconstrictor (adenosine) i. Acts on the afferent arteriole to reduce glomerular filtration b. Causes macula Densa cells to send signals to the juxtaglomerular cells i. Stimulates release of renin Renin-Angiotensin System: 1. Renin is released into the blood by juxtaglomerular cells a. Cleaves angiotensin to angiotensin I 2. Angiotensin-converting enzyme (ACE) forms angiotensin II a. ACE is expressed in endothelial cells of the vasculature b. Ang II conserves Na+ and ultimately raises blood pressure i. Stimulates release of aldosterone from the adrenal gland 1. Increases sodium/water retention and potassium excretion Angiotensinogen: 1. Continually released from the liver a. 1000 times higher than plasma angiotensin I and angiotensin II concentrations b. Large protein (452 amino acid residues) c. Renin cleaves into 10 amino acid residues to form angiotensin I 2. Renin conversion of angiotensinogen into angiotensin I is the rate limiting step of angiotensin II formation a. Once angiotensin I forms, it is rapidly converted to angiotensin II i. Widespread expression of ACE throughout blood vessels b. Increases in angiotensinogen yield increased angiotensin II levels and increased BP 3. Angiotensinogen plasma levels increased by a. Corticosteroids, thyroid hormone, inflammation Angiotensin II: 1. Is a potent vasoconstrictor 2. INCREASES aldosterone synthesis and secretion 3. Stimulates antidiuretic hormone (ADH) release 4. Promotes Na+ reabsorption in proximal tubule 5. Stimulates thirst center in hypothalamus 6. Contributes to numerous pathological processes Pharmacological Targets in the Renin-Angiotensin Pathway: 1. Renin: a. Conversion of angiotensinogen to Ang I b. Released from kidney JGA cells c. Inhibitor: Aliskiren 2. ACE: a. Angiotensin converting enzyme b. Cleaves Ang I to Ang II c. Inhibitors: CAptopril, Enalapril, Fosinopril, Lisinopril, Ramipril 3. AT1: a. Ang II receptor b. AT1 receptor is most closely associated with hypertension c. Inhibitors: Losartan, Candesartan, Valsartan Aliskiren Brand Tekturna Name Class Only member of the renin inhibitor class of antihypertensives MOA Direct renin inhibitor - Binds directly to the catalytic site of renin - Inhibits the metabolic activity (protease activity) oto convert angiotensinogen into angiotensin I Therapeutic plasma concentrations reduce plasma renin activity by 60% - Decrease angiotensin II levels - Lowers BP 10-15 pts - No therapeutic advantage over ACE inhibitors or ARBs - Not recommended for initial treatment, less widely used PK Aliskiren is poorly absorbed from GI tract: - Substrate of intestinal P-glycoprotein which limits bioavailability - Absorption decreased by high fat meals - Avoiding administration with high fat meals is recommended - Limited information on metabolism and drug interactions Half Life 24 hours Once daily dosing produces steady state blood levels after 1 week Disease related dosage adjustments: - No change in dosing based on renal impairment or liver function has been provided by the manufacturer Combining with ACEI or ARB: - INCREASES risk for renal impairment, hyperkalemia, hypotension ADRs 1. Hyperkalemia a. Greater risk when combined with K+ sparing diuretics or other RAS inhibiting medications 2. Hypotension a. Most often during the initiation of therapy b. When used with other agents inhibiting the RAS system c. Not a CI for further use Warnings 1. Fetal toxicity a. Common to all RAS drugs b. Greatest risk in 2nd/3rd trimesters i. d/c immediately upon detection of pregnancy c. Oligohydramnios i. Reduction of amniotic fluid volume ii. Resulting from decreased fetal renal function Angiotensin Converting Enzyme (ACE): 1. ACE forms AngII from Ang I 2. ACE degrades bradykinin a. Bradykinin is a vasodilator and airway smooth muscle constrictor 3. Inhibition of ACE a. Decrease ANG II levels b. Increases bradykinin levels c. Increases vasodilation 4. ACE is primarily located on luminal surface of endothelial cells a. Widely expressed in numerous tissues 5. Secondary biological consequences of ACE inhibition a. Increased levels of Ang I b. No known biological effects from increased angiotensin I levels ACE Inhibitors: 1. Hypertension a. ACE inhibitors may be used for monotherapy i. Thiazide like diuretics or dihydropyridine calcium channel blockers often preferred (prevention of heart failure and stroke) b. Addition of a diuretic or other antihypertensive may be required to achieve blood pressure goals c. Use of ACE inhibitors in hypertensive patients with comorbidities i. Additional labeled indications 1. Heart failure 2. Myocardial infarction with left ventricular dysfunction 2. Mechanisms for Treating hypertension: a. Peripheral arteriolar vasodilation (decreased TPR) and increased large artery compliance b. No change in cardiac output/heart rate c. Aldosterone secretion reduced but no eliminated Adverse Effects of ACEI: 1. Hypotension: a. May accuse reduction in BP after first dose i. More common in patients with high plasma renin activity ii. Dehydrated patients, patients treated with multiple antihypertensives, chronic heart failure (CHF) iii. Start with lower dose and titrate 2. Cough a. ACE inhibitor induced persistent dry cough in 10% of patients i. Most common adverse effect of ACE inhibitors ii. Causes ⅕ of patients to d/c ACE inhibitor iii. Not dose related iv. Class effect occurring with all ACE inhibitors v. May begin when starting, or after months of treatment b. Caused by INCREASED bradykinin levels 3. Angioedema a. Swelling of nose, mouth, throat, larynx, lips, tongue i. Results in airway obstruction b. May be life threatening c. May occur after first dose or any time during treatment d. Occurs in 0.3% of patients i. Increased occurrence 1. Patients with hereditary angioedema 2. Concomitant use of neprilysin inhibitor (sacubitril) e. Resolves upon d/c; treated as anaphylaxis (epinephrine, antihistamin) f. Visceral angioedema can occur independent of oropharyngeal angioedema i. Vomiting, diarrhea, abdominal pain g. Fetal toxicity: i. Oligohydramnios (kidney injury), death 4. Hyperkalemia a. Increased risk in patients with renal impairment, taking K+ sparing diuretics, or K+ supplements b. ACEI decrease aldosterone release which reduces potassium excretion from the kidney 5. Reduced renal function or acute renal failure a. In patients with low renal blood flow (renal artery stenosis, heart failure) or volume depletion from dehydration i. AngII maintains efferent arteriolar constriction and GFR Angiotensin II: 1. Two types of AngII receptors a. AT1 and At2 b. Both are G-protein coupled receptors 2. AT1 receptors mediate a. Most known effects of Ang II i. Vasoconstriction ii. Release of antidiuretic hormone (ADH) iii. Secretion of aldosterone 3. AT2 receptors mediate vasodilation a. Pathological functions are less well described Ang II Receptor Antagonists: 1. Angiotensin receptor blockers (ARBs) bind AT1 receptors with high affinity a. 10,000x more selective for At1 versus At2 b. Although inhibition is competitive, the affinity is much higher than that of Ang II i. Essentially irreversible inhibition 2. ARBs and ACEIs are less effective in low renin hypertension: a. Between low renin hypertension and high renin hypertension i. Greater than a 10 fold difference in plasma renin activity Comparison of ARBs to ACEIs: 1. ARBs reduce activation of AT1 receptors more effectively than ACEIs a. ACEIs do not block non-ACE pathways of AngII generation (chymase) 2. ARBs permit activation of AT2 receptors a. Both ARBs and ACEIs increase renin levels, but AngII levels are increased only with ARBs b. At2 receptors mediate vasodilatory effects i. Clinical significance not known 3. ACEIs but not ARBs increased bradykinin levels a. Bradykinin is potentially beneficial vasodilator, but also produces adverse effects 4. BOTH decrease systolic BP by similar amounts Ang II Receptor Antagonists: 1. Therapeutic Effects: a. Used to treat hypertension, heart failure, chronic kidney disease, and after myocardial infarction b. Efficacy is similar to that of other antihypertensives c. Well tolerated and similar to ACEIs d. ACE inhibitors remain recommend first line treatment i. ARBs used in ACE inhibitor intolerant patients Adverse Effects of Ang II Receptor Antagonists: 1. Lower incidence of some adverse effects compared to ACEIs a. Cough b. Angioedema 2. Fetal toxicity primarily associated with maternal use in the second and third trimesters 3. Use with caution in patients with low renal blood flow a. May cause renal failure from efferent arteriolar dilation and reduced GFR 4. May cause hyperkalemia a. In renal disease b. With K+ supplements with K+ sparing diuretics 5. Combinations of ARBs and ACEIs a. Increased risk of hyperkalemia without additional benefit and is not recommended Calcium Channel Blockers: CCBs: Basis for Use in Hypertension: 1. Ca++ channel blockers (CCBs) LOWER blood pressure by relaxing arteriolar smooth muscle a. DECREASE total peripheral resistance 2. BLOCK L-Type voltage gated Ca++ channels on cell membrane a. INHIBIT Ca++ entry into cells necessary for contraction b. Extenet of vasodilation varies i. Dihydropyridines (amlodipine, nicardipine, felodipine etc) >> diltiazem > verapamil ii. Baroreceptor reflex activation may cause reflex tachycardia and INCREASED CO with dihydropyridines 1. Less with verapamil or diltiazem 2. Reports of short acting nifedipine a. INCREASED risk of myocardial infarction in patients treated for hypertension b. Only extended release form of nifedipine approved for HTN CCBs: basis for Use in Hypertension: 1. CCBs lower blood pressure by decreasing cardiac contractility AND conduction 2. Verapamil (Heart) > diltiazem (Heart and BV) >> dihydropyridines (BV) 3. Decrease heart rate and cardiac output a. CCBs not used in patients with: i. Heart failure ii. In post MI patients iii. Patients with cardiac action potential conduction defects 4. CCB Efficacy a. Most effective in low renin hypertension!!! b. May be combined with other agents Pharmacological Properties: 1. CV Effects: a. DECREASED Ca++ entry into: i. Vascular smooth muscle cells: 1. Causes relaxation and arteriolar vasodilation; minimal effect on veins (dihydropyridines) ii. Cardiac myocytes: 1. Decreases contractility of heart muscle and decreased CO a. Most evident with verapamil and diltiazem iii. Cardiac pacemaker cells 1. Leads to slowed conduction and decreased HR a. Most evident with verapamil and diltiazem b. CCBs increased coronary blood flow by coronary vasodilation i. Dihydropyridines >> diltiazem > verapamil Mechanism of Action: 1. Multiple types of voltage gated Ca++ channels a. Differ in voltage sensitivity and conductivity b. L and T types are best characterized c. Only L-Type is sensitive to CCBs 2. L-type Ca++ channels are made up of multiple subunits a. Voltage sensitive subunit responds to depolarization of the cell i. Changes confirmation of pore forming subunit b. Tissue specific expression of separate isoforms expressed in arteries c. Non-dihydropyridines bind isoforms expressed in cardiac muscle and cardiac conduction cells Pharmacokinetics of CCBs: 1. Well absorbed but bioavailability reduced by first pass hepatic metabolism a. Highly bound to plasma proteins b. Half lives vary from 3 hour like nifedipine to 50 hour c. Rapidly absorbed CCBs i. Produce rapid reduction in blood pressure 1. May precipitate adverse cardiovascular events d. Longer acting drugs have slower onset of action i. ER formulations or longer half lives preferred 1. Amlodipine half life elimination 50 hours e. Verapamil is a CYP3A4 substrate i. May need lower doses with reduced liver function 2. Dihydropyridine and nondihydropyridine may be COMBINED! a. Different sites of action Adverse Effects of CCBs: 1. Hypotensive effects are MORE common with dihydropyridines 2. Dizziness, headache, flushing, syncope 3. Peripheral edema (lower legs and ankles) a. Increases with higher doses 4. Myocardial ischemia with dihydropyridines a. Excessive hypotension triggers baroreceptor activation to INCREASE HR b. Increased O2 demand from tachycardia c. Cardiac ischemia d. Most evident with immediate release formulation 5. Non-dihydropyridines a. Bradyarrhythmias i. Most likely with verapamil ii. May be dangerous in patients with conduction defects b. Acute decompensated heart failure i. Most likely with verapamil ii. In patients with left ventricular systolic dysfunction Potassium Sparing Diuretics: Aldosterone Regulates Fluid Volume: 1. Aldosterone is the principal mineralocorticoid a. Synthesized in the adrenal cortex (outermost zone) b. Released in response to: i. Angiotensin II ii. Hyponatremia iii. Hyperkalemia 2. Aldosterone promotes the recovery of Na+ in the late distal tubule and collecting duct a. Retention of Na+ promotes water reabsorption i. Yields increase in plasma volume (and blood pressure) b. Promotes K+ loss in exchange for Na+ c. Aldosterone plays an important role in controlling Na+ excretion and fluid volume Aldosterone Antagonists: 1. Spironolactone (Aldactone) 2. Eplerenone (Inspra) a. Competitive antagonists of aldosterone at the mineralocorticoid receptor b. Approved for HTN unresponsive to other therapies c. Not recommended for the initial treatment of hypertension 3. Aldosterone activation of the mineralocorticoid receptor (MR): a. MR is a member of the cytosolic steroid/thyroid/vitamin D receptor b. Epithelial cells in the late distal tubule and collecting duct i. Contain cytosolic MRs with high aldosterone affinity c. Aldosterone binding increases expression and activity of the epithelial Na+ channel i. Results in INCREASED Na+ entry into cells and increased sodium recovery into bloodstream 1. Loss of positive charges from Na+ in renal tubule lumen, makes it more negatively charged 2. Increased K+ secretion occurs secondarily to counterbalance sodium recovery Limitations of Aldosterone Antagonists: 1. Diuretic effectiveness is dependent on a. Na+ delivered to late distal tubule (DT) and collecting duct (CD) 2. Normally 2% of filtered Na+ reaches late DT and CD a. Aldosterone antagonists most effective in combination with other diuretics that INCREASE Na+ delivery to late DT and CD (thiazide diuretics) 3. Aldosterone antagonists are not effective in the absence of circulating aldosterone a. Diuretic effect is proportional to aldosterone levels b. Drugs of choice in patients with primary aldosteronism i. High aldosterone levels due to adrenal hyperplasia or adrenal adenomas Spironolactone Adverse Effects: 1. Spironolactone is a progesterone derivative a. Activates progesterone and estrogen receptors b. In males produces anti-androgenic effects i. Reduces androgen levels ii. Gynecomastia, impotence c. In females produces estrogenic effects i. Menstrual irregularities 2. Hyperkalemia: a. Increased serum K+ levels b. Risk INCREASES with renal impairment, excessive potassium intake 3. Labeled indications include: a. Management of chronic hypertension unresponsive to other therapies Eplerenone: 1. Greater specificity for the mineralocorticoid receptor than spironolactone a. Structure is not related to progesterone i. Very low affinity for progesterone receptors b. Does not have anti-androgen or progesterone like effects i. Lower incidence of sex hormone related adverse effects 2. Drug Interactions: a. Cleared by CYP3A4 metabolism i. CI: concurrent use with strong CYP3A4 inhibitors 3. Adverse Effects: a. Primary adverse effect: hyperkalemia 4. Labeled indications include: a. Management of chronic hypertension i. Not recommended for the initial treatment Hyperkalemia with Aldosterone Antagonists: 1. Monitor serum potassium a. Prior to therapy and during therapy b. Renal insufficiency increases the likelihood 2. Aldosterone antagonists may increase hyperkalemic effect of ACE inhibitors or angiotensin II receptor blockers 3. K+ supplements are CONTRAINDICATED 4. Avoid combination with other K+ sparing diuretics (amiloride) a. Increases risk of hyperkalemia i. Contraindication for eplerenone Other K+ Sparing Diuretics: 1. Amiloride a. Inhibitor of epithelial Na+ channels i. Less commonly used than aldosterone antagonists 2. Boxed Warnings: a. Elevation of serum potassium potentially fatal if not corrected b. Hyperkalemia occurs commonly when used without a potassium excreting diuretics c. When used in combination with thiazide diuretic the risk of hyperkalemia is reduced 2% d. Incidence is greater in patients with renal impairment, diabetes, or in the elderly e. Essential to monitor serum potassium level 3. Epithelial Na+ channels: a. Expressed on luminal membranes of the late distal tubules and collecting ducts b. Channels that provide conductive pathway for Na+ entry into the cell down the electrochemical gradient created by the basolateral Na+/K+ ATPase c. A higher permeability of the luminal membrane for Na+ i. Increases activity of the Na+/K+ ATPase on the basolateral membrane ii. Provides a driving force for the secretion of K+ into the lumen through K+ channels 1. Diuretics that INCREASE Na+ delivery to the LDT and CD enhance the gradient and increase K+ excretion Sympatholytics for Hypertension: Sympatholytics: 1. NOT recommended as first line therapy 2. Decrease blood pressure by acting on the central or peripheral nervous systems a. Peripheral adrenergic receptor blockade i. Alpha 1 blockers ii. Beta blockers iii. Mixed alpha and beta blockers b. REDUCE sympathetic outflow from the CNS i. Alpha 2 agonists act presynaptically to inhibit neuronal transmission Alpha 1 Receptor Antagonists: (PTD) 1. Prazosin (Minipress), terazosin, doxazosin (Cardura) a. Block the postsynaptic alpha receptor b. Alpha 1 receptors on vascular smooth muscle cause vasoconstriction 2. DO NOT block presynaptic alpha 2 receptors a. Presynaptic alpha 2 activation terminates norepinephrine release b. Do not affect the release of NE from sympathetic nerve terminals 3. DO NOT block postsynaptic alpha 2 receptors a. Postsynaptic alpha 2 receptors i. Minor contribution to sympathetic vasoconstriction Alpha 1 Blockers: Pharmacological Effects: 1. Arteriolar vasodilation and venodilation a. Due to blockade of vasoconstricting alpha 1 receptors b. Rapid decrease in blood pressure results initially in reflex sympathetic stimulation (baroreceptor reflex) i. Increase in HR and CO ii. Long term vasodilation persists but effects on the heart return to normal 2. Postural hypotension “First dose effect:” a. May be severe with sudden loss of consciousness (syncope) i. Especially within 30 to 90 minutes of the first dose 3. Inhibition of smooth muscle contraction a. Urinary bladder sphincter i. Reduces bladder outlet obstruction b. Second line agent for HTN in benign prostatic hypertrophy Pharmacokinetic of Alpha-1-Blockers: 1. Plasma half life a. Prazosin (3 hour) b. Terazosin (12 hour) c. Doxazosin (20 hour) Adverse Effects of Alpha-1-Blockers: 1. Adverse effects relate to peripheral vasodilation a. Dizziness, postural hypotension, edema b. First dose effect with doxazosin is usually less severe than prazosin i. More slowly absorbed c. Adverse effects generally diminish with continued use 2. Drug Interactions: a. Combination with other antihypertensives i. May cause excessive fall in blood pressure Use of Alpha-1-Blockers in Hypertension: 1. Not recommended for initial monotherapy a. Increased risk of heart failure compared to a thiazide diuretic (chlorthalidone) b. Used when patients not well controlled on other medications i. May be used in combination with other antihypertensive drugs c. Does not affect uric acid excretion i. As do thiazide diuretics ii. Does not increase the risk of gout Beta-receptor Antagonists: 1. Beta blockers are not recommended as first line agents a. Unless patient has ischemic heart disease or heart failure 2. Non-selective beta-blockers were not anticipated to be beneficial in hypertension a. Blockade of vascular beta-2 receptors was expected to promote vasoconstriction i. Vascular beta-2 receptors produce minimal vasodilation 3. Non-selective and beta-1 selective a. Both types effective antihypertensive agents b. Reduce cardiac contractility and HR, reduce CO 4. Beta blockers reduce the secretion of renin and lower plasma angiotensin II levels a. Reduced RAS activation from beta-1 receptors contributes to the mechanism Beta-Receptor Antagonists: Pharmacology: 1. Effectiveness is independent of beta-1 selectivity a. Heart expresses more beta-1 receptors than beta-2 receptors i. Both receptors produce increased heart rate and force of cardiac contraction 2. Nonselective beta-blockers a. Propranolol, nadolol, timolol 3. Beta-1 selective beta-blockers a. Acebutolol, atenolol, betaxolol, bisoprolol, metoprolol 4. Partial agonists with intrinsic sympathomimetic activity (ISA): a. Production less reduction of i. Heart rate ii. Force of cardiac contraction iii. Cardiac output iv. Blood pressure b. Hypertension Guidelines: generally avoid beta-blockers with ISA c. Acebutolol, pindolol Vasodilating Beta-Blockers: 1. Carvedilol (Coreg): a. Nonselective beta-receptor antagonist with alpha-1 blocking activity i. Reduces HR and CO, and produces vasodilation to lower total peripheral resistance (TPR) 1. Potential for producing hypotension 2. Labetalol (Normodyne): a. Nonselective beta blocker with ISA i. Modest effect on HR and CO from ISA b. Alpha 1 receptor blocking produces vasodilation i. Potential for producing hypotension 3. Nebivolol (Bystolic): a. Highest specificity for beta-1 of any beta-blocker b. Beta-3 adrenergic receptor agonist i. Activates nitric oxide synthase in endothelial cells ii. To stimulate nitric oxide production iii. Nitric oxide diffuses into smooth muscle cells in the blood vessel wall iv. NO activates guanylyl cyclase to increase production of cyclic GMP (cGMP) v. cGMP causes relaxation of smooth muscle cells and vasodilation Adverse Effects of BetaBlockers: 1. Bronchoconstriction a. Beta-2 adrenergic receptors important for bronchodilation b. In patients with obstructive pulmonary disease i. Beta 2 receptor blockade will cause bronchoconstriction ii. Beta 1 selective agents are safe in COPD patients 2. Bradycardia a. INCREASED severity in patients with cardiac electrical conduction problems 3. Patients with heart failure may not tolerate the initial drop in CO 4. Insulin dependent diabetes a. Masks the sympathetic nervous activation that accompanies hypoglycemia 5. Blocked Warning: a. Abrupt withdrawal of beta blockers has been shown to cause cardiac ischemia in patients with ischemic heart disease 6. Cardiac muscle ischemia may produce a myocardial infarction (MI) 7. D/C should include a slow reduction over a period of 1-2 weeks 8. CNS effects a. Fatigue, dizziness, depression Centrally Acting Alpha-2 Agonists: 1. Alpha 2 agonists decrease blood pressure by reducing sympathetic outflow a. Act by presynaptic alpha 2 stimulation to decrease central neurotransmitter release b. Decreased sympathetic outflow to the heart, kidneys, and peripheral vasculature i. Reduction in cardiac output, TPR and BP 2. Generally reserved as last line therapy a. Significant CNS adverse effects, especially in older adults b. Used in cases of resistant hypertension c. May be used in conjunction with other antihypertensives Centrally Acting Alpha-2 Agonists: Methyldopa 1. Methyldopa is an analog of DOPA a. Metabolized to alpha-methylnorepinephrine (MNE) b. MNE is stored in neuronal vesicles, replacing NE 2. MNE is selective alpha 2 agonist a. Acts in brainstem to reduce sympathetic outflow 3. MNE is not degraded by monoamine oxidase a. Allows MNE to accumulate to greater levels than occurs with NE b. Replaces NE’s non-selective receptor effects 4. Adverse effects: a. CNS: sedation, inattentiveness, depression b. Cardiovascular: Hypotension, bradycardia, syncope Centrally Acting Alpha-2 Agonists: 1. Clonidine (Catapres) and guanfacine (Intuniv) 2. Significant adverse effects limit use a. Cardiovascular: hypotension, bradycardia, syncope b. CNS adverse effects: sedation, lethargy, depression c. Sudden d/c may produce withdrawal syndrome i. Especially with clonidine 1. Excess blood pressure, tachycardia Hypertension: Risk Factors: 1. Modifiable: a. Tobacco use b. Diabetes c. Dyslipidemia d. Overweight/obesity e. Physical inactivity f. Unhealthy Diet 2. Non-Modifiable: a. Chronic kidney disease b. Family increased age c. Low socioeconomic/educational status d. Male sex e. Obstructive sleep apnea f. Psychological stress Causes of HTN: 1. Primary Hypertension: a. No pinpoint cause b. Contributing factors likely include genetics and environmental factors 2. Secondary Hypertension a. Renovascular disease b. Renal parenchymal disease c. Pheochromocytoma d. Primary aldosteronism e. Obstructive sleep apnea f. Drug or alcohol induced Medications that May Raise Blood Pressure: 1. Amphetamines 2. Antidepressants 3. Atypical antipsychotics 4. Caffeine 5. Decongestants 6. Herbal supplements 7. Immunosuppressants 8. Oral contraceptives 9. NSAIDs 10.Recreational drugs 11. Systemic steroids Ambulatory Blood Pressure Monitor: 1. Used to obtain out of office readings 2. Takes readings over a set time usually 24 hours which includes while asleep 3. Takes readings every 15-30 minutes during the day and 30-1 hour at night Hypertension Treatment: 1. When do we start pharmacologic treatment for hypertension? a. Secondary prevention i. BP > 130/80 b. Primary Prevention: i. 10 year ASCVD risk > 10% and BP > 130/80 ii. 10 year ASCVD risk < 10% and BP > 140/90 2. If ASCVD risk < 10% and BP 130-139/80-89 → lifestyle modifications alone with repeat screening in 3-6 months Blood Pressure Treatment Goal: 1. < 130/80 mm Hg for everyone Lifestyle Modifications: 1. Weight loss a. 5-10% of body weight; calorie deficit 2. Healthy diet a. Ex. DASH eating plan 3. Sodium Restriction a. < 1500 mg/day 4. Potassium intake a. 3,500-5,000 mg/day 5. Exercise a. 150 minutes/week of moderate intensity aerobic exercise 6. Limit alcohol use a. < 2 drinks/day for men b. < 1 drink/day for women 7. Limit caffeine Choice of Initial Antihypertensive: 1. General non-black population: a. ACE-I or ARB b. Thiazide type diuretic c. Dihydropyridine CCB 2. General black population a. Thiazide type diuretic b. Dihydropyridine CCB c. NO ACE or ARB Patients with Comorbidities: 1. Atrial fibrillation: a. ARBs may theoretically be more beneficial than CCB or beta blockers b. ARBs not compared to thiazides or ACE-1 2. Chronic Kidney Disease a. With CKD stage III or I-II with albuminuria i. Use ACE-I or ARB if ACE-I not tolerated b. CKD stage I-II with no albuminuria, any first line for most patients 3. Diabetes: a. Any first line option for most patients b. Consider ACE-1/ARB if albuminuria 4. Heart Failure (HFrEF) a. Beta blockers b. ACE-I or ARB or ARNI c. Spironolactone d. Isosorbide/hydralazine in black population e. Do not use non-DHP CCB 5. Heart Failure (HFpEF): a. Diuretics b. Beta blockers c. ACE-I or ARB 6. Stable Ischemic Heart Disease a. Beta blockers and ACE-I/ARB as indicated b. Add on additional classes as needed i. CCB with angina 7. Stroke/TIA a. Thiazide type diuretic b. ACE-I or ARB c. Combination of thiazide + ACEI Special Populations Considerations: Elderly Pregnancy 1. Individualized blood pressure 1. First line agents goals a. Labetalol 2. Less aggressive with combination b. Nifedipine therapy initiation 2. Second Line agents 3. More likely to experience side a. Methyldopa effects at higher doses b. Hydralize 4. Pill burdens/polypharmacy 3. AVOID due to teratogenicity a. ACE-I or ARB b. MRA Medication Selection Number of Agents to Start: HTN Diagnosis Initiating Therapy # of Agents to Start Stage I HTN 1 Stage II HTN AND BP >20/10 over goal 2 Follow Up: 1. Nonpharmacologic therapy AND antihypertensive agent → reassess in 1 month → BP Goal Met → yes or no a. NO: i. Assess and optimize adherence and consider intensification of therapy b. YES i. Reassess in 3-6 months Hypotension: 1. Hypotension is defined as BP 4 medications Potential Causes of Secondary Hypertension: 1. Chronic kidney disease 2. Primary aldosteronism 3. Pheochromocytoma 4. Renal artery stenosis 5. Obstructive sleep apnea When to Screen for Secondary Hypertension: 1. Resistant hypertension 2. Abrupt onset of hypertension 3. Onset of hypertension < 30 years old 4. Exacerbation of previously controlled hypertension 5. Unprovoked or excessive hypokalemia 6. Hypertensive emergency Resistant HTN Management: 1. First line for resistant HTN a. Spironolactone 2. Additional Options a. Beta blockers b. Loop diuretics c. Direct vasodilators d. A1 antagonists e. A2 agonist Spironolactone Dose 12.5-50 mg once daily Consideration for Use Renal Function: 1. May increase Scr 2. Use NOT recommended eGFR 2.5 mg/dL Hyperkalemia: 1. Do NOT initiate if K > 5 mEq/L 2. Stop treatment if K >5.5 mEq/L Other potential side Gynecomastia (Eplerenone with lower risk) effects Monitoring BMP within 1 week of initiation or dose change to monitor SCr and potassium Additional Antihypertensive Options: 1. Beta blockers: a. Preferred options: carvedilol, labetalol, metoprolol, or bisoprolol i. Carvedilol and labetalol also have alpha blockade ii. TAKE CARVEDILOL with FOOD b. BBW: for reflex tachycardia (do not stop abruptly) 2. Direct Vasodilators: a. Hydralazine, minoxidil b. Side effects: i. Fluid retention, postural hypotension, angina, reflex tachycardia c. Hydralazine: drug induced lupus like syndrome at HIGHER doses d. Minoxidil: can cause hirsutism e. Recommended to use with beta blockers and diuretic 3. Alpha-1 Antagonist: a. Doxazosin, prazosin, terazosin b. May be considered second or third line in patients with BPH c. Side effects: orthostatic hypotension d. Could exacerbate underlying myocardial dysfunction, so this class of medications should be avoided in patients with CVD, specifically HF 4. Alpha-2 Agonist: a. Preferred options: Clonidine patch and guanfacine b. Clonidine tablets may cause recount HTN c. Side effects: i. Significant CNS effects, rebound HTN, dizziness, dry mouth, constipation Antihypertensives Requiring taper: 1. Clonidine a. Can lead to severe rebound HTN b. Taper about every 3-7 days in 0.1 mg increments 2. Beta Blockers a. Can lead to acute HTN, tachycardia, and/or ischemia b. Should be tapered over 1-2 weeks Screening for Concerning Symptoms: 1. Visual disturbances 2. Headache 3. Confusion 4. Weakness or numbness of extremities 5. Shortness of breath 6. Edema 7. Sweating 8. Chest pain or pressure 9. Referred arm or jaw pain Hypertensive Urgency versus Emergency Treatment: 1. Emergency a. Admit to intensive care unit (ICU) b. Use IV medications for immediate reduction c. For most, lower BP by no more than 25% in the hour then to 160/100-110 over 2-6 hours, then to normal over 24-48 hours 2. Urgency: a. No indication to send to ED or hospital b. For most patients, lower blood pressure slowly during the first 24-48 hours using ORAL medications Direct Acting Vasodilators for HTN: Direct Vasodilators: 1. Not recommended for the initial treatment of HTN 2. Vasodilators directly relax arteriole smooth muscle a. Do not directly affect the sympathetic nervous system 3. Direct vasodilators do not cause venodilation a. Minimizes postural hypotension 4. Direct acting vasodilators currently approved for HTN a. Hydralazine b. Minoxidil 5. REDUCTION in blood pressure cause by arterial vasodilation a. Activates neural compensatory reflexxes i. INCREASED SNS activity 1. INCREASES: vasoconstriction, CO, HR, renin release b. Activates humoral compensatory reflexes i. Juxtaglomerular cells of the afferent arteriole act as intrarenal baroreceptors 1. Detect reduced blood pressure a. Increase renin secretion i. Increased Ang II, vasoconstriction, aldosterone, release c. Used in combination with other antihypertensives i. Combined with diuretics and/or beta blockers 1. Prevents INCREASED Co, renin release, and promotes Na+/water loss Mechanism of Action and Use: 1. Hydralazine (Apresoline) a. Not completely defined i. Inhibits calcium release from arterial smooth muscle sarcoplasmic reticulum 1. Inhibits myosin phosphorylation, actin interaction, contraction b. For moderate to severe HTN not controlled by other meds 2. Minoxidil a. Activated K+ channel opening to INCREASE outward flow of K+ b. Fwer positively charged K+ ions inside the cell c. Reduces opening of voltage dependent calcium channels d. Decreases intracellular calcium levels e. Reduces interaction of actin and myosin to decrease contraction f. Indications: i. Management of HTN that is not controlled with maximum therapeutic doses of a diuretic plus 2 other antihypertensive agents ii. Use in midler degrees of HTN is NOT recommended Hemostasis and Antiplatelet Pharmacology: Aspirin Overview of Hemostasis: 1. The physiological system that preserves integrity of the circulation a. During NORMAL conditions i. Regulated to promote blood fluidity b. During loss of blood i. Designed to clot rapidly at specific site of injury c. After healing i. Restore blood flow and perfusion to tissues supplied by the damaged vessel 2. Major components of the hemostatic system a. Vessel wall i. Endothelial cells b. Platelets i. Cell fragments from bone marrow megakaryocytes c. Plasma proteins i. Coagulant proteins ii. Anticoagulant proteins iii. Fibrinolytic proteins Phases of Hemostasis: 1. Vascular phase: a. The INITIAL trigger to activate hemostatic processes i. Tissue injury causes smooth muscle cell contraction ii. Lasts up to 30 minutes 2. Platelet Phase: a. Platelets circulate in an inactive state until needed b. Platelets do not normally adhere to the vascular wall c. Adherence: i. Binding to subendothelial collagen and von Willebrand factor (vWF) is mediated by receptors on platelets d. Activation: i. Mediated by adhesion and agonists that are released from endothelial cells and other platelets ii. Activation by thromboxane A2, thrombin, and collagen receptors on platelets lead to secretion of granule contents iii. Granule secretion: multiple factors including ADP e. Aggregation: i. Platelets stick together to form the platelet plug 1. Glycoprotein IIb/IIIa receptor (GP IIb/IIIa) expression a. Fibrinogen or vWF binds to two GP IIb/IIIa molecules to cross link receptors on separate platelets 2. Thromboxane A2 (TXA) is produced in platelets a. I

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