CV 1 Exam 5 Angina and Coronary Heart DZ PDF

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Lecture notes for exam 5....

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CV 1 Exam 5: Angina and Coronary Heart DZ Questions: 1) Perfuses myocardium with oxygen rich blood: circumflex artery (Not pulm vein/artery, vena cava) 2) NSTEMI: Sx of ischemia, labs will show elevated troponins, leads to partial thickness damage, full occlusion of minor coronary artery, partial occlusion of major coronary artery 3) Pts should have access to SL NTG for tx of current angina episode 4) Pts experiencing frequent episodes or in whom angina is affecting QOL should receive chronic therapy 5) Goal of chronic therapy is to provide complete or near complete sx relief of angina 6) Mech of chronic therapy is typically to prevent increase of O2 demand 7) Initial goal to lower the pts resting HR to 50-60 and exercise HR to 20 min may be indicative of acute MI ○ Progressively worsening of sx and increased frequency is a sign of MI ● Gradual onset, gradual offset ● More frequent in morning ○ Increase in sympathetic tone ■ ↑ HR, BP, vessel tone and resistance, and platelet aggregability ● Can be evaluated with angiogram and get elective stent to keep artery patent and prevent MI (can get elective CABG- too if occlusion is so extensive) ● The thicker the plaque → more frequent episodes of angina ○ 70% occlusion can block blood flow at rest ■ Prinzmetal Angina: (AKA: variant angina or vasospastic angina) ● Spontaneous angina associated with ST segment elevation on ECG ● Smooth muscle hyperreactivity: ○ Blood flow is constricted during an artery spasm ○ May coincide with microvascular angina ○ Possible vagal/sympathetic angina ● Pain is not caused by exertion, can occur at rest ● Most common in early AM (circadian effect) ● More common in women ● Associated DZ: ○ Vasospastic disorders (Raynaud's, migraines) ○ Can have life-threatening cardiac arrhythmias during episodes of spasm ■ Cardiac Syndrome X ● Chest pain with exertion ● ST segment depression on exercise stress test ● Dx: ○ Normal arteriography ○ Can’t induce coronary artery vasospasm with ergonovine or ACh ○ More in women than men 4

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Presentation: effort related pain that persists for 10+ min after stopping activity ○ Nitrates: inconsistent effects ● Pathophys: microvascular dysfxn Unstable angina: ● Presentation: ○ Sx of ischemia w/o elevated troponins ■ May take hours to detect elevated troponins ○ Often present as NSTEMI ○ W/ or W/O ECG changes indicative of ischemia ● Pathophys: plaque is disrupted → platelet aggregation ○ Clot formation can cause partial or complete artery block ● Not alleviated by NO or rest ● Pain > 20 min can → infarction ● Management: ○ Disperse platelet from thrombus: thrombolytic drugs, antiplatelets ○ Give O2 in acute phase ○ Reduce work of heart + coronary vasodilator

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History, Symptoms, Characteristics of chest pain, Provoking factors Differential Dx: ● MS pain, Rheumatic DZ ● Herpes zoster ● GERD ● PE, Lung Ca, COPD, pneumothorax ● Med induced: triptan antimigraine agents ■ Dx testing: ● Resting ECG ● Stress ECG: exercise tolerance test or treadmill test ○ Increase incline or resistance during testing and note when and how ○ Can use med stress test (dobutamine, adenosine, dipyridamole) ● Echocardiogram: heart wall abn d/t ischemic damage ● Stress imaging (Myocardial perfusion) ○ Radionuclides test for myocardial fxn and blood flow after stress test ● Ambulatory monitoring (Holter monitor) ○ Can determine episodes of silent ischemia ○ Prognostic indicators: ■ Dependent on anatomy of vessels, # of vessels involved, L vent dysfxn ■ Immediate post-MI care aimed at prevention and preservation of myocardium Pharmacologic management of Angina: ● Methods: ○ Reduce preload (venodilators) ○ Reduce afterload ( arteriodilators) ○ Decrease HR (Bblock and CCB) Treatment of Stable CHD ● GOALS OF TREATMENT ○ Reduce/eliminate number and severity of angina episodes ○ Increase exercise tolerance ○ Improve quality of life (QOL) 5

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○ Prevent or slow disease progression ○ Decrease episodes of silent myocardial ischemia ○ Prevent cardiac complications (MI, HF, revascularization, sudden death) OVERVIEW OF THERAPEUTIC OPTIONS ○ Remove drug-induced causes ○ Treat underlying medical conditions ■ Hypertension, Tachyarrhythmias ■ Hyperthyroidism ■ Anemia ■ Hypoxemia ■ Valvular heart disease ○ Risk factor modification ■ Smoking: Ask, Advise, Assess, Assist, Arrange, Avoid ■ Overweight/obesity ● BMI 18.5-24.9 kg/m2 ● Initial goal to lose 5-10% from baseline ■ Physical inactivity ■ Hyperlipidemia ■ Hypertension: BP ≤140/90 or ≤130/80 ■ Metabolic syndrome ■ Diabetes ● Hemoglobin A1C ≤7% ● Avoid rosiglitazone ■ Stress reduction ● Treat anxiety/depression ○ Anti-anginal drugs ■ Acute attacks ● Can be monotherapy in pts w/ angina no more than once every few days ● Sublingual nitroglycerin ■ Chronic prophylaxis ● Should be used in patients with daily angina episodes ● Beta blockers ● Calcium channel blockers ● Long-acting nitrates ● Ranolazine ■ Other agents ● Antiplatelets ● ACE inhibitors/ARBs ● Influenza vaccine ○ Nonpharmacologic therapies ■ Exercise training ■ Revascularization procedures (reserved until optimized pharm strategies fail) ● Surgery: Coronary artery bypass grafting (CABG) ● Percutaneous coronary intervention (PCI) ○ Balloon angioplasty ○ Stent placement (bare metal or drug-eluting) PHARMACOLOGIC THERAPY ○ Beta blockers 6

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Indication ● Prevention of angina ○ Drug of first choice for classic angina prophylaxis ○ Improve symptoms 80% of the time ○ Use as monotherapy or in combo w/ long acting nitrates and/or CCBs ● Not effective for acute attacks due to slow onset MOA: competitively inhibit B1 and B2 receptors ● → reduces HR Mechanism of benefit ● SA node: blocks sympathetic stimulation → reduced HR ● AV node: conduction blocked → reduced HR ● Ventricular myocardium: blocks sympathetic stim → reduced contractility ○ Decreases SV → decreases CO = decreased work and O2 demand ● **Protect against cardioacceleration ● Decrease O2 demand ● Slight increase in myocardial oxygen supply ● Improve exercise capacity in those previously limited by angina symptoms ● Decrease number of angina attacks ● Decrease NTG consumption ● Most effective agent in decreasing silent ischemia ● Reduce early morning peak in ischemic activity ● Reduce mortality in systolic HF and post-MI ● Efficacy is reduced in continued smokers Useful in the following patients with angina: ● Angina where/with: ○ Physical activity predominantly affects attacks ○ High resting heart rate ○ Fixed threshold angina ○ Anxiety ● Hypertension ● Post-MI ● Tachyarrhythmia ● Migraine ● Heart failure ● GERD (nitrates and CCBs may aggravate or induce) Agents: ● Nonselective: Carvedilol, Labetalol, Propranolol ○ Generally have a double ring structure ● Selective B1: Atenolol, Bisoprolol, Metoprolol (just have less beta 2 action ○ Single benzene ring with para substituents Selection ● Little evidence to support superior efficacy of any drug within the class ○ Avoid agents w/ intrinsic sympathomim action: may worsen angina at rest ● Agents differ by half-life, lipophilicity, selectivity, and cost ● Cardioselective agents are useful to minimize some adverse effects 7

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○ Cardioselectivity: dose-dependent & often lost at dose required for angina ■ Dosing: Begin at lower end of usual dosage range ● Titrate to response ● Usually need doses at higher end of usual dosage range ■ Adverse effects ● Fatigue, Insomnia ● Hypotension ● Decompensated heart failure if used incorrectly ● Bronchospasm ● Depression ● Erectile dysfunction ● Abrupt withdrawal → tachycardia, increased contractility ○ d/t upregulation of beta receptors ■ Contraindications/Concerns regarding DZ states: ● COPD/Asthma: ○ Beta 2 block in lungs → loss of bronchodilation → worsened obstruction ● Diabetes: ○ Low glucose → sympathetic outflow → hypoglycemia sx ○ BB block these sx → pt unaware of hypoglycemic state and can worsen ○ B2 mediates glycogenolysis (glycogen to gluc to counter hypoglycemia) ○ B3 mediates gluconeogenesis (gluc formation to counter hypoglycemia) ○ **Stops warning signs and compensatory mech of hypoglycemia ● Raynaud's, PAD, vasospasm (Prinzmetal’s) ○ Vasospasticity in peripheral vessels ○ Blocks B2 peripheral vasodilation → more vaso spasticity ○ Carvedilol/labetalol with alpha blockade okay ○ Nebivolol with direct vasodilation okay ● Sinus bradyarrhythmias and AV nodal blocks ● Depression Nitrates (aka nitrodilators, organic nitrates) ■ Chemical structure: ● Nitrate esters ● Volatile: potential loss of active from dosage form ● Can be explosive in pure concentrated form ● Lipophilic → fast absorption through membranes ● Free tissue sulfhydryl groups increase venodilation effect of nitroglycerin ■ Indication: Angina ● Class of choice in tx of acute angina episodes ● Prevention of angina ○ Use long-acting oral or transdermal preps in combo w/ beta blockers and/or CCB when angina persists despite beta blocker/CCB therapy ○ Not used for chronic monotherapy prophylaxis d/t concerns w/ tolerance ○ SL NTG may be used 5 minutes prior to activity known to induce angina ● Dependent on duration of action ○ Short acting: prophylaxis/termination of acute angina ○ Long acting: prophylaxis and management of CAD 8

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MOA: 2 types ● Release NO spontaneously (sodium nitroprusside) ● Organic nitrates that require enzymatic process to form NO ○ Nitrate group + intracellular sulfhydryl → NO ● → NO activates guanylyl cyclase → increased cGMP → vasodilation by decreasing intracellular Ca and K (hyperpolarization) ● Also: inhibit platelet aggregation by increasing cGMP in platelets Mechanism of benefit ● Vasodilation of systemic veins → decreased preload ● Vasodilation of coronary arterioles → decreases TPR ● → decreased myocardial workload and O2 demand Reduction in myocardial oxygen demand: increase NO → peripheral venous and arterial dilation → reduction in left ventricular wall stress ● Some increase in myocardial oxygen supply: dilation of large and small coronary arteries and coronary stenosis and relief of coronary vasospasm ● Not as effective as beta blockers ● Improve exercise capacity (prophylaxis forms) ● Decrease number of angina attacks (prophylaxis forms) ● Decrease NTG consumption (prophylaxis forms) ● Lack other beneficial effects Useful in the following patients with angina: ● Heart failure ● Prinzmetal’s angina Pharmacokinetics ● Very short half-life (except isosorbide mononitrate) ● Variable absorption ● Metabolism: nearly complete 1st pass metabolism ○ Isosorbide dinitrate: liver, metabolite is still vasodilator Products ● Acute relief: Glyceryl Trinitrate (GTN) - AKA Nitroglycerin (NTG) ○ SL NTG tablets ■ Relieves pain in 75% of patients within 3 minutes and another 15% in 5-15 minutes ■ Should be replaced every 6 months ○ Lingual NTG spray ■ More expensive than sublingual tablets ■ Useful if low saliva production ■ Shelf-life 3 years ○ Buccal NTG ○ IV NTG: Used in ACS setting ● Chronic prophylaxis ○ Transdermal NTG patches ■ Avoids first-pass effect by liver ■ Onset 30 minutes; duration 8-14 hours ■ Sustained blood levels for 24 hours BUT must remove for nitratefree period due to tolerance ○ Oral isosorbide dinitrate (ISDN) ●

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■ Large first-pass effect and variable bioavailability ■ Onset 15-30 minutes; duration 3-6 hours ■ Dosed 2-3 times daily ○ Oral isosorbide mononitrate (ISMO) ■ Active metabolite of ISDN with longer half-life & no first-pass effect ■ No more efficacious than ISDN ■ Dosed twice daily or sustained release product once daily ○ NTG ointment ■ Difficult to apply over consistent area with varied response ■ Must be applied every 4-6 hours ■ Individuals other than the patient should avoid contact ● SL NTG still effective with long-acting nitrate therapy Tolerance and endothelial dysfunction ● Occurs with frequent dosing → decreased efficacy ○ Use smallest effective dose + infrequent or irreg dosing to avoid ● Controversy over all chronic nitrate products exists due to development of tolerance and adaptive mechanisms that limit efficacy ● Tolerance develops within 24-48 hours ● Min hemodynamic & antianginal effect after 1 wk continuous (24 h/d) therapy ● Mechanism ○ ?? Depletion of free sulfhydryl groups responsible for conversion of organic nitrates to nitric oxide → decreased cyclic GMP and vasodilation ○ Also may be due to activation of RAAS and SNS from vasodilation ● Off-set may be just as rapid allowing for chronic therapy with daily nitrate-free interval of at least 8 hours; better if 12 hours ○ Nitrate-free during night best in patients with exertional angina ○ Nitrate-free during day best in patients with nocturnal angina or HF (orthopnea or paroxysmal nocturnal dyspnea) ● Intermittent therapy may cause rebound ischemia during nitrate-free period ● Other methods to reduce nitrate tolerance ○ Folic acid ○ L-arginine ○ Hydralazine ○ Antioxidants: vitamin C, vitamin E, carvedilol ○ ACE inhibitors/ARBs ○ Diuretics ● Deleterious changes in endothelial function have also been shown Adverse effects ● Headache ● Orthostatic hypotension ● Reflex tachycardia → can worsen angina ● Nausea ● Rash ● Abrupt withdrawal may worsen angina ● Tolerance develops to some side effects Drug interactions ● Sildenafil, vardenafil within 24 hours and tadalafil within 48 hours 10

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● → life-threatening hypotension, impaired coronary perfusion ■ Patient counseling for SL NT ● Place one tablet under the tongue in response to chest discomfort/pain ● Sit down and rest ● Number of doses and calling EMS: ○ Traditional approach was to take one tablet every 5 minutes x 3 doses before calling EMS (max 3 doses in 15 minutes) ○ 2004 ACC/AHA MI guidelines state improved or worsening chest pain after 5 minutes is suggestive of acute coronary synd and recommend 9-11 be called to access EMS if no relief after 5 minutes of first dose ● May cause tingling/burning under tongue, headache, dizziness, fainting ● Keep in original, tightly closed container ● Avoid mixing with other medication ● Not an analgesic and is not harmful or addicting ● Not to be used with ED drugs Nitric Oxide Donor: Molsidomine (Corvaton) ■ Oral vasodilator ■ PK: ● Great oral bioavailability ● Renal elimination ● Short PK → increased dose interval ● Metabolized in liver to intermediate that can then release NO in presence of O2 ■ Use: alternative to organic nitrates in stable angina, coronary spasm, HF ■ Concerns: ● Significant antiplatelet activity at therapeutic doses ● Forms superoxide when NO released Calcium channel blockers ■ Indication ● Prevention of angina ○ Use in combination with beta blockers with or without long-acting nitrates when angina persists despite beta blocker therapy ○ Use as monotherapy when beta blockers are contraindicated or not tolerated Prinzmetal/vasospastic ● Not effective for acute attacks ■ MOA: ● Bind to Ltype voltage gated Ca channels → decrease Ca influx ● DHP: act on arterial smooth muscle ● Non DHP: act on arterial smooth muscle and myocardium ■ Effect: ● Decreased HR ● Decreased conduction velocity ● Decreased contractility ■ Mechanism of benefit ● Reduction in myocardial oxygen demand ● Slight improvement in myocardial oxygen supply: dilation of coronary arteries may → inhibition of coronary artery vasospasm or improved coronary blood flow through areas of fixed coronary obstruction 11

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● Comparable efficacy to beta blockers ● Improve exercise capacity ● Decrease number of angina attacks ● Decrease NTG consumption ● Modest reduction in progression of coronary atherosclerosis Useful in the following patients with angina: ● Angina with variable threshold/Prinzmetal’s ● Hypertension ● Tachyarrhythmia (non DHPs) ● Conduction defects (DHPs) ● Migraine (non DHPs) ● Raynaud’s disease (beta blockers may aggravate) ● Peripheral vascular disease ● Severe ventricular dysfunction (DHPs) Agents: ● DHP: ○ Amlodipine ○ Nifedipine ■ Relaxation of coronary and other arterioles in body ■ Can cause reflex tachycardia ● Non DHP: ○ Diltiazem: Acts strongly on heart and arterial smooth muscle ○ Verapamil ■ Mainly blocks heart not vascular smooth muscle ■ Can cause heart block and → HF Selection ● All agents have similar efficacy for angina symptoms ● Agents differ by chemical class, adverse effects, half-life, and cost ● Non DHPs may be used as monotherapy titrated to goal pulse rate HR 50-60 ● DHPs should not be used as monotherapy d/t reflex tachycardia: ● Consider side effect profiles as relates to comorbidities and interacting drugs ● Short-acting DHPs should not be used Adverse effects ● DHPs: ○ Headache ○ Flushing ○ Reflex tachycardia ● Non DHPs: Bradycardia and AV block ● Hypotension ● Peripheral edema ● Nausea, constipation (mostly verapamil) ● GERD ● Gingival hyperplasia (verapamil) ● No tolerance or withdrawal issues Dihydropyridines chem: Can be chiral ● Agents: Nifedipine, amlodipine, felodipine ● PK: ○ Extensive 1st pass metabolism in liver

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■ Dose adj in liver DZ ■ Avoid excessive grapefruit ■ Interxn d/t CYP3A4. ○ High protein binding → interxn (digoxin, anticoag) ■ Drug interactions ● All metabolized by CYP3A4 ● Verapamil and diltiazem inhibit CYP3A4 ● Verapamil increases digoxin levels ● Non DHPs with beta blockers or digoxin may cause heart block Late Sodium Current Inhibitor: Ranolazine (Ranexa®) ■ Indication ● Prevention of angina (used in chronic angina) ○ Reserve for ps w/ inadequate response or CI/AE to other antianginals ● Not effective for acute attacks ■ Can be used with other antianginal drugs (nitrates, beta blockers, and CCBs) ■ MOA: Blocks late inward Na currents in myocytes → decreasing intracellular Na levels → affects Na dependent Ca channels during ischemia ● Blocking Na and Ca overload in cells ■ Mechanism of benefit ● Contributes toward cardioprotective effects ● Indirect: prevents Ca overload that → cardiac ischemia ● Reduction in myocardial oxygen demand: ○ Inhibits late sodium current in myocardial tissue preventing calcium overload in ischemic myocytes and subsequent increase in left ventricular wall stress; improvement in myocardial fxn and perfusion ○ No chronotropic, inotropic, or hemodynamic effect ● Does not improve myocardial oxygen supply ● Improves exercise capacity ● Decreases number of angina attacks, Decrease NTG consumption ● Hemoglobin A1C reduction of ~0.5-0.6% ■ Dosing ● 500 mg BID initially ● 1000 mg BID within 1-2 weeks if needed based on clinical response ■ Adverse effects ● Headache, Dizziness ● Nausea, constipation ● QT interval increase (dose-dependent): can → TdP and ventricular tachycardia ○ Contraindicated in pts w/ QT interval prolongation or hepatic impairment ● No tolerance or withdrawal issues ■ PK: ● Good oral bioavailability ● Metabolism: CYP3A4 and CYP2D6 ● Elimination: t ½ for ER formulation is 7-9 H ■ Drug interactions ● CYP3A4 inhibs (e.g. verapamil, diltiazem, azoles, macrolides, protease inhibs) ● CYP2D6 inhib/inducers ● Other QT prolonging drugs 13

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● Ranexa is a Pgp transport inhibitor → Digoxin levels may be increased ○ Other Therapies ■ Antiplatelet Agents: use in all pts ● Agents: ○ ASA: 81-325 mg ○ Clopidogrel: 75 mg ● Oral anticoags are effective but ↑ bleeding risk ○ Not recommended unless indicated for another condition ○ Addition of aspirin to warfarin is not needed for stable coronary disease ● Aspirin resistance ○ Up to 10% may not achieve complete platelet inhibition from standard doses: may → poorer outcomes ○ Currently no standard definition, preferred test, or recs available ○ For pts w/ an event on ASA: verify compliance, consider clopidogrel, and avoid NSAIDS that interfere with aspirin effect on COX-1 ■ RAAS inhibitors ● ACEI: recc d/t strong evidence for benefit in patients with stable angina and: ○ MI, LVEF 130 (Class I, Level A) ■ Influenza vaccine (Class I, Level B) ● Highest recommendation, medium amt of evidence ■ SL NTG (Class I, Level B) ■ Beta blockers as initial therapy for relief of symptoms (Class I, Level B) ■ CCBs or long-acting nitrates when...