Pharm Exam 3 .docx

- HEART FAILURE: o Indicate when medications are indicated in heart failure (beta blockers, ACE inhibitors/ARBs, sacubitril/valsartan [ARNi], SGLT2 inhibitors, MRAs, diuretics, hydral-nitrates, ine, digoxin) BB Patients with reduced LVEF <40%. All patients with HF should receive a BB as pa...

- HEART FAILURE: o Indicate when medications are indicated in heart failure (beta blockers, ACE inhibitors/ARBs, sacubitril/valsartan [ARNi], SGLT2 inhibitors, MRAs, diuretics, hydral-nitrates, ine, digoxin) BB Patients with reduced LVEF <40%. All patients with HF should receive a BB as part of therapy. ACEI/ARBS All patients with HF (NYHA class I-IV) should receive ACEI/ARBS regardless of symptoms Sacubitril/Valsartan (ARNi) NYHA Class II-IV patients to reduce hospitalizations and cardiovascular death NYHA Class II-III patients who are symptomatic in place of ACEI or ARB to further improve morbidity and survival (alternative first-line option) SGLT2 Inhibitors Patients with NYHA II-IV, symptomatic chronic HFrEF. Recommended to reduce hospitalization for HF and cardiovascular mortality. MRA NYHA III/IV with HFrEF <35% HFrEF Post-MI <40% Mild HF symptoms (NYHA II) to reduce hospitalizations Diuretics Used to relieve symptoms of congestion and edema (Present in all HF cases) No mortality benefits Hydral-Nitrates Indicated in patients who cannot tolerate a ACEI/ARB due to poor renal function/history of angioedema, or hyperkalemia Indicated in African American patients with NYHA III or IV HF who are still symptomatic despite ACEI/ARB/ARNi and BB treatment Ivabradine Adjunct therapy for following conditions NYHA II-III HF LVEF <35% Sinus Rhythm w/resting HR 70 BPM On maximally tolerated BB or have contraindications to BB Digoxin For patients who remain symptomatic despite normal treatment with ACEI/ARB and a BB No mortality benefit, but reduces hospitalizations o Identify which medications are indicated for HFrEF vs HFpEF § Which medications have proven clinical benefits? HFrEF Digoxin BB (Carvedilol) ACEI/ARBS MRA/ARA HFpEF SGLTi o beta blockers § Explain the rationale for using beta blockers (BB) in left ventricular (LV) systolic dysfunction based on the neurohormonal model of HF. BB blocks the effects of neurohormonal activation. BB reverse hypertrophy, slow LV dilation, and reduce levels of NE, AT2, and Endothelin-1. Decreased NE levels results in up-regulation of Beta-1 receptors improving contractility of the heart. § State the types of HF patients that should not receive beta blockers (BB). Clinically unstable and hospitalized in ICU Required IV positive inotropic support Severe fluid overload or depletion Symptomatic bradycardia or advanced heart block History of poorly conmtrolled reactive airways disease § o ACE inhibitors/ARBs § State the MOA ACEI Reduce synthesis of angiotensin II; also block the degradation of bradykinin (vasodilation, cough, and angiodema) ARB Block AT2 from binding ATR1 receptors § Describe the mortality benefits Reduce mortality § Explain the mechanism by which angiotensin converting-enzyme inhibitors (ACEI) interrupt the cycle of heart failure (HF). By blocking effects of AT2 they decrease afterload, decreasing TPR. Reduce preload by reducing aldosterone effects of volume retention Inhibits detrimental effects of cardiac remodeling caused by AT-2 § o sacubitril/valsartan [ARNi] § Explain the use of ARNi vs ACE inhibitor use in HF ARNi counteract RAAS activation while ACEi reduce RAAS activation § Explain the mechanism of action for each agent Neprilysin is responsible for degradation of vasodilatory peptides (natriuretic peptide, adrenomedullin, substance P and bradykinin) Inhibition will lead to counteraction of the effects of RAAS § State the indication and which patients are candidates for its use NYHA class II-IV NYHA class II-III who are symptomatic and tolerate ACEI/ARB § o SGLT2 inhibitors § Explain the MOA and benefits in patients with HF Inhibition of sodium-glucose cotransporter 2 reducing reabsorption of filtered glucose, and filtered sodium. May lower both preload and afterload of the heart and downregulate sympathetic activity. Can reduce mortality and hospitalization in patients NYHA II-IV with chronic HFrEF. o MRAs § Describe the beneficial effects of aldosterone antagonists (AA) in HF and the NYHA stage patients who should be considered for AAs Reduce Na/H2O retention, cardiac remodeling and risk of sudden cardiac death NYHA III-IV § State the common ADRs of MRAs Hyperkalemia Increased serum creatinine Gyno Increased TG o Diuretics § Describe the effects on mortality, relative potency and efficacy in renal disease, development of diuretic resistance and solutions No mortality benefits in HF patients, usually contraindicated in those with renal diseases. Will develop resistance in HF due to distal tubule hypertrophy and reabsorption of Na while increasing amounts of Na are being delivered. o hydral-nitrates § Explain the mechanism of action of the isosorbide dinitrate/hydralazine combination in HF, the effects on preload and afterload, and whether a mortality benefit occurs. Nitrates increased availiability of Nitric Oxide that causes venous vasodilation (Decrease preload) Hydralazine is a direct arterial vasodilator (Decrease Afterload) Decrease Mortality o Ivabradine § explain the indication and intended use in patients Adjunct therapy for patients that are: NYHA class II-III HF LVEF <35% Sinus Rhythm >70BPM On maximally tolerated BB or contraindications for BB Reduces risk of hospitalizations for worsening HF § state the effects on HR and BP Slows HR without lowering BP (hypertension is an ADR) § effect on mortality DOES NOT REDUCE MORTALITY o digoxin § state the MOA and inotropic effects Inhibits Na/K ATPase pump resulting in increased CO Exerts parasympathetic effect at AV node. Decreasing HR § Identify the ADRs of digoxin and how ADRs are enhances Dizziness, mental disturbances, HA, N/V/D, abnormal color vision, colored halos around objects Enhancing Digoxin Toxicity Hypokalemia Metabolic Alkalosis Hypomagnesemia Hypercalcemia Renal dysfunction Hypothyroidism Advanced Age § Explain the rationale for the new target plasma level of digoxin (0.5-0.9, or <= 1.0 ng/mL) based on the neurohormonal model of HF. Increased sensitivity to Na-K ATPase in vagal afferent nerves causing an increase in vagal tone that opposes the increased activation of SANS. Digoxin also opposes Na-K ATPase activity in the Kidney reducing reabsorption of sodium § State patients that receive the greatest benefits Presence of S3 gallop rhythm Cardiomegaly on chest X-Ray NYHA class III-IV § State the effects on mortality and QOL No significant impact on mortality. Improves QOL o Explain the rationale for using aldosterone antagonists (AA) in severe HF. Reduce Na/H2O retention, cardiac remodeling and risk of sudden cardiac death o Describe the properties of B-type natriuretic peptide (BNP) with regard to: § endogenous source Ventricular Muscles § role as a “counterregulatory hormone” Antagonist to AT2 and RAAS actions § effects on urine flow and sodium excretion Increase urine flow 5X and sodium secretion 10X § net effects on pulmonary capillary wedge pressure (PCWP), TPR, plasma aldosterone levels, sodium and water retention, preload, and afterload Reduces PCWP, TPR, decreased aldosterone which lowers sodium and water retention Inhibit vasopressin secretion Block salt appetite and thirst centers in hypothalamus Decrease preload Decrease afterload o Describe the clinical uses of inotropic agents in the management of HF(dobutamine, dopamine, milrinone, epinephrine, norepinephrine) Used in patients with acute HF and low CO Those with symptomatic hypotension Will improve cardiac index, stroke volume, and CO o State the preferred agent for preload reduction in severe HF and the vasodilator of choice for severe HF and acute MI. NTG is considered the DOC for both situations o Describe the hemodynamic and cardiac effects of angiotensin II (AT2) and state the neurotransmitters and hormones affected by AT2. Significant increase in cardiac index and stroke volume Reductions (shouldn't it increase??) in LV filling pressures, TPR, MSAP, and HR AT2 stimulates aldosterone to be released o For all of the drugs used in management of HF, state which: § are teratogenic ACEI § have demonstrated mortality benefits Beta Blockers ACEI/ARB ARA Hydralazine SGLT2i § are not associated with improved survival Digoxin Loop diuretics § cause hyperkalemia ACEI/ARBs ARNi Aldosterone Antagonist § cause hypokalemia Loop diuretics Digoxin??? → (digoxin toxicity exacerbates hypokalemia; I do not think it causes it) - ANTIARRHYTHMICS: o Explain the Vaughan Williams Classification and the medications within those classes Categories based on dominant electrophysiological effect Most frequently; used, but controversial due to: Not classifying all antiarrhythmic drugs Some agents have mechanisms that overlap between classes Does not incorporate use/indication Class I Class II Class III Class IV Ia: -Disopyramide -Quinidine -Procainamide Ib: -Lidocaine -Mexiletine Ic: -Flecainide -Propafenone Beta Blockers -Dronedarone -Dofetilide -Sotalol -Ibutilide -Amiodarone -Verapamil -Diltiazem o State the MOA of the medications in Vaughan Williams Classifications Class IA (Quinidine, Disopyramide, Procainamide) Na-blockade and slowing of Phase 0 Block K-channels; prolongs action potential duration APD: Moderate Increase ERP Moderate Increase Increase QT; increased QRS at high dose **Effective supraventricular and ventricular arrhythmias Class IB (lidocaine, mexiletine) Na-Channel Blockers Blocks Phase 0 depolarization Little effect on refractory period Decrease Automaticity ERP: Less than IA **Effective in ventricular arrhythmias Class IC (Flecainide, Propafenone) Na-channel blockers APD: Minimal ERP: Minimal Widened QRS (More than Class IA) Marked slowing of Phase 0 **Effective supraventricular and ventricular arrhythmias Class II (Beta Blockers) Blocks response to adrenergic stimulation at B-Receptor Indirectly blocks Ca-channels in SA and AV nodes Automaticity: Decreased Refractories: Increased Conduction Velocity: Decreased Indications Acebutolol: PVC only Propranolol: IR forms only Esmolol: Rapid control of ventricular rate in AF or Aflutter Class III Delay phase 3 repolarization Prolonged APD and refractory period Amiodarone Na-Channel Block: Decreased conduction velocity; increased APD K-Channel Block: Increased APD and ERP Ca-Channel Block: Decreased SA and AV node conduction Sotalol Non-selective beta blocker decreases HR and AV node conduction Blocks K channels ERP: Increase APD: Increase Dofetilide: Pure K-channel blockade CCB Type IV Block L-type slow calcium channels in cardiac tissue Slows AV and SA node conduction velocity Automaticity: Decrease ERP: Increase o Describe the effects/properties of the medications in the Vaughan Williams Classifications Class I Blockade of fast sodium channels Split into A,B,C based on effects on upstroke of Phase 0 IA Moderate slow of phase 0 upstroke Moderate increase Action Potential Duration (APD) and Effective Refractory Period (ERP) Increased QRS and QT intervals **Effective for supraventricular and ventricular arrhythmias IB Lesser effect on Phase 0 and Effective Refractory Period Decrease automaticity **Effective for ventricular arrhythmias IC Significant slowing of Phase 0 upstroke and conduction Effective for supraventricular and ventricular arrhythmias Minimal effects on APD and ERP Beta Blockers Myocardial depressants for ventricular and ventricular rhythm disturbances **Most useful in tachycardias Class III Increases Action Potential Duration (APD) and delays repolarization (Phase 3) Blocks potassium channels Class IV CCB Blocks slow calcium channels slowing conduction of SA and AV nodes Depolarization depends on calcium influx **Effective for reentrant tachycardias (PSVT+WPW) o State the indications for the medications in the Vaughan Williams Classifications Quinidine Afib-prophylaxis to convert to NSR Conversion of PVC to NSR Life-threatening ventricular arrhythmias Procainamide Life-Threatening Ventricular arrhythmias Disopyramide Life-Threatening Ventricular Arrhythmias Lidocaine Acute management of ventricular arrhythmias during myocardial infarction or digoxin toxicity Conversion of non-sustained ventricular tachycardia to NSR Mexiletine Reserve for life-threatening ventricular arrhythmias Propafenone Life-Threatening ventricular arrhythmias PSVT with disabling symptoms Maintenance of NSR in paroxysmal Afib/flutter with no structural heart disease Flecainide Life-Threatening ventricular arrhythmias Prevention of Afib/flutter with disabling symptoms PSVT with disabling symptoms in absence of structural heart disease Esmolol Rapid control of ventricular rate in AF or AFlutter Noncompensatory sinus tachycardia where rapid heart rate requires intervention Amiodarone Life-threatening recurrent ventricular fibrillation Life-threatening recurrent hemodynamically unstable ventricular tachycardia Sotalol Life-threatening ventricular arrhythmias Maintenance of NSR in Afib Ibutilide Recent onset of Afib/Aflutter for conversion to NSR Dofetilide Conversion to and maintenance of NSR in Afib Dronedarone Paroxysmal or persistent Afib to reduce risk of hospitalization For patients who already are in NSR Type IV CCB’s Rapid conversion to NSR of PSVT including those associated with bypass tracts (WPW) Temporary control of rapid ventricular rate in AF or AFlutter except when associated with accessory bypass tracts o Describe the major contraindications to use quinidine and the ADR of cinchonism. Quinidine Contraindications Avoid in patients with G6PD (May cause hemolysis) History of prolonged QT History of Torsades de Pointe Thrombocytopenia Use with quinolone Abx that prolong QT Cinchonism ADR Tinnitus Headache Dizziness Confusion o Explain the total body clearance of procainamide and: Cleared 50% renally and 50% hepatic metabolism § how the major metabolite NAPA is formed the principal metabolite is N-acetylprocainamide (NAPA) formed by acetylation (conjugation) in the liver § the pharmacologic actions of NAPA active metabolite NAPA contributes to the overall antiarrhythmic activity by exerting Class III effects; may be responsible for production of torsades when it accumulates in renal failure patients o State the drug which is the most frequent cause of drug-induced lupus. Procainamide o State the medications at risk of causing blood dyscrasias Procainamide Mexiletine o State the warnings with disopyramide Increased mortality in non-life threatening ventricular arrhythmias Proarrhythmic Anticholinergic: Caution in BPH/Urinary retention, narrow angle glaucoma, myasthenia gravis Negative Inotropy: Caution hypotension, HF o Describe the activity of lidocaine against: § AF or atrial flutter Ineffective § nonsustained VT Converts to NSR o Explain the dosage form of lidocaine Parenteral use only (first pass effect) o State the major ADR of flecainide and the limitations on its clinical use. Dizziness Visual Disturbances Dyspnea not recommended for use in patients with chronic AF; PVCs, VT, VF, and death may occur o Explain why Class II antiarrhythmics are useful in thyrotoxicosis best potential to control ventricular rate in patients whose AF is caused by enhanced sympathetic activity, eg, thyrotoxicosis o Explain the “Pill in the Pocket” Propafenone or Flecainide Can terminate Afib in outpatient already taking beta blockers NonDHP o State the indications for esmolol and describe its duration of action. Rapid control of ventricular rate in AFib and AFlutter Noncompensatory sinus tachycardia where rapid heart rate required intervention DOA: Short lasting 30 minutes o Describe the effects of amiodarone on the APD, ERP, automaticity, conduction velocity, and AV nodal conduction time. APD: Increased ERP: Increased Automaticity: Inhibitory effects Conduction Velocity: Decreased AV Nodal Conduction Time: Increased o For the antiarrhythmic agents listed below, identify/describe/explain the associated topics. § amiodarone: · ADRs Hypotension Bradycardia Corneal Microdeposits CNS-Dizziness, ataxia, constipation, tremor Drug-Induced Lupus Erythematosus Pulmonary Fibrosis · Contraindications · Warnings Hypothyroidism Neurotoxicity Optic Neuropathy Severe necrotizing skin reactions Photosensitivity § Sotalol: · ADR CNS: Depression, Confusion, Nightmares, Insomnia CV: Fatigue, Dizziness, Bradycardia, CHF, Hypotension, Dyspnea, Bronchospasm · MOA Non-selective beta blocker decreases HR and AV node conduction. Blocks K channels · nonselective beta blocker · proarrhythmic effects ERP: Increase APD: Increase Prolong QT Interval § Ibutilide: · indication Recent onset of AFib/AFlutter for rapid conversion to NSR · proarrhythmic effects (precautions: monitoring, serum potassium and magnesium) May cause sustained polymorphic ventricular tachycardia § Dofetilide: · indication Conversion to and maintenance of NSR in AFib · proarrhythmic effects QT interval prolongation with torsades Increased risk in patients with history of long QT syndrome, hypokalemia, or taking other agents that prolong repolarization · contraindications Congenital or acquired long QT syndrome QT> 440 msec Severe renal impairment Use with cimetidine, dolutegravir, hydrochlorothiazide, itraconazole, ketoconazole, megostrol, prochlorperazine, trimethoprim, verapamil § Dronedarone: Indicated for paroxysmal or persistent Afib to reduce risk of hospitilization; indicated for patients already in NSR (I think this is contraindicated for NYHA IV heart failure) § Verapamil: · effects on AV nodal conduction velocity and time and the ERP Slows AV conduction Prolongs AV nodal conduction time ERP: Increased · use in control of ventricular rate and exceptions to use Temporary control of rapid ventricular rate in AF or AFlutter EXCEPT when these arrhythmias are associated with accessory bypass tracts (WPW syndrome) · major contraindication CONTRAINDICATED IN WPW SYNDROME ACCOMPANIED BY AF OR AFLUTTER § Adenosine: · effects on AV nodal conduction velocity, time, and ERP Slows AV nodal conduction Prolonged AV conduction time ERP: Increased · indication Rapid Conversion of PSVT to NSR · ADR: heart block, transient asystole, effects in bronchospastic conditions Vasodilation SOB, burning sensation in chest § Digoxin: · Mechanism Blocks Na-K ATP-ase pump; blocks at AV node lead to decreased conduction velocity, increased ERP · Reversal agent -antidote for life-threatening digoxin intoxication = digoxin immune fab (ovine), DigiFab · Therapeutic monitoring Monitoring required if toxicity suspected · Indications Ventricular rate control in Supraventricular Arrhythmias (Afib) · Signs of severe toxicity Blurred/double vision, altered color perception, greenish-yellowish halos around lights or objects - Specific arrhythmias: o Afib: § Identify the listed complications of untreated atrial fibrillation (AF). Increased risk of cerebral thromboembolism Development of HF Increased Mortality Increased LA pressure and volume Decreased diastolic filling time AV valvular regurgitation Irregular and rapid ventricular rate § Explain the selection for rate vs rhythm control Drug selection based on safety and concurrent heart disease Risks vs Benefits § State the drugs most commonly used for rate control in AF. Beta Blockers are first-line nonDHP CCB=Verapamil or Diltiazem Avoid in LV dysfunction and decompensated HF (HFrEF) Dont use when Aflutter is associated with WPW Digoxin Not used as monotherapy Can consider in patients with HF Adjunct with BB/CCB § For rhythm control in AF: · state the most commonly used agents Class IC Flecanaide, Propafenone Avoid in patients with structural heart disease Class III Sotalol Not efficacious for conversion to NSR Beneficial in prevention of recurrence Amiodarone More effective than others %61-68 success Used after other methods Dofetilide High risk of Torsades developing Dronedarone Included in guidelines, contraindications in HF and permanent AF limits usage · state the restrictions placed on Class IC agents Limited to patients without structural heart disease · explain why amiodarone is the most commonly used agent from any class Highly efficient in preventing recurrence Safe for patients with structural heart damage § For pharmacologic cardioversion (conversion to NSR), state the : · DOC Class I Dofetilide, Ibutilide Class IC Flecainide and Propafenone Class IIa Amiodarone · agents which are not recommended (digoxin, sotalol) Dofetilide § Explain the CHA2DS2VASC score and when anticoagulant therapy is recommended Used to predict stroke risk among patients When score is >= 2 § Explain the HAS-BLED score and utilization in therapy Bleeding risk scores quantify hemorrhage risk Scores over 3 indicates potentially high risk o State the medications of choice for the following arrhythmias: § Long QT syndrome Beta Blockers § Torsades de Pointes Magnesium § Wolff-parkinson-white syndrome IV Procainamide Class 1A and Class 1C § AV nodal reentrant tachycardias IV Adenosine Alternative is IV Verapamil - ANTIANGINAL DRUGS: o Identify the which anginal situations NTG would be indicated (stable, unstable, prinzmetal, silent) Stable Angina Prinzmetal’s Angina Not indicated for Unstable Angina o State which antianginal drugs are indicated and contraindicated in vasospastic angina. Beta Blockers: Contraindicated DHP-CCB: Indicated for vasospastic angina o Identify the clinical uses and mechanisms of primary drug therapies for angina (HR, BP, diastolic perfusion, contractility, oxygen demand/consumption, LV pressure) Beta Blockers CCB’s Nitroglycerin Ranolazine o State the first, second, and third line therapies First Line Beta Blockers Second Line CCB, NTG Third Line Ranolazine o State indications for antianginal therapies Beta Blockers Indicated for unstable angina, contraindicated in vasospastic angina. First-line for prophylaxis, daily maintenance monotherapy of chronic stable angina More effective than nitrates, CCBs in reducing Ischemia, early AM peak of ischemic activity, mortality after Q-wave MI Used in combination with nitrates to prevent/diminish reflex tachycardia DHP CCB Stable and prinzmetal’s angina Non-DHP CCB Unstable angina (Verapamil), stable angina, prinzmetal’s angina o NTG: § Describe the first-pass metabolism of nitroglycerin (NTG) and organic nitrates and how bioavailability by the oral and sublingual routes is affected. Bioavailability of NTG is low due to First-Pass Effect taken orally Sublingual avoids the first-pass effect. Rapid onset 1-3 minutes § Explain the mechanism of action of nitrates in producing vascular smooth muscle relaxation and vasodilation. Organic nitrates serve as a source for nitric oxide (NO) NO activates guanyl cyclase to increase cyclic GMP cGMP activates cyclic GMP-dependent protein kinase which phosphorylates various proteins in smooth muscle This activated phosphatase then inhibits any contractile response § State the three major effects of nitrates on the venous smooth muscle and preload, and the major ADR that may occur. Decreased preload Relaxation of venous smooth muscle Dizziness/lightheadedness, flushing, syncope § Explain the reflex tachycardia that occurs with nitrates and the effects on oxygen Demand. Reflex tachycardia, increased contractility; may cause paradoxical increase in oxygen demand § Differentiate between short acting and long acting NTG Short Acting: Patients with angina for immediate relief Long Acting: Used for prophylaxis and maintenance · State the major uses for both rapid onset, short duration and slower onset, long duration dosage forms of nitrates, and be able to identify which dosage forms belong in these categories. Fast Acting Sublingual packet Sublingual Tablet Translingual Solution Aerosol Solution Intravenous Long Acting Transdermal patch Transdermal Ointment Oral Extended release Capsule § Explain the effects of NTG on: · coronary vascular resistance Decreases Coronary Vascular Resistance · redistribution of coronary flow caused by NTG and its beneficial effects. Produces a redistribution of coronary blood flow through collateral vessels in favor of the subendocardial regions of the heart that have undergone the greatest reduction in blood flow due to atherosclerosis § State the types of angina for which nitrates are indicated. Exertional Angina Variant Angina Unstable Angina § Describe the indication for using sublingual NTG for relief of anginal pain, the accompanying side effects, and the proper use and storage of NTG sublingual tablets. - Sublingual NTG is to be used in rapid relief of angina/chest pain - Store in a dry place at room temperature - Side effects from vasodilation include dizziness, headache, flushing, faintness, postural hypotension § Explain the consequence of continuous nitrate use and the methods for preventing tolerance. Continuous nitrate administration results in development of tolerance to the antianginal effect. Therapy should be interrupted for a interval every day to prevent tolerance Nocturnal: Apply at bedtime, remove at 10 am Ointment: Apply early AM, stop in PM (8-12 hr nitrate-free interval) IV Infusion: Tolerance can develop if infusion goes past 12 hours Patch: Early AM to 7 PM (12 hours on, 12 hours off) o Beta Blockers: § Explain the mechanisms by which beta blockers relieve anginal pain, and state which types of angina have beta blocker indications. Beta Blockers decrease HR, BP, and contractility. Therefore oxygen demands are reduced. Maintenance of chronic stable angina Indicated for unstable angina § State the precautions for beta blocker use with concomitant asthma, diabetes, and peripheral vascular disease. Asthma: Contraindicated Diabetes and PVD: Use cardioselective Beta Blocker with great caution. o CCBs: § Explain the mechanism of antianginal action for calcium channel blockers (CCB). Inhibits calcium entry/release. This will limit contraction of cardiac muscle and contraction of vascular smooth muscle Decreases cardiac workload and oxygen demand. Decreases coronary vascular resistance increasing myocardial blood supply. Peripheral vasodilation decreasing TPR. § State which of the calcium channel blockers (nifedipine, verapamil, diltiazem) causes: (repeat objective) · the greatest amount of reflex tachycardia Nifedipine (DHP) · the most potent peripheral vasodilation Nifedipine most potent Verapamil/Diltiazem mild/moderate · the greatest amount of flushing, headache, hypotension Nifedipine · the most constipation Verapamil § Explain why the chronotropic and inotropic effects of verapamil and diltiazem may be highly variable. These drugs block AV node and decrease HR Verapamil has high risk of depressed contractility CAUTION WITH OTHER NEGATIVE INOTROPES SUCH AS BBs o Ranolazine: § State MOA, indication, ADRs, and warnings Decrease myocardial oxygen demand by decreasing late phase sodium current. Which facilitates calcium entry via the Na-Ca exchanger Decreased ventricular tension, decreased cardiac contractility and improved blood flow Used for patients intolerant to BB or need additional symptom relief ADRS: Constipation, nausea, dizziness, headaches Warnings: QT interval prolongation; can lead to torsade de pointes and ventricular tachyarrhythmia - ACS: o Explain the difference between unstable angina, NSTEMI, and STEMI § Symptoms, cardiac enzymes, ECG changes, Blockage Unstable Angina (“Pre-Infarction”) No ECG changes No troponin Partial Blockage NSTEMI Positive enzyme (Troponin) changes No ECG changes Partial Blockages STEMI Complete Occlusion ST-Elevation Positive Cardiac Enzyme changes § Define troponin levels Biochemical Marker (TnT or Tnl) Appear in blood within 6 hours of MI, stay elevated for 10 days. Identification of MI is indicated by rise or fall of Troponin Positive Level: >.04 (troponin I), >.01(troponin T) o Identify which parenteral anticoagulants are indicated with PCI UFH and Bivalirudin Use Bivalirudin monotherapy in preference to combination (UFH+GP IIb/IIIa Receptor Antagonist) o STEMI: § State the treatments (with relation to short term or long term goals) for treatment of STEMI Short Term Restore Blood Flow Early Prevent death and MI-Related Complications Prevent Re-Occlusion Relieve Ischemic Chest Discomfort Resolution of ST-Segment and T-Wave Changes Long-Term Control CV Risk Factors Prevention of Additional CV Events Improved QOL § State prehospital management for patients with STEMI Aspirin 162-325mg Establish venous access Review reperfusion checklist Obtain 12-lead ECG Relay information to facility § State the essential pharmacological components of ER management of STEMI and explain the reasons for using each of these therapies. Morphine Treat chest symptoms refractory to nitrates - not all patients Oxygen Patients with arterial oxygen desaturation <90% Nitroglycerin Reduces symptoms of chest discomfort Aspirin 25% reduction in death, reinfarction, and stroke in STEMI setting GPIIb/IIIa Receptor Inhibitor Prevents platelet aggregation Anticoagulants Inhibit clotting factors P2Y12 Receptor Inhibitors Inhibit platelet aggregation Beta Blockers Decrease O2 demand by decrease BP, HR, and contractility Decrease Ischemia, reinfarction, and arrhythmias Ace Inhibitors Inhibit angiotensin converting enzyme blocking AT2l § State the alternatives to PCI for patients that do not qualify (identify when a patient would not qualify) Fibrinolytic therapy § Describe the benefits of using thrombolytic reperfusion therapy in specific time intervals Target time for reperfusion therapy is within 30 min of hospital presentation for thrombolytics and within 90 min or less for primary PCI; faster time to reperfusion means lower mortality and more myocardium preserved § State the recommendations for avoidance of use of nitroglycerin (NTG). SBP<90 mmHg, HR <50BPM, RV infarction, concurrent PDE-5 inhibitor in last 24-hours (48-hour for tadalafil) § Compare on the use of NTG to control ischemia post-STEMI during the · first 24-48 hr period Tachyphylaxis occurs · after 48 hr. Loses effects § State the recommended antiplatelet therapy for post-STEMI patients regardless of whether they received reperfusion therapy. Aspirin P2Y12 Antiplatelet Agent Clopidogrel, Prasugrel, Ticagrelor GpIIb/IIIa Receptor Inhibitor Abciximab, High Bolus Dose Tirofiban, Double Bolus Eptifibatide § State the approved antiplatelet therapies (double check!) MOA: Inhibit P2Y12 receptor on platelets, inhibits platelet aggregation Ticagrelor or clopidogrel can be given in medical management as well as with PCI (ticagrelor given preference) Prasugrel only if undergoing PCI Patients should get a loading dose followed by a maintenance dose Do not give in patients undergoing CABG § State the contraindications for beta blocker use in STEMI patients Signs of HF Evident low-output state Increased risk for cardiogenic shock § Describe the recommendations for use of beta blockers: · for STEMI patients who did not receive BBs in the first 24 hr Start them on BB and continue indefinitely · for patients who received thrombolytic therapy or PCI Use oral antib\\iotics in patients with no contraindications · in patients with early contraindications in the first 24 hr of STEMI. Be reevaluated for BB administration § Explain the goals of late BB therapy and how long BBs should be given. Prevention of reinfarction and death § Describe the use of angiotensin converting-enzyme inhibitors in STEMI patients, when they should be started, and how long they should be continued. Administer in first 24 hours Continue indefinitely LVEF<40%, HTN, DM, or CKD § Describe the use of aldosterone antagonists in post-STEMI patients: · contraindications Renal Dysfunctions · concurrent conditions Patients should be on ACEI and BB and have no contraindications. § Explain the role of calcium channel blockers in the management of STEMI. Limited role. Not shown to lower mortality Verapamil and Diltiazem given when there is persistent angina and hypertension, but are unresponsive to BB § Describe the use of aspirin (dosage, how long) in post-discharge therapy of STEMI patients: · after stent placement 81-162 mg/day · with no stent 162-325 mg/day § Describe the use of clopidogrel (75 mg/day) in post-discharge therapy of STEMI patients for: · after stent placement At least 12 months · no stent 14 days · for patients at low CV risk for both types of stents § State the medications to avoid in an acute setting and why Immediate-Release Nifedipine (DHP-CCB) Dose-Related increase in mortality in patients with CAD NSAIDS (except ASA) Increased mortality risk, reinfarction, hypertension, cardiac rupture, renal insufficiency, and heart failure. § Explain the use of statin therapy and indication Use in all STEMI patients with no contraindications and continue therapy. o NSTEMI/UA: § State the initial medication (anti-ischemic and analgesic therapy) for NSTEMI and when each is indicated MONA-same indications as for STEMI § State the use of antithrombotic therapy (antiplatelet and anticoagulation) in patients with NSTEMI § Describe the use of the TIMI risk score and purpose in therapy Risk calculator for Thrombolysis in Myocardial Infarction § Identify when standard medical therapies are recommended in NSTEMI · Antithrombotic, beta blocker, ACEi/ARB, CCBs, statins, NSAIDs, PPIs Antithrombotic (Dual Antiplatelet Therapy) 12 months Beta Blockers within 24 hours ACEi/ARB similar to BB within 24 hours CCBs not beneficial Satin used high intensity in patient with no contraindications NSAIDS: Avoid PPI triple therapy with Dual Antiplatelet Therapy and Anticoagulants § Identify when GPIs are indicated in NSTEMI therapy If no P2Y12 inhibitor used prior to PCI ANTIPLATELETS: o Explain the physiologic actions of COX-1 and COX-2 COX-1 Involved in synthesis of Thromboxane A2 Platelet Activation Platelet Aggregation Vasoconstriction COX-2 Found in endothelial cells and inflammatory cells Synthesis of prostacyclin Lower platelet aggregation Vasodilation o Aspirin: § Describe the mechanism of the antiplatelet actions of aspirin. How long do these actions affect the platelet? Irreversibly binds and inhibits COX-1 and COX-2 enzymes Lasts lifetime of platelet (10 days) § Explain the dose-dependent effect of aspirin Low-Dose COX-1 Inhibition leads to antiplatelet effect Medium Dose COX-1 and COX-2 inhibition; blocks PG production leads to analgesic and antipyretic effects High Dose Effective as anti-inflammatory agents in rheumatic disorders; toxicities at such high dosages (Tinnitus/GI Intolerance) § State indications of aspirin therapy Acute Coronary Syndrome (ACS) STEMI, NSTEMI/UA, Avoid enteric-coated 162-325 mg/day Post ACS 81mg TIA or minor noncardioembolic stroke Reduces risk of stroke or death, vascular death, MI, or stroke Post-Coronary Stent Prevents Stent Thrombosis; Dual AntiPlatelet Therapy (DAPT) § Compare formulations and clinical uses (I will talk about the specifics for this objective during lecture and it will be on a slide) Use chewable and not enteric-coated. Enteric-coated will delay the release of the Aspirin § State the major side effects, contraindications, and drug interactions with aspirin therapy Side Effects Bleeding Dyspepsia Heartburn Nausea Contraindications NSAID or Salicylate allergy Syndrome of rhinitis, nasal polyps, and asthma Children and teenagers with viral infections (risk of Reyes Syndrome) DI Increase bleeding risk Excess alcohol NSAIDs Anticoagulants Other antiplatelet agents Antidepressants o Dipyridamole: § State the antiplatelet mechanism of action and approved indications for oral dipyridamole. Increases cAMP in platelets, promoting Ca uptake Inhibits platelet activation and aggregation Used for Heart Valve Replacement Prevention of postoperative thromboembolic complications Radionuclide Myocardial Perfusion Alternative to exercise in imaging § Identify when dipyridamole is indicated in therapy Secondary stroke prevention to reduce the risk of strokes in patients who have already had a completed ischemic stroke or TIA Also indicated for thromboprophylaxis in patients undergoing hemodialysis o P2Y12 inhibitors: § State the MOA of P2Y12 inhibitors Bind the ADP P2Y12 platelet receptor, inhibiting ADP-Induced aggregation § State the indications of ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor Ticlopidine Secondary prevention of stroke after thrombotic stroke/TIA Prevention of stent thrombosis with ASA Better than ASA alone or warfarin for preventing death Clopidogrel ACS and secondary prevention of MI, stroke, and PAD Prasugrel ACS in patients being manage with percutaneous coronary intervention Ticagrelor ACS Cangrelor PCI to reduce risk of periprocedural MI in patients who have not been pre-treated with any of the other ADP receptor antagonists and are not receiving GPIIb/IIIa inhibitor. § Compare ticlopidine and clopidogrel with regard to: · cross-reactivity with aspirin Ticlopidine has no cross-reactivity with aspirin Clopidogrel has no cross-reactivity with ASA · mechanism of antiplatelet action Ticlopidine inhibits primary and secondary phases of platelet aggregation induced by ADP and Fibrinogen Clopidogrel ADP-selective platelet aggregation inhibitor 3 times potency of Ticlopidine · incidence of severe hematological ADR Ticlopidine has black-box warning of life threatening Clopidogrel has no incidence of bleeding disorders · efficacy of antiplatelet actions compared to aspirin Ticlopidine works about the same as aspirin Clopidogrel is more efficacious than aspirin § Explain the potential problems for patients taking clopidogrel if they are: · deficient in the normal amount of CYP2C19 Increased risk of CV events · taking PPIs (know specific PPI interactions) Poor CV outcomes § For each indication of P2Y12 inhibitor therapy, state the duration of use. Maintenance Dose up to 12 months § What are the class ADRs for P2Y12 inhibitors Ticlopidine Hematological ADR Clopidogrel Thrombotic thrombocytopenic purpura Prasugrel Bleeding Ticagrelor Higher risk of spontaneous hemorrhagic events than clopidogrel Cangrelor Bleeding Dyspnea o Identify specific scenarios where aspirin, P2Y12 inhibitors, or antithrombotics may be chosen over the other. Aspirin ?? Unsure ?? o Describe the two indications for which combined aspirin-clopidogrel therapy has been proven beneficial. Stent replacement or CABG o Explain DAPT Dual AntiPlatelet Therapy Use of two separate antiplatelet medications o GIIb/IIIa: § Describe the MOA Inhibit final step in platelet aggregation Block platelet GPIIB/IIIa receptor on platelets Inhibits cross-binding of fibrinogen § List the indications for eptifibatide and tirofiban Eptifibatide Treatment of patients with acute coronary syndrome including medically managed patients and those undergoing PCI Tirofiban For use with heparin for treatment of ACS including medically managed patients and those undergoing PTCA or Atherectomy § State the class and specific side effects for eptifibatide and tirofiban ALL Bleeding , Thrombocytopenia Eptifibatide Bleedings, hypotension; not immunogenic Tirofiban Bleeding, edema, leg or pelvic pain, vasovagal reactions, bradycardia, CA dissection, dizziness, sweating; not immunogenic. § Identify when GIIb/IIIa antagonists are indicated in therapy Treatment of ACS (UA/NSTEMI) Patients undergoing percutaneous coronary intervention (PCI) with or without stent placement to reduce risk of death. o PAR1 antagonist § State the MOA and indication in therapy Inhibition of the PAR1 receptor and removal of platelet activation Indication Reduction of the risk of thrombotic and CV events in patients with a history of MI or peripheral arterial disease. Combined with low-dose ASA and/or clopidogrel. Most appropriate use is in patients at very high CV risk due to high risk of bleeding from Vorapaxar.