Heart Failure*.pdf

Heart Failure Advanced Pharmacology Performance Objectives 1. Describe the pathophysiology and compensatory mechanisms in HF. 2. Describe treatment strategies and major drug groups used in the treatment of HF. 3. Explain the differences in pharmacokinetics of the different cardiac glycosides, part...

Heart Failure Advanced Pharmacology Performance Objectives 1. Describe the pathophysiology and compensatory mechanisms in HF. 2. Describe treatment strategies and major drug groups used in the treatment of HF. 3. Explain the differences in pharmacokinetics of the different cardiac glycosides, particularly metabolism and excretion, and give reasons for selection of these agents for specific uses. Performance Objectives 4. Describe the pharmacodynamics of nonglycoside inotropic agents, their indications in HF, and possible adverse effects. 5. Explain the beneficial effects of non-inotropic agents in treatment of HF. 6. Describe the management of acute vs. chronic heart failure. Update • Paradigm shift from Hemodynamic Hypothesis to Neurohormonal Hypothesis • Addition to the functional New York Heart Association Classification I-IV (NYHA) with structural ACCF/AHA Staging A to D. • Terminology shift from Congestive Heart Failure to just Heart Failure. • Introduction of HF with preserved EF (HFpEF) and HF with reduced EF (HFrEF). • Guideline-directed medical therapy (GDMT) Update-FYI Circulation, 2013, pg. 1816, Table 4 Update-FYI Circulation, 2013, pg. 1816, Table 3 Update-FYI Circulation, 2017, pg. e140 Table 1 Katzung, 15th ed., pg. 220, Fig. 13-1 Katzung, 15th ed., pg. 221, Fig. 13-3 Goodman & Gilman, 12th ed. Pg. 791, Fig. 28-1 THERAPEUTIC STRATEGIES TO IMPROVE MORBIDITY 1. 2. 3. • INCREASE CARDIAC OUTPUT RELIEVE CONGESTION RELIEVE EDEMA DO THESE WITH DRUGS THAT: – DECREASE AFTERLOAD – DECREASE PRELOAD – INCREASE CARDIAC CONTRACTILITY THERAPEUTIC STRATEGIES TO IMPROVE MORTALITY • DO THIS WITH DRUGS THAT REDUCE THE RATE OF CARDIAC REMODELING – ACE-I – ARB (in ACE-I intolerant individuals) – BETA-BLOCKERS – ALDOSTERONE ANTAGONISTS – FIXED DOSE HYDRALAZINE/ISOSORBIDE – NEPRISLYN INHIBITOR Study Questions • Why does decreasing afterload improve HF? – Katzung, p. 213 • Why does decreasing preload improve HF? – Katzung, p. 213 • To understand this more deeply, keep superimposing the effect of afterload reduction (next graph) onto the graph following that (preload) until both graphs make sense Afterload Reduction Afterload reduction (reduction in resistance to outflow) moves the point on the curve for stroke volume to the left, resulting in greater output in the failing heart. When there is less systemic resistance, more volume comes out with each stroke. Preload Reduction Diuretics (D) alone decrease ventricular filing pressure (thus improve congestive signs) but do not improve stroke volume. In contrast, vasodilators (V) shift the ventricular function curve upward (afterload affect) and also relieve congestion. Inotropic agents (I) also shift the curve, but do not necessarily relieve congestion. Combinations of drugs have predictable effects based upon these properties. DRUG CLASSES USED IN HF • NON-INOTROPIC DRUGS • POSITIVE INOTROPIC DRUGS – ACE INHIBITORS – ANGIOTENSIN1 ANTAGONISTS – VASODILATORS • ARTERIODILATORS • VENODILATORS – DIURETICS – BETA BLOCKERS – ALDOSTERONE ANTAGONISTS – NATURETIC PEPTIDE-BNP – BI-DIL – NEW AGENTS – CARDIAC GLYCOSIDES – ADRENORECEPTOR AGONISTS – PHOSPHODIESTERASE INHIBITORS Non-Inotropic Drugs-ACE Inhibitors 1. Decrease production of angiotensin II 2. Increase circulating bradykinin • Next slide shows the key role of the angiotensin converting enzyme (ACE, which is identical to kininase II – ACE is associated with angiotensin; kininase is associated with bradykinin) Goodman & Gilman, 12th ed. Pg. 794, Fig. 28-3 ACE/Chymase and Angiotensin II • The major pathway for angiotensin II activation is through ACE • Many patients tx with ACEIs show return to near baseline levels of angiotensin II, which occurs by activation of the chymase pathway. Nonetheless, the ACEIs continue to be efficacious. Goodman and Gilman, 12thed. Pg. & Goodman 728. Fig 26-6 th Gilman, 12 ed. Pg. 794 Effects of Angiotensin II • Potent vasoconstrictor • Promotes Na and H2O retention by releasing aldosterone • Potentiates release of catecholamines (NE) • Promotes vascular hyperplasia • Promotes myocardial hypertrophy • Stimulates myocyte death Results of Blocking Angiotensin II Production • • • • Vasodilation Decreased Na and H2O retention Decreased response to sympathetics Decreased tissue remodeling • Net effect: decreased preload; decreased afterload; decreased mortality (slower disease progression) Results of Increasing Bradykinin Levels • Vasodilator – promotes NO formation – increases synthesis of prostacyclin • Prevents vascular and cardiac cell growth • Stimulates tPA release • “Kinin” autocoids produce tissue irritation and pain, which likely accounts for a major sideeffect of ACEIs ACEIs: Effects on Morbidity 1. relieve dyspnea 2. prolong exercise tolerance 3. decrease need for emergency care • These effects observed in mild, moderate and severe HF ACEIs: Effects on Mortality • Several trials (SOLVD, V-HeFT, CONSENSUS) have shown that pts treated with ACE-Is have a decreased risk of death • Slow cardiac remodeling and disease progression (increased bradykinin effect? reduced aldosterone effect? reduced angiotensin II effect?) ACE inhibitors: Uses in HF • ALL patients with left ventricular systolic dysfunction should be on ACE inhibitors – use with diuretic in those with fluid retention • Patients with left ventricular systolic dysfunction who have no symptoms – slows remodeling • Advise patients about side effects, and that improvement may take weeks to months ACE inhibitors: Uses in HF • Generally not to be used in acute failure (use after stabilization) – Acute HF occurs for example following myocardial infarction or valve rupture. – Hypotension is often a problem initially, which contraindicates vasodilators. – In addition, the renin-angiotensin-aldosterone system is highly active in acute HF, and sudden reduction of this tone can lead to cardiovascular collapse. ACE inhibitors Adverse Effects/Contraindications • Dry, persistent cough – bradykinin related – often intolerable • Severe hypotension in pts who are hypovolemic (watch out for hypovolemia in pts taking diuretics) ACE inhibitors Adverse Effects/Contraindications • Acute renal failure (particularly in renal artery stenosis) – In renal hypotension, angiotensin II maintains efferent arterial tone in the glomerulus, which maintains glomerular filtration • Hyperkalemia – Lowers aldosterone, which decreases Na/K exchange in the distal tubule – Watch for interaction with sparing diuretics (spironolactone is used in HF) ACE inhibitors Adverse Effects/Contraindications • Angioneurotic edema – Rapid swelling in the upper respiratory tract – lifethreatening – 0.1-0.2% incidence – Typically occurs within first week of therapy, often with the first dose – Not immune mediated – Bradykinin is listed as a culprit, but the evidence is not compelling • Contraindicated in pregnancy ACE-I induced angioedema ACE Inhibitors • Choice of an ACE Inhibitor – Presumably, all will be efficacious, but several have been shown to be beneficial in large clinical trials (captopril, enalapril, lisinopril) – Begin at low dose, increase as doses are tolerated – Captopril is probably a lesser choice • Multiple times/day administration Non-Inotropic Drugs— Angiotensin II Antagonists • Note: You may see these referred to as Angiotensin II Blockers (blockers of the compound angiotensin II). Two receptor subtypes for angiotensin II – AT1 • responsible for the effects of angiotensin II that must be diminished in HF. “Sartan” drugs block this receptor. – AT2 • Role of these receptors is less clear. Some evidence that their activation opposes effects of AT1 ARBs: Uses in HF • For pts who fail on ACE-Is • Approved only for hypertension – But also found as a benefit for HF patients who are intolerant of ACE-I, this has been demonstrated with candesartan, losartan and valsartan in ELITE-I, VaHeFT and CHARM clinical trial. ARBs: Adverse Effects • Incidence similar to placebo • Do not elevate bradykinin – No cough Non-Inotropic Drugs-Vasodilators • Arteriodilators – decrease afterload – Hydralazine • Venodilators – decrease preload – Organic nitrates HYDRALAZINE • Mechanism is unknown • Decreases systemic vascular resistance (decreases afterload), which leads to increased stroke volume • Has minimal effects on venous capacitance • Therefore, most effective when combined with venodilators • When combined with isosobide dinitrate, the combination has been shown to decrease mortality in HF (but not as effective as ACEIs) HYDRALAZINE: Adverse Effects • Tachycardia, angina – Why does selective afterload reduction cause these effects? • Drug-induced lupus syndrome – Dose-related – Incidence of 5-10% – reversible on discontinuing the drug VENODILATORS • Useful in pts with high filling pressure • Organic nitrates – Isosorbide dinitrate – Nitroglycerin • Sodium nitroprusside ORGANIC NITRATES • Pharmacodynamics – Decrease preload – Increase exercise capacity – Decrease symptoms of congestion • Mechanism/Toxicity – Review angina material – Tolerance is a significant issue such that pts must be drug free 6-8 hrs per day. Organic Nitrates: Uses • Combined with hydralazine, decrease mortality • Used by themselves, they decrease congestion – Nitroglycerin is used i.v. in acute HF to decrease ventricular filling pressures SODIUM NITROPRUSSIDE • Mechanism – Rapidly hydrolyzed to NO and CN • Pharmacodynamics – Decreases both preload and afterload • Indications – Short term therapy in acute HF • Adverse Effects – Hypotension – CN is rapidly metabolized to thiocyanate –thiocyanate and/or cyanide toxicity limit duration of drug use Non-Inotropic Drug DIURETICS USE IN HF • Review material concerning thiazides, loop diuretics and spironolactone • All patients with symptoms who have fluid retention – Loop diuretics for acute HF – Most HF pts require loop diuretics chronically to maintain euvolemia – Resistance occurs to loop agents; if so, add metolazone (thiazide-like diuretic) DIURETICS: USES IN HF • Should seldom be used alone, even if symptoms are well-controlled – Monotherapy with a diuretic may cause adverse neurohormonal activation due to volume depletion – Mortality is improved by other drugs Diuretics: Adverse Effects • Review from previous material • Diuretic-induced hypokalemia is particularly important for pts taking cardiac glycosides (see later part of topic) Non-Inotropic DrugsBeta Blockers and HF • In the acute, decompensated stages of HF, beta-blockers are contraindicated – Sympathetics are highly active in acute HF – Beta-blocker poses a significant danger of reducing cardiac output to intolerable levels Beta Blockers and HF • • When HF is under control (ACE-I and diuretics), a beta-blocker is useful in slowing the remodeling of the heart. Mechanism is not entirely clear: two most likely candidates are 1. High sympathetic tone in HF causes betareceptor down regulation. Beta-blockers may counteract this effect by inducing receptor spread. 2. Beta-blockade may directly prevent remodeling caused by catecholamines. b (and a) Adrenergic Antagonist: Carvedilol • Approved for class II and III heart failure • Use results in decreased hospitalizations and all-cause mortality • Improves symptoms and slows progression • Nonselective b-blocker; also has a1 blocking effects Carvedilol, others • Dramatically decrease mortality in Class II and III pts (class IV is less clear) • Adverse effects – – – – Symptomatic hypotension common initially Fluid retention: may have to ­diuretics Bronchospasm danger in asthmatics Heart failure may worsen initially • Other approved agents include metoprolol, bisoprolol Non-Inotropic Drugs SPIRONOLACTONE • Technically, a diuretic – Enhanced Na and H2O excretion is so small as to be relatively unimportant as a diuretic • As a diuretic, inhibits aldosterone effects on the collecting ducts – Decreases Na/K exchange • promotes hyperkalemia, but this is usually slight if no other factors are present • Hyperkalemia can be pronounced when coupled with an ACEI SPIRONOLACTONE • Aldosterone receptor antagonist – Recently demonstrated to improve mortality and morbidity in patients with severe (Class IV) HF – Lends support to hypothesis that aldosterone effects on the heart are a major contributor to tissue remodeling Non-Inotropic DrugsBrain natriuretic peptide (BNP) • Natriuretic Peptide – MOA-via receptor binding to guanylate cyclaseA and cGMP production ie. NO like – Reduce preload, afterload, increase contractility and no increase HR – IV bolus and then IV infusion Inotropic Drugs—DIGOXIN--MOA • Inhibits cell membrane NA/K-ATPase – Relatively selective for cardiac enzyme • Binds preferentially to and stabilizes the phosphorylated form of the enzyme • An inverse relationship exists between extracellular K+ regulates and phosphorylation of the enzyme – Elevated K+ decreases the affinity of the ATPase for cardiac glycosides – Low levels of K+ increases the affinity of the ATPase for cardiac glycosides • Inhibition of the Na/K-ATPase leads to enhanced Ca++ inside the cell. – Higher Ca concentrations lead to enhanced contractility DIGOXIN Na-K ATPase Na+ K+ K+ Na+ Na-Ca Exchange Na+ Myofilaments Ca++ Ca++ CONTRACTILITY MECHANICAL EFFECTS OF GLYCOSIDES ON THE HEART • Due to increased intensity of actin-myosin interaction – Increased myocardial contractile force (+ inotropic effect) – Increased velocity of contraction (+ dromotropic) – Decreased duration of systole (small effect) ELECTRICAL EFFECTS OF GLYCOSIDES ON THE HEART • Sinoatrial node – Slowing of the sinus rate – Through indirect (vagal) effects • AV node (antiarrhythmic effect) – Indirect effects (predominant) • Inc. in ERP • Dec. in conduction velocity – Direct effects • Same as indirect. In combination (indirect + direct) get a high likelihood of AV block if the dose is too high. • Purkinje fibers, ventricle – Indirect effects – negligible – Direct effects (high doses) • Decrease in ERP • Decrease action potential duration • Increase in conduction velocity • GI EXTRA-CARDIAC EFFECTS--TOXICITY – Anorexia, nausea, vomiting-excitation of chemoreceptor trigger zone (CTZ) – Diarrhea, abdominal discomfort--direct irritant • Headache, fatigue, malaise and drowsiness – Occur early in digitalis intoxication • Mental symptoms – Disorientation, confusion, delirium, hallucinations (“digitalis delirium”), nightmares, depression (elderly) • Vision – Blurred vision – White vision-white halos on dark object – Color vision—yellow and green common Inotropic DrugPHOSPHODIESTERASE INHIBITOR • • • • Milrinone Inotropic Vasodilatory For short-term therapy – Parenteral use MILRINONE • Mechanism of action – Increase inward calcium flux in the heart & – Inhibition of cAMP phosphosdiesterase Increase cAMP • In heart: increase cardiac output • In vasculature: decrease SVR, decrease pulmonary capillary wedge pressure • Net result: improved hemodynamics MILRINONE • Half-life = 2-3 hours • Indications • Short-term therapy – PDE inhibitor of choice for short-term tx of acute failure – Parenteral administration MILRINONE • Adverse Effects – Short Term • Fewer than inamrinone (removed from US), which reported nausea/vomiting, thrombocytopenia, and liver damage in significant number of patients. – Long Term • Increased Mortality • Arrhythmias Inotropic DrugsDOBUTAMINE • Pharmacodynamics/Mechanism of Action – Increase in cardiac output; decrease in ventricular filling pressure – Beta1 (predominant) and beta2 agonist effects • Indications – Short-term support of cardiac output in advanced HF – Tolerance prohibits long-term use • Adverse Effects – Tachycardia with possible increase in myocardial oxygen consumption (angina) Inotropic DrugsDOPAMINE • MECHANISM OF ACTION – Agonist effects at beta1 and dopamine1 receptors • Indications – Short-term therapy only – Especially useful to increase splanchnic and renal blood flow • Adverse Effects – Tachycardia (worse than dobutamine) – At higher doses, increase in systemic vasuclar resistance (see next slide); mechanism is alpha agonist – Dobutamine is generally a better choice HR PCP (mm Hg) SVR Various drip rates (ug/min) are shown for dopamine (DA) or dobutamine (DB). Both agents have positive inotropic effects (note the greater effect of DB (Xaxis). At higher doses of DA, an increase in systemic vascular resistance (SVR) limits cardiac output and worsens congestion (PCP). The inotropic effect of DB occurs with little change in heart rate (HR). DRUG TREATMENT OF ACUTE DECOMPENSATED HEART FAILURE • Adrenergics agents – Dobutamine is usually drug of choice – Dopamine is preferred in some situations (low blood pressure) • PDE inhibitors • Vasodilators – NTG – Nitroprusside • Diuretics and morphine as needed • BNP WHAT’S NEW IN HEART FAILURE • CORLANOR (Ivabradine) & • PARADIGM HF TRIAL (NEJM, SEPT. 3, 2014) – ANGIOTENSIN-RECEPTOR AND NEPRILYSIN INHBITION WITH Entresto™ (SACUBITRIL AND VALSARTAN) – NEPRILYSIN IS A NEUTRAL ENDOPEPTIDASE INVOLVED IN THE METABOLISM OF A NUMBER OF VASOACTIVE PEPTIDES. THE INHIBITOR BLOCKS THE ACTION OF NEPRILYSIN, RESULTING IN HIGHER LEVELS OF PEPTIDES SUCH AS NATRIURETIC PEPTIDES, WHICH HAVE VASODILATOR PROPERTIES, FACILITATES SODIUM EXCRETION AND MOST LIKELY HAS EFFECTS ON REMODELING. Neprilysin Substrates Substrates Most Relevant to Cardiovascular Physiology Metabolism of natriuretic and other vasoactive peptides* by NEP1-9 ANP, BNP, CNP § NEP substrates can have opposing biological actions1 Ang-II § The overall CV effect is dependent on Ang-I the net effect of NEP metabolism on individual substrates1 Adrenomedullin Substance P NEP Bradykinin Endothelin Urodilatin Inactive fragments or metabolites *Does not include all the substrates of NEP; only the most relevant substrates for CV physiology are listed. Ang, angiotensin; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; CV, cardiovascular; NEP, neprilysin 1. Langenickel TH, et al. Drug Discovery Today: Ther Strateg. 2012;9:e131-139; 2. Potter LR. FEBS J. 2011;278:1808-1817; 3. Erdos EG, et al. FASEB J. 1989;3:145-151; 4. Stephenson SL, et al. Biochem J. 1987;243:183-187; 5. Kenny AJ, et al. Biochem J. 1993;291:83-88; 6. Murphy LJ, et al. Br J Pharmacol. 1994;113:137-142; 7. Jiang W, et al. Hypertens Res. 2004;27:109-117; 8. Ferro CJ, et al. Circulation. 1998;97:2323-2330; 9. Forssmann W, et al. Cardiovasc Res. 2001;51(3):450-462 69