CV Pharmacology
Pharmacological Management of Congestive Heart Failure Companion Reading (Notes): Pharmacological Treatment of Heart Failure (Klabunde) Drugs Acting on the Cardiovascular System (Cray) Formative Assessment Cardiovascular Pharmacology Review Test
http://www.emedicine.com/emerg/TOPIC108.HTM
Prepared and Presented by: Marc Imhotep Cray, M.D. BMS & CK Teacher
Clinical: e-Medicine article Congestive Heart Failure and Pulmonary Edema
Learning Objectives: 1. 2.
3. 4. 5.
By the end of this presentation the learner should:
Understand the underlying hemodynamic abnormalities in heart failure and the therapeutic approaches to its treatment Understand the properties of angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and vasodilators used to treat heart failure and the rationale behind their use Understand the properties of intravenous agents (dobutamine, dopamine and PDE inhibitors) used in the treatment of heart failure Understand the actions of beta blockers and the rationale for their use in the treatment of heart failure Know the pharmacologic action, toxicities and uses of cardiac glycosides
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Definition of HF
Chronic heart failure (HF) is an imbalance in pump function in which heart fails to adequately maintain circulation of blood. The most severe manifestation of HF, pulmonary edema, develops when this imbalance causes an increase in lung fluid secondary to leakage from pulmonary capillaries into the interstitium and alveoli of the lung…
See cloud e-Medicine Article Congestive Heart Failure and Pulmonary Edema
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Classification of HF There are many different ways to categorize heart failure, including: 1. 2.
3.
4.
5.
The side of the heart involved, (left heart failure versus right heart failure) Whether the abnormality is due to contraction or relaxation of the heart (Systolic Dysfunction vs. Diastolic Dysfunction ) Whether the problem is primarily increased venous back pressure (behind) the heart, or failure to supply adequate arterial perfusion (in front of) the heart (backward vs. forward failure) Whether the abnormality is due to low cardiac output with high systemic vascular resistance or high cardiac output with low vascular resistance (low-output heart failure vs. high-output heart failure) The degree of functional impairment conferred by the abnormality (as in the NYHA functional classification) 4
Congestive Heart Failure: Causes •Myocardial infarction •Coronary artery disease •Valve disease •Idiopathic cardiomyopathy •Viral or bacterial cardiomyopathy •Myocarditis •Pericarditis •Arrhythmias •Chronic hypertension •Thyroid disease •Pregnancy •Septic shock 5
Congestive Heart Failure: Causes (cont.) 1.
Arrhythmias: In patients with heart disease and with a history of congestive failure, an acute arrhythmia is a common precipitating cause of HF
Tachyarrhythmias decrease filling time and as a result decrease cardiac output A-V dissociation results in loss of the atrial contribution to ventricular filling.
end-diastolic volume is reduced with an attendant reduction in cardiac output
Abnormal intraventricular conduction may cause a reduced synchronicity of contraction with a reduction in myocardial performance Severe bradycardia in the absence of increased stroke volume can seriously reduce cardiac output and thus precipitate HF
Increased stroke volume may not be possible if the patient has significant heart disease
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Congestive Heart Failure: Causes (cont.) 2.
Myocardial Infarction: A myocardial infarction, reducing left
3.
Pulmonary Embolism: Physically inactive patients with low
4.
Systemic Hypertension: Rapid increases in arterial blood
ventricular function, may precipitate HF in a previously hemodynamically compensated patient
cardiac output may develop deep venous thrombi which may produce pulmonary emboli and elevation of pulmonary arterial pressure • Increased pulmonary artery pressure may worsen or cause left ventricular failure pressure with associated increases in peripheral resistance can increase afterload to an extent sufficient to produce heart failure.
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Congestive Heart Failure: Causes (cont.) 5.
Other causes: • Thyrotoxicosis • Pregnancy • Infection • Anemia • Rheumatic and other forms of Myocarditis • Physical, dietary, fluid • Environmental and emotional excesses • Infective Endocarditis 8
Pathophysiology in HF
HF is summarized best as an imbalance in Starling forces or an imbalance in the degree of end-diastolic fiber stretch proportional to the systolic mechanical work expended in an ensuing contraction.
Cardiac and Vascular Changes Accompanying Heart Failure Cardiac Decreased SV and CO Increased end-diastolic pressure Vascular Increased SVR Decreased arterial pressure Decreased venous compliance Increased venous pressure Increased blood volume
http://www.cvpharmacology.com/clinical topics/heart failure-2.htm 9
Pathophysiology in HF(2) Compensatory Mechanisms During Heart Failure Cardiac Frank-Starling mechanism Ventricular dilation or hypertrophy Tachycardia Autonomic Nerves Increased sympathetic adrenergic activity Reduced vagal activity to heart Hormones Renin-angiotensin-aldosterone system (RAAS) Vasopressin (antidiuretic hormone/ADH) Circulating catecholamines Natriuretic peptides 10
Pathophysiology in HF (2)
The fundamental abnormality in heart failure is embodied in: depression of the myocardial force-velocity relationship and length-active tension curves that result in impairment of myocardial contractility (see Figure, right) When a normal heart transitions from the resting state (1) to exercise (2) a significant increase in ventricular performance occurs. By contrast in the failing heart, the exercise-induced increases in ventricular performance are minimal (3' to 3).
From: http://www.pharmacology2000.com/Cardio/HF/HFobj1.htm 11
The renin-angiotensinaldosterone system (RAAS)
Source: http://cvphysiology.com/BloodPressure/BP015.htm 12
Physiologic Effects of AII Constricts resistance vessels (via AII [AT1] receptors) thereby increasing systemic vascular resistance and arterial pressure Stimulates sodium transport (reabsorption) at several renal tubular sites, thereby increasing sodium and water retention Acts on adrenal cortex to release aldosterone, which in turn acts on kidneys to increase sodium and fluid retention Stimulates release of vasopressin (antidiuretic hormone, ADH) from the posterior pituitary, which increases fluid retention by kidneys Stimulates thirst centers within the brain Facilitates norepinephrine release from sympathetic nerve endings and inhibits norepinephrine re-uptake by nerve endings, thereby enhancing sympathetic adrenergic function Stimulates cardiac hypertrophy and vascular hypertrophy N.B.The RAAS is modulated by natriuretic peptides (ANP and BNP) released by the heart. These natriuretic peptides acts as an important counter-regulatory system 13
Pathophys. & Pharm. in HF Illustrated
Source: http://www.mc.uky.edu/pharmacology/instruction/pha824hf/PHA824hf.html 14
Clinical Perspective and Considerations Heart failure, inability of circulatory system to meet metabolic demands of body, is a multifaceted “disease state� (syndrome) involving several organ systems and neurohumoral factors including heart, kidney, vascular system and brain There are several forms of heart failure with multiple etiologies The treatment of heart failure is a particularly difficult therapeutic problem with no single drug or drug class adequate to provide complete relief from the signs and symptoms of the syndrome
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Clinical Perspective and Considerations (2) The drugs used and their specific therapeutic approaches depend on underlying pathophysiology and severity of the disease While drug therapy is capable of symptomatic relief, it does not correct the underlying pathology Regardless of treatment, 50 % of individuals die within 5 years of developing HF. In an era where morbidity and mortality from other cardiovascular diseases are decreasing, deaths from HF are increasing 16
Framingham Criteria for Congestive Heart Failure Diagnosis of HF requires the simultaneous presence of at least 2 major criteria or 1 major criterion in conjunction with 2 minor criteria. Major criteria: •Paroxysmal nocturnal dyspnea •Neck vein distention •Rales •Radiographic cardiomegaly (increasing heart size on chest radiography) •Acute pulmonary edema •S3 gallop •Increased central venous pressure (>16 cm H2O at right
atrium)
•Hepatojugular reflux •Weight loss >4.5 kg in 5 days in response to treatment 17
Framingham Criteria for Congestive Heart Failure (2) Minor criteria: •Bilateral ankle edema •Nocturnal cough •Dyspnea on ordinary exertion •Hepatomegaly •Pleural effusion •Decrease in vital capacity by one third from maximum recorded •Tachycardia (heart rate>120 beats/min.) N.B. Minor criteria are acceptable only if they can not be attributed to another medical condition (such as pulmonary hypertension, chronic lung disease, cirrhosis, ascites, or nephrotic syndrome) http://www.fpnotebook.com/CV/Exam/FrmnghmHrtFlrDgnstcCrtr.htm 18
New York Heart Association (NYHA) Functional Classification
The New York Heart Association (NYHA) Functional Classification provides a simple way of classifying the extent of heart failure It places patients in one of four categories based on how much they are limited during physical activity limitations/symptoms are in regards to normal breathing and varying degrees in shortness of breath and or angina pain
http://www.fpnotebook.com/CV/Exam/FrmnghmHrtFlrDgnstcCrtr.htm 19
New York Heart Association (NYHA) Functional Classification (2) Source: http://www.medicalcriteria.com/criteria/nyha.htm NYHA Class
Symptoms
I
No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc.
II
mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.
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Rationale for Drug Therapy ď Ž
The primary goal of drug therapy in heart failure is to improve cardiac function and reduce the clinical symptoms associated with heart failure (e.g., edema, shortness of breath, exercise intolerance).
(Clickable)
B
D= Vasodilator Effect
B
E= Inotropic Effect 21
DRUGS AND DRUG CLASSES USED TO TREAT HEART FAILURE
(See last slide for complete list) 1. Vasodilators - Drugs that decrease either preload or afterload ACE inhibitors, AT1 blockers, and other vasodilators and diuretics a) Arterial selective vasodilators decrease PVR and afterload on the failing myocardium reduction in afterload leads to an increased CO and improved tissue perfusion
b) Venous selective vasodilators increase venous capacitance, thus decreasing preload A small reduction in venous tone can result in a pooling of large amounts of blood This would decrease left ventricular filling pressure and pulmonary congestion 22
DRUGS AND DRUG CLASSES USED TO TREAT HEART FAILURE (2) c) The major vasodilators used are ACE inhibitors and angiotensin II receptor antagonists (ARBs) d) Other agents include organic nitrates, hydralazine and nitroprusside ( all 3 reduce both preload & afterload) e) In addition, diuretics promote the elimination of edematous fluid, improving tissue perfusion and pulmonary function N.B. Chronic thiazide diuretic Tx also results in relaxation of resistance vessels) 23
DRUGS AND DRUG CLASSES USED TO TREAT HEART FAILURE (3) 2. Positive Inotropic Agents Drugs that increase contractile force; beta1 receptor agonists, cAMP PDE inhibitors, cardiac glycosides 3. Beta blockers (not acute HF, but decrease mortality in chronic HF) 4. Diuretics Cornerstone drugs in the treatment of heart failure. Noteworthy are loop diuretics and aldosterone receptor antagonists. N.B. In addition to effects on circulatory system, some of these agents also block the cellular responses that lead to cardiac remodeling and hypertrophy
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Overview of HF Pharmacological Management Treatment of HF aims
to relieve symptoms, to maintain a euvolemic state (normal fluid level in the circulatory system), and to improve prognosis by delaying progression of heart failure and reducing cardiovascular risk
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Overview of HF Pharmacological Management(2) Drugs used include: Related Terms: 1. contractility (inotropy), 1. diuretic agents, 2. vasodilator agents, 2. heart rate (chronotropy) 3. positive inotropes, 3. conduction velocity 4. ACE inhibitors, (dromotropy) 5. beta blockers, 6. aldosterone antagonists
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Overview of HF Pharmacological Management (3) Angiotensin-modulating agents ACE inhibitor (ACE) therapy is recommended for all patients with systolic heart failure, irrespective of symptomatic severity or blood pressure
ACE inhibitors improve symptoms, decrease mortality and reduce ventricular hypertrophy
Angiotensin II receptor antagonist therapy (also referred to as AT1-antagonists or angiotensin receptor blockers/ARBs), particularly using candesartan, is an acceptable alternative if the patient is unable to tolerate ACEI therapy
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Overview of HF Pharmacological Management(4) Angiotensin-modulating agents cont. ď Ž ACEIs and ARBs decrease afterload by antagonizing the vasopressor effect of angiotensin, thereby decreasing the amount of work the heart must perform ď Ž
It is also believed that angiotensin directly affects cardiac remodeling, and blocking its activity can thereby slow deterioration of cardiac function 28
Cardiorenal Effects of ACEIs Vasodilation (arterial & venous) - reduce arterial & venous pressure - reduce ventricular afterload & preload Decrease blood volume - natriuretic - diuretic Depress sympathetic activity Inhibit cardiac and vascularhttp://cvpharmacology.com/vasodilator/ACE.htm hypertrophy 29
Overview of HF Pharmacological Management (5) Many ACE inhibitors have been developed
Captopril was the first agent developed and hence is the prototype Enalapril is a prodrug that is de-esterified by plasma esterases to enalaprilat Most of the ACEIs are activated in this fashion Benazepril - Metabolized to benazeprilat Captopril Enalapril - Metabolized to enalaprilat Fosinopril - Metabolized to fosinoprilat Lisinopril Moexipril- Metabolized to moexiprilat Quinapril - Metabolized to quinaprilat Ramipril - Metabolized to ramiprilat Trandolapril-Metabolized to tandolaprilat Perindopril - metabolized to perindoprilat
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Overview of HF Pharmacological Management (6) Commonly used Angiotensin Converting Enzyme (ACE) Inhibitors
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Overview of HF Pharmacological Management(7) MOA of Angiotensin Converting Enzyme (ACE) Inhibitors
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Overview of HF Pharmacological Management (8) Diuretics Diuretic therapy is indicated for relief of congestive symptoms. Several classes are used, with combinations reserved for severe heart failure
Loop diuretics (e.g. furosemide, bumetanide) – most commonly used class in HF, usually for moderate HF Thiazide diuretics (e.g. hydrochlorothiazide, chlorthalidone, chlorthiazide) – may be useful for mild HF, but typically used in severe HF in combination with loop diuretics, resulting in a synergistic effect 33
Overview of HF Pharmacological Management (9) Diuretics cont. Potassium-sparing diuretics (e.g. amiloride) – used first-line use to correct hypokalaemia. Spironolactone is used as add-on therapy to ACEI plus loop diuretic in severe HF Eplerenone (Inspra®) is specifically indicated for post-MI reduction of cardiovascular risk 34
Overview of HF Pharmacological Management (10) Beta blockers Until recently (within the last 20 years), βblockers were contraindicated in HF, owing to their negative inotropic effect and ability to produce bradycardia – effects which worsen heart failure However, current guidelines recommend βblocker therapy for patients with systolic heart failure due to left ventricular systolic dysfunction after stabilization with diuretic and ACEI therapy, irrespective of symptomatic severity or blood pressure 35
Overview of HF Pharmacological Management (11) Beta blockers cont. As with ACEI therapy, the addition of a β-blocker can decrease mortality and improve left ventricular function Several β-blockers are specifically indicated for HF including: 1. bisoprolol, 2. carvedilol, and 3. extended-release metoprolol antagonism of β1 inotropic and chronotropic effects decreases the amount of work the heart must perform
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Overview of HF Pharmacological Management (12) Beta blockers cont. It is also thought that catecholamines and other sympathomimetics have an effect on cardiac remodeling, and blocking their activity can slow the deterioration of cardiac function See: The Importance of Beta Blockers in the Treatment of Heart Failure American Academy of Family Physicians
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Overview of HF Pharmacological Management (13) CARDIAC GLYCOSIDES (Digitalis ) (Some history) Cardiac glycosides are one of the oldest groups of drugs used in cardiovascular therapeutics There is evidence of use in Egyptian and Roman times William Withering published medical accounts of use of the "foxglove" for the treatment of "dropsy." Originally, extracts of d. purpurea were used Two active principals, digoxin and digitoxin, are now used in cardiovascular therapeutics The uses of these drugs are in heart failure and supraventricular tachyarrhythmias. These agents have a low therapeutic index
Digitalis purpurea
(Common Foxglove) 38
Overview of HF Pharmacological Management (14) N.B. Cardiac glycosides not first line Tx for HF due to risk of toxicities
Positive inotropes ď Ž Digoxin / Cardiac glycosides (a mildly positive inotrope and negative chronotrope), once used as first-line therapy, is now reserved for control of ventricular rhythm in patients with atrial fibrillation; or where adequate control is not achieved with an ACEI, a beta blocker and a loop diuretic ď Ž There is no evidence that digoxin reduces mortality in HF, although some studies suggest a decreased rate in hospital admissions ď Ž It is contraindicated in cardiac tamponade and restrictive cardiomyopathy 39
Overview of HF Pharmacological Management(15) Cardiac glycosides Mechanism of Positive Inotropic Action
Cardiac glycosides inhibit the myocardial cell Na+, K+, ATPase This enzyme is responsible for maintaining ionic gradient of myocardial cell.
Inhibition of the Na+, K+, ATPase results in an increase in intracellular Na+. Decrease in Na+ gradient diminishes exchange of Na+ for Ca2+
http://cvpharmacology.com/cardiostimulatory/digitalis.htm
Increase in intracellular Ca2+ is responsible for the positive inotropic action 40
Overview of HF Pharmacological Management(15) Cardiac glycosides Antiarrhythmic Actions Cardiac glycosides also work in the carotid arch and baroreceptors to increase the sensitivity of these sites results enhanced neural traffic to CNS cardiovascular centers resulting in enhanced vagal outflow to the myocardium At the SA node this increase in vagal tone:
1.
Increases SA nodal refractory period
2.
Slows SA nodal conduction velocity
At the AV node (major site of antiarrhythmic action) the increase in vagal tone: 1.
Increases AV nodal refractory period
2.
Slows AV nodal conduction velocity 41
Overview of HF Pharmacological Management(16) Cardiac glycosides Pharmacokinetics of Cardiac Glycosides AGENT
GASTRO INTESTINAL ABSORPTION
ONSET OF ACTION (MIN)
PEAK EFFECT (HR)
AVERAG E HALF LIFE
PRINCIPAL METABOLIC ROUTE (EXCRETORY PATHWAY)
Digoxin
30 to 100%
15 to 30
1 1/2 to 5
36 to 48 hours
Digitoxin
90 to 100%
25 to 120
4 to 12
4 to 6 days
AVERAGE DIGITALIZING DOSES
USUAL DAILY ORAL MAINTENAN CE DOSES
oral
IV
Renal; some gastrointestinal excretion
1.25 to 1.5 mg
0.75 to 1.00 mg
0.25 to 0.5 mg
Hepatic; renal excretion of metabolites
0.7 to 1.2 mg
1.00 mg
0.1 mg
Special Considerations / Next Slide
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Special Considerations Factors that can alter the therapeutic response to cardiac glycosides: Renal disease decreased renal clearance of digoxin Drug Interactions that: a) Decrease bioavailability Cholestyramine b) Decrease renal clearance Amiodarone ,Verapamil , Quinidine
Hypokalemia and Electrolytes Hypokalemia increases the likelihood of toxicity Alterations in potassium levels could be exacerbated by co-administration of diuretics Age elderly are more sensitive to cardiac glycosides Hypoxia increases the likelihood of toxicity 43
Overview of HF Pharmacological Management(17) Positive inotropes cont. ď Ž The inotropic agent dobutamine is advised only in the short-term use of acutely decompensated heart failure, and has no other uses (Bata1 receptor agonist) ď Ž
Phosphodiesterase inhibitors such as milrinone are sometimes utilized in severe cardiomyopathy (increase cAMP/See phosphodiesterase inhibitors ) ďƒ˜
The mechanism of action is through antagonism of adenosine receptors, resulting in inotropic effects and modest diuretic effects
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Overview of HF Pharmacological Management (18) Alternative vasodilators ď Ž The combination of isosorbide dinitrate/hydralazine is the only vasodilator regimen, other than ACE inhibitors or angiotensin II receptor antagonists, with proven survival benefits ď Ž This combination appears to be particularly beneficial in HF patients with an African American background, who respond less effectively to ACEI therapy
See next slide
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Overview of HF Pharmacological Management (19) Exner DV, Dries DL, Domanski MJ, Cohn JN (2001). "Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction". N Engl J Med. 344 (18): 1351–7. doi:10.1056/NEJM200105033441802. Taylor AL, etal; (2004). African-American Heart Failure Trial Investigators. "Combination of isosorbide dinitrate and hydralazine in blacks with heart failure". N Engl J Med 351 (20): 2049–57. doi:10.1056/NEJMoa042934.
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Drugs Used in Heart Failure: Schematic Summary
From: Medical Pharmacology at a Glance, 7th Ed. Michael J. Neal. 2012 John Wiley & Sons, Ltd: Pg. 49
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END OF PRESENTATION
THANK YOU FOR YOUR ATTENTION 48
Recommended links and resource for further study: Classes of drugs used in the treatment of heart failure by Richard E. Klabunde, PhD are given below. Clicking on the drug class will link you to the page describing the pharmacology of that drug class. Diuretics - thiazide diuretics - loop diuretics - natriuretic peptides Vasodilators (dilate arteries and veins) - angiotensin converting enzyme (ACE) inhibitors - angiotensin receptor blockers (ARBs) - direct acting arterial dilators - nitrodilators - natriuretic peptides - phosphodiesterase inhibitors Cardiostimulatory or inotropic drugs (stimulate contractility) - digitalis - beta-agonists (sympathomimetic drugs) - phosphodiesterase inhibitors Cardioinhibitory - beta-blockers - calcium-channel blockers (for diastolic dysfunction)
Cardiovascular Physiology Concepts, 2nd edition, LLW (2011)