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ANTI-CARDIAC FAILURE DRUGS - Pharmacology Lecture, Study notes of Pharmacology

University of British ColumbiaPharmacology

Introduction II. Pathophysiology III. Causes IV. Classification V. Types VI. Clinical Manifestations VII. Diagnosis VIII. Clinical Management IX. Drugs commonly Used in Heart Failure X. Non-Pharmacological Management XI. Chronic Heart Failure

Typology: Study notes

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ANTI-CARDIAC FAILURE DRUGS
Pharmacology (Lecture)
Dr. Ma. Luisa Crisostomo | March 18, 2021 | Topic 3
INTRODUCTION
Ø Heart failure: inability of the heart to pump an
adequate amount of blood to the body’s needs
Ø Congestive heart failure: refers to the state in which
abnormal circulatory congestion exists a result of
heart failure
PATHOPHYSIOLOGY
IMPAIRED CARDIAC FUNCTION
Ø Failure to pump: failure to empty ventricles and
reduced delivery of blood into circulation (↓ CO)
Ø Increased ventricular pressures
Ø Elevated pulmonary and systemic pressures
Ø Further ↓ CO
Ø Series of compensatory mechanisms
COMPENSATORY MECHANISMS OF LOW CARDIAC
OUTPUT
1) SNS stimulation: increased heart rate and cardiac
contractility à increased cardiac output
2) Starling’s law: ventricular dilation à increased
cardiac output
3) Ventricular hypertrophy: cardiac contractility à
increased cardiac output
4) Decreased renal blood flow: increase Na and H2O
à increase blood volume, heart rate and cardiac
output
PATHOPHYSIOLOGY OF CARDIAC PERFORMANCE
INTRINSIC COMPENSATORY RESPONSE
Ø MYOCARDIAL HYPERTROPHY
• Increase in muscle mass to help maintain cardiac
performance
• Ischemic changes, impairment of diastolic filling,
alterations in ventricular geometry
Ø REMODELLING
• Dilatation and other slow structural changes that
occur in the stressed myocardium
• Proliferation of connective tissue cells and
myocardial cells
• Accelerated apoptosis
CAUSES OF HEART FAILURE
Ø Final common pathway of many kinds of heart
diseases
• Ischemic, alcoholic, restrictive, hypertrophic
• Optimal treatment requires identification of
primary and secondary factors leading to CHF
• HELPFUL RESULT of dilatation: increases
cardiac output
• HARMFUL RESULT of dilation: more wall
tension, more oxygen is needed to produce any
given stroke volume
CLASSIFICATION OF CARDIAC HEART FAILURE
1) By ejection fraction
• Reduced ejection fraction (<40-50%): systolic
heart failure
• Preserved ejection fraction (>40-50%): diastolic
heart failure
2) By time course
• Chronic heart failure
• Acute heart failure (cardiogenic shock)
3) Anatomically
• Left-sided heart failure
• Right-sided heart failure
4) By output
• High output failure: thyrotoxicosis, Paget’s
Overview
I. Introduction
II. Pathophysiology
III. Causes
IV. Classification
V. Types
VI. Clinical Manifestations
VII. Diagnosis
VIII. Clinical Management
IX. Drugs commonly Used in Heart Failure
X. Non-Pharmacological Management
XI. Chronic Heart Failure
Frank starling law of the heart represents the relationship
between SV and EDP. The law states that the SV of the
heart increases in response to an increase in the volume
of blood in the ventricles before contractions, when all
other factors remain constant.
!
Genome expression, molecular, cellular and interstitial
changes that are manifested clinically as changes in size,
shape and function of the heart after cardiac injury
!
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ANTI-CARDIAC FAILURE DRUGS

Dr. Ma. Luisa Crisostomo | March 18, 2021 | Topic 3

INTRODUCTION

Ø Heart failure : inability of the heart to pump an adequate amount of blood to the body’s needs Ø Congestive heart failure : refers to the state in which abnormal circulatory congestion exists a result of heart failure PATHOPHYSIOLOGY IMPAIRED CARDIAC FUNCTION Ø Failure to pump : failure to empty ventricles and reduced delivery of blood into circulation (↓ CO) Ø Increased ventricular pressures Ø Elevated pulmonary and systemic pressures Ø Further ↓ CO Ø Series of compensatory mechanisms **COMPENSATORY MECHANISMS OF LOW CARDIAC OUTPUT

  1. SNS stimulation** : increased heart rate and cardiac contractility à increased cardiac output 2) Starling’s law : ventricular dilation à increased cardiac output 3) Ventricular hypertrophy : cardiac contractility à increased cardiac output 4) Decreased renal blood flow : increase Na and H 2 O à increase blood volume, heart rate and cardiac output

PATHOPHYSIOLOGY OF CARDIAC PERFORMANCE

INTRINSIC COMPENSATORY RESPONSE

Ø MYOCARDIAL HYPERTROPHY

  • Increase in muscle mass to help maintain cardiac performance
  • Ischemic changes, impairment of diastolic filling, alterations in ventricular geometry Ø REMODELLING
  • Dilatation and other slow structural changes that occur in the stressed myocardium
  • Proliferation of connective tissue cells and myocardial cells
  • Accelerated apoptosis CAUSES OF HEART FAILURE Ø Final common pathway of many kinds of heart diseases
  • Ischemic, alcoholic, restrictive, hypertrophic
  • Optimal treatment requires identification of primary and secondary factors leading to CHF
  • HELPFUL RESULT of dilatation : increases cardiac output
  • HARMFUL RESULT of dilation : more wall tension, more oxygen is needed to produce any given stroke volume **CLASSIFICATION OF CARDIAC HEART FAILURE
  1. By ejection fraction**
  • Reduced ejection fraction (<40-50%): systolic heart failure
  • Preserved ejection fraction (>40-50%): diastolic heart failure 2) By time course
  • Chronic heart failure
  • Acute heart failure (cardiogenic shock) 3) Anatomically
  • Left-sided heart failure
  • Right-sided heart failure 4) By output
  • High output failure : thyrotoxicosis, Paget’s Overview I. Introduction II. Pathophysiology III. Causes IV. Classification V. Types VI. Clinical Manifestations VII. Diagnosis VIII. Clinical Management IX. Drugs commonly Used in Heart Failure X. Non-Pharmacological Management XI. Chronic Heart Failure Frank starling law of the heart represents the relationship between SV and EDP. The law states that the SV of the heart increases in response to an increase in the volume of blood in the ventricles before contractions, when all other factors remain constant. Genome expression, molecular, cellular and interstitial changes that are manifested clinically as changes in size, shape and function of the heart after cardiac injury

ANTI-CARDIAC FAILURE DRUGS

Dr. Ma. Luisa Crisostomo | March 18, 2021 | Topic 3

disease, anemia, pregnancy, AV fistula

  • Low output failure SYSTOLIC DYSFUNCTION Ø Inadequate force is generated to eject blood normally Ø Reduce cardiac output, ejection fraction (< 45%) Ø Typical of acute heart failure Ø Secondary to AMI Ø Responsive to inotropics DIASTOLIC DYSFUNCTION Ø Inadequate relaxation to permit normal filling Ø Hypertrophy and stiffening of myocardium Ø Cardiac output may be reduced Ø Ejection fraction may be normal Ø Do not respond optimally to inotropic agents HIGH OUTPUT FAILURE Ø Increase demand of the body with insufficient cardiac output Ø Hyperthyroidism, beri-beri, anemia, AV shunts Ø Treatment is correction of underlying cause ACUTE HEART FAILURE Ø Sudden development of a large myocardial infarction or rupture of a cardiac valve in a patient who previously was entirely well, usually predominant systolic dysfunction CHRONIC HEART FAILURE Ø Typically observed in patients with dilated cardiomyopathy or multivalvular heart diseases that develops or progresses slowly TYPES OF HEART FAILURE NEW CLASSIFICATION Ø Left ventricular systolic dysfunction with Reduced Ejection Fraction (HF-REF) Ø HF with preserved ejection fraction (HF-PEF)
  • ½ the cases
  • More often in older, female patients
  • Often have hypertension, atrial fibrillation
  • Less coronary artery disease
  • Mortality less than for HF-REF
  • Morbidity similar NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATION Ø CLASS I : no limitations on ordinary physical activities and symptoms that occur only with greater than ordinary exercise Ø CLASS II : slight limitation of ordinary activities, which result in fatigue and palpitations with ordinary physical activity Ø CLASS III : results in no symptoms at rest, but fatigue with less than ordinary physical activity Ø CLASS IV : associated with symptoms even when the patient is at rest PRECIPITATING CAUSES OF HEART FAILURE Ø Infection Ø Anemia Ø Thyrotoxicosis and pregnancy Ø Arrythmias Ø Rheumatic, viral and other forms of myocarditis Ø Infective endocarditis Ø Systemic hypertension Ø Myocardial infarction Ø Physical, dietary, fluid, environmental and emotional excesses Ø Pulmonary embolism CLINICAL MANIFESTATIONS PULMONARY EDEMA Ø Most severe manifestation of left heart failure Ø Fluid leaks into the pulmonary interstitial spaces (pulmonary congestion/edema) Ø Hypoxia and poor O 2 exchange Ø When the heart's output decreases, the body does many things to try and compensate for it. It will release hormones to make the heart beat stronger. The heart will beat faster. Many of these reflexes however, only create a short-term gain, and may ultimately hurt the heart's function. Ø When the kidneys sense a decrease in flow, they release hormones which cause the body to hold sodium and water. In the short term, this will lead to an increase in the volume of blood which is circulating, and provide the kidneys with the blood volume they are looking for. However, this extra volume of fluid is more than can be held in the blood vessels, and it will start to exude out into the tissues of the body Ø Develops when the imbalance in pump function causes an increase in lung fluid secondary to leakage from pulmonary capillaries into the interstitium and alveoli of the lung. Ø Life threatening situation in which the lung alveoli In practice, HF-PEF is diagnosed when typical clinical HF findings are accompanied by PEF and the absence of significant valvular abnormalities. The reported mortality rate for HF-PEF is less than found for HF with REF (HF- REF), although it is unacceptably high; however, the studies have generally shown that morbidity, especially in HF hospitalizations, is similar to HF-REF

ANTI-CARDIAC FAILURE DRUGS

Dr. Ma. Luisa Crisostomo | March 18, 2021 | Topic 3

giving a large initial dose in a process called "digitalization"

  • Metabolism and excretion ü Digoxin : not extensively metabolized, 2/ excreted unchanged in the kidneys ü Digitoxin : metabolized in the liver and excreted into the gut via the bile
  • Mechanical effects ü Inhibit the monovalent cation transport enzyme coupled Na+- K+ ATPase and increased intracellular Na+ content] increases intracellular Ca2+ through a Na+ - Ca2+ exchange carrier mechanism ü Increases myocardial uptake of Ca2+ augments Ca2+ release to the myofilaments during excitation] invokes a positive inotropic response Table 2. Pharmacokinetics of digoxin and digitoxin Parameter Digoxin Digitoxin Lipid solubility Medium High Oral bioavailability

Half-life 40 hours 168 hours Plasma protein binding 20 - 40 hours >90 hours Percentage metabolized

Volume of distribution 6.3 L/kg 0.6 L/kg

  • Electrical effects ü Produces alterations in the electrical properties of both contractile cells and the specialized automatic cells] increased automaticity and ectopic impulse activity ü Prolongs the effective refractory period of the AV node] slow ventricular rate in atrial flutter and fibrillation - Effects in heart failure ü Stimulates myocardial contractility ü Improves ventricular emptying ü Increase cardiac output ü Augments ejection fraction ü Promotes diuresis ü Reduces elevated diastolic pressure and volume and end – systolic volume ü Reduces symptoms resulting from pulmonary vascular congestion and elevated systemic venous pressure - Parasympathomimetic effects ü Decreased conduction velocity in the AV node ü Increased effective refractory period in the AV ü Heart block (toxic concentrations DIGITALIS Ø Therapeutic uses : congestive heart failure, atrial fibrillation Ø Overall benefit to myocardial function : cardiac output and efficiency, decreases heart rate and size à no survival benefit Ø Other beneficial benefits : restoration of baroreceptor sensitivity, reduction in sympathetic activity, increased renal perfusion with decreased edema formation Ø Adverse effects : AV block, bradycardia, ventricular extrasystole, arrhythmias Ø **Serum electrolytes that affect toxicity
  1. Potassium** ü Digitalis competes for K binding at Na/K ATPase ü Hypokalemia : increase toxicity ü Hyperkalemia : decrease toxicity 2) Magnesium ü Hypomagnesemia : increases toxicity 3) Calcium ü Hypercalcemia : increases toxicity Ø Interactions
  • POTASSIUM ü HYPERKALEMIA : reduces enzyme inhibiting actions of digitalis, abnormal

ANTI-CARDIAC FAILURE DRUGS

Dr. Ma. Luisa Crisostomo | March 18, 2021 | Topic 3

cardiac automaticity is inhibited ü HYPOKALEMIA: facilitates enzyme inhibiting actions

  • CALCIUM ü Facilitates the toxic actions digitalis by accelerating the overloading of intracellular calcium stores that appears to be responsible for abnormal automaticity ü HYPERCALCEMIA : increases the risk of digitalis induced arryhythmia
  • MAGNESIUM ü Opposite to those of calcium Ø Intoxication
  • Serious and potentially fatal complication
  • Anorexia, nausea and vomiting : earliest signs of digitalis intoxication
  • Arrythmias : ventricular premature beats, bigeminy, ventricular and atrial tachycardia with variable AV block
  • Chronic digitalis intoxication : exacerbations of heart failure, weight loss, cachexia, neuralgias, gynecomastia, yellow vision, delirium Ø Treatment of digitalis intoxication
  • Tachyarrythmias : withdrawal of the drug, treatment with beta blocker or lidocaine
  • Hypokalemia : potassium administration by the oral route
  • Digitoxin Ab (Fab fragments)
  • Reduce dose : 1st^ degree heart block, ectopic beats
  • Atropine : advanced heart block
  • KCl : increased automaticity
  • Antiarrythmics : ventricular arrhythmias
  • Fab antibodies : toxic serum concentration; acute toxicity PHOSPHODIESTERASE INHIBITORS BIPYRIDINES Ø Inamrinone and Milrinone Ø Levosimendan Ø Parenteral forms only Ø Half-life : 2-3 hours Ø 10 - 40% excreted in the urine Ø Mechanism of action : increase inward calcium influx in the heart during action potential and inhibits phosphodiesterase Ø Adverse effects : nausea, vomiting, thrombocytopenia, liver enzyme changes Ø Therapeutic use
  • Short term support in advanced cardiac failure
  • Long term use not possible Ø Adverse effects
  • Cardiac arrhythmias
  • GI : nausea and vomiting
  • Sudden death BETA-ADRENOCEPTOR AND DOPAMINE RECEPTOR AGONISTS Ø Dobutamine
  • Increases cardiac output
  • Decrease in ventricular filling pressure
  • Given parenterally
  • Contraindications : pheochromocytoma, tachyarrythmias
  • Adverse effects : precipitation or exacerbation of arrhythmia
  • Therapeutic use : management of acute failure only
  • Adverse effects : tolerance, tachycardia Ø Dopamine
  • Raise blood pressure
  • Therapeutic use : restore renal blood in acute failure
  • Adverse effects : tachycardia, arrhythmias, peripheral vasoconstriction DRUGS WITHOUT POSITIVE INOTROPIC EFFECTS USED IN HEART FAILURE DIURETICS Ø Reduce salt and water retention : reduce ventricular preload Ø Reduction in venous pressure : reduction of edema and its symptoms, reduction of cardiac size à improved efficiency of pump function Ø Mechanism of action in cardiac failure
  • Preload reduction : reduction of excess plasma volume and edema fluid
  • Afterload reduction : lowered blood pressure
  • Reduction of facilitation of sympathetic nervous system ANGIOTENSIN-CONVERTING ENZYME INHIBITORS Ø Reduce peripheral resistance : reduce afterload Ø Reduce salt and water retention (by reducing aldosterone secretion): reduce preload Ø Reduce the long term remodelling of the heart vessels (maybe responsible for the observed reduction in the mortality and morbidity) Ø Therapeutic uses
  • Drugs of choice in heart failure (with diuretics)
  • Current investigational use : acute myocardial infarction
  • ATII antagonists

ANTI-CARDIAC FAILURE DRUGS

Dr. Ma. Luisa Crisostomo | March 18, 2021 | Topic 3

R E F E R E N C E S

  1. Anti-CHF drugs. Dr. Crisostomo, 2021. (Annotated Lecture)
  2. Basic and Clinical Pharmacology. (14th^ ed). Katzung.