Drugs Used for Treatment of Congestive Heart Failure PDF

Drugs Used for Treatment of Inspire Empower Elevate Congestive Heart Failure Dr Htet Htet MBBS, MMedSc, PGCertHPE, FBPhS...

Drugs Used for Treatment of Inspire Empower Elevate Congestive Heart Failure Dr Htet Htet MBBS, MMedSc, PGCertHPE, FBPhS Senior Lecturer Department of Pathology & Pharmacology [email protected] Lesson outcomes At the end of the plenary, students should be able to: 1. Describe therapeutic objectives for the treatment of congestive heart failure. 2. Classify drug used in congestive heart failure and give commonly used drugs for each drug class. 3. Describe the mechanism of action, pharmacological effects, important pharmacokinetic features, pharmacological basis of therapeutic uses based on their roles and common/major adverse effects of drugs used in congestive heart failure. 4. Describe the predisposing factors, symptoms and treatment of digitalis toxicity with digibind. What is heart failure? is a state in which the heart is unable to pump blood at a rate commensurate with the requirements of the body’s tissues or can do so only at elevated filling pressure. In mild to moderate forms, symptoms occur only when the metabolic demand increases during exercise or some other form of stress. is a progressive disease that is characterized by a gradual reduction in cardiac performance, punctuated in many patients by episodes of acute decompensation, often requiring hospitalization. Pathophysiology of heart failure Heart failure  CO Baroreceptor  renal perfusion Sympathetic activation/  RAA activation NE ɑ1 1 Angiotensin II Aldosterone activation activation ­ Afterload Salt & water ­ FOC 1. Vasoconstriction by retention ­ TPR ­ Renin secretion ­ Preload by 2. Remodelling ­ VR Neurohumoral activation and compensatory mechanisms in heart failure. There is a vicious circle in progressive heart failure. Therapeutic objectives 1. To improve quality of life by  relief of symptoms and delay progression of symptoms  ↓ hospitalization 2. To delay death (mortality) due to cardiac failure Drug therapy aims to achieve the above goals by counteracting the harmful compensatory mechanisms (while controlling the cause of cardiac failure) The above “2” therapeutic objectives can be achieved by 5 treatment principles 1. Neurohumoral Modulation 2. Preload Reduction 3. Afterload reduction 4. Increasing Cardiac Contractility 5. Heart Rate Reduction  Therapeutic Drug/drug classes involved objective Treatment Principle I: ACEI Enalapril Neurohumoral ARB Losartan 1 Modulation β Adrenergic Receptor Antagonists Metoprolol Mineralocorticoid Receptor Spironolactone Antagonist Treatment Principle II: Loop diuretics Frusemide Preload Reduction Thiazide diuretics Hydrochlorothiazide K+-Sparing Spironolactone 2 Diuretics/Mineralocorticoid Receptor Antagonist Nesiritide Natriuretic peptide Treatment Principle Direct vasodilators Hydralazine 3 III: Nitrates GTN, ISDN Afterload Reduction Treatment Principle cAMP-Dependent Milironone IV: Inotropes/bipyridines levosimendan 4 Increasing Cardiac Myofilament Ca2+ Sensitizers Digoxin Contractility/ Inotropic Cardiac Glycosides Dopamine/dobutamine Agents Sympathomimetics/beta agonists Treatment Principle V: Direct bradycardiac Ivabradine  Treatment Principle I: Neurohumoral Modulation  ACEI & ARB Mechanism of action Pharmacological effects Therapeutic uses Adverse effects ACEI Inhibits ACE which converts Ang I to Ang II ¯ Ang II production ↓ TPR ¯ Vasoconstriction ↓ afterload First dose hypotension ¯ Aldosterone production Hyperkalaemia Heart failure ¯ Salt and water retention Angioedema ¯ Preload Dry cough (not with ARB) & other uses …. ARB ↓ cardiac workload Block angiotensin receptors ¯ Vasoconstriction ¯ Aldosterone production Pharmacological basis of ACEI in CHF 1. Reduces sympathetic activation & improve symptoms 2. Reduction of afterload Prevents formation of vasoconstrictor angiotensin II (present in high conc. in heart failure) Increases vasodilator bradykinin 3. Reduction of preload by reducing aldosterone formation (reduced salt and water retention) 4. Prevention of cardiac remodeling process (Esp after MI) 5. Prolong life/reduction of mortality, reduction of rate of hospitalization Neurohumoral activation and sites of action of drugs used in the treatment of heart failure  Adverse effects of ACEI 1) Persistent dry cough; related to accumulated bradykinin 2) Angioneurotic edema 3) Hyperkalaemia 4) Deterioration of renal function Contraindications Hypersensitivity to ACEI, pregnancy Bilateral renal artery stenosis  What you should tell to the What you should know? patient? Start with a small dose at bedtime to To take the first few doses before going to bed avoid first dose hypotension; gradually Do not get up and walk about increase the dose. unaided for a few hours. Elderly: admit to hospital if without help Report to the doctor: at home. Persistent dry cough Blood biochemistry (urea, creatinine, Swelling of mouth and face electrolytes) - (1-2 weeks after starting (angio-oedema) the drug) and after each dosage increment Regular follow up Measure plasma potassium if the patient is also taking a potassium sparing drug. ACEIs are prodrugs and must undergo some form of chemical conversion to form the active drug. Organ insufficiency such as liver cirrhosis can reduce the activation and render ineffective.  Beta adrenoreceptor antagonists Previously contraindicated (negative inotropic activity) Now a cornerstone of modern evidence based treatment of heart failure Use as an add-on drug Drug(s) used; Metoprolol,?? Can be used in chronic stable heart failure only Not in acute heart failure 14 Pharmacological basis of beta adrenoreceptor antagonists in treatment of cardiac failure/ Why beta blockers can be used in congestive heart failure? reduce the harmful compensatory mechanisms of high background sympathetic tone in CHF protect the patient from the effects of norepinephrine excess (arrhythmias, poor ejection fraction, high O2 consumption) improve survival in HF reduce morbidity (↓ hosp. admission) and mortality (all cause mortality & sudden death) in patients with heart failure https://www.medscape.com/viewarticle/463477 15  Aldosterone antagonists/Potassium sparing diuretics Mechanism of action (spironolactone) Pharmacological Therapeutic uses Adverse effects effects 1. Block aldosterone Increase Na and heart failure Hyperkalaemia receptor in renal decrease K excretion - to avoid excessive (clinically important collecting tubule potassium especially for those reduction in heart depletion who are taking failure mortality - enhance the ACEI/ARB or renal natriuretic effects insufficiency) of other diuretics. - has a favorable Gynaecomastia effect on cardiac function in people with heart failure. Treatment Principle 2: Preload Reduction  Therapeutic Drug/drug classes involved objective Treatment Principle I: ACEI Enalapril Neurohumoral ARB Losartan 1 Modulation β Adrenergic Receptor Antagonists Metoprolol Mineralocorticoid Receptor Spironolactone Antagonist Treatment Principle II: Loop diuretics Frusemide Preload Reduction Thiazide diuretics Hydrochlorothiazide K+-Sparing Spironolactone 2 Diuretics/Mineralocorticoid Receptor Antagonist Nesiritide Natriuretic peptide Treatment Principle Direct vasodilators Hydralazine 3 III: Nitrates GTN, ISDN Afterload Reduction Treatment Principle cAMP-Dependent Milironone IV: Inotropes/bipyridines levosimendan 4 Increasing Cardiac Myofilament Ca2+ Sensitizers Digoxin Contractility/ Inotropic Cardiac Glycosides Dopamine/dobutamine Agents Sympathomimetics/beta agonists Treatment Principle V: Direct bradycardiac Ivabradine  Loop diuretics (Furosemide/frusemide) Mechanism of action Pharmacological Therapeutic uses Adverse effects effects Block Na/K/2Cl transporter in Reduce blood volume 1. moderate to severe Electrolyte imbalance renal loop of Henle Greater efficacy heart failure, oral loop Dehydration diuretic - to reduce Hypokalaemia severe congestion & many more (refer to (volume overload), drugs used for treatment symptoms of hypertension lecture) (breathlessness) & relief of peripheral oedema 2. acute pulmonary oedema Acute LVF Furosemide (IV) for its venodilatation action, which occurs before the https://www.medindia.net/patients/patientinfo/pulmonary-edema.htm diuresis and helps in Thiazide diuretics Mechanism of action Pharmacological effects Therapeutic uses Adverse effects 1. Inhibits Na-Cl symporter in ↓serum K+ (Hypokalaemia) distal convulated tubule (DCT) (clinically important especially for of kidney those who are taking digitalis or  those with arrhythmia) Promotes water and Magnesium depletion (↓ Mg2+) sodium loss from the used in mild heart Impair glucose tolerance kidney Diuresis (Salt and water loss) failure to reduce  serum lipid ¯ Blood volume fluid overload & relieve  uric acid (can precipitate gout) 2. Direct action on vascular ¯ Preload oedema smooth muscle ¯ Venous return + Vasodilatation Other uses? Nesiritide https://slideplayer.com/slide/12863937/ Recombinant brain natriuretic peptide (BNP) produced primarily by the Mechanism of action & pharmacological effect ventricular myocardium in increases cGMP in smooth muscle cells response to volume and pressure Vasodilatation & reduces venous and arteriolar overload tone Diuresis Therapeutic use Mainly use for acute HF Significant pharmacokinetics Short half life https://www.cvphysiology.com/Blood%20Pressure/BP017 Treatment Principle 3: Afterload reduction  Therapeutic Drug/drug classes involved objective Treatment Principle I: ACEI Enalapril Neurohumoral ARB Losartan 1 Modulation β Adrenergic Receptor Antagonists Metoprolol Mineralocorticoid Receptor Spironolactone Antagonist Treatment Principle II: Loop diuretics Frusemide Preload Reduction Thiazide diuretics Hydrochlorothiazide K+-Sparing Spironolactone 2 Diuretics/Mineralocorticoid Receptor Antagonist Nesiritide Natriuretic peptide Treatment Principle Direct vasodilators Hydralazine 3 III: Nitrates GTN, ISDN Afterload Reduction Treatment Principle cAMP-Dependent Milironone IV: Inotropes/bipyridines levosimendan 4 Increasing Cardiac Myofilament Ca2+ Sensitizers Digoxin Contractility/ Inotropic Cardiac Glycosides Dopamine/dobutamine Agents Sympathomimetics/beta agonists Treatment Principle V: Direct bradycardiac Ivabradine Vasodilators Hydralazine (an arteriolar dilator) & Nitrates (predominant venodilators) The low cost and availability make these drugs useful in treating CHF ISDN (isosorbide dinitrate) The main effect is “venous pooling” and reduction of diastolic filling pressure (preload) with little effect on systemic vascular resistance (which is regulated by small-to-medium arterioles). Sustained monotherapy is compromised by nitrate tolerance. Hydralazine a direct vasodilator and could prevent nitrate tolerance The fixed-combination formulation can be used for CHF Adverse effects Hypotension, dizziness and headache and DLE Treatment Principle 4: inotropes  Therapeutic Drug/drug classes involved objective Treatment Principle I: ACEI Enalapril Neurohumoral ARB Losartan 1 Modulation β Adrenergic Receptor Antagonists Metoprolol Mineralocorticoid Receptor Spironolactone Antagonist Treatment Principle II: Loop diuretics Frusemide Preload Reduction Thiazide diuretics Hydrochlorothiazide K+-Sparing Spironolactone 2 Diuretics/Mineralocorticoid Receptor Antagonist Nesiritide Natriuretic peptide Treatment Principle Direct vasodilators Hydralazine 3 III: Nitrates GTN, ISDN Afterload Reduction Treatment Principle cAMP-Dependent Milironone IV: Inotropes/bipyridines levosimendan 4 Increasing Cardiac Myofilament Ca2+ Sensitizers Digoxin Contractility/ Inotropic Cardiac Glycosides Dopamine/dobutamine Agents Sympathomimetics/beta agonists Treatment Principle V: Direct bradycardiac Ivabradine  Digoxin Mechanism of inotropic action Inhibition of cardiac Na+/K+ ATPase pump ↑ intracellular Na+ ↓Na+/Ca++ exchange ↑ intracellular Ca++ ↑Ca++ release from SR ↑Actin-myosin interaction ↑ Contractile force (without increase in O2 consumption)  FOC  CO Pharmacological Cardiac effect effects of digoxin Mechanical  FOC  CO Electrical Low conc stimulate vagal efferents & causes increased parasympathetic and decreased sympathetic tone ↓conduction velocity (Negative dromotropic effects)  HR useful for atrial fibrillation High conc ↑ excitability  arrhythmia (Adverse effect) Extra-cardiac effects affect all excitable tissues (smooth muscle, CNS etc) GIT is the most common site of digitalis toxicity outside the heart. anorexia, nausea, vomiting, and diarrhea (signs of toxicity) CNS effects - vagal and chemoreceptor trigger zone stimulation  visual disturbances & vomiting Gynaecomastia Interactions with electrolytes Hypokalemia, hypercalcaemia & hypomagnesaemia – worsen CG toxicity Benefits of digoxin in heart failure Positive Inotropic Effect  CO provides symptomatic relief in patients with heart failure  CO sympathetic nerve tone & consequently, heart rate and peripheral vascular resistance drop.  preload & afterload reduce chamber dilation & wall stress (which is a strong determinant of myocardial O2 consumption) Increase renal perfusion lowers renin production and increases diuresis, further decreasing preload. Important pharmacokinetics of digoxin Distribution Large Vd due to tissue protein binding; Need loading dose in emergency conditions Other drugs (e.g., amiodarone) can displace digoxin (↑digoxin by 2 x plasma level) Metabolism and excretion not extensively metabolized & 2/3 is excreted unchanged by the kidneys. half-life is 36–40 hours in patients with normal renal function. Need dosage adjustment for patients with renal impairment. Therapeutic uses of digoxin 1. Cardiac failure - for symptomatic relief Improves exercise tolerance. Reduces hospital admissions due to exacerbations. But does not reduce mortality 2. Atrial arrhythmias (SVT) Delays AV conduction and thus controls the ventricular rate, useful for SVT (atrial fibrillation and atrial flutter) Adverse effects of digoxin Early signs: Anorexia, nausea, vomiting, diarrhea, Later signs: Xanthopsia/seeing “yellow”/visual disturbance, disorientation , pulsus bigemenus (couple beat) Cardiac: healthy persons (extreme bradycardia, atrial fibrillation, and AV block) ventricular arrhythmias are rare. In patients with structural heart disease, frequent signs of CG toxicity are ventricular extrasystoles, ventricular tachycardia, and fibrillation. Contraindication: ventricular tachycardia Digoxin toxicity Management of Toxicity: Dose reduction or cessation of CG medication for early symptoms of toxicity Extreme sinus bradycardia, sinoatrial block – atropine or temporary pacemaker Tachycardic ventricular arrhythmias and hypokalemia: K+ infusion Digibind – antidigoxin immunotherapy (antidigoxin antisera) & it is given to achieve a fully neutralizing effect Electrolyte interactions as ↓ K+, ↓Mg++,↑ Ca++ (all increase toxicity) Caution with diuretics ↑K loss Dopamine effects vary with dose Low doses infusion direct stimulation of D2 receptors increase renal blood flow & maintain an adequate GFR and cause diuresis Intermediate dose stimulates cardiac β1 receptors to enhance myocardial contractility. High dose α receptor stimulation & mediated peripheral arterial and venous constriction Dobutamine Mechanism of action Selective beta 1 agonist action at cardiac beta 1 receptors Therapeutic use β adrenergic agonist of choice for the management of patients with acute CHF with systolic dysfunction. Side effect Tachycardia and increase in myocardial oxygen consumption Bipyridines Milrinone inhibits phosphodiesterase isozyme 3 (PDE-3)  cAMP degradation cAMP positive inotropic and chronotropic effects in the heart dilation of resistance and capacitance vessels, effectively decreasing preload and afterload https://www.cvpharmacology.com/vasodilator/PDEI Levosimendan Known as calcium sensitizer cardiac inotrope & vasodilator Mechanism of inotropic action sensitizes the troponin C to calcium inhibit phosphodiesterase enzyme Mechanism of vasodilatation opens ATP-sensitive K channels on vascular smooth muscle causes coronary and systemic vasodilation Citation: Therapy of Heart Failure, Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2017. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=170271080 Accessed: September 08, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Treatment Principle 5: bradycardiac agents  Therapeutic Drug/drug classes involved objective Treatment Principle I: ACEI Enalapril Neurohumoral ARB Losartan 1 Modulation β Adrenergic Receptor Antagonists Metoprolol Mineralocorticoid Receptor Spironolactone Antagonist Treatment Principle II: Loop diuretics Frusemide Preload Reduction Thiazide diuretics Hydrochlorothiazide K+-Sparing Spironolactone 2 Diuretics/Mineralocorticoid Receptor Antagonist Nesiritide Natriuretic peptide Treatment Principle Direct vasodilators Hydralazine 3 III: Nitrates GTN, ISDN Afterload Reduction Treatment Principle cAMP-Dependent Milironone IV: Inotropes/bipyridines levosimendan 4 Increasing Cardiac Myofilament Ca2+ Sensitizers Digoxin Contractility/ Inotropic Cardiac Glycosides Dopamine/dobutamine Agents Sympathomimetics/beta agonists Treatment Principle V: Direct bradycardiac Ivabradine  Ivabradine a selective inhibitor of cardiac pacemaker channels/If current/ treatment of heart failure and stable angina pectoris in patients not tolerating β blockers or in whom β blockers did not https://www.youtube.com/watch?v=aUIqd0LUNPY sufficiently lower heart https://www.shift-study.com/ivrabradine/mode-of-action/ Management of acute heart failure (Acute pulmonary oedema) Action Effect Sit the patient up Reduce preload High flow oxygen Corrects hypoxia Vasodilators: IV Nitrates (nitroglycerin or Reduce preload and afterload nitroprusside; caution for hypotension), Loop diuretics Combat fluid overload (frusemide IV) I.V. Morphine to reduce anxiety, pulmonary venous congestion I.V. antiemetic To reduce side effect of morphine (emesis) dobutamine, dopamine, milrinone, Inotropes References Prescribed textbook Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.) (2023). Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 14e. McGraw-Hill. https://accessmedicine-mhmedical-com.ezp2.imu.edu.my/book.aspx?bookid=3191 Recommended textbook Katzung B.G.(Ed.), (2021). Basic & Clinical Pharmacology, 15e. McGraw-Hill. https://accessmedicine-mhmedical-com.ezp2.imu.edu.my/book.aspx?bookid=2988 Ritter, J., Flower, R., Hendersen, G., Loke, Y., MacEwan, D., & Rang, H. (2024). Rang & Dale’s Pharmacology, 10e. Elsevier. https://www-clinicalkey-com.ezp2.imu.edu.my/#!/browse/book/3-s2.0-C20200033281 Other sources https://www-clinicalkey-com.ezp2.imu.edu.my/#!/browse/book/3-s2.0-C2016004202X Other resources: 2020 International Society of Hypertension Global Hypertension Practice