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Drug therapy of congestive heart failure

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Drug therapy of congestive heart failure

  1. 1. Dr Htet Htet MBBS, MMedSc Drug therapy of congestive heart failure All rights reserved
  2. 2. OBJECTIVES OF LECTURE • To understand the basic pathophysiology & complications of congestive heart failure (recall for pharmacology of drugs) • To be able to discuss the pharmacological basis of different drugs used in the treatment of heart failure and their important pharmacokinetic & pharmacodynamic actions.
  3. 3. Lecture outline • What is congestive heart failure? How does a heart fail? • Types of treatment for heart failure • Pathophysiological changes of heart failure (for pharmacological basis of drugs) • What are our pharmacological targets? • Objectives of drug therapy • Pharmacology of individual drugs
  4. 4. What is Heart Failure? • A disorder in which the heart loses its ability to pump blood efficiently throughout the body. ↓Cardiac Output • Heart failure occurs when CO is inadequate to provide the oxygen needed by the body.
  5. 5. HOW DOES A HEART FAIL? – Varies with the underlying etiology , –  workload to overcome pressure or volume overload – Becomes Hypertrophy – Leads to cardiac dilatation (left ventricle fails to eject its normal end diastolic volume) – CO
  6. 6. Types of treatment • is a progressive disease • Characterized by gradual reduction in cardiac performance • With many episodes of acute decompensation, often requires hospitalization. • Treatment is directed at two conditions with somewhat different goals: –  symptoms and slowing progression as much as possible during relatively stable periods – Managing acute episodes of decompensated heart failure.
  7. 7. WHAT ARE THE CONSEQUENCES OF DECREASED CARDIAC OUTPUT? Pathophysiological changes Mainly as compensatory to maintain CO & tissue perfusion
  8. 8. Pathophysiological changes 1. Venous return 2. Outflow resistance 3. Contractility of myocardium/Heart rate 4. Salt and water retention
  9. 9. Venous return (preload) • Due to  CO   blood volume remains after systole   stretch of myocardial fibers (which tries to increase stroke volume in normal heart due to Frank Starling mechanism) • But in failed heart  did not response • As heart failure worsens   preload (increased venous pressure) contributes to symptoms – Dyspnoea (due to increased venous pressure in lungs) – Hepatic enlargement (hepatomegaly) – Ascites – Dependent oedema
  10. 10. Afterload (outflow resistance) • Afterload is the resistance against which the heart must pump blood. • Pulmonary resistance & systemic resistance •  systemic resistance   CO • Consequence: – Due to  CO   blood pressure  activation of baroreceptors  leads to sympathetic activation   catecholamine – Due to  CO   RBF → activation of RAA system → which also contributes to sympathetic activation – Tries to increase CO – But chronic sympathetic activation leads to deleterious effect further causing increase burden on failed heart.
  11. 11. Myocardial contractility & Heart rate – Due to  CO   BP  activation of baroreceptors  activation of sympathetic system (activate β1 of heart)  which tries to increase FOC & HR  to maintain CO – But chronic sympathetic activation leads to deleterious effect further causing increase burden on failed heart.
  12. 12. Salt and water retention • Due to  CO & RBF  increase RAA activation (renin angiotensin aldosterone activation) – Angiotensin  sympathetic activation – Aldosterone  causes salt and water retention via renal tubules – Both tries to compensate the low CO & low BP – But it can worsen the venous pressure (preload) – more fluid accumulation in the interstitium – Worsens the signs of heart failure.
  13. 13. Myocardial remodeling in heart failure • LV remodeling is a process of progressive alteration of ventricular size, shape and function owing to the influence of mechanical, neurohumoral and possibly genetic factors in several clinical conditions including: – Myocardial infarction – Cardiomyopathy – Hypertension – Valvular heart disease • Hall marks are : hypertrophy, loss of myocytes and interstitial fibrosis. • Remodelling continues for months after initial insult: finally to significant impairment of overall function of the heart as a pump.
  14. 14.  CARDIAC OUTPUT  RENAL BLOOD FLOW  RAA ANGIOTENSIN ALDOSTERONE SYMPATHETIC ACTIVATION Vasoconstriction Salt and water retension Oliguria  Plasma volumeGeneralized edema  VR in pul : vein Pulmonary congestion Pulmonary edema Dyspnoea, cyanosis RV hypertrophy Right sided HF Liver congestion Splenomegaly Ascities Leg edema  HR
  15. 15. What are our pharmacological targets? • Preload • Afterload • Contractility • Chronic sympathetic activation • Remodelling process Treatment is directed at two conditions with somewhat different goals:  symptoms and slowing progression as much as possible during relatively stable periods (chronic stable heart failure) Managing acute episodes of decompensated heart failure.
  16. 16. DRUG THERAPY • To increase force of contraction – Digoxin – β agoists (dobutamine, dopamine) – Bipyridines (milrinone) • To reduce cardiac workload – To decrease preload (venodilators) (diuretics, nitrates) – To decrease afterload (arterial vasodilators) – To decrease preload and afterload (ACEI, ARB) (nitrates, sodium nitroprusside) • To prolong the survival – β adrenoreceptor blockers
  17. 17. CARDIAC GLYCOSIDES “Digitalis” is used in a generic sense when referring to any of preparations from various species of fox glove Source Digitalis purpurea (Common Foxglove) Was described as early as 1250 AD “Digoxin” is the only derivative of digitalis in current use.
  18. 18. SR RyR2 Na+-K+ ATPase 3Na+ 2K+ L-type Ca+ channel Ca2+ Ca2+ 2Na+ Ca2+ Ca2+ Digoxin  Na+ intracellularly  Ca2+ intracellularly
  19. 19. Failed heart  FOC
  20. 20. (a) Mechanism of action of digoxin • cardiac glycosides increases intracellular Ca2+ concentration. • It is the result of 2 step process. • First, inhibit Na+/K+ pump by binding on K+- binding site Na+/K+- ATPase on the cell membrane which causes a rise in intracellular sodium. • Secondly, a rise in intracellular sodium can slow down the extrusion of calcium • because extrusion of calcium is by a Na+/Ca2+ exchange mechanism. • Increased cytoplasmic calcium is transported to sarcoplasmic reticulum, • Finally, increases the amount of calcium released by the action potential.
  21. 21. (b) Pharmacological action of digoxin • Can be generally divided into two portions – Cardiac effect – Effect on other organs 1. Cardiac effect At therapeutic dose • Direct - increased FOC of heart • Indirect - decreased HR ( d/t vagal stimulation & decreased sympathetic activity ) may lead to AV block, sinus bradycardia, cardiac arrest. At higher concentration, • Direct - increase automaticity of heart • Indirect - sympathetic activation • Both may lead to ventricular arrhythmias
  22. 22. 2. Effects on other organs • CNS - through vagal and CTZ stimulation: - disorientation, hallucination, visual disturbances (aberration of color perception) • GIT - by direct and through CNS (chemoreceptor trigger zone) effect. - ANVD (anorexia, nausea, vomiting, diarrhoea) - gastrointestinal tract is most common site of digitalis toxicity outside the heart • d/t steroid structure - gynaecomastia (rare)
  23. 23. (c) Therapeutic Uses of digoxin 1. Heart failure with atrial fibrillation (use only when diuretics and ACEI have failed to control the symptoms) – Mild symptoms – slow loading dose – Acute heart failure – rapid digitalization 2. Treatment of atrial arrhythmia (atrial fibrillation & flutter)
  24. 24. (d) Adverse effects of digoxin • CNS - disorientation, hallucination, visual disturbances (aberration of color perception) • GIT - ANVD (anorexia, nausea, vomiting, diarrhoea) - gastrointestinal tract is most common site of digitalis toxicity outside the heart • d/t steroid structure - gynaecomastia (rare) • CVS - ventricular arrhythmia. • interaction with electrolytes: hypokalaemia, hypercalcaemia can worsen the toxicity. • Narrow therapeutic index drug.
  25. 25. (e) Treatment of digitalis toxicity • Check serum potassium. • Digitalis antibodies (digoxin immune Fab)
  26. 26. How digoxin corrects heart failure? • Due to FOC   CO   RBF (relieve oliguria) • Due to better tissue perfusion  relieve cyanosis • Due to blockage of AV node, conducting tissues → slow ventricular rate  relieve tachycardia [stronger, slower heartbeat (increased efficiency) without increased demand] • Due to  CO  better emptying of the ventricles  increased venous return  better drainage from the tissues with relief of congestion in the lungs and liver and reduction of oedema, relief of dyspnoea, - Better results are obtained in patients with atrial fibrillation than with normal rhythm - narrow Therapeutic Index (safety margin) → side-effects common
  27. 27. Why digoxin is used in atrial fibrillation, flutter? - in atrial flutter and fibrillation, - d/t its cardioselective parasympathomimetic effects on atrioventricular conduction - it controls an excessively high ventricular rate, - improvement is due to direct effect of digitalis as well as the effect of vagus on the SA node and conducting tissue. - In atrial fibrillation, reduction of ventricular rate is the best measure of glycoside effect
  28. 28. DRUG THERAPY • To increase force of contraction – Digoxin – β agoists (dobutamine, dopamine) – Bipyridines (milrinone) • To reduce cardiac workload – To decrease preload (venodilators) (diuretics, nitrates) – To decrease afterload (arterial vasodilators) – To decrease preload and afterload (ACEI, ARB) (nitrates, sodium nitroprusside) • To prolong the survival – β adrenoreceptor blockers
  29. 29. Dobutamine Mechanism of action • Selective agonist on cardiac β1 activity. Pharmacological action • Increase CO – Most commonly used inotropic agent other than digitalis – Mainly inotropic rather than chronotropic action. Route of administration - given by IV infusion. Adverse effects: cardiac arrhythmia. Therapeutic use (clinical use) • Mainly used in “Acute decompensated heart failure”.
  30. 30. Dopamine Mechanism of action • Dose related action on D1, β1 & 1 Pharmacological action • Low dose  activate D1  causes increase in RBF • Intermediate dose  activate β1  causes increase FOC, HR, CO Route of administration - given by IV infusion. Adverse effects: cardiac arrhythmia. Therapeutic use (clinical use) • Mainly used in “Acute decompensated heart failure”.
  31. 31. DRUG THERAPY • To increase force of contraction – Digoxin – β agoists (dobutamine, dopamine) – Bipyridines (milrinone) • To reduce cardiac workload – To decrease preload (venodilators) (diuretics, nitrates) – To decrease afterload (arterial vasodilators) – To decrease preload and afterload (ACEI, ARB) (nitrates, sodium nitroprusside) • To prolong the survival – β adrenoreceptor blockers
  32. 32. Bipyridines (milrinone) Mechanism of action • Inhibits phosphodiesterase type 3 enzyme • Decrease cAMP breakdown   cAMP  FOC of heart Pharmacological action • causes increase FOC Route of administration - parentral Adverse effects: cardiac arrhythmia. Therapeutic use (clinical use) • Only for acute heart failure or severe exacerbation of chronic heart failure.
  33. 33. DRUG THERAPY • To increase force of contraction – Digoxin – β agoists (dobutamine, dopamine) – Bipyridines (milrinone) • To reduce cardiac workload – To decrease preload (venodilators) (diuretics, nitrates) – To decrease afterload (arterial vasodilators) – To decrease preload and afterload (ACEI, ARB) (nitrates, sodium nitroprusside) • To prolong the survival – β adrenoreceptor blockers
  34. 34. Diuretics (Thiazide) Mechanism of action • Hydrochlorothiazide, Chlorthalidone (Milder diuretics) inhibits Na+-Cl- symport in PCT (primary convulated tubule) of nephrons Pharmacological action • Mild diuresis action + venodilation action • Can cause salt and water excretion & reduction of preload Route of administration: Long duration of action. Given orally. Adverse effects: electrolyte imbalance (esp hypokalaemia which can worsen digitalis toxicity) Therapeutic use (clinical use) • chronic heart failure, usually in combination with others
  35. 35. Diuretics (Furosemide) Mechanism of action • Highly potent loop diuretics, inhibits Na+-K+-Cl- symport in Loop of Henle of nephrons Pharmacological action • diuresis action + venodilation action + decrease in LV filling pressure • Can cause salt and water excretion & reduction of preload • benefits patients with pulmonary edema even before diuresis ensues Route of administration: available as oral as well as IV.
  36. 36. ADVANTAGES IN HEART FAILURE • Quick onset, short duration → repeated as necessary THERAPEUTIC USE:- first choice in acute CHF, to relieve morbidity - as necessary, in chronic heart failure UNTOWARD EFFECTS • hypotension (advantage in hypertensive HF) • dehydration; hypokalaemia (offset by K-sparing diuretics) • temporary deafness, with large doses (OTOTOXICITY)
  37. 37. DRUG THERAPY • To increase force of contraction – Digoxin – β agoists (dobutamine, dopamine) – Bipyridines (milrinone) • To reduce cardiac workload – To decrease preload (venodilators) (diuretics, nitrates) – To decrease afterload (arterial vasodilators) – To decrease preload and afterload (ACEI, ARB) (nitrates, sodium nitroprusside) • To prolong the survival – β adrenoreceptor blockers
  38. 38. Nitrates • MOA (refer to antianginal lecture) • PA – Reduction in preload (low dose – venodilation) – Reduction in afterload (high dose – arterial dilation) • Usefulness of nitrates in heart failure – Choice of vasodilators depend on patient’s symptoms: – Nitrates are useful for patients with pulmonary congestion, dyspnoea symptoms – In patients with severe chronic heart failure – problem involves both elevated venous filling pressures & decreased cardiac output – therefore, dilation of both arteries and veins is required.
  39. 39. DRUG THERAPY • To increase force of contraction – Digoxin – β agoists (dobutamine, dopamine) – Bipyridines (milrinone) • To reduce cardiac workload – To decrease preload (venodilators) (diuretics, nitrates) – To decrease afterload (arterial vasodilators) – To decrease preload and afterload (ACEI, ARB) (nitrates, sodium nitroprusside) • To prolong the survival – β adrenoreceptor blockers
  40. 40. (HYDRALAZINE) ARTERIAL VASODILATORS Hydralazine Why it is useful in heart failure (Pharmacological basis) • Dilation of arteries  decreases afterload • More helpful in patients with low LV cardiac output are primary symptoms (fatigue).
  41. 41. DRUG THERAPY • To increase force of contraction – Digoxin – β agoists (dobutamine, dopamine) – Bipyridines (milrinone) • To reduce cardiac workload – To decrease preload (venodilators) (diuretics, nitrates) – To decrease afterload (arterial vasodilators) – To decrease preload and afterload (ACEI, ARB) (nitrates, sodium nitroprusside) • To prolong the survival – β adrenoreceptor blockers
  42. 42. ACE INHIBITORS Captopril, Enalapril, Lisinopril Angiotensin converting enzyme inhibitor Mechanism of action • Inhibits angiotensin converting enzyme (which converts Angiotensin I to angiotensin II) • Reduce formation of antiogensin II (angiotensin II is a potent vasoconstrictor in body & it causes production to aldosterone, which causes salt and water retention from kidney).
  43. 43. Pharmacological action ACEI decrease the formation of Ang II and aldosterone • arterial dilatation → ↓ afterload • venous dilatation → ↓ preload • ↓aldosterone action → ↓ salt & water retention → ↓ vascular volume • improve remodelling, slow ventricular dilatation •  sympathetic activation
  44. 44. THERAPEUTIC USE • First line therapy in chronic heart failure along with diuretics (especially patients with LV dysfunction) UNTOWARD EFFECTS • first dose phenomenon (severe first dose hypotension) • dry irritative cough ( breakdown of bradykinin)
  45. 45. Angiotensin II Receptor Blockers (ARB) Losartan, Valsartan As alternative, in patients who cannot tolerate ACEIs do not produce local kinin effects → no cough as side-effect. Otherwise, similar to ACEIs
  46. 46. • ACEI can also inhibit or delay cardiac remodelling process. • This is also an advantage of ACEI for usage in heart failure.
  47. 47. Initial infarct Expansion of infarct (hours to days) Global remodeling (days to months) Normal heart Hypertrophied heart (diastolic heart failure) Dilated heart (systolic heart failure)
  48. 48. DRUG THERAPY • To increase force of contraction – Digoxin – β agoists (dobutamine, dopamine) – Bipyridines (milrinone) • To reduce cardiac workload – To decrease preload (venodilators) (diuretics, nitrates) – To decrease afterload (arterial vasodilators) – To decrease preload and afterload (ACEI, ARB) (nitrates, sodium nitroprusside) • To prolong the survival – β adrenoreceptor blockers
  49. 49. BETA-BLOCKERS Carvedilol, Bisoprolol, Metoprolol - Paradox: cardio-depressant in heart failure
  50. 50. - Use of β blockers in heart failure are based on hypothesis that excessive tachycardia and adverse effects of high catecholamine levels on the heart contribute to the downward course of heart failure. - Initiated cautiously at low dose • Not all β blockers – (bisoprolol, metoprolol, carvedilol and nebivolol)
  51. 51. - Beneficial effects may be due to: - preventing changes caused by chronic activation of sympathetic nervous system. - ↓ HR → - ↓ renin release - preventing direct effect of noradrenaline and angiotensin on cardiac muscle fibres (remodelling) - antihypertensive action (where applicable) - Improvements: - Rise in ejection fraction - Slower heart rate - Reduction of symptoms
  52. 52. Drawbacks: - initial exacerbation of symptoms (worsening of HF). - Therefore, very low starting dose, titrated gradually to effective doses. In chronic stable HF. • Only by experienced cardiologists. • beneficial effects seen after months (delayed) • NOT recommended: in acute HF
  53. 53. CARDIAC RESYNCHRONIZATION THERAPY (disease condition) CARDIAC RESYNCHRONIZATION THERAPY (after CRT)
  54. 54. References
  55. 55. 1. Tripathi, KD. 2008. Essentials of Medical Pharmacology. 6th Edition. India: Jaypee Brothers Medical Publishers (P) Ltd. 2. http://www.ncbi.nlm.nih.gov/pubmed/14727944 3. https://www.youtube.com/watch?v=GnpLm9fzYxU 4. https://www.youtube.com/watch?v=3YddwXPWVSc 5. https://www.youtube.com/watch?v=zy_fK1P2odM References

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