Congestive Heart Failure

Dr Bhaskar H Nagaiah

07/15/12

Congestive Heart Failure (CHF)

Contractility / Cardiac output (COP) is not adequate to provide blood / oxygen needed by the body. Lethal disease, five years mortality rate is 50% Common cause - Coronary artery disease Prevalence of CHF is increasing due to increase in survival of pts with myocardial infraction Systolic failure reduce in myocardial contractility & ejection fraction reduced COP Diastolic failure stiffening & inadequate relaxation of heart during diastole reduced COP
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Congestive Heart Failure (CHF)

Force of contraction of heart mainly depends on amount of free Calcium inside the cytoplasm. Amount of free Calcium, is proportional to amount Calcium stored and released from sarcoplasmic reticulum (SR) Amount Calcium stored depends on influx of Ca through L- type of calcium channels & efflux of Ca through NaCa Exchanger, antiport (activation depends on Na concentration) Na concentration is maintained by Na-K ATPase (Sodium pump)
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Congestive Heart Failure (CHF)

Predisposing factors HTN (increase in TPR) Myocardial infarction / IHD Myocarditis Congenital abnormalities AS, AR High output failure (because the increase the thyroid hormone, stimulate the myocardium, and the heart can cope with the stimulation, also with anemia makes it work harder) Thyrotoxicosis 07/15/12 Anemia

Neurohumoral mechanisms in CHF

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Congestive Heart Failure (CHF)

Remodeling Proliferation of connective tissue and abnormal myocardial cells (fetal myocytes) in place of normal cardiac muscle. Normal cardiac myocytes gradually die due to apoptosis. Heart gradually loses the contractility / FOC Signs and symptoms tachycardia, decrease in exercise tolerance, shortness of breath /dysnoea, peripheral and pulmonary edema, cardiomegaly, rapid muscular fatigability
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Congestive Heart Failure (CHF)

Acute Heart Failure Symptoms severe sudden onset, after infart LHF pulmonary edema Chronic Heart Failure Slow progression Left sided heart failure LVF leads to RVF Right sided heart failure
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Cardiac performance in CHF 1. Pre-load increased in CHF (due to increase in blood volume and venous tone), increase left ventricular filling pressure. Overstretching cardiac fibers (increased End-diastolic fiber length) and fall in stoke volume 2. After-load increased due to increase in systemic vascular resistance / TPR 3. Contractility of the myocardium- reduced / shortening of muscle 4. Heart rate increased 5. Cardiomegaly
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Pathophysiology - CHF

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Congestive Heart Failure (CHF)

Main defect in excitation and contraction coupling in myocardium Other processes and organs involved are Sympathetic NS (we must reduce this) Kidneys Renin-angiotensin-system & aldosterone (RAS-A) Peptides atrial natriuretic peptide

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Congestive Heart Failure (CHF)

Pharmacotherapy is aimed at: To decrease 1. Decreasing Preload End diastolic pressure / fiber length 2. Decreasing After load reduce cardiac work (stupid kidney increase the Afterload, b/c increase in TPR) 3. Increasing cardiac Contractility increase efficiency
4.

Decreasing the Remodeling of cardiac muscles- to prevent further worsening / progress We got to stop this remode
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stop it then they live long must arrest it!

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Congestive Heart Failure (CHF)

Methods of treatment Reduce the work load on heart - physical activity, body weight & control HTN

Decrease sodium in diet Vasodilators reduce preload & afterload Diuretics reduce blood volume & preload Inotropic drugs increase FOC & COP
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VASODILATORS ACE inhibitors ARBs (angiotensine receptor blockers) Direct vasodilators: Sodium nitroprusside Hydralazine Nitrates: -Nitroglycerine -Isosorbide dinitrate

DIURETICS -Loop diuretics -Thiazides -K Sparring diuretics -Spironolactone -Eplerenone

INOTROPICS cardiac glycosides -Digoxin Beta agonists -Dopamine -Dobutamine Phosphodiesterase inhibitors -Amrinone -Milrinone

BETA BLOCKERS Metoprolol Carvedilol In chronic CHF, beta blockers have been found to prevent the remodeling changes in the heart.

Arrest / reversal of disease progression and prolongation of survival

ACE inhibitors / AT1 receptor blockers (ARBs) Beta blockers Aldosterone antagonists Spironolactone Eplerenone

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VASODILATORS ACE inhibitors / ARBs

ACE inhibitors & AT1 receptor blockers reduce Aldosterone secretion Salt and Water retention Reduce Vascular resistance, preload & afterload They reduce morbidity & mortality in Chronic Heart Failure Are first line drugs for Chronic Heart Failure, along with Diuretics
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ACE inhibitors
Captopril Lisinopril Know these Enalpril Ramipril

Quinapril Moexipril Perindopril Trandolapril Fosinopril Benzapril

Non renal elimination

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Mechanism of action of ACE inhibitors in CHF

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ACE Inhibitors
Acts by inhibiting ACE (angiotensin converting enzyme); Decreases Angiotensin II levels Vasodilatation of both arterioles & veins and decrease in preload & after-load Increase in cardiac output & ejection fraction

Reduce blood volume (preload) by inhibiting retention of sodium & water

Arrest/reverse the remodeling changes in the myocardium 07/15/12

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Adverse effects of ACE Inhibitors :

Dry irritating cough (due to bradykinin) Angioedema Hypotension during initial doses Hyperkalemia Skin rashes, Urticaria Dysgeusia (metallic taste) Acute renal failure contraindicated in bilateral renal artery stenosis <<<one side renal artery stenosis, the renin system is actually saving the kideny, lose this and u are screwed. Fetal damage (Teratogenicity) acute renal failure >>>so if preg, give calcium blockers instead.
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Angiotesin II receptor blockers (ARBs)

Losartan, valsartan, Candesartan, eprosartan, Irbesartan, telmisartan

Benefits similar to ACE inhibitors Used in pts intolerance to ACE inhibitors Less AEs dry cough, angioedema No effect on bradykinin metabolism
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Diuretics
but

but

se

Loop diuertics - are preferred in acute CHF Furosemide Bumetanide Thiazide diuretics Potassium sparing diuretics Spironolactone (an Aldosterone Antagonist) Amiloride Triamterene Spironolactone aldosterone antagonist, reduces the morbidity & mortality, Reduces myocardial & vascular fibrosis 07/15/12 25

DIURETICS
Decreases plasma volume excretion of Na+ & H2O Decrease Venous Return Reduce preload and end diastolic pressure Reduce cardiac workload (Oxygen demand) More efficient cardiac contraction (COP)
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Aldosterone antagonist: Eplerenone

Selective aldosterone antagonist Decreases Na and water reabsorption, decrease blood volume

More selective to aldosterone receptors blocker than Spironolactone. Less affinity to androgen receptors Less antiandrogenic AEs than spironolactone
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Nesiritide
Recombinant human Brain natriuretic peptide (BNP) Mechanism of Action Increases cGMP Cause relaxation of arteries and veins Induce diuresis

Short half life IV bolus Used acute CHF

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Other Vasodilators

Hydralazine Arteriolar dilator reduce afterload Isosorbide dinitrate Predominantly venodilator Reduce preload Used acute LVF

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INOTROPIC AGENTS

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Inotropic agents

Cardiac glycosides (Digitalis compounds) Digoxin Digitoxin Beta agonists Dopamine Dobutamine Phosphodiesterase inhibitors Inamirinone (Amrinone) Milrinone
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Normal myocardial cell

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Cardiac glycoside digoxin

Mechanism of Action: Inhibit Na-K pump (Na+/K+ ATPase) Increase intracellular Na Suppress Na+- Ca+ exchanger Increase intracellular Ca2+ Increases FOC & Cardiac output
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Cardiac glycosides

Increase in ejection fraction, FOC & COP Enhance renal perfusion Reduces compensatory mechanisms Reduce Sympathetic overactivity TPR HR Myocardial oxygen demand Leading to more efficient contraction without increasing Oxygen demand Systole is shortened & diastole is prolonged
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Cardiac glycosides Therapeutic Uses Congestive heart failure - Inotropic agent used in left ventricular Systolic failure Other uses: In Atrial fibrillation To control the ventricular rate. Parasympathomimetic effects of digilatis (stimulate central Vagal N) Decreases AV conduction by increasing refractory period of AV node & PR interval
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Cardiac glycosides PK

Digoxin Plasma half life is short compared to digitoxin Fast onset of action Excreted unchanged in urine Digitoxin (not available in US) Extensive extra-vascular binding Metabolized in liver Excreted in feces
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Cardiac glycosides
Digoxin
Half-Life (hours) Protein Binding Route of elimination Vagal Stimulation
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Digitoxin
180 hrs 70 - 90%

36 40 hrs 20-40%

Renal (60%)
+++

Hepatic
+
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Adverse effects: are more due to narrow TI Extra cardiac: Stimulation of vagus nerve causes increase in GI effects common, anorexia, diarrhea nausea, vomiting (stimulation of CTZ centre), Gynecomastia visual disturbances (diplopic, aberration in color perception) Cardiac AE: Can induce all types of cardiac arrhtythmias ventricular bigeminy, ventricular arrhythmias, AV block, bradycardia, 07/15/12 39

Cardiac glycosides Digoxin

Digitalis toxicity
Hypokalemia enhance digitalis toxicity Signs/Symptoms of Digitalis toxicity GIT: nausea, vomiting, diarrhea

CNS : headache, hallucinations, fatigue, confusion Vision disturbances - blurred vision, alteration of color perception, haloes
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Signs/Symptoms of Digitalis toxicity.

On Heart: Ectopic beats/ premature ventricular beats Delayed after depolarization (due increased intracellular Ca2+ concentration) Ectopic beats, Ventricular arrhythmias Sinus bradycardia First-degree AV block Complete heart block
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Digitalis toxicity
Predisposing factors Hypokalemia - binding of digoxin to Na-K ATPase Drugs Loop diuretics or thiazide - induce Hypokalemia Quinidine - decreases digoxin renal clearance & displace digoxin from plasma protein binding - toxicity Hypomagnesemia

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Rx of digitalis toxicity:
Treatment Stop Digoxin treatment Correct the Potassium & magnesium deficiency: K sparing diuretic or KCl For arhythmia: give antiarrhythmic drugs lidocaine or Phenytoin to control Ventricular fibrillation

Anti digoxin antibodies (Digibind) in severe toxicity / other therapies are not effective (not perferred, only in severe toxicities)
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Beta agonists

Dopamine Dobutamine Used in acute CHF Disadvantage of Dopamine over Dobutamine and digoxin Dopamine increase heart rate & oxygen demand Dobutamine increases contractility more than HR Preferred in acute CHF than other inotropic agent
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Phosphodiesterase Inhibitors (Bipyridines)

Inamrinone (Amrinone) and Milrinone Mechanism of Action: Inhibits phosphodiesterase (PDE) enzyme & increase in cAMP level Increase cytoplasmic Ca2+ concentration & cardiac contractility Dilates the blood vessels -

Used in acute cardiac failure Not used in chronic CHF

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Drugs contraindicated in CHF

Drugs contraindicated in CHF: Ca2+ channel blockers (verapamil, diltiazem) Beta blockers in high dosage (we now only admin in small doses) Antiarrhythmic drugs Combination of Verapamil & diltiazem with Beta blockers

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Role of Beta-receptor antagonists

Beta blockers like Metoprolol, Carvedilol Reduce progression of Chronic Heart Failure. By increasing the Ventricular ejection fraction & exercise tolerance and reduce mortality rate. May by Up-regulation of receptors & reduces remodeling Not beneficial/ no value in Acute failure detrimental if systolic dysfunction is marked

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Treatment

Acute CHF Most common cause is Acute MI Treat with inotropics, loop diuretics, vasodilators Chronic CHF Reduce work load Restrict Na & water (if require but rarely) Give diuretics ACE inhibitors / ARBs Digoxin Beta blockers & vasodilators
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