Congestive Cardiac Failure

Dr. E. McIntosh October 2011

Introduction to Heart Failure

Heart unable to provide adequate perfusion of peripheral organs to meet their metabolic requirements Characterized by: 1. Reduction in cardiac output 2. Increased TPR
Progressing to congestive heart failure (CHF) is accompanied by peripheral and pulmonary edema.

Acute Vs Chronic HF
In a patient with acute heart failure, the short-term aim is stabilization by providing symptomatic treatment through intravenous interventions. Management of chronic heart failure is multifaceted, with the long-term aims of:
relieving symptoms improving hemodynamics improving quality of life and decrease mortality.

Cardiac Vs Noncardiac targets

Conventional belief that the primary defect in HF is in the heart Reality is that HF involves many other processes and organs Research has shown that therapy directed at noncardiac targets are more valuable than cardiac targets

Compensation in HF
Heart failure is usually accompanied by an increase in: 1. Sympathetic nervous system (SNS) 2. Chronic up-regulation of the reninangiotensin-aldosterone system (RAAS) and effects of aldosterone on heart, vessels, and kidneys. CHF should be viewed as a complex, interrelated sequence of events involving hemodynamic, and neurohormonal events.

Compensation contd..
In a failing heart, the loss of contractile function leads to a decline in CO and a decrease in arterial BP. Baroreceptors sense the hemodynamic changes and initiate countermeasures to maintain support of the circulatory system. Activation of the SNS serves as a compensatory mechanism in response to the earlier This helps maintain adequate cardiac output by: 1. Increasing myocardial contractility and heart rate (1adrenergic receptors) 2. Increasing vasomotor tone (1-adrenergic receptors) to maintain systemic blood pressure

Consequences of hyperadrenergic state

Over the long term, this hyperadrenergic state leads to irreversible myocyte damage, cell death, and fibrosis. In addition, the augmentation in peripheral vasomotor tone increases LV afterload This places an added stress upon the left ventricle and an increase in myocardial O2 demand (ventricular remodeling). The frequency and severity of cardiac arrhythmias are enhanced in the failing heart

 Figure p.203 kat

Therapeutic Overview
Problem Reduced force of contraction Decreased cardiac output Increased total peripheral resistance Inadequate organ perfusion Development of edema Decreased exercise tolerance Ischemic heart disease Sudden death Ventricular remodeling and decreased function

Goals and drug therapy

Goals Alleviation of symptoms, improve quality of life Arrest ventricular remodeling Prevent sudden death Nondrug therapy Reduce cardiac work; rest, weight loss, low Na+ diet Drug therapy Chronic heart failure
ACE-I, -blockers, ARB, aldosterone antagonists, digoxin, diuretics

Acute heart failure

Intravenous diuretics, inotropic agents, PDE inhibitors, vasodilator

Drugs for CCF

Drugs for CCF

Diuretics : These are useful in reducing the symptoms of volume overload by decreasing the extra cellular volume decreasing the venous return

Drugs for CCF

Diuretics : Loop diuretics like furosemide and bumetanide are the most effective and commonly used. Thiazides are effective in mild cases only.

Drugs for CCF

Diuretics : Adverse effects : Loop diuretics and thiazides cause hypokalemia. Potassium sparing diuretics help in reducing the hypokalemia due to these diuretics.

Drugs for CCF

Potassium Sparing Diuretics : Spironolactone : Aldosterone inhibition minimize potassium loss, prevent sodium and water retention, endothelial dysfunction and myocardial fibrosis.

Drugs for CCF

Spironolactone : Aldosterone antagonist Spironolactone can be added to loop diuretics to modestly enhance the diuresis; more importantly, improve survival.

Renin angiotensin system

Baroreceptor mediated activation of the SNS leads to an increase in renin release and formation of angiotensin II Angiotensin II acts through AT1 and AT2 receptors (most of its actions occur through AT1 receptors) This causes vasoconstriction and stimulates aldosterone production RAS remains the most important target of chronic CHF therapy

Effects of AT-II

MOA
ACE-Inhibitors and ARBs Blockade of ACE Decreased AT-II Decreased aldosterone Decreased fluid retention Vasodilation Reduced preload and afterload Slows cardiac remodeling

Advantages
Improves symptoms significantly Improves exercise tolerance Slows progression of the disease Prolong survival in established cases

ADR
What are the ADR of ACEIs? Cough (why?) Hyperkalemia (possible Drug interactions?) Contraindicated in pregnant women (1st trimester) Rare: angioedema

Other Vasodilators:
Mechanism 2:
Direct smooth muscle relaxants Nitrates
Venous dilators Reduce preload Eg: sodium nitropruside

Nitrates in CCF

Inotropes
Increase force of contraction All increase intracellular cardiac Ca++ concentration Eg:
Digitalis (cardiac glycoside) Dobutamine (-adrenergic agonist) Amrinone (PDE inhibitor)

Cardiac glycosides
Digitalis Sourced from foxglove plant 1785, Dr. William Witherings monograph on digitalis Has a profound effect on the cardiac contractility

Pck
Two drugs (digoxin, digitoxin) Well absorbed orally 10% of population have bacteria in the gut, which inactivate digoxin, needing an increased dose in such Beware of using antibiotics in such patients Digoxin has a very narrow ther. Margin

Pck
Taken orally Enters CNS (so what?) Renal clearance proportional to Creatinine Clearance To be used with extreme caution in patients suffering from renal impairment

MOA
Regulation of cytosolic Ca metabolism: Reversibly combine with sodium-potassium ATPase of the cardiac cell membrane Results in inhibition of pump activity This leads to in intracellular Na conc. This favors Ca ions in the cell Ca levels result in increased systolic force of contraction

Digoxin MOA

Na/K ATPase inhibition

Additional MOA
Force of contraction resembles that of the normal heart Improved circulation leads to reduced sympathetic activity This reduces PVR All this leads to reduction in HR Vagal tone is enhanced Finally myocardial O2 demand is reduced

Electrophysiological effects on the heart

Direct SA Node No effect at therapeutic dose Atrial muscle High dose increases rate of spontaneous depolarization AV node Increased refractory period Decreased conduction velocity His-Purkinje Increased refractory period system Decreased conduction velocity High dose increases triggered activity Toxic doses enhance pacemaker Indirect (increased vagal tone) No effect at therapeutic dose High dose decreases rate of spontaneous depolarization Decreased conduction velocity Increased refractory period Increased refractory period Decreased conduction velocity None

Uses
Severe LV systolic dysfunction Only after initiation of diuretics and vasodialtor therapy Management of patients with chronic atrial fibrillation Cannot arrest the progression of pathological changes causing heart failure, and does not prolong life in patients with CHF

ADR
Digitalis toxicity is one among most commonest encountered (why?) Therapeutic concentration- 0.5-1.5 ng/ml Often the first step is discontinuation of Rx Digoxin levels must be monitored closely

Signs of digoxin toxicity

CNS: Malaise, confusion, depression, vertigo, vision (abnormalities in color vision) GI: Anorexia, nausea, intestinal cramping, diarrhea Cardiovascular: Palpitations, syncope, arrhythmias, bradycardia, AV node block, tachycardia

Factors increasing the possibility of digoxin toxicity

Pharmacological and toxic effects are greater in hypokalemic patients. K+-depleting diuretics are a major contributing factor to digoxin toxicity.

Management
Arrhythmias may be converted to normal sinus rhythm by K+. when the plasma K+ conc. is low or within the normal range. When the plasma K+ conc. is high, antiarrhythmic drugs, such as lidocaine, procainamide, or propranolol, can be used.
Severe toxicity treated with Digibind, an antidigoxin antibody.

What could it be???

A 96-year-old AAF was admitted from a nursing home with complaints of abdominal pain, N/V, dizziness, confusion and double vision for 5 days. She was discharged from the hospital just 4 days ago. Digoxin was started during that previous hospitalization for control of tachycardia in atrial fibrillation. One day prior to discharge, digoxin level was 1.8 mg/mL and digoxin dose was decreased to 125 mcg PO Q 48 hr. PMH Hypertension, atrial fibrillation, coronary artery disease, stroke, congestive heart failure. Medications Metoprolol, Digoxin, ASA, lisinopril, Lasix, Coumadin, Nexium

Dopamine
Dopamine acts at a variety of receptors (dose dependant)
Dopamine receptors at low dose Beta 2 at intermediate dose Alpha 1 at high dose

Rapid elimination- can only be administered as a continuous infusion Treatment for acute, severe heart failure (LVF) esp. with low BP

Dobutamine
Stimulates beta-adrenergic receptors and produces a positive inotropic response Unlike the vasoconstriction seen with high doses of dopamine, dobutamine produces a mild vasodilatation Used in acute heart failure with normal or high BP

MOA

PDE inhibitors
Amrinone and Milrinone (bipyridines) Acts by inhibiting the enzyme Phosphodiesterase Thus lead to increase of intracellular concentrations of cAMP cAMP is responsible for the conversion of inactive protein kinase to active form Protein kinases are responsible for phosphorylation of Ca channels Thus causing increased Ca entry into the cell.

MOA
Increase myocardial contractility by increasing the Ca influx during AP Also have vasodilating effect Selective for PDE isoenzyme-3 (found in cardiac and smooth muscle)

Current status
Both are orally active Only available in parenteral forms Limited efficacy Clinical trials- increased mortality (oral) Still new drugs are under trial

ADR
Amrinone: nausea, vomiting, arrhythmias, thrombocytopenia and liver enzyme changes Withdrawn in some countries Milrinone: arrhythmias, less likely to cause other ADR

(BNP)-Niseritide
Brain (B-type) natriuretic peptide (BNP) is secreted constitutively by ventricular myocytes in response to stretch BNP binds to receptors in the vasculature, kidney, and other organs, producing potent vasodilation with rapid onset and offset of action by increasing levels of cGMP Niseritide is recombinant human BNP approved for treatment of acute decompensated CHF.

BNP contd..
It reduces systemic and pulmonary vascular resistances, causing an indirect increase in cardiac output and diuresis. Effective in HF because cause reduction in preload and afterload ADR- hypotension

Beta blockers
Overwhelming evidence to support the use of -blockers in CHF, however Mechanism involved remain unclear Part of their beneficial effects may derive from slowing of heart rate and decrease myocardial O2consumption. This would lessen the frequency of ischemic events and potential for development of a lethal arrhythmia.

Beta blockers
Suggested mechanisms also include reduced remodeling -Blockers may be beneficial through resensitization of the down-regulated receptor, improving myocardial contractility. Recent studies with bisoprolol, carvedilol and metoprolol showed a reduction in mortality in patients with these drugs CI in unstable cases

Management of Chronic HF (combination of drugs)

Limit physical activity Reduce weight Reduce water intake Control HT Na restriction Diuretics ACE-Is Digitalis (ther. margin, DI with quinidine) Beta blockers Vasodilators

Management of acute HF
Diuretics Vasodilators Inotropic drugs Life support Treating cause (surgery to correct valvular disorders)