Drugs used in heart failure

Introduction Heart failure (HF) is a major contributor to morbidity and mortality worldwide Definition: clinical condition in which an individual expels less than 40% of the blood from the left ventricle per heartbeat (ejection fraction [EF] 40%) HF is due to an impaired ability of the heart to adequately fill (diastolic failure) with and/or eject blood (systolic failure)

Signs & symptoms of HF The primary signs and symptoms of all types of heart failure include tachycardia, decreased exercise tolerance, shortness of breath, peripheral and pulmonary edema, and cardiomegaly Decreased exercise tolerance with rapid muscular fatigue is the major direct consequence of diminished cardiac output The other manifestations result from the attempts by the body to compensate for the intrinsic cardiac defect

Introduction Physiology of Muscle Contraction The myocardium, like smooth and skeletal muscle, responds to stimulation by depolarization of the membrane, which is followed by shortening of the contractile proteins and ends with relaxation and return to the resting state Cardiac muscle cells are electrically excitable. Cardiac cells owe their electrical excitability to voltage-sensitive plasma membrane channels selective for various ions, including Na+, K+ and Ca2+ These ions pass through channels in the sarcolemmal membrane and, thus, create a current

Introduction Physiology of Muscle Contraction Ca2+ that enters the cell via the L-type Ca2+ channel during depolarization triggers the release of stored intracellular Ca2+ into the cytosol from the sarcoplasmic reticulum via the ryanodine receptor (RyR) Ca2+-induced Ca2+ release increases the level of cytosolic Ca2+ available to interact with the contractile proteins, thereby increasing the force of contraction The force of contraction of the cardiac muscle is directly related to the concentration of free (unbound) cytosolic calcium

Introduction Physiology of Muscle Contraction If free cytosolic calcium levels were to remain high, the cardiac muscle would be in a constant state of contraction rather than showing a periodic contraction Mechanisms of removal include two alternatives: Sodium-calcium exchange: the capacity of the exchanger to extrude Ca2+ from the cell depends on the intracellular Na+ concentration Na+/K+-ATPase, by removing intracellular sodium, is the major determinant of sodium concentration in the cell Uptake of calcium by the sarcoplasmic reticulum and mitochondria (sarcolemmal Ca2+-ATPase)

Sarcoplasmic Reticulum Myofibrils Ca++ 2 Ca++ 3 Na+ 3 Na+ 2 K+ L-Type Calcium Channel ATP 2 Ca++ 3 Na+ 3 Na+ 2 K+ Sarcoplasmic Reticulum Ca++ Ca++ Ca++ Myofibrils

Pathophysiology of heart failure The failing heart evokes three major compensatory mechanisms to enhance cardiac output: Increased sympathetic activity Activation of the renin-angiotensin system Myocardial hypertrophy & remodelling

Pathophysiology of heart failure Increased sympathetic activity: The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure Baroreceptor sensory input to the vasomotor center is reduced even at normal pressures; sympathetic outflow is increased, and parasympathetic outflow is decreased

Pathophysiology of heart failure Increased sympathetic activity: This results in an increased heart rate and a greater force of contraction of the heart muscle (β1 receptors) In addition, vasoconstriction (α1-mediated) enhances venous return and increases cardiac afterload, which further reduces ejection fraction and cardiac output

Pathophysiology of heart failure Increased sympathetic activity: After a relatively short exposure to increased sympathetic drive, complex down-regulatory changes in the cardiac β1-adrenoceptors take place that result in diminished stimulatory effects Excessive activation can lead to leakage of calcium from the SR via RyR channels and contributes to stiffening of the ventricles and arrhythmias Prolonged activation also increases caspases, the enzymes responsible for apoptosis

Sympathetic Activation in Heart Failure  CNS sympathetic outflow  Cardiac sympathetic activity  Sympathetic activity to kidneys + peripheral vasculature 1- receptors 2- 1- Activation of RAS 1- b1- Myocardial toxicity Increased arrhythmias Vasoconstriction Sodium retention Disease progression Packer. Progr Cardiovasc Dis. 1998;39(suppl I):39-52.

Pathophysiology of heart failure Activation of the renin-angiotensin system: A fall in cardiac output decreases blood flow to the kidney, prompting the release of renin, with a resulting increase in the formation of angiotensin II Increased angiotensin II production leads to increased aldosterone secretion (with sodium and water retention) which augments preload, to increased afterload, and to remodeling of both heart and vessels

Pathophysiology of heart failure Activation of the renin-angiotensin system: Blood volume increases, and more blood is returned to the heart. If the heart is unable to pump this extra volume, venous pressure increases and peripheral edema and pulmonary edema occur Vascular resistance is further increased by angiotensin II

Compensatory Mechanisms: Renin-Angiotensin-Aldosterone (RAAS) Angiotensinogen Renin Angiotensin I Angiotensin Converting Enzyme Angiotensin II AT I receptor Vasoconstriction Vascular remodeling Oxidative Stress LV remodeling Cell Growth Proteinuria

Pathophysiology of heart failure Myocardial hypertrophy & remodelling: The heart increases in size, and the chambers dilate and become more globular Initially, stretching of the heart muscle leads to a stronger contraction of the heart However, excessive elongation of the fibers results in weaker contractions, and the geometry diminishes the ability to eject blood (systolic HF)

Pathophysiology of heart failure Myocardial hypertrophy & remodelling: When the ability of the ventricles to relax and accept blood is impaired by structural changes, such as hypertrophy, the thickening of the ventricular wall and subsequent decrease in ventricular volume decrease the ability of heart muscle to relax (diastolic HF)

Pathophysiology of heart failure Myocardial hypertrophy & remodelling: Remodeling is the term applied to dilation (other than that due to passive stretch) and other slow structural changes that occur in the stressed myocardium It may include proliferation of connective tissue cells as well as abnormal myocardial cells with some biochemical characteristics of fetal myocytes

Treatment of HF Treatment is directed at two somewhat different goals: Reducing symptoms and slowing progression as much as possible during relatively stable periods Managing acute episodes of failure

Pharmacological treatment of HF Drugs with postive inotropic effects (e.g. cardiac glycosides) Drugs without positive inotropic effects (e.g. Diuretics)

I. Drugs without positive inotropic effect These are the first-line therapies for chronic heart failure Are directed at noncardiac targets is more valuable in the long-term treatment of HF than traditional positive inotropic agents

I. Drugs without positive inotropic effect The drugs most commonly used are Diuretics ACE inhibitors Angiotensin receptor antagonists Aldosterone antagonists β-blockers

a. Diuretics Diuretics are the mainstay of HF management They have no direct effect on cardiac contractility Their major mechanism of action in HF is to: Decrease venous return to the heart (preload), without a reduction in cardiac output Reduce the symptoms of volume overload

a. Diuretics Loop diuretics (frusamide) is a very useful agent for immediate reduction of the pumonary congestion and edema associated with HF Monotherapy with thiazide diuretics has a limited role in CHF. However, combination therapy with loop diuretics is often effective in those refractory to loop diuretics alone

a. Diuretics Aldosterone antagonists (Spironolactone & eplerenone) have the additional benefit of decreasing morbidity and mortality in patients with severe heart failure, who are also receiving ACE inhibitors and other standard therapy

b. Angiotensin antagonists: ARBs and ACEIs The renin-angiotensin system plays a central role in the pathophysiology of heart failure Angiotensin antagonists have been shown to reduce morbidity and mortality in chronic heart failure They have no direct positive inotropic effect These drugs reduce peripheral resistance and thereby reduce afterload; they also reduce salt and water retention (by reducing aldosterone secretion) and in that way reduce preload

b. Angiotensin antagonists: ARBs and ACEIs The reduction in tissue angiotensin levels also reduces sympathetic activity through diminution of angiotensin's presynaptic effects on norepinephrine release They also reduce the long-term remodeling of the heart and vessels Angiotensin receptor blockers should be considered in patients intolerant of ACE inhibitors because of incessant cough

c. Vasodilators Agents : organic nitrates, hydralazine, & recombinant brain natriuretic peptide (BNP) (e.g. nesiritide) Vasodilator drugs can be divided into selective arteriolar dilators, venous dilators, and drugs with nonselective vasodilating effects Vasodilators are effective in acute heart failure because they provide a reduction in preload (through venodilation), or reduction in afterload (through arteriolar dilation), or both Some evidence suggests that long-term use of hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart

c. Vasodilators Nesiritide: A synthetic form of the endogenous peptide brain natriuretic peptide (BNP) is approved for use in acute (not chronic) cardiac failure The natriuretic peptides: atrial natriuretic peptide (ANP), BNP, and C-type natriuretic peptide, are a family of endogenous neurohormones that possess potent natriuretic, diuretic, and vasodilator properties

c. Vasodilators Plasma concentrations of endogenous BNP rise in most patients with heart failure and are correlated with severity In the setting of heart failure, the effects of BNP counteract the effects of angiotensin and norepinephrine by producing vasodilation, natriuresis, and diuresis

c. Vasodilators The BNP receptor is the extracellular domain of type A guanylyl cyclase, GC-A Activation of GC-A by nesiritide (BNP) increases cyclic GMP content in target tissues, including vascular, endothelial, and smooth muscle cells Elevated cyclic GMP leads to relaxation of vascular smooth muscle and vasodilation in both the venous and arterial systems Nesiritide also causes diuresis

c. Vasodilators The peptide has a short half-life of about 18 minutes and is administered as a bolus/loading intravenous dose followed by continuous infusion Reports of significant renal damage and deaths have resulted in extra warnings regarding this agent, and it should be used with great caution

d. Beta-blockers Agents used: bisoprolol, carvedilol, metoprolol, and nebivolol Most patients with chronic heart failure respond favorably to certain β-blockers in spite of the fact that these drugs can precipitate acute decompensation of cardiac function Several months of therapy may be required before improvement is noted; this usually consists of a slight rise in ejection fraction, slower heart rate, and reduction in symptoms

d. Beta-blockers The benefit of β-blockers is attributed to their ability to: Prevent the changes that occur because of the chronic activation of the sympathetic nervous system, including decreasing the heart rate and inhibiting the release of renin Prevent the direct deleterious effects of norepinephrine on the cardiac muscle fibers, decreasing remodeling, hypertrophy and cell death

II. Drugs with positive inotropic effect Positive inotropic agents enhance cardiac muscle contractility and, thus, increase cardiac output These drugs act by different mechanisms, in each case the inotropic action is the result of an increased cytoplasmic calcium concentration that enhances the contractility of cardiac muscle

II. Drugs with positive inotropic effect These include: Digitalis Beta-adrenoceptor agonists Phosphodiesterase Inhibitors: Bipyridines

a. β-Adrenergic Agonists Agents used: Dobutamine Used for the short-term of acute HF. They are most useful in patients with severe hypotension It acts via stimulation of the cardiac myocyte β1 adrenergic receptor, leading to stimulation of the Gs-adenylyl cyclase-cyclic AMP-PKA pathway. The catalytic subunit of PKA phosphorylates a number of substrates that enhance Ca2+-dependent contraction and speed relaxation

b. Phosphodiesterase inhibitors/ Bidyridines Agents: milrinone They are active orally as well as parenterally but are available only in parenteral forms used only intravenously and only for acute heart failure or severe exacerbation of chronic heart failure

b. Phosphodiesterase inhibitors/ Bidyridines Bipyridine derivatives and relatively selective inhibitors of PDE3 (heart-specific subtype (type III) of phosphodiesterase, that inactivate cGMP and cAMP These drugs directly stimulate myocardial contractility and accelerate myocardial relaxation In addition, they cause balanced arterial and venous dilation with a consequent fall in systemic and pulmonary vascular resistances and left and right-heart filling pressure

c. Cardiac glycosides: digoxin The cardiac glycosides are often called digitalis or digitalis glycosides, because most of the drugs come from the digitalis (foxglove) plant They increase the contractility of the heart muscle and, therefore, are used in treating HF Digoxin  is the prototype and is the most important therapeutically The digitalis glycosides have a low therapeutic index

c. Digoxin Pharmacokinetics (digoxin) Dogxin is administered orally or, in urgent situations, intravenously Digoxin is 65–80% absorbed after oral administration It widely distributed to tissues, including the central nervous system i.e. large volume of distribution (4 to 7 liters/kg) Almost two thirds is excreted unchanged by the kidney with a clearance rate that is proportional to the glomerular filtration rate/ creatinine clearance

c. Digoxin Pharmacokinetics (digoxine) The elimination half-life for digoxin is 36 to 40 hours in patients with normal or near-normal renal function. The half-life of the drug is increased substantially in patients with advanced renal insufficiency (to approximately 3.5 to 5 days) In patients with CHF and marginal cardiac reserve, an increase in cardiac output and renal blood flow with vasodilator therapy or sympathomimetic agents may increase renal digoxin clearance, necessitating adjustment of daily maintenance doses

c. Digitalis Pharmacokinetics (digoxine) Both the volume of distribution and the clearance rate of the drug are decreased in the elderly. As a result, the drug must be used with caution in patients with renal insufficiency and in the elderly

a. Cardiac glycosides Mechanism of action Regulation of cytosolic calcium concentration All cardiac glycosides are potent and highly selective inhibitors of the active transport of Na+ and K+ (Na+/K+ ATPase) across cell membranes The inhibition of cellular Na+ pump activity results in a reduction in the rate of active Na+ extrusion and a rise in cytosolic Na+ By inhibiting the ability of the myocyte to actively pump Na+ from the cell, cardiac glycosides decrease the Na+ concentration gradient and, consequently, the ability of the Na+/Ca 2+-exchanger to move calcium out of the cell

↑Na+ Ca++ Ca++ 2 Ca++ 3 Na+ 3 Na+ 2 K+ 2 Ca++ 3 Na+ 3 Na+ 2 K+ Ca++ L-Type Calcium Channel ATP 2 Ca++ 3 Na+ 3 Na+ 2 K+ ↑Na+ Ca++ Sarcoplasmic Reticulum Ca++ Ca++ Myofibrils

↑Na+ ↑Ca++ Ca++ 2 Ca++ 3 Na+ 3 Na+ 2 K+ 2 Ca++ 3 Na+ 3 Na+ 2 K+ Ca++ L-Type Calcium Channel ATP 2 Ca++ 3 Na+ 3 Na+ 2 K+ ↑Na+ ↑Ca++ Sarcoplasmic Reticulum Ca++ Ca++ Myofibrils

The most likely mechanism is as: a. Cardiac glycosides Mechanical effect Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free calcium concentration in the vicinity of the contractile proteins during systole The most likely mechanism is as: Glycosides inhibit the Na+/K+ pump Increased Na+ slows extrusion of Ca2+ via the Na+/Ca2+ exchange transporter Increased Ca2+ is stored in the sarcoplasmic reticulum, and thus increases the amount of Ca2+ released by each action potential

a. Cardiac glycosides Mechanical effect Increased myocardial contraction leads to a decrease in end-diastolic volume, thus increasing the efficiency of contraction (increased ejection fraction), and increased renal perfusion The resulting improved circulation leads to reduced sympathetic activity

a. Cardiac glycosides Electrophysiologic Actions Digoxin is a fat-soluble steroid that crosses the BBB and enhances vagal tone: reduction in heart rate, preload, and afterload permit the heart to function more efficiently Because cholinergic innervation is much richer in the atria, these actions affect atrial and AV nodal function more than Purkinje or ventricular function Digoxin decreases automaticity and prolongs the effective refractory period and decreases conduction velocity in AV nodal tissue

a. Cardiac glycosides Electrophysiologic Actions At higher concentrations, resting membrane potential is reduced (made less negative) as a result of inhibition of the sodium pump and reduced intracellular potassium promoting delayed afterdepolarization (DADs)

a. Cardiac glycosides Electrophysiologic Actions When DADs reach threshold, they elicit action potentials (premature depolarizations, ectopic "beats") that are coupled to the preceding normal action potentials At toxic levels, sympathetic outflow is increased that influences cardiac tissue automaticity Together, these decrease the threshold for generation of a propagated action potential and predisposes to malignant ventricular arrhythmias

Effects of Digoxin on Electrical Properties of Cardiac Tissues Tissue or Variable Effects at Therapeutic Dosage Effects at Toxic Dosage Sinus node Decrease rate Atrial muscle Decrease refractory period Decrease refractory period, arrhythmias Atrioventricular node Decrease conduction velocity, increase refractory period Purkinje system, ventricular muscle Slight decrease refractory period Ectopic heartbeats, tachycardia, fibrillation Electrocardiogram Increase PR interval, Decrease QT interval Tachycardia, fibrillation, arrest at extremely high dosage

a. Cardiac glycosides Interactions with Calcium and Magnesium Calcium ion facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular calcium stores that appears to be responsible for digitalis-induced abnormal automaticity Hypercalcemia therefore increases the risk of a digitalis-induced arrhythmia The effects of magnesium ion are opposite to those of calcium

a. Digitalis Clinical uses Digoxin is indicated in patients with heart failure who are in atrial fibrillation, or for patients who diuretics and ACE inhibitors have failed to control symptoms The drug has no net effect on mortality and has never been shown to improve survival Therefore, digoxin is no longer viewed as a first-line agent in the treatment of CHF

a. Digitalis Adverse effects (digitalis toxicity) Digitalis toxicity is one of the most commonly encountered adverse drug reactions The relationship between digoxin toxicity and the serum digoxin level is complex; clinical toxicity results from the interactions between digitalis, various electrolyte abnormalities, and their combined effect on the Na+/K+ ATPase pump

a. Digitalis Adverse effects (digitalis toxicity) Cardiac effects: the common cardiac side effect is arrhythmia, characterized by slowing of AV conduction associated with atrial arrhythmias A decrease in intracellular potassium is the primary predisposing factor in these effects Serum digoxin and potassium levels and the electrocardiogram should always be monitored during therapy of significant digitalis toxicity. Electrolyte status should be corrected if abnormal

a. Digitalis Adverse effects (digitalis toxicity) GIT effects: include anorexia, nausea, vomiting, and diarrhea CNS effects: include headache, fatigue, confusion, blurred vision, alteration of color perception, and halos on dark objects Hyperkalemia: severe digitalis intoxication, primarily in the acute setting, can precipitate hyperkalemia because the inhibition of the Na+,K+-ATPase activity of skeletal muscle

a. Digitalis Adverse effects (digitalis toxicity) Hyperkalemia: Severe digitalis intoxication, primarily in the acute setting, can precipitate hyperkalemia because the inhibition of the Na+,K+-ATPase activity of skeletal muscle

a. Digitalis Factors predisposing to digitalis toxicity Electrolytic disturbances (hypokalemia): Digoxin toxicity is more pronounced in the presence of metabolic and electrolyte disturbances Those patients who develop hypokalemia, hypomagnesaemia, hypercalacemia, alkalosis, hypthyroidism or hypoxia are at particular risk of toxicity A decrease in the intracellular potassium is the primary predisposing factor

a. Digitalis Factors predisposing to digitalis toxicity Electrolytic disturbances (hypokalemia): Reduction of serum potassium levels is most frequently observed in patients receiving thiazide or loop diuretics, and this usually can be prevented by use of a potassium-sparing diuretic or supplementation with potassium chloride

a. Digitalis Factors predisposing to digitalis toxicity Electrolytic disturbances (hypokalemia): The cardiac glycoside binds preferentially to the phosphorylated form of the a subunit of the Na+,K+-ATPase Extracellular K+ promotes dephosphorylation of the enzyme as an initial step in this cation's active translocation into the cytosol, and also thereby decreases the affinity of the enzyme for cardiac glycosides

a. Digitalis Factors predisposing to digitalis toxicity Drugs: Quinidine, verapamil, and amiodarone can cause digoxin intoxication, both by displacing digoxin from tissue protein-binding sites and by competing with digoxin for renal excretion Potassium-depleting diuretics, corticosteroids, and a variety of other drugs can also increase digoxin toxicity

a. Digitalis Management of digitalis toxicity Therapy for toxicity manifested as visual changes or GIT disturbances generally requires no more than reducing the dose of the drug If cardiac arrhythmia is present and can be ascribed to digitalis, serum digoxin and potassium levels and the ECG should always be monitored Treatment to restore serum potassium may be required

a. Digitalis Management of digitalis toxicity Severe digoxin toxicity resulting in ventricular tachycardia may require administration antibodies to digoxin (digoxin immune Fab), which bind and inactivate the drug