3/24/04 Cardiac Inotropic Drugs. 3/24/04 Pathogenesis of congestive heart failure A number of compensatory mechanisms come into play during the development

Cardiac Inotropic Drugs

Pathogenesis of congestive heart failure

A number of compensatory mechanisms come into play during the development of chronic heart failure in the body's attempt to maintain perfusion pressure and increase cardiac output: • Augmented sympathetic activity • Sodium and water retention • Myocardial hypertrophy • Ventricular dilatation


There is an initial lesion which leads to the failure of the myocardium to generate an appropriate velocity of shortening for a given load; this appears to be related to either:

• A lack or loss of contractile tissue (regional dysfunction, as occurs in myocardial infarction)

• An intrinsic defect of the muscle (global dysfunction, as in dilated cardiomyopathy)


As the result of decreased ventricular function, there is a decrease in cardiac output that activates a variety of neuroendocrine adaptive mechanisms which normally come into play in response to shock, dehydration, and exercise:

• Increased sympathetic nervous system activity

• Increased activity of the renin-angiotensin-aldosterone system

• Increased release of arginine-vasopressin


These compensatory mechanisms may paradoxically exacerbate the pathogenesis of CHF by increasing the afterload on the failing heart, leading to a further reduction in ventricular performance

• The vasopressor-sodium retentive mechanisms are offset somewhat by the release of vasodilator-natriuretic substances:

• Atrial natriuretic factor (ANF) • Dopamine • Prostaglandins (PGE2 and PGI2)


• Myocardial hypertrophy which can impair oxygen diffusion due to a decrease in capillary density and increase in distance between capillaries in the myocardium

• Elevation of ventricular end-diastolic pressures and volume (preload), which normally increases myocardial performance via the Frank-Starling mechanism


• In the failing heart the relationship between preload and force production is depressed and flattened

• Increases in end-diastolic pressures in CHF promotes pulmonary and systemic venous congestion and the formation of pulmonary and peripheral edema


• Increasing preload in CHF eventually causes ventricular dilatation, which increases the afterload on the heart

• An increase in systolic wall tension occurs according to the Laplace equation:

Wall tension = Pressure x Ventricular radius

2(Wall thickness)

Changes ("remodeling") of the heart and vasculature in CHF

• Changes in the structure and biochemical properties of the myocardium and peripheral vasculature occur during the development of CHF and these changes can contribute to further impairment of cardiovascular function

remodeling

Myocardial changes : Remodeling

• In addition to hypertrophy, there are also changes in some of the contractile proteins (such as myosin) in the failing heart.

• Changes in the mass, volume, and shape of the left ventricle appear to be critical to further development of heart failure.


• Pressure and volume overload are known to be important determinants in the development of cardiac hypertrophy

• Norepinephrine and angiotensin are both elevated in the plasma of patients with heart failure and have been implicated in stimulating ventricular hypertrophy


• Renal sodium and water retention may increase the rate of ventricular remodeling by increasing end-diastolic volume and wall tension

• Systemic vasoconstriction increases afterload, causing progressive hypertrophy and dilatation


• Indications that remodeling of the ventricles is an important aspect of heart failure pathogenesis is indicated by several studies: • Following anterior myocardial infarction, left ventricular

end-diastolic volume is a better predictor of subsequent mortality than the extent of coronary disease

• Distortion of the normal ellipsoid shape of the left ventricle to a shape that is more spherical correlates with the degree of reactive hypertrophy following transmural infarction

• Patients with the most severely distorted left ventricles after anterior infarctions demonstrate the poorest functional class and are at the greatest risk for developing CHF


• Reactive hypertrophy and ventricular dilatation following acute myocardial infarction can be reduced by captopril (an ACE inhibitor). This may improve exercise tolerance and long-term survival

• It is not yet clear whether captopril is acting just through a non-specific effect on load, or also through a reduction in the plasma concentration of the putative trophic factor, angiotensin II.


• Changes in guanine nucleotide regulatory proteins (G proteins) have also been noted in the failing human heart.

• There appears to be an "uncoupling" of myocardial beta-receptors from Gs in some forms of heart failure


• There also appears to be an increase in Gi in dilated cardiomyopathy which inhibits myocardial adenyl cyclase and is known to be coupled to the adenosine (A1) receptor

• Blocking the adenosine (A1) receptor with pharmacologic antagonists may therefore improve cardiac contractility in the failing heart

• Captopril, an ACE inhibitor that is commonly used to treat heart failure, has been shown to increase lymphocyte Gs and increase myocardial beta-1 receptor density

Peripheral vasculature: Remodeling

• The relative contribution of changes in caliber and distensibility of the arterial vasculature in relation to the pathogenesis of CHF is poorly understood, but may have important therapeutic implications in the treatment of CHF

• In addition to the load (preload and afterload) placed on the failing heart by increases in vascular tone and ventricular dilatation, long-term remodeling of the vasculature could result in changes in vascular compliance.

Peripheral vasculature: Remodeling

• Since the impedance load on the heart is related to vascular resistance as well as the distensibility of the vasculature, loss of arterial compliance could cause considerable reduction in left ventricular stroke volume, particularly in the case of the failing heart seeing a high afterload.

• Development of future pharmacologic agents for the treatment of CHF may therefore attempt to minimize vascular remodeling and employ vasodilators that maximize vascular compliance.

Pharmacology of inotropic drugs

Digitalis (cardiac glycosides): • Digitalis has been used clinically for over 200 years

to treat heart failure and edema (dropsy), but its present use in treating CHF is controversial

• Cardiac glycosides inhibit the Na+/K+ ATPase pump, which increases intracellular Na+, slowing the rate of the Na+/Ca++ exchanger, and thereby causing an increase in intracellular Ca++

• Although widely used, digitalis is associated with an appreciable risk of toxicity and many patients do not derive any benefit!

• Digoxin is the most widely used preparation of digitalis (half-life = 1-2 days), although digitoxin (half-life = 7 days) is also used in situations where long half-life may be an advantage.

Digitalis (cardiac glycosides):

• It is possible that digitalis may be effective in decreasing the rate of progression of cardiac damage in some patients, particularly those where a progressive increase in end-diastolic pressure and volume will occur.

• There is recent evidence that digitalis may act directly to blunt baroreceptor response and thereby have beneficial effects through reduction of sympathetic tone.

Beta-Adrenergic agonists

1-adrenergic agonists (dopamine, dobutamine, prenalterol, xamoterol) have been used to treat acute and chronic heart failure, but have limited usefulness in chronic CHF because of their:• arrhythmogenic effects, • short duration of action, • the development of tolerance, and • necessity of parenteral administration.


Dopamine (i.v.) is used in acute heart failure to increase blood pressure and increase cardiac output:

• Short duration of action • At high doses dopamine has potent peripheral

vasoconstrictor effects (-receptor stimulation) in addition to its inotropic effects.

• Low dose dopamine has a renal artery dilating effect and may improve sodium and water excretion in patients refractory to loop diuretics.

• When systolic pressure is greater than 90 mm Hg, nitroprusside can be added to reduce ventricular filling pressure and reduce afterload.

Dopamine

• MechanismEndogenous catecholamine that stimulates D1, 1, and 2 (D > > ).

• D1: renal and splanchnic vasodilation. 1: (Gs increased cAMP) leading to increased HR and inotropy.2: (Gs increased cAMP) leading to smooth muscle relaxation: bronchial, vascular (including the coronary arteries), and uterine.1: (PIP2 cascade) with vascular smooth muscle contraction (increased SVR), pupillary dilator muscle contraction (mydriasis), and pilomotor contraction.

DopamineClinical • Enhances natriuresis in patients with poor renal

perfusion (although does not prevent or treat renal failure per se; it merely increases renal blood flow and hence facilitates natriuresis).

• Treatment of decompensated congestive heart failure, especially when associated with hypotension and poor renal perfusion.

DopamineDosage:0.5 - 2g/kg/min = vasodilation renal,

mesenteric, coronary, cerebral arterioles

2-10 g/kg/min = inotropic effects via the 1

5-20 g/kg/min = peripheral vasoconstriction via the

Dopamine

Side Effects:• Arrhythmias.

Metabolism:• Action terminated by reuptake into

presynaptic nerve terminal. • Also inactivated by COMT and MAO

enzymes.


Dobutamine is a moderately selective 1-adrenergic agonist that lacks vasoconstrictor activity and causes minimal changes in heart rate

• It is frequently added to nitroprusside when blood pressure is adequate to increase cardiac output

• It is administered as an i.v. infusion to treat acute severe heart failure

• It has a short half-life (2.4 min) and is only used on a short-term basis, although long-term beneficial effects on cardiac function have been noted

• After 72 hours of therapy, tolerance can develop • Dobutamine can enhance AV conduction and worsen

atrial tachycardias.

Dobutamine

Mechanism

Synthetic analog of dopamine that stimulates 1-adrenoceptors and to a lesser extent 2- and 1-adrenoceptors.

1,: (Gs increases cAMP) leading to increased HR and inotropy.

2: (Gs increases cAMP) leading to smooth muscle relaxation: bronchial, vascular (including the coronary arteries), and uterine.

Dobutamine

Mechanism • A minor effect may be through the 1 (PIP2

cascade) which causes vascular smooth muscle contraction (increased SVR), pupillary dilator muscle contraction (mydriasis), and pilomotor contraction.

• The net effect is increased cardiac contractility, increased HR and therefore increased CO.

Dobutamine

• Tends to decreased SVR but overall effect on BP is variable and depends on balance between increased CO and decreased SVR.

• Despite causing increased HR, dobutamine can actually decreases myocardial oxygen demand by increased inotropy and decreased SVR.

Dobutamine

Clinical

• Short-term management of decompensated congestive heart failure.

• After -1 week of continuous therapy, down-regulation of receptors decrease in efficacy of drug.

Dobutamine

Side Effects:

• Arrhythmias. Possible hypotension.Contraindications. Hypotension. Hypertrophic cardiomyopathy (worsens outflow tract obstruction).

Metabolism

• Inactivated by COMT and MAO enzymes.

Cyclic nucleotide phosphodiesterase

(PDE-III, cGMP-inhibitable PDE) inhibitors:

(PDE-III, cGMP-inhibitable PDE) inhibitors

• There are several agents that increase myocardial and vascular smooth muscle cAMP through inhibition of cyclic nucleotide phosphodiesterase PDE-III, cGI PDE) activity.

• These agents should therefore simultaneously increase cardiac output and reduce afterload.


• The bipyridines, amrinone and milrinone, are potent PDE-III inhibitors that can be given orally or parenterally

• They can be given orally, are generally well-tolerated, but can have significant non-cardiac side-effects (nausea, vomiting, thrombocytopenia)

• Duration of action is several hours in patients with CHF.


• Amrinone, the prototype, is approved for use in the U.S. for short-term management of CHF patients who have not responded to digitalis, diuretics or vasodilators


• Milrinone has positive inotropic and vasodilator effects and is being used on an investigational basis.

• A recent clinical trial (1989) indicated that milrinone was less effective and more arrhythmogenic than digoxin in patients with moderately severe CHF. Furthermore, the combination of digoxin and milrinone was no more effective than digoxin alone

Milrinone (Primacor)

Mechanism • A bipyridine compound that inhibits

phosphodiesterase (PDE) III, which is found in cardiac and smooth muscle.

• PDE III inactivates cAMP, therefore PDE III inhibitors increase cAMP via decreasing degradation.

• In the myocardium this leads to and increase in Ca2+ influx and an increase in cardiac contractility.


Mechanism • In the vascular smooth muscle this leads

to myosin light-chain phosphorylation and inactivation leading to smooth muscle relaxation and peripheral vasodilation.

• Milrinone's cAMP-mediated effects on vascular smooth muscle are analogous to albuterol's cAMP-mediated effect on bronchial smooth muscle.

Milrinone (Primacor)Clinical • Treatment of heart failure: increases inotropy and

decreases afterload thereby increases CO and decreases pulmonary capillary wedge pressure.

• Given its serious side effect profile, use of milrinone is generally restricted to patients with refractory CHF who have failed to respond to vasodilators, diuretics, and digoxin.

• In fact, chronic use of oral PDE III inhibitors in patients with heart failure has been shown to increase mortality.


Side Effects:

• Potentially life-threatening ventricular arrhythmias, Hypotension, hepatotoxicity, and thrombocytopenia.


• AMRINONE (Inocor) is a less potent PDE III inhibitor with a greater rate of side effects.

• CILOSTAZOL (Pletal) is an oral PDE III inhibitor that mainly causes peripheral vasodilation and is used to treat claudication

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3/24/04 Cardiac Inotropic Drugs. 3/24/04 Pathogenesis of congestive heart failure A number of compensatory mechanisms come into play during the development