Drugs Used in Heart Failure Flashcards
Pathophysiology of Cardiac Performance
Preload, Afterload, Contractility, and Heart Rate
Cardiac performance is a function of four primary factors:
(1) Preload can be defined as the force stretching the ventricles. Preload is usually increased in HF because of increased blood volume and venous tone. According to the Frank-Starling phenomenon the force of contraction of myocardial cells depends on the length that they are stretched. Therefore, an increase in ventricle stretching (due to the increase in preload) will result in an increased force of contraction. However, preload can be too high! Preloads greater than 20-25 mmHg result in pulmonary congestion due to volume overload. At this point increasing preload results in a decrease in stroke volume.
(2) Afterload can be defined as the force which ventricles must act against. Afterload is dependent on vascular resistance. As cardiac output falls in HF, a compensatory increase in vascular resistance occurs (see below).
(3) Contractility. Even in chronic HF, positive inotropic agents are capable of producing some increase in contractility.
(4) Heart rate. As the heart fails and stroke volume diminishes, an increase in heart occurs due to sympathetic activation of B1-adrenoceptors.
Pathophysiology of Heart Failure
Chronic heart failure is a long-term condition (months/years) that is associated with the heart undergoing adaptive responses (e.g., dilation, hypertrophy) in order to try and maintain cardiac output.
Cardiac Remodeling
In response to a sustained decrease in cardiac output, myocardial hypertrophy occurs. This increase in muscle mass helps maintain cardiac performance. However, after an initial beneficial effect, hypertrophy can lead to ischemic changes, impairment of diastolic filling, and alterations in ventricular geometry. Remodeling is the term applied to dilation and other slow changes that occur in the stressed myocardium.
The reduction in cardiac output associated with heart failure also precipitates changes in systemic and pulmonary vascular function, and renal function. These changes occur as the result of venous pooling of blood, reduced organ perfusion, and activation of neurohumoral compensatory mechanisms.
Neurohumoral Compensatory Responses that occur during HF
Neurohumoral compensation involves two major mechanisms: the sympathetic nervous system and the renin-angiotensin-aldosterone system. In addition, there is increased release of both antidiuretic hormone (ADH) and atrial natriuretic peptide (ANP).
Inotropy, Chronotropy, Dromotropy and Lusitropy
(1) Positive inotropy can be defined as an increase in cardiac contractility (ie. force).
(2) Positive chronotropy can be defined as an increase in heart rate.
(3) Positive dromotropy can be defined as an increase in conduction velocity.
(4) Positive lusitropy can be defined as an increase in rate of relaxation.
Therapy of Systolic vs. Diastolic Heart Failure
The treatment of heart failure caused by systolic failure follows clear clinical guidelines based upon numerous clinical trials. Diastolic failure, however, is more difficult to treat and there is no clear consensus regarding the best therapeutic options other than targeting clinical symptoms related to fluid retention.
Systolic Failure
This form of failure results from a loss of intrinsic contractility and is generally associated with a dilated ventricle. A decrease in stroke volume coupled to an increase in ventricular end-diastolic volume leads to a significant reduction in ejection fraction. Subsequently, preload is increased due to compensatory increases in blood volume. The ideal drug therapy would thus lead to an increase in stroke volume and reductions in both preload and afterload.
Diastolic Failure
This type of ventricular failure is related to impaired ventricular filling caused by hypertrophied (less compliant) ventricles or by impaired ventricular relaxation.
Diuretics can be used to treat any resulting pulmonary edema; however removing too much volume can significantly reduce end-diastolic volume and therefore stroke volume in these stiff ventricles, so they must be used cautiously. Calcium channel blockers have shown to be beneficial in the treatment of diastolic failure. These drugs are contraindicated in systolic failure because they reduce inotropy and stroke volume, but inotropy may be normal in diastolic dysfunction so these drugs do not seriously impair stroke volume in these patients. Calcium-channel blockers seem to have their benefit by improving ventricular relaxation and reducing heart rate (which permits more time for filling). -blockers have also shown to be effective and have similar beneficial effects to calcium-channel blockers. Positive inotropes are not used for the treatment of diastolic failure due to the fact that increasing inotropy can lead to increased outflow obstruction.
Diuretics
Clinical Applications
Diuretic therapy is recommended in all HF patients with evidence of fluid retention. However, because they do not alter disease progression or prolong survival, they are not considered mandatory for patients without fluid retention.
Thiazide diuretics (eg, hydrochlorothiazide) are relatively weak diuretics and are used alone infrequently in HF. Thiazides may be preferred over loop diuretics in patients with only mild fluid retention and elevated blood pressure because of their more persistent antihypertensive effects.
Loop diuretics (eg, furosemide) are usually necessary to restore and maintain euvolemia in HF. Unlike thiazides, loop diuretics maintain their effectiveness in the presence of impaired renal function.
Aldosterone antagonists (eg, spironolactone). The diuretic effects of aldosterone antagonists are minimal and are instead used for their other beneficial effects eg, attenuation of cardiac fibrosis and remodeling. They have been shown to decrease mortality and morbidity when combined with ACEI and other standard therapy. Recent evidence also suggests an important role in reducing the systemic proinflammatory state and oxidative stress caused by aldosterone.
Mechanism of Action
For details on individual mechanisms of action of diuretics see ‘Diuretics’ lecture notes.
The primary use for diuretics in heart failure is to reduce pulmonary and/or systemic congestion and edema, and associated clinical symptoms (e.g., dyspnea). They reduce venous pressure and ventricular preload. The reduction in preload does not significantly reduce cardiac output due to the Frank-Starling curve in systolic dysfunction being relatively flat.
Adverse Effects
For details on individual adverse effects of diuretics see ‘Diuretics’ lecture notes.
Inhibitors of Angiotensin
ACE Inhibitors
Studies demonstrate that ACE inhibitors improve symptoms, decrease incidence of hospitalization and MI, and prolong survival in patients with HF and reduced LVEF (Stage C). These patients should receive ACE inhibitors unless contraindications are present. ACE inhibitors should also be used to prevent the development of HF in at-risk patients (Stages A and B).
By reducing peripheral resistance, ACE inhibitors are able to reduce afterload; they also reduce Na+ and H20 retention (by reducing aldosterone secretion) and therefore decrease preload. ACE inhibitors also have been shown to reduce sympathetic activity (by inhibiting norepinephrine release) and the long-term remodeling of the heart and vessels.
ARBS
Although, data suggests that long-term therapy with ARBs reduces the risk of death, MI and other CV events in a comparable manner to ACE inhibitors, the ACC/AHA guidelines recommend use of ARBs only in patients with Stage A, B, or C heart failure who are intolerant of ACE inhibitors. Some trials have demonstrated added benefit when candesartan is added to an ACE inhibitor; however there is also an increased risk of adverse effects.
In contrast, the Cochrane review in 2012 found that ARBs were no better than placebo or ACE inhibitors in reducing the risk of death, disability, or hospital admission for any reason. In addition, adding an ARB to an ACEI did not reduce the risk of death, disability, or hospital admission for any reason as compared to ACEI alone, although more patients taking the combination stopped early due to side effects.
In summary, addition of an ARB may still be considered in patients who remain symptomatic despite receiving optimal conventional therapy.
Candesartan and valsartan are the only ARBs currently approved by FDA for treatment of HF.
Renin Inhibitors
Aliskiren, a renin inhibitor recently approved for hypertension, is in clinical trials for heart failure. Preliminary results suggest an efficacy similar to that of ACE inhibitors.
Mechanism of Action & Adverse Effects
For details on individual mechanisms of action and adverse effects of ‘Inhibitors of Angiotensin’ see ‘Antihypertensive’ lecture notes.
Isosorbide Dinitrate
Direct Vasodilators
Hydralazine AND Isosorbide Dinitrate
Clinical Applications
Concurrent use of two oral vasodilators: hydralazine and isosorbide dinitrate has been shown to produce sustained improvement in LVEF. In particular, mortality, hospitalizations and quality of life is improved in African Americans who receive these vasodilators along with standard therapy.
Current guidelines recommend adding hydralazine and isosorbide dinitrate as part of standard therapy in African Americans with moderately severe to severe HF. The drugs may also be reasonable for patients of other ethnicities with persistent symptoms despite optimized therapy with an ACE inhibitor/ARB and -blocker. In addition, they can also be used as first-line therapy in patients unable to tolerate ACE inhibitors or ARBs due to renal insufficiency or hyperkalemia. They are usually given along with a diuretic and -blocker to counteract side effects.
Mechanism of Action
Isosorbide dinitrate and hydralazine were combined originally because of their complementary hemodynamic actions. Nitrates are primarily venodilators, thus produce reductions in preload. Hydralazine is a vasodilator that acts primarily on arterial smooth muscle to reduce peripheral vascular resistance and increase stroke volume and cardiac output. Some evidence suggests that combination therapy can also reduce cardiac remodeling.
For further details on individual mechanisms of action and adverse effects of ‘Oral Vasodilators’ see ‘Antihypertensive’ lecture notes
Pharmacokinetics
A fixed-dose combination product is available in the US containing both hydralazine and isosorbide dinitrate. Patients need to be dosed 3-times daily.
Adverse Effects – Combination Therapy
Hypotension
Reflex tachycardia and Na+ & H20 retention
Headache, dizziness, GI disturbances.
Carvedilol and Metoprolol
Clinical Applications
B-blockers are used in the treatment of hypertension, angina, myocardial infarction, arrhythmias and heart failure.
Heart Failure: There is overwhelming evidence that certain B-blockers slow disease progression, decrease hospitalizations, and reduce mortality in patients with HF, despite the fact these drugs can precipitate acute decompensation of cardiac function.
The ACC/AHA guidelines recommend use of -blockers in all stable patients with HF and a reduced LVEF in the absence of contraindications or a clear history of B-blocker intolerance. Patients should receive a -blocker even if symptoms are mild or well- controlled with ACE inhibitor and diuretic therapy. B-blockers are also recommended for asymptomatic patients with a reduced LVEF (Stage B) to decrease the risk of progression to HF.
Diastolic Failure: B-blockers have a number of beneficial effects in the treatment of diastolic heart failure, including slowing the heart rate, reducing myocardial oxygen demand and reducing blood pressure.
Mechanism of Action
A full understanding of the beneficial effects of B-blockers in HF is lacking but may result from antiarrhythmic effects, slowing or reversing ventricular remodeling, improving LV systolic function, decreasing heart rate and ventricular wall stress and thereby reducing myocardial oxygen demand, and inhibiting plasma renin release. These effects are largely due to -blockers blocking excessive, chronic sympathetic influences on the heart, which are known to be harmful to the failing heart.
Because of their negative inotropic effects, B-blockers should be started in very low doses with slow upward titration to avoid symptomatic worsening or acute decompensation.
Adverse Effects
Drug withdrawal: Abrupt cessation of -blocker therapy may produce unstable angina, MI or even death in patients with coronary disease.
Cardiovascular effects: Bradycardia, reduced exercise capacity, heart failure, hypotension, AV block. Considerable care needs to be exercised if a B-blocker is given in conjunction with cardiac selective calcium-channel blockers (e.g., verapamil) because of their additive negative inotropic effects.
Disturbed lipid metabolism
Hypoglycemia Bronchoconstriction
CNS effects
Contraindications
Reactive airway disease (asthma, COPD): Non-selective B-blockers (propranolol) should be avoided.
Patients with sinus bradycardia and partial AV block: Symptoms will be exacerbated by B-blocking effects
Digoxin
Clinical Applications
Cardiac Glycosides
Digoxin: Derived from digitalis (foxglove) plant
Clinical Applications
Digoxin has been shown to decrease the symptoms of HF, increase exercise tolerance and decrease rate of hospitalization. However, it DOES NOT INCREASE SURVIVAL.
Digoxin is indicated in patients with HF and supraventricular tachyarrhythmias such as atrial fibrillation, it should be considered early in therapy to help control ventricular response rate.
For patients in normal sinus rhythm, effects on symptom reduction and quality-of-life improvement are evident in patients with mild to severe HF. Therefore it should be used together with standard HF therapies in patients with symptomatic HF to reduce hospitalizations.
Digoxin Mechanism of Action
Mechanism of Action
The beneficial effects of digoxin in the treatment of HF have been attributed to its positive inotropic effect on failing myocardium and efficacy in controlling the ventricular rate response to atrial fibrillation. Autonomic nervous system activity is also modulated and contributes substantially to digoxin’s efficacy in the management of HF.
Digoxin is both positively inotropic (increases contractility of heart) and negatively chronotropic (decreases heart rate).
Positive Inotropic Effect
Digoxin is a selective and potent inhibitor of the cellular Na+/K+-ATPase.
An increase in intracellular calcium is required for cardiac muscle cells to contract. This occurs by Ca2+ entering the myocyte via voltage-sensitive Ca2+ channels during depolarization which triggers Ca2+-induced Ca2+ release from Ca2+ stores.
For cardiac muscle to relax, intracellular calcium has to decline. This occurs during repolarization by intracellular Ca2+ being re-sequestered by the sarcoplasmic reticulum together with removal from the cell via the Na+-Ca2+ exchanger. The capacity of the exchanger to remove Ca2+ from the cell depends on the intracellular Na+ concentration. Digoxin, by inhibiting the Na+,K+ ATPase causes a rise in cytosolic Na+. This increase in Na+ reduces the transmembrane gradient that drives Ca2+ exit during repolarization. Thus, the net effect of digoxin is Ca2+ accumulation in the myocyte. Increased Ca2+ causes more Ca2+ to be released during Ca2+-induced Ca2+ release which leads to an increase in contractility.
Inhibition of the Na+/K+-ATPase in vascular smooth muscle causes depolarization, which causes smooth muscle contraction and vasoconstriction.
Digoxin binds preferentially to the phosphorylated form of the subunit of the Na+,K+- ATPase. Extracellular K+ promotes dephosphorylation of the enzyme and thereby decreases the affinity of the enzyme for digoxin.
Electrophysiological Actions
At therapeutic concentrations, digoxin decreases automaticity and increases maximal diastolic resting membrane potential in atrial and AV nodal tissues, due to an increase in vagal tone and a subsequent decrease in SNS activity. In addition, there is prolongation of the effective refractory period and decreased conduction velocity in AV nodal tissue.
At higher concentrations, digoxin can increase SNS activity and directly affect automaticity in cardiac tissue, actions that contribute to the genesis of atrial and ventricular arrhythmias.
Baroreceptor Sensitization
Digoxin has been shown to cause baroreceptor sensitization. This offsets baroreceptor desensitization that is present in heart failure, which contributes to sustained elevation of plasma norepinephrine, renin etc.
Pharmacokinetics of Digoxin
Pharmacokinetics
Determining the optimal level of digoxin may be difficult due to its narrow therapeutic window.
Half-life is 36-40 h in patients with normal renal function thus permits once-daily dosing.
Digoxin has a large volume of distribution (distribution phase 6-8 h). Pharmacologic effects are delayed and do not correlate well with serum concentrations during the distribution phase. Loading dose is required if acute digitalization is required.
Digoxin is excreted by the kidney and the half-life is increased substantially in patients with advanced renal disease and the elderly, therefore must be used with caution.
Adverse Effects of Digoxin
Adverse Effects
Due to its narrow therapeutic window, digoxin toxicity is one of the most common adverse drug reactions.
Cardiac Effects: The major side effect of digoxin compounds is cardiac arrhythmias, especially atrial tachycardias and atrioventricular block.
GI Effects: Anorexia, nausea and vomiting
CNS Effects: Headache, fatigue, confusion, blurred or yellow vision, alteration of color perception, halo on dark objects
Interactions with K+, Ca2+ and Mg2+
Because potassium decreases the affinity of the Na+/K+-ATPase for digoxin, hypokalemia results in increased digoxin binding and thereby enhances therapeutic and toxic effects of digoxin. Hyperkalemia has the opposite effect and reduces digoxin toxicity.
Hypercalcemia enhances digoxin-induced increases in intracellular Ca2+, which can lead to overloading of Ca2+ stores and increased susceptibility to digoxin-induced arrhythmias.
Hypomagnesemia sensitizes the heart to digoxin-induced arrhythmias. (Mg2+ antagonizes the the effects of Calcium)
Drug and Disease Interactions and Contraindications of Digoxin
Drug & Disease Interactions
Quinidine (class I antiarrhythmic), amiodarone (class III antiarrhythmic), verapamil and NSAIDs compete with digoxin for binding sites and depress renal clearance of digoxin.
Diuretics can indirectly interact with digoxin because of their potential for decreasing plasma potassium levels.
Hypothyroidism – use with caution as higher digoxin concentrations may result.
Hyperthyroidism – due to decreased absorption digoxin concentrations may be lower.
Renal failure – digoxin levels must be closely monitored. Dosage adjustments may be required.
CONTRAINDICATIONS
- in patients with diastolic or right-sided HF (can lead to outflow obstruction)
- in the presence of uncontrolled hypertension
- in the presence of bradyarrhythmias
- in non-responders or intolerance
- in patients who are hypokalemic
TREATMENT OF DIGOXIN TOXICITY
In the case of digoxin toxicity the following actions should be taken:
Withdraw drug (if possible) or lower dose
Adjust electrolyte status (K+, Ca2+, Mg2+)
Treat ventricular tachyarrhythmia’s with lidocaine and/or Mg2+
If toxicity is severe treat with digitalis antibodies (Digoxine immune fab or digibind) which bind and inactivate the drug.
Inamrinone and Milrinone
Inotropic Agents Used in Acute Cardiac Failure
Phosphodiesterase (PDE) III Inhibitors
Clinical Applications
PDE III inhibitors are used for short-term therapy in patients with intractable heart failure.
Long term therapy with PDE inhibitors has been shown to increase mortality.
Mechanism of Action
Both inamrinone and milrinone inhibit myocardial PDE activity, resulting in an increase in cAMP levels. Increased cAMP produces positive inotropic and arterial and venous vasodilating effects.
Pharmacokinetics
Both agents are given IV for short-term therapy.
Adverse Effects
Arrhythmia
Hypotension
THROMBOCYTOPENIA: This occurs rarely and is more common with inamrinone than milrinone.
Dopamine
Dopamine
Clinical Applications
Used in the treatment of shock (eg, MI, open heart surgery, renal failure, cardiac decompensation) which persists after adequate fluid volume replacement.
Mechanism of Action
Dopamine is a dose-dependent dopaminergic (D1) and adrenergic agonist (1, 1, 2). At low doses mainly D1 mediated vasodilation occurs; as doses increase positive inotropic effects mediated primarily by 1 receptors become prominent. At high doses, chronotropic and 1-mediated vasoconstricting effects become more prominent.
In addition at low doses, dopamine induces natriuresis and has a diuretic effect, potentially increasing urine output from 5 ml/kg/hr to 10 ml/kg/hr.
NB. Dopamine also causes release of norepinephrine from nerve terminal, which contributes to its effects on the heart.
Dopamine is useful in shock due to it raising blood pressure by stimulating the heart and increasing blood flow to the kidneys (vasodilation).
Adverse Effects
A major side effect of dopamine is cardiac arrhythmia.
Especially at higher doses, dopamine’s effects can increase myocardial oxygen demand and potentially decrease myocardial blood flow, worsening ischemia in some patients with coronary artery disease.
Dobutamine
Clinical Applications
Used to increase cardiac output in the acute management of heart failure (cardiogenic shock, MI).
Mechanism of Action
Dobutamine is administered as a racemic mixture. The (-) isomer is an Alpha1-receptor agonist and a weak B1 agonist. The (+) isomer is an Alpha1-antagonist, a potent B1 agonist and a mild B2 agonist.
At therapeutic levels the stimulation of B1-receptors predominate, leading to a potent inotropic effect (with little change in heart rate). The net vascular effect is usually vasodilation (B2-receptors).
Dobutamine is able to increase cardiac output without significantly elevating the oxygen demands of the myocardium. This is a major advantage over other sympathetic drugs.
Adverse Effects
Dobutamine is less arrhythmogenic than dopamine.
