Lecture 9 Drugs Used in the Treatment of Heart Failure

Pharmacology

Lecture 9 Drugs Used in the Treatment of Heart Failure

1)List drugs used in the treatment of acute and chronic heart failure.

Acute Heart Failure – Diuretics (hydrochlorothiazide, furosemide), Digoxin, and vasodilators including ACE inhibitors (captopril) or hydralazine + isosorbide dinitrate.

Chronic Heart Failure–Diuretics (if signs and symptoms are present), Digoxin, ACE inhibitor (captopril), β-blocker (metoprolol), and Spironolactone.

2)For each drug listed above describe its pharmacodynamic actions and relate these actions to the beneficial action(s) when used in therapy of heart failure.See Table.

3)For each drug listed in 1 describe the serious adverse reactions and contraindications for use. See Table.

4)Indicate which of the drugs listed in 1 reduce morbidity (need for hospitalization) and which confer a survival benefit.

Drug / Pharmacodynamic actions / Benefits in Heart Failure / Adverse reactions / Contra-indications / Reduce morbidity/confer survival benefit
Hydrochlorothiazide / inhibits Na+/Cl- symport in distal convoluted tubule / ↓pulmonary and peripheral edema / Fluid electrolyte imbalance / Hypokalemia / Reduces morbidity
Furosemide / inhibit Na+/K+/2Cl- symporter of the loop of Henle / ↓pulmonary and peripheral edema / Fluid & electrolyte imbalance / Anurea, electrolyte depletion / Reduces morbidity
Digoxin / inhibits membrane Na+/K+-ATPase / Slows HR and increases cardiac output / Cardiac arrhythmia Fatigue, anorexia, nausea and vomiting, altered yellow-green vision and confusion / Hypokalemia ventricular fibrillation / Reduces morbidity
Captopril / Inhibits ACE - ↓ angiotensin II, ↑ bradykinin / Interferes with proliferative actions of angiotensin and aldosterone / HTN w/1st dose, Cough, renal insufficiency, hyperkalemia / Pregnancy Hypotension / Reduces morbidity and confers survival benefit (25%)
Hydralazine + isosorbide dinitrate / ↓TPR, ↓preload, and ↑cardiac contractility / Hypotension,
SLE-like symptoms / β blockers, other vasodilators / Reduces morbidity (39%) and confers survival benefit (43%)
Metoprolol / Cardioselective β1 receptor blockade / ↓sympathetic activation = ↑ejection fraction, contractility, and performance / Depression, worsen CHF and occlusive peripheral vascular disease, bronchospasm / Asthma, COPD, CHF, A-V block / Reduces morbidity (40%) and confers survival benefit (30%)
Spironolactone / antagonist of aldosterone receptors in the distal tubule and collecting duct / ↓Na+, ↑K+, ↑parasympathetic, ↓sympathetic, ↑vascular compliance / Hyperkalemia / NSAIDs, extra K+, ACE-I, and K+ sparing diuretics / Reduces morbidity (30%)

5)Describe the chemistry of Digoxin. Digoxin is a glycoside (sugars with non-sugar entitiy) where the activity resides in a steroid with the attached sugars affecting solubility, potency, and toxicity.

6)List the pharmacodynamic actions of digoxin, including actions on cardiac mechanical function and cardiac electrophysiology. Digoxin increases the force of myocardial contraction, a positive inotropic action seen in normal and failing hearts. Digoxin influences cardiac electrical activity by changing excitability, automaticity, conduction velocity and refractory periods.

7)Describe the biochemical mechanisms of the cellular action of digoxin. At therapeutic concentrations digoxin inhibits membrane Na+/K+-ATPase activity resulting in increased intracellular Na+ with augmented exchange for extracellular Ca2+ and decreased intracellular K+. This increase in intracellular Ca2+ enhances myocardial contractility.

8)Describe the overall benefits of digoxin when used in the management of mild to moderate congestive heart failure associated with sinus rhythm.Digoxin confers the added benefitsof reduced hospitalization and slowed progression to persons with mild to moderate heart failure receiving diuretics and ACE inhibitors. It does not reduce mortality and should therefore only be used to reduce symptoms in patients who do not experience relief with optimal medical treatment including β blockers and ACE inhibitors.

9)Describe the cardiovascular actions of digoxin when it is used to treat atrial fibrillation with a rapid ventricular response.Digoxin slows ventricular rate with associated increase in cardiac output. This is accomplished byvagal stimulation, baroreceptor sensitization and sympathetic withdrawal. These actions combine to prolong the effective refractory period of the A-V node and slow conduction through the node.

10)Characterize the pharmacokinetics of digoxin in terms of absorption, excretion and half-life.The oral bioavailability is 50-80%. Elimination is accomplished by the kidney and dosing should be adjusted according to kidney function tests, i.e. creatinine clearance. The half-life with normal kidney function is 30-36 hours.

11)List the clinical indications for the use of digoxin and describe the benefits of its use in the treatment of chronic heat failure.Therapeutic indications for digoxin use are atrial fibrillation and congestive heart failure. In congestive heart failure the role of digoxin has been controversial, but presently it is thought that in patients with impaired ventricular systolic function and normal sinus rhythm, digoxin improves symptoms and exercise tolerance.

12)Describe the utility and limitations of estimations of the plasma digoxin concentration.Plasma digoxin concentration is not extremely useful because there isn’t a clear value for toxic blood concentration. This is because other factors such as serum K+ concentration, when low, will result in digoxin toxicity at serum digoxin levels that would otherwise be “therapeutic”.

13)Describe the interaction between verapamil and digoxin.Verapamil, a calcium channel blocker, will increase plasma digoxin levels by blocking digoxin uptake into cells. Co-administration with digoxin requires a 50% reduction of digoxin dose. Giving digoxin with verapamil or β blockers, both of which act on the A-V node, may result in a high degree heart block.

14)List the risk factors for digoxin intoxication.Digoxin has a small therapeutic index, is used in high doses to treat fatal disease, has a long half-life, and its therapeutic endpoint is indistinct. Risk factors include the use of K+-wasting diuretics and renal insufficiency (impaired elimination).

15)List the signs and symptoms of digoxin intoxication.The manifestations of digoxin intoxication may be cardiac (arrhythmias of any type) or extracardiac, which include fatigue (probably due to K+ loss), anorexia, nausea and vomiting, altered yellow-green vision and confusion.

16)Describe the management of digoxin intoxication.Treatment of digoxin intoxication requires hospitalization with cardiac monitoring. Potentiating factors should be identified and corrected (renal insufficiency or low serum K+ and Mg2+). When the serum K+ is low intravenous K+ will displace digoxin from its receptor, the Na+/K+-ATPase. There is a digoxin antibody available for treatment of severe intoxications and lidocaine can be used to treat digoxin induced arrhythmias.