Last updated on June 16, 2019 at 19:01
Heart failure is the condition where the heart is unable to supply the body with enough cardiac output. The goal of drug therapy in heart failure is to improve the cardiac function and reduce the symptoms associated with heart failure, like oedema, tachycardia, dyspnoea and fatigue. This can be accomplished pharmacologically in several ways:
- Decreasing preload
- Decreasing afterload
- Increasing inotropy (myocardial contractility)
- Inhibiting excessive compensatory catecholamine effects
Recall from pathophysiology that preload actually increases contractility through the Frank-Starling mechanism. However, that mechanism has a limit – myocardial contractility won’t continue to increase indefinitely as preload increases. There comes a point where increasing the preload actually decreases the contractility, and most heart failure patients are at this point. By this logic will decreasing the preload actually improve the cardiac function in these patients.
Recall also that one of the compensatory mechanisms of heart failure is sympathetic activation. This increases the contractility and heart rate, however the tachycardia may be disturbing to the patient, and the vasoconstriction causes increased afterload. Beta blockers are used in heart failure to prevent the promotion of hypertrophy (which the sympathetic activation promotes) and to decrease afterload and tachycardia.
The myocardial contractility depends on intracellular Ca2+ concentration, O2 concentration, glucose concentration and the availability of ATP. We’ll focus on the Ca2+ concentration.
The following types of drugs are used:
- To increase inotropy – cardiotonic agents like the glycosides
- To decrease preload – venous vasodilators (nitrates), diuretics
- To decrease afterload – arterial vasodilators, ACE or aldosterone inhibitors
- To decrease excessive catecholamine effects – beta blockers
Only the first group will be discussed in this topic. Nitrates are discussed in topic 6, diuretics in topic 3, RAAS inhibitors in topic 2 and so on.
The most important drugs in the treatment of chronic heart failure are ACE inhibitors, loop diuretics, beta blockers, digitalis and nitrates.
The glycosides are substances found in the foxglove plant. The only important one is digoxin. Previously were digitoxin and deslanoside important as well. I’ll focus on digoxin, however the following information probably counts for the others as well. Digoxin has the following effects on the heart:
- Positive inotropy
- Positive bathmotropy (increased excitability)
- Negative chronotropy (decreased heart rate)
- Negative dromotropy (decreased AV conduction)
- Atrial fibrillation or flutter
- As supplementary treatment in chronic heart failure patients that aren’t adequately treated with ACE inhibitors, beta blockers and diuretics
Mechanism of action:
Digoxin has positive inotropic effects, meaning that it increases myocardial contractility. They work by inhibiting the Na+/K+ ATPase, which indirectly increases the intracellular Ca2+ level. It also increases the Ca2+ release from the sarcoplasmic reticulum into the cytoplasm, which also increases IC Ca2+.
The negative chronotropy and dromotropy is beneficial. It occurs due to stimulation of vagal nuclei in the CNS and by direct activation of peripheral vagal nerves. If overdosed however can they lead to bradycardia and AV block.
The positive bathmotropy however is not beneficial. It increases the risk for ventricular extrasystole and even arrhythmias like ventricular tachycardia or ventricular fibrillation.
- Nausea, vomiting, constipation (due to vagal stimulation)
- Headache, confusion, hallucination, disturbance of colour vision
The therapeutic window or index of digoxin is only 1.5, which is very low. This means that the lethal dose is just 50% larger than the therapeutic dose.
Digoxin is orally absorbed. It has 60% plasma protein binding, while digitoxin has 97%. They’re both widely distributed in the body. Digoxin is eliminated by renal excretion while digitoxin is eliminated by hepatic elimination.
Orally or parenterally. The loading dose of digoxin is 1.8mg and 1.2mg for digitoxin. Digoxin has a half-life of 36 hours and digitoxin of 4-5 days, so the maintenance dose for digitoxin is lower than for digoxin.
May occur when there is decreased renal function, decreased serum K+ or increased plasma Ca2+. Drugs like kinidin, verapamil, amiodarone and propafenone increase the plasma concentration of digoxin by displacing it from plasma proteins, by reducing digoxin’s excretion and by releasing digoxin from tissue stores.
Digoxin is contraindicated when there is slow AV conduction, sinus bradycardia, sick sinus syndrome, ventricular extrasystole, WPW syndrome, hypertrophic cardiomyopathy, previous AMI or impaired kidney function
Drugs which increase IC cAMP
The important drugs here are the adrenergic agonists dobutamine and dopamine, and the phosphodiesterase inhibitors amrinone and milrinone.
Dopamine and dobutamine are used in acute heart failures and types of shock where increased inotropy, but not increased blood pressure is needed. This mostly applies to cardiogenic shock.
Amrinone and milrinone are also used for acute decompensated heart failure.
Mechanism of action:
Dobutamine and dopamine are strong β1 agonists, by which they induce a positive inotropic effect. They bind to the β1 adrenergic receptor, which activates adenylyl cyclase, which produces more cAMP. Increased cAMP increases Ca2+ levels, which increases contractility.
Phosphodiesterase inhibitors inhibit PDE, the enzyme which degrades cAMP intracellularly. This indirectly increases IC Ca2+.
The important drug here is levosimendan.
It’s used in acute decompensated heart failure as a supplement where conventional therapy isn’t adequate.
Mechanism of action:
These drugs bind to troponin and makes it more sensitive to Ca2+. This gives equal effect as the increased intracellular Ca2+. They also cause peripheral vasodilation.
Because these drugs don’t cause any change in ion flow, they don’t increase the energy need of the myocardium. This may be beneficial as the myocardial oxygen requirement isn’t increased. They’re also not arrhythmogenic, which is good.
4. Antiarrhythmic drugs
6. Antianginal drugs