CONGESTIVE HEART FAILURE (CHF)

Occurs when ventricular contraction is compromised and the heart cannot meet the demand for blood. First, hypertrophy occurs to compensate for an increased demand upon the heart muscle. Soon, size increase is not matched by coronary circulation increase, and the load demand on the heart does not decrease, so the heart becomes insufficient and heart failure ensues. Clinical features include reduced force of cardiac contraction, reduced cardiac output, reduced tissue perfusion, and edema.


Common diseases which can lead to CHF include cardiomyopathy, ischemia and infarction, hypertension, valve disease, congenital heart disease, and coronary heart disease. These diseases do not automatically lead to CHF—for instance a diagnosis of hypertension could mean many different things…it could be well controlled with no cardiac consequences, the EKG will look normal. On the other hand, a patient could have an abnormal EKG showing left ventricular hypertrophy and still function on a relatively normal basis, but he is on a path of no return towards CHF. So there is a difference between a hypertensive patient with a normal electrocardiogram and one with left ventricular hypertrophy.


At the point in left ventricular hypertrophy in which the heart cannot adequately continue to pump blood, the blood begins to pile up before the left ventricle in the lungs—pulmonary edema. If there is increased resistance to pulmonary blood flow, then the right heart will begin to strain and when it cannot pump the blood you will have a piling up of the blood in circulation leading to edema, swollen ankles, and right heart failure.


You can have viral or autoimmune diseases that can affect the whole heart. In this case you have heart failure not due to overload, but to degenerative disease of the heart. The bottom line is, how can we influence this… to prevent or to treat heart failure? We can sometimes prevent things like hypertension by drugs or lifestyle changes, but what about treating heart failure after it has occurred?


We must look into the internal working of the cells and how they contract. Contraction follows the influx of calcium, which can come from externally and from within the sarcoplasmic reticulum. The muscle will relax when the calcium is gone. So most of the pharmacologic interventions are based on some kind of interference with the calcium regulation mechanism, with the general hope that we can fix this calcium in a favorable way.



During the action potential the voltage dependent channel will give a little bit of calcium influx. This calcium does two things: 1) goes to the internal stores and releases more calcium; 2) goes to the contractile proteins and triggers contraction. We hope that by making more calcium available, the contractile proteins will work faster or longer or stronger, to help with our CHF. How do we get rid of the calcium? There is a pump which actively transports the Ca out of the cell, using ATP. There is another system, which is a sodium/calcium exchanger. This Na/Ca exchanger protein takes advantage of the fact the extracellular Na concentration is higher than the intracellular concentration, when some charge from the sodium is brought into the cell, some calcium is kicked out. These different mechanisms can be influenced by drugs.



One classical drug that has been used for heart failure is Digitalis. The funny thing is, we have found that this drug is not really too good, in fact patients’ life duration is not increased by this drug!! Understand though, digitalis is a very effective drug… but is the effect worthwhile?! Anyway, digitalis is a steroid… there is a sugar and a lactone ring attached. The lactone ring of digitalis is necessary for the cardiac effects, and is what distinguishes it from other steroids.



From the subcellular point of view, we know that the sodium pump is inhibited by digitalis. The sodium pump is that protein that uses ATP to pump Na out and K into the cell. When you inhibit this, there wont be so much sodium outside the cell with respect to inside. Thus, the sodium-calcium exchange will not have so much sodium to take calcium out of the cell—the assumption is that when you inhibit this calcium will be left in the cell for a longer time and hopefully increase the contraction. Increasing the contraction is known as an INOTROPIC effect. Under some conditions, digitalis increases the contraction… but this inotropic effect is also partly due to some diuretic effects which occur at the same time, and to some vagal parasympathetic effects. So these effects are very complex, we will see that digitalis can be used beneficially even in some disturbances of cardiac rhythm. However, there are problems with digitalis because in some cases it increases depolarization, specifically oscillatory pathway depolarization. This will end up giving you ventricular tachycardia.


BETA-1 ADRENORECEPTOR AGONISTS

These drugs, such as dobutamine, are sympathetic agonists and positive inotropes (improve cardiac contractility). Dobutamine works by stimulating the calcium influx through the cell membrane and intracellular storage of calcium by the sarcoplasmic reticulum calcium pump. Using a sympathetic agonist is dangerous because it is also chronotropic (increases heart rate) as well—we don’t want this! So these drugs aren’t given.


PHOSPHODIESTERASE INHIBITORS

These drugs (amrinone, milrinone) inhibit the breakdown of cyclic AMP and therefore improve mechanisms of calcium homeostasis within the cardiac muscle cell.

There are also alternate drugs that are not really inotropes, but since they are not directly increasing the contraction, we’re happy. For instance there’s diuretics. Of course, if you have edema and take a diuretic which reduces fluid the heart is relieved. Another type of drug is an Angiotensin Converting Enzyme Inhibitor (ACE inhibitor), which reduces systemic vascular resistance and induces diuresis with potassium conservation. Also, there are Notrovasodilators, which reduce periferal vascular resistance and increase vascular capacitance, thus reducing cardiac load.



Cardiac drugs all have secondary effects. For instance digitalis causes arrhythmias, and has a narrow therapeutic index. Beta-1 adrenoreceptor agonists cause a fast heart rate and long term deterioration. Diuretics cause electrolyte imbalance and disturbance of cardiac rhythm… for instance diazide takes away too much potassium. In summary, the cardiac drugs are very fickle!

Category: Pharmacology Notes