Beta Blockers – Cardiovascular Pharmacology

00:01 So, let’s start talking then about the drugs. The first class of drugs that I am going to talk about are so-called “beta blockers.” What do I mean by a “blocker”? What’s a blocker? Well, it turns out that on the surface of heart cells, as well as other cells in the body, there are little, let’s call them “keyholes”, in which certain keys are fit which then result in changes going on within the cell. So, let me tell you one example. One example… example would be adrenaline. Adrenaline is released from nerve endings and it’s released from the adrenal glands. We are going to talk about that system in just a moment. But, it’s important to realize that when adrenaline plugs into the keyhole, into the receptor on the cell membrane, it results in a number of biochemical changes within that cell. And those biochemical changes are not just restricted to heart cells, but throughout the body, and of course, that can lead to the side effects or the complications that we just talked about. So, why are beta blockers useful? Beta blockers are useful because they decrease heart rate, they decrease blood pressure and they decrease heart contractility. And you are going to see, what they do is they block some of the actions of the autonomic nervous system. Beta blockers were discovered by this man, Dr. James Black, who was a chemist with Imperial Chemistry Company in England in the 1960s.

01:36 And by the way, for discovering beta blockers, he won the Nobel Prize in 1988.

01:43 So, what was the reason for developing beta blockers? Well, I think most of you are aware is that our entire circulatory system, our digestive system, many of the organs in the body are controlled by the brain. And one of the ways that the brain controls things is through something called the “autonomic nervous system.” I like to call it the “automatic nervous system.” It has two parts - a sort of an accelerator system and a brake system.

02:13 The accelerator system, also called the “flight-or-fight system”, is the sympathetic nervous system.

02:19 That’s the one that squeezes out adrenaline when you are in a near car accident or when you are threatened by somebody. It revs up your blood pressure, it revs up your energy; you are ready to flight or fight. Now, the opposite effect occurs from the parasympathetic nervous system. That’s when you eat a meal and you feel a little sleepy and you lie back and you relax. That nervous system increases the digestive activities, which of course, are the exact opposite of what you would want if you were flying or fighting. You would want to be revved up, not lying back, relaxing and digesting. And these two nervous systems interact constantly depending upon what you are doing. If you are vigorously exercising, you are going to be turning on the sympathetic nervous system. If you are relaxing after eating a large meal, you are going to be turning off the sympathetic nervous system and turning on the parasympathetic nervous system. The parasympathetic nervous system is also run through a very large nerve that runs throughout the body called the “vagus nerve”. And sometimes, it will actually activate at a time where it drops blood pressure and even can cause people to feel lightheaded or faint. That’s a little excessive activity by the parasympathetic nervous system. Now, the excess activity on the part of the vagus system or the parasympathetic system can slow the heart. It can decrease the blood pressure and it basically sets you up for what we call a “vegetative state”, that is for a digestive resting state. The sympathetic nervous system, of course, does the opposite.

04:01 It revs you up, ready to fight or to flee depending upon the circumstances. Raises your blood pressure, increases your heart rate, increases the pumping activity of the heart and starts putting a lot more blood flow into the muscles to get you ready to run away.

04:17 So, what do beta blockers do? Beta blockers block the effect of the sympathetic nervous system so that you can’t increase your heart rate so much, you can’t increase your contractility, you can't increase your blood pressure. Why would that work in a patient with ischemic heart disease, a patient with coronary artery disease? Of course. Remember, we talked about the imbalance between the demand on the heart in terms of metabolic supply and the supply, because of a blocked artery, there’s decreased supply. So, what beta blockers do is by decreasing the metabolic demand of the heart, they reestablish the balance between cardiac demand and cardiac nutritional supply - oxygen and nutrients. They plug into the little receptors in the heart that speed up the heart and when they do that, they stop adrenaline from getting into those receptors and therefore, the heart rate doesn’t increase, even though the sympathetic nervous system is pushing. Now, it turns out that there have been three levels or three classes of beta blockers. There are ones that are a little more specific for the heart.

05:31 There are some that are a little less specific for the heart, but more specific for the lung.

05:37 There are some that are a mixture of heart and lung and then there are some that are either a mixture for heart and lung, but also dilate blood vessels and therefore, even accentuate the drop in blood pressure. The first group, β-1 receptor blockers are used for angina and particularly also, for patients with heart failure. Again, we are trying to assist the heart a little bit by not making such high demands on it. The β-2 receptor blockers are used in a variety of ways also, sometimes for heart disease, sometimes for arrhythmias and sometimes for hypertension. And the β-3 group, the most recent ones, are used for heart failure patients. Again, they decrease the contractility of the heart, they decrease the blood pressure, they decrease the work of the heart so that a damaged heart can heal a little bit. We are going to talk about that some more in a moment.

06:33 I don’t expect you to read and memorize this list, but here it shows you all of the actions of the β-1 and the β-2 blockers. As you can see, they have actions throughout the body - on blood vessels, on the heart, on the lungs. And of course, what this means is, it gives you potential for complications. Let’s say we have a patient with high blood pressure and angina - that is the feeling of chest discomfort when there’s an imbalance between blood supply and blood demand. We put the patient on beta blocker. But, we forgot the patient has a history of asthma in the past. When we block the β-2 in the lung, we make their asthma worse. So, we did something good for the heart, but we did something bad for the lungs. So again, this list shows you all the different effects of beta blockers throughout the body and a lot of them are potential sources for complications.

07:31 Here, in a little diagram, you see what I just said. In the top arrow, you can see the β-1 or heart-blocking effects - reduces contractility, reduces blood pressure, makes the work of the heart less. You can also see, in the second little drawing, the lungs. If there’s β-2 effects, you may increase the bronchial constriction, that is the constriction of the small tubes in the lung that lead to asthma. And then you can see, down below, the beta blockers that dilate the blood vessels are particularly good for heart failure.

08:08 Now, let’s think for a second about the potential of the non-specific beta blockers, the one that block both β-1 and β-2. These are the ones that have the greatest potential for causing lung side effects when given for the heart. But, it turns out that selectivity of β-1 and β-2, I call it “semi-selectivity.” Because if you take a β-1 selective blocker and you give it at a very low dose, it’s going to mostly block the beta receptors in the heart. But, if you need to push the dose even into moderate levels, there’s some spillover onto β-2. So, even if you are giving a β-1 blocker to a patient with heart disease for angina or for hypertension or for heart failure and that patient has a tendency to develop asthma. When you push the dose of that beta blocker into a reasonable range, you may well worsen their asthma. And almost the only way to find that out is to try it and see what happens, particularly if you have a real need for that beta blocker. And the same thing is true, sometimes we give β-2 stimulants to improve lung function by dilating the bronchioles and sometimes that results in cardiac arrhythmias because of spillover in the β-1 area. So, again, all of these drugs are not perfectly selective, they have effects throughout the body. And again, this relates to the art of using these drugs because of their potential for effects in other parts of the body.

09:42 This complex diagram right here shows you all the effects of beta blockers on the heart.

09:50 I’m not going to spend a lot of time talking about it. You’re welcome to look at it at great detail on your own, but you can see what happens in the heart with beta blockers.

10:00 They decrease contractility, they decrease the heart rate, they help to prevent certain kinds of electrical short circuits - cardiac arrhythmias. We are going to talk about that later, particularly atrial fibrillation. In a sense, they quiet the heart down in a number of ways. They improve the metabolic balance, right, the demand-supply relationship within the heart that stabilizes the situation in patients with ischemic heart disease. It helps patients who are hypertensive, that is have too high blood pressure, gets them back down into a more normal range. And it generally quiets down the heart. Particularly some individuals are prone to markedly increase their heart rate even with small disturbances and beta blockers also are very, very useful in helping in that regard.

10:51 Here you see a summary of the full spectrum of cardiovascular effects of the beta blockers and their indications. Beta blockers are particularly useful for angina or for ischemic heart disease, for heart failure. Actually, we have seen sometimes hearts improve when patients have been treated with beta blockers for heart failure, and also for hypertension, all very effective and then a little less effective for controlling arrhythmias and some of the other problems. But, because angina and heart failure are so common, we use a lot of beta blockers. Fortunately, almost all of them now are generic, so they are relatively inexpensive and usually in moderate doses, they are well tolerated. When you start to push the doses up, you increase the risk for effects in other organ systems and you increase the risk for complications.

11:47 So, let’s talk a little bit about the mechanism of benefit of beta blockers in ischemic heart disease - that is hardening of the arteries with blockage of blood flow into the heart muscle. Well, what we are trying to do is rebalance the situation, right? We can try and improve blood flow down the coronary arteries.

12:07 We will talk about a strategy to do that in a moment. But, the most important effect is to try and decrease the demand of the heart for oxygen and nutrients. We do that by dropping the heart rate, by dropping the blood pressure and by dropping contractility. So this is...

12:24 all three mechanisms work in the patient with ischemic heart disease and very often a patient who has angina with normal activity. For example, let’s say, climbing a flight of stairs.

12:35 Oh, they get chest discomfort. When we give them beta blockers, their heart rate doesn’t accelerate as much when they go up the stairs, their blood pressure doesn’t rise as much and they don’t have angina now when they go up the stairs. And that’s the goal, as you will see when we talk about ischemic heart disease. We want patients who don’t have symptoms, who can lead a normal active life as long as they are not trying to race up and down stairs, but that they can do normal daily activities without having angina.

13:01 Again, here you see a slide, quite complex, listing all of the beneficial effects, and some of the potential non-beneficial effects, of beta blocker in a patient with ischemic heart disease. You see the heart rate is down, the blood pressure is down. Unfortunately, what happens is sometimes, because of the decreased contractility, the heart may dilate a little bit and that has a tendency to increase myocardial oxygen consumption or myocardial oxygen demand for nutrients and oxygen. But, that’s a minor player in comparison to the decreases in the demand that you get from lowering heart rate and lowering blood pressure.

13:42 So, again, you might want to peruse this slide in a little more detail at your leisure and of course, you can also read further about this in all the standard textbooks of cardiology and some of the references which we give at the end of this lecture.

13:57 Now, what about the so-called “anti-arrhythmic” effects of beta blockers? We haven’t talked a lot about arrhythmias. Remember, I showed you the cardiogram with the P wave, the QRS and the T; P wave being the atrial depolarization, the electrical depolarization; the QRS being the ventricular one. And that’s the normal sequence of electrical activity passing through the heart. It turns out, particularly in older individuals and even occasionally in some younger individuals, you can have electrical... what I call “electrical short circuits”, in which suddenly the heart will start to race or there will be abnormal activity in the atria, so you will lose the P wave and the heart will race in a… in a very abnormal way. Remember, I showed you an electrocardiogram of a patient in atrial fibrillation. Instead of the nice, regular “lub-dub, lub-dub, lub-dub,” what you had was (fast and inconsistent heart sounds) and of course, when that happens, the heart could be going as fast as 150 beats per minute. Even people with normal hearts will feel uncomfortable with that and especially individuals who have a lack of blood flow, getting… normal blood flow getting into the heart because of coronary artery disease. When you increase the heart rate like that, it’s very likely that they will develop an imbalance in the supply-demand relationship, angina, and they might even have a small heart attack. So, we try and also control the… the arrhythmias, these atrial arrhythmias, and also some ventricular arrhythmias and beta blockers often help with that. For example, early on in the phase of a heart attack - a myocardial infarction, the administration of beta blockers decreases the chance that the patient will have a cardiac arrest. We are going to talk a lot about arrhythmias in a total unit where we talk about diseases of the heart and I’ll also be talking about some therapy at that time. But, it’s important for you to realize that the beta blockers not only help to control the supply–demand imbalance in the heart with ischemic heart disease, not only can they help with high blood pressure, but they also can help control arrhythmias. They are not a powerful controller of arrhythmia, but they are much more benign than many of the other drugs that we use that have a lot of side effects. More about that in a later lecture. Let’s talk about heart failure. This is a revolution that’s occurred in the last 15 to 20 years. When I was in training, we were told, “Don’t ever give a beta blocker to a patient with heart failure because it depresses the contractility - the 'oomph' of the ventricle, and you are going to make the heart failure worse.” Well, it turned out that in Sweden, the doctors weren’t so convinced that beta blockers were a bad idea and they did a series of large clinical trials in which they demonstrated that actually, early on in heart failure, the beta blockers might have made things a little worse. But long-term, many of the hearts remarkably improved. Well, this was a revolutionary thought. Something I had been taught in medical school and training, “Don’t ever give a beta blocker to a patient with heart failure!”, was now the exact opposite, “You better be sure and give a beta blocker to a patient with heart failure.” So, what was the benefit there? Well, there were several benefits. First of all, again, even if the heart failure wasn’t due to ischemic heart disease - to lack of blood flow in the heart, but was due to sick heart cells. By decreasing the work of the heart, decreasing the heart rate, decreasing the blood pressure, you actually allowed some of those heart cells to recover.

17:30 In addition, by blocking the beta receptors on the surface of these heart cells - the myocardial cells, it actually caused the cells to produce more beta receptors and then there was effect from the adrenaline hitting those beta receptors that increased the contractility of the heart when this was done long term. And of course, then, there was a decrease in arrhythmias as well. All that put together, beta blockers turned out to be a huge benefit in heart failure patients. And recently, over the last 10 to 15 years, the beta blockers that also dilate blood vessels and therefore, lower the blood pressure have been shown to be the best beta blockers for patients with heart failure. I can tell you, and when I saw this the first time, I thought, “I made a mistake.” A patient that had terrible heart function, six months later had normal heart function after being put on beta blockers. When this happened, I said to myself, “I must have misremembered. I must have made a mistake.

18:32 It couldn’t have been that the heart function was that bad early on and now became normal.” When we checked back, it turned out I was absolutely right. The heart failure state had been associated with bad left ventricular function initially and it became normal after six months. And I’ve now seen that happen a number of times in a number of patients.

18:51 Of course, the patients and their families are ecstatically happy when this happens, but even in people who don’t totally normalize, there’s often an improvement in heart function with beta blockers. It’s the most important advance in heart failure therapy in the history of cardiology.

19:07 In patients with heart failure, data blockers are not used globally but are part of the initial therapy for most patients with heart failure with a reduced ejection fraction, less than 50% HFrEF.

19:20 Beta blockers are not recommended as part of the primary therapy for heart failure with a preserved ejection fraction of 50% so-called HFpEF.

19:29 Trials have been done and they have not been effective.

19:33 Unfortunately, they're very good for HFrEF not good for HFpEF.

19:37 And the same is true for the angiotensin renin blockers on ACE inhibitors and RB.

19:44 They have been shown not to be helpful in patients with HFpEF.

19:49 You know, they can occasionally be used in HFpEF to help treat angina or hypertension but they're but it's just HFpEF. alone.

19:59 They're not shown to be beneficial.

20:02 And in fact, if you look at Eugene Braunwald, who is probably the number one cardiologist in the world and one of my mentors and teachers, if you look in his textbook, he says, “Beta blockers are first choice, of course, for heart failure, of course, for ischemic heart disease, and for hypertension and arrhythmias as well.” Although hypertension and arrhythmias, they are sort of in second place. But, for angina and heart failure, they are number one.