Positive inotropic medications PDF

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Chapter 17 notes on intropic, chrontropic and drop tropic. Discussion goes in deep of cardiac cycle....

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Positive inotropic medications, as their name implies, are a diverse group of medications that increase the strength of heart muscle contraction. As a result, they increase the stroke volume and thus, the cardiac output. Positive inotropic medications include cardiac glycosides, like digoxin; beta agonists, like dobutamine; and phosphodiesterase inhibitors, like milrinone. They are used in conditions where the heart can’t pump enough blood to the body’s tissues, like in systolic heart failure. Alright, the heart needs to squeeze out a certain volume of blood each minute, called the cardiac output, which can be rephrased as the heart rate multiplied by the stroke volume, which is the volume of blood squeezed out with each heartbeat. Okay, now the stroke volume depends on the preload, or the amount of blood that returns to the heart; the afterload, or peripheral resistance; and the strength of the contraction, or contractility, of the cardiac muscle. Now, muscle contraction is initiated with an action potential which modifies receptors allowing calcium ions to flow from the sarcoplasmic reticulum into the sarcoplasm. This allows myosin heads to bind to the actin. These two proteins are ultimately responsible for cell contraction. In order for a muscle to relax, calcium ions must be pumped back into the sarcoplasmic reticulum. When the frequency of stimulation is increased, more calcium ions accumulate in the sarcoplasm, and the strength of contraction increases. Alright, now there are conditions in which the strength of the heart’s contraction is impaired, and the heart can’t pump out enough blood to meet the body’s demands, this is called heart failure. For example, in systolic heart failure, the heart’s ventricles can’t pump blood hard enough during systole, so as a result, the cardiac output decreases. This is typically due to some kind of damage to the myocardium so the heart can’t contract as forcefully or pump blood as efficiently. Ischemic heart disease caused by coronary artery atherosclerosis, or plaque buildup, is the most common cause. Alright, now, positive inotropic medications can increase the strength of heart contraction and can be used for the treatment of these conditions. So let’s start with the cardiac glycosides which are also known as digitalis glycosides because they’re derived from the plant digitalis.

The prototype cardiac glycoside is digoxin. Digoxin acts by inhibiting the sodium/potassium ATPase pump, at the cell membrane of the cardiomyocyte. Na+/K+ ATPase normally moves 2 potassium ions into the cell for every 3 sodium ions out. Now, with digoxin, potassium can’t enter the cell and sodium can’t leave it, resulting in an increase in sodium inside the cell. But sodium finds another way to get out of the cell via the sodium/calcium exchanger that moves calcium into the cell and sodium out. Once this extracellular calcium gets inside, it binds to receptors on the sarcoplasmic reticulum. This releases even more calcium into the cell via a process called calciuminduced calcium release. Now, calcium increases interaction of the two contractile proteins, actin and myosin, and ultimately improves cardiomyocyte contractility and cardiac function to reduce the symptoms of chronic heart failure. Digoxin also exerts parasympathetic effects by inhibiting the Na+/K+ ATPase found at the cell membrane of vagal neurons leading to a decrease in heart rate. But because parasympathetic innervation is much richer in the atria, these effects mainly involve the atria and so digoxin can also be used for the treatment of atrial arrhythmias, such as atrial flutter and atrial fibrillation. Notice that digoxin is not considered first line treatment for heart failure or atrial arrhythmias because it has a narrow therapeutic window and it doesn’t reduce mortality in individuals with heart failure. However, it’s a useful agent in individuals with chronic heart failure and concomitant atrial arrhythmia. Now the narrow therapeutic window means it’s easy to overdose and digoxin has some nasty side effects. The more common side effects include gastrointestinal disturbances such as nausea, vomiting, anorexia and diarrhea. It could also cause electrocardiographic abnormalities, such as T wave changes, a short QT interval, ST depression, and arrhythmias. The most common type of arrhythmia is premature ventricular contractions, although any type of arrhythmia can occur. Also, by stimulating the vagus nerve, digoxin can lead to bradycardia and heart block.

Another side effect of digoxin is hyperkalemia, or elevated potassium levels, because digoxin doesn’t permit the potassium to enter the cells and so it accumulates in the circulation. Now, other side effects include neurologic symptoms such as confusion, disorientation, and visual disturbances like xanthopsia, which is when objects appear yellow. Alright, now factors that predispose to toxicity include electrolyte abnormalities like hypokalemia, or low potassium levels, hypomagnesemia, or low magnesium levels, and hypercalcemia, or elevated calcium levels. Okay, now digoxin is excreted through the kidneys, so serum levels can increase if there’s renal dysfunction. It can also increase because of medications that inhibit renal clearance of digoxin such as amiodarone, verapamil, diltiazem, and quinidine. Alright, now treatment of digoxin toxicity includes reversing electrolyte abnormalities such as hypokalemia, antiarrhythmics, and digoxin specific antibody fragments or digoxin Fabs. Okay, let’s switch gears and move on to dobutamine, which is a beta agonist that is highly selective for beta 1 receptors. Normally, the beta receptors are coupled to the protein Gs, which stimulates an enzyme that is known as adenylate cyclase. Activated adenylate cyclase transforms ATP into cyclic adenosine monophosphate or cAMP. cAMP accumulates inside the cell leading to increased activation of an enzyme called protein kinase A, or PKA. PKA phosphorylates the calcium channels at the cell membrane leading to an increase in calcium influx into the cells. As a result, activation of the beta receptors causes in an increase in the force of cardiac muscle contraction. Also, increased levels of cAMP inside the smooth muscle cells of the vessels prevents them from contracting, which results in vasodilation. Beta-1 adrenergic receptors are mainly located in the heart, and by activating them, dobutamine increases the heart rate and contractility, which makes the heart work harder, and pump more blood out, thereby increasing its oxygen and energy demands. On the other hand, dobutamine also exhibits some beta 2 activity and by activating beta-2 receptors in vessel walls, it causes vasodilation and lowers the peripheral vascular resistance.

Due to its powerful cardiac-stimulant effect, dobutamine is used to stimulate the heart in individuals with acute heart failure or cardiogenic shock. Notice that dobutamine is not appropriate for chronic heart failure because of tolerance, which is when the body adapts to the stimulation from the medication and gradually the agonist will produce a weaker response. Moving on to side effects, since it increases heart rate, dobutamine can cause tachycardia, palpitations, and even arrhythmias. Okay, now let’s move onto the phosphodiesterase inhibitors. The major representative of this group is milrinone. Phosphodiesterase normally breaks down cAMP. Now, milrinone selectively inhibits phosphodiesterase-3 which is found in cardiomyocytes, and this leads to decreased breakdown of cAMP. cAMP accumulates inside the cell, leading to increased activation of PKA. PKA phosphorylates the calcium channels at the cell membrane of the cardiomyocyte leading to an increase in calcium influx into the cells. As a result, there is an increase in the force of heart contraction and vasodilation. Now, milrinone is used for the treatment of acute heart failure and should not be used in chronic heart failure because it increases the morbidity and mortality. Alright, now side effects include arrhythmias and hypotension due to significant vasodilation. Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts about the positive inotropic medications. Okay, so let’s set the scene at the “Pumping Hearts” campground. The tents are where we’ll put the medications that affect cAMP and the 2 faucets in the camp are labeled Na+ and K+ and we can place the Na+/K+ ATPase inhibitors here. So by the faucets let’s have an ox with a shovel digging a hole to get more water, and he represents digoxin. Inside the hole there’s an old and broken heart-shaped music box that’s playing notes off beat, and this will help you remember digoxin is used to treat people which chronic heart failure and arrhythmias. Now this ox is pretty clumsy, so he smashed a small nearby window, which represents its narrow therapeutic window. Around him are a couple of other strange objects that he dug up which will represent the important side effects. First, there’s a large banana for hyperkalemia. Next, is a broken ECG monitor and a heart shaped shield

for ECG abnormalities and heart block. Finally, there’s a brain wearing a pair of yellow tinted sunglasses to represent neurotoxicity and xanthopsia. Okay, let’s take a look at the tents for the drugs that increase cAMP. There’s a tent with the word “beta 1” on it which will be for our beta agonists, and by this tent there’s a double sleeping bag for dobutamine. Next let’s have a tent surrounded by a fence that stops people from taking it down. This tent represents phosphodiesterase inhibitors which prevent cAMP break down. The owner of this tent is a millionaire rhino who represents milrinone. Now, the tents have sharp, or acute, angles to help you remember that they’re used to treat acute heart failure. Now one of the campers is sitting between the tents, and playing his bongos off beat. He represents arrhythmias which is a potentially dangerous side effect caused by both medications. The rich rhino’s wife is swooning over the musician, fainting in the process, and this will help you remember milrinone can cause light headedness due to hypotension.

Summary All right, as a quick recap… Positive inotropic agents are a group of medications used primarily in systolic heart failure and cardiogenic shock. They have a positive inotropic effect on the heart, meaning that they increase the strength of the cardiac muscle contraction. Cardiac glycosides, such as digoxin, are used in chronic heart failure to reduce symptoms, and for the treatment of atrial arrhythmias, such as atrial flutter and atrial fibrillation. Common side effects include gastrointestinal disturbances, electrocardiographic abnormalities, arrhythmias, hyperkalemia, neurological symptoms, and visual disturbances such as xanthopsia. Dobutamine, a beta adrenergic receptor agonist, and phosphodiesterase inhibitors, such as milrinone, are used in acute heart failure. Dobutamine can cause tachycardia, palpitations, and arrhythmias, while side effects of milrinone include arrhythmias and hypotension....