Positive inotropic medications

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Positive inotropic medications

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Positive inotropic medications

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is a trace element that is used to treat digoxin toxicity.

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A 75-year-old woman comes to the emergency department because of nausea and vomiting, abdominal pain, double vision and describes seeing green/yellow outlines around objects. She reports a history of NYHA Class III heart failure, atrial fibrillation, and bipolar disorder. Her current medication list is quite extensive and includes ramipril, bisoprolol, spironolactone, digoxin, amiodarone, and lithium. Which of her medications is most likely to be responsible for her symptoms? 

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Transcript

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 calcium-induced 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.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Digoxin in Heart Failure with a Reduced Ejection Fraction: A Risk Factor or a Risk Marker?" Cardiology (2016)
  5. "Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome" Cochrane Database of Systematic Reviews (2018)
  6. "Treatments targeting inotropy" European Heart Journal (2018)
  7. "Therapeutic achievements of phosphodiesterase inhibitors and the future" European Heart Journal (1989)