Module 43

Question 1

Several drugs, such as flecainide, are very effective in the suppression of premature ventricular contractions, and yet they have been found to significantly increase mortality due to “sudden death”. How is this believed to happen? What EKG (electrocardiogram) sign seems to correlate with this increase in mortality?

Answer 1

• It was known that patients who had premature ventricular contractions (PVCs) after a heart attack were at increased risk of sudden death. Therefore, agents were developed that decreased the number of PVCs. These agents were prescribed widely for decades. Then a study was finally performed to look at the more important end-point, i.e. death (the Cardiac Arrhythmia Suppression Trial - CAST study). This study found that these agents actually increased mortality, and not by just a small amount.
  
  • Specifically, the characteristic of these agents that correlates with an increased risk of sudden death is an increase in the QT interval on the EKG. This can lead to a serious arrhythmia called Torsade de point (twisting around a point, named for the appearance of the EKG during the arrhythmia, which is associated with uncoordinated contraction of the ventricles.), which is usually fatal.
  • Many other drugs such as fluoroquinolones and many antipsychotic agents can also increase the QT interval, and such agents should be used with caution in patients with a history of arrhythmias. Now new drugs in development are tested for their propensity to cause arrhythmias, which includes determination of effects on QT interval and also other features such as effects on the potassium channel.

Question 2

A woman with mitral valve prolapse is brought to the ER with paroxysmal supraventricular tachycardia, and she is in a lot of distress. Simple vagal stimulation was ineffective at converting the arrhythmia, and the decision was made to treat her with IV adenosine. This was also ineffective. On further questioning it was learned that she also has asthma. She cannot remember the names of the medications that she takes for asthma. How could her asthma therapy be responsible for the failure of the adenosine to convert her arrhythmia?

Answer 2

Theophylline, a drug used to treat asthma, blocks the effects of adenosine. Caffeine has a similar effect.

Question 3

In addition to possible antiarrhythmic therapy, what other treatment is appropriate for atrial fibrillation?

Answer 3

• Most patients have a decreased cardiac output when they are in atrial fibrillation, but they can tolerate it. However, when the atrium is not emptied because of atrial fibrillation, clots can form in the stagnant blood. When clots are formed in the left atrium, blood clots can produce emboli that go to the brain and cause a stroke. Therefore, patients who are in chronic atrial fibrillation should be treated with an anticoagulant.
  Aspirin is not as effective as warfarin, but the newer anticoagulants such as dabigatran and rivaroxaban are likely to replace warfarin because they are easier to use and appear to be slightly safer

Question 4

Why are women at higher risk of torsade de pointe than men?

Answer 4

Testosterone decreases the QT interval and this decreases the risk of torsade de pointe; however, males can certainly develop this arrhythmia

Question 5

Describe the pharmacokinetics of amiodarone.

Answer 5

Although it is a basic amine and mostly ionized, its water solubility is low. Its protein binding is very high (99.98%), and its volume of distribution is very high (66 L/kg). Therefore, it has a long half-life (25 days), even though clearance is relatively high.

- It deposits in tissues such as the liver (The liver becomes radiopaque because it deposits in the liver, and iodine has a high atomic mass and absorbs X-rays.)
- Amiodarone also forms deposits in the cornea although they do not interfere much with vision. With extended treatment it causes a blue-grey discoloration in the skin, and can cause pulmonary fibrosis.
- There are interactions with many drugs. Given all of these issues most physicians avoid amiodarone, but it is a very effective antiarrhythmic agent in some patients. It is interesting that it prolongs QT but rarely causes torsade de pointe.