The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone

Article Abstract:

The sodium-channel-blocking drug propafenone shares structural similarities to propranolol, a drug that is commonly prescribed for arrhythmias (irregular heart rhythm). However, patient response to propafenone is highly variable. One potential source of this variable response is individual genetic differences in the way the drug is metabolized. Propafenone, as well as many other drugs, can be metabolized in the liver by enzymes of the cytochrome P-450 system, a group of enzymes which show great genetic variability in humans. To test the hypothesis that genetic differences may account for the variability of response to propafenone, 14 healthy volunteers agreed to take part in a study which involved the induction of a racing heartbeat (tachycardia) using the compound isoproterenol and treadmill exercise; this was followed by experimental treatment with propafenone. Nine volunteers were classified as genetic 'extensive metabolizers' following a test injection of debrisoquin, while the remaining five were considered 'poor metabolizers', based on the relative inability of their cytochrome P-450 to metabolize the test compound. Clinically effective beta-blockade was observed in all 14 patients when high doses of propafenone were used. However, at lower doses, effective beta-blockade was observed only in the poor metabolizer patients. It was surmised that when less of the drug is metabolized by the liver, more clinically effective drug is available in the blood. The results indicate that the apparent random variation in the response of patients to the anti-arrhythmic effects of propafenone is actually a predictable response, based on the genetics of liver enzymes. It should be emphasized that while poor metabolizers have an easier time maintaining therapeutically effective levels of propafenone in their blood, they are also more likely to be subject to adverse side effects. (Consumer Summary produced by Reliance Medical Information, Inc.)

Genetic aspects, Cytochrome P-450

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Propafenone

Article Abstract:

Propafenone, or rythmol, has recently been approved in the United States for oral use in the treatment of ventricular arrhythmias. Propafenone is similar in effect to two other anti-arrhythmic medications, encainide and flecainide. Because these two drugs increase mortality among patients with nonsustained arrhythmias after myocardial infarction, they are now indicated for use only in patients with documented sustained arrhythmias which are life-threatening. The similar nature of propafenone suggests that, in the absence of evidence to the contrary, the use of propafenone should be similarly restricted. Propafenone works by blocking sodium channels in the heart, thereby reducing the upstroke slope of the ventricular contraction. Clinical trials have shown that propafenone suppresses sustained ventricular tachycardia, an excessively fast beating of the heart, in 60 to 85 percent of patients. Non-cardiac side effects occur in roughly 8 percent of patients, and these can include dizziness, blurred vision, and taste disturbances. Less common are vomiting, nausea and anorexia. Serious cardiac side effects may occur in as many as 14 percent of patients, including worsening of congestive heart failure. These effects are dose-related and thought to be a result of more advanced underlying heart disease. Propafenone provides beneficial effects for sustained ventricular arrhythmias, and although there might be reason to think that other patients might benefit as well, use of propafenone must be based on reasons to think that the benefits outweigh the potential risks. (Consumer Summary produced by Reliance Medical Information, Inc.)

Ventricular fibrillation, Anti-arrhythmia drugs, Antiarrhythmia agents

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Racial differences in drug response: altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American Whites

Article Abstract:

Propranolol is a beta-adrenergic blocking agent which decreases the heart rate and output, reduces blood pressure and is used effectively to prevent migraine headaches. Propranolol is generally administered in much smaller doses in China than in the United States. To determine if people of different races react differently to various dosages of propranolol, two groups were given the drug: a group of American white men and a group of men of Chinese descent. The responses to the drug were measured by reduction in heart rate, and by blood pressure in an upright position (standing), lying down (supine), and during exercise. The Chinese group was twice as sensitive to the effects of propranolol as the white group. The heart rate of the Chinese group dropped 20 percent in the supine and upright positions, and during exercise. Their blood pressure dropped by 10 percent in supine and upright positions. The white group metabolized the drug more slowly than the Chinese group. Chinese men are apparently more sensitive to the effects of propranolol on heart rate and blood pressure than white men.

Research, Analysis, Measurement, Physiological aspects, Dosage and administration, Blood pressure, Chinese, Chinese (Asian people), Propranolol hydrochloride, Propranolol, Drug metabolism, Pharmacogenetics, Pharmacogenomics, Blood pressure measurement, White men, Pharmacokinetics

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