Dofetilide
Encyclopedia
Dofetilide is a class III antiarrhythmic agent.
It is marketed under the trade name Tikosyn by Pfizer
, and is available in the United States
in capsules containing 125, 250, and 500 µg
of dofetilide.
Due to the pro-arrhythmic potential of dofetilide, it is only available by prescription by physicians who have undergone specific training in the risks of treatment with dofetilide. In addition, it is only available by mail order or through specially trained local pharmacies to individuals who are prescribed dofetilide by a physician who is registered as being able to prescribe the pharmaceutical.
in individuals prone to the formation of atrial fibrillation
and flutter
, and for the chemical cardioversion
to sinus rhythm from atrial fibrillation
and flutter
.
of dofetilide is roughly 10 hours, however this is variable based on many physiologic factors (most significantly creatinine clearance), and ranges from 4.8 to 13.5 hours.
This causes the refractory period of atrial tissue to increase, hence its effectiveness in the treatment of atrial fibrillation and atrial flutter.
Dofetilide does not affect Vmax (The slope
of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential.
There is a dose-dependent increase in the QT interval and the corrected QT interval (QTc). Because of this, many practitioners will initiate dofetilide therapy only on individuals under telemetry monitoring or if serial EKG measurements of QT and QTc can be performed.
80% of dofetilide is excreted by the kidney
s, so the dose of dofetilide should be adjusted in individuals with renal insufficiency, based on creatinine clearance.
In the kidneys, dofetilide is eliminated via cation exchange (secretion). Agents that interfere with the renal cation exchange system, such as verapamil
, cimetidine
, hydrochlorothiazide
, itraconazole
, ketoconazole
, prochlorperazine
, and trimethoprim
should not be administered to individuals taking dofetilide.
About 20 percent of dofetilide is metabolized in the liver via the CYP3A4
isoenzyme of the cytochrome P450 enzyme system. Drugs that interfere with the activity of the CYP3A4
isoenzyme can increase serum dofetilide levels. If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via the CYP3A4
isoenzyme system.
The risk of inducing torsade de pointes can be decreased by taking precautions when initiating therapy, such as hospitalizing individuals for a minimum of three days for serial creatinine
measurement, continuous telemetry
monitoring and availability of cardiac resuscitation .
with left ventricular
dysfunction. Because of the results of the DIAMOND study, many physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction.
It is marketed under the trade name Tikosyn by Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
, and is available in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
in capsules containing 125, 250, and 500 µg
Microgram
In the metric system, a microgram is a unit of mass equal to one millionth of a gram , or 1/1000 of a milligram. It is one of the smallest units of mass commonly used...
of dofetilide.
Due to the pro-arrhythmic potential of dofetilide, it is only available by prescription by physicians who have undergone specific training in the risks of treatment with dofetilide. In addition, it is only available by mail order or through specially trained local pharmacies to individuals who are prescribed dofetilide by a physician who is registered as being able to prescribe the pharmaceutical.
Uses
It is used for the maintenance of sinus rhythmSinus rhythm
In medicine, sinus rhythm is the normal beating of the heart, as measured by an electrocardiogram . It has certain generic features that serve as hallmarks for comparison with normal ECGs.- ECG structure :...
in individuals prone to the formation of atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
and flutter
Atrial flutter
Atrial flutter is an abnormal heart rhythm that occurs in the atria of the heart. When it first occurs, it is usually associated with a fast heart rate or tachycardia , and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with...
, and for the chemical cardioversion
Cardioversion
Cardioversion is a medical procedure by which an abnormally fast heart rate or cardiac arrhythmia is converted to a normal rhythm, using electricity or drugs. Synchronized electrical cardioversion uses a therapeutic dose of electric current to the heart, at a specific moment in the cardiac cycle...
to sinus rhythm from atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
and flutter
Atrial flutter
Atrial flutter is an abnormal heart rhythm that occurs in the atria of the heart. When it first occurs, it is usually associated with a fast heart rate or tachycardia , and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with...
.
Pharmacokinetics
The elimination half-lifeHalf-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
of dofetilide is roughly 10 hours, however this is variable based on many physiologic factors (most significantly creatinine clearance), and ranges from 4.8 to 13.5 hours.
Mechanism of action
Dofetilide works by selectively blocking the rapid component of the delayed rectifier outward potassium current (IKr).This causes the refractory period of atrial tissue to increase, hence its effectiveness in the treatment of atrial fibrillation and atrial flutter.
Dofetilide does not affect Vmax (The slope
Slope
In mathematics, the slope or gradient of a line describes its steepness, incline, or grade. A higher slope value indicates a steeper incline....
of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential.
There is a dose-dependent increase in the QT interval and the corrected QT interval (QTc). Because of this, many practitioners will initiate dofetilide therapy only on individuals under telemetry monitoring or if serial EKG measurements of QT and QTc can be performed.
Metabolism
A steady-state plasma level of dofetilide is achieved in 2–3 days.80% of dofetilide is excreted by the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s, so the dose of dofetilide should be adjusted in individuals with renal insufficiency, based on creatinine clearance.
In the kidneys, dofetilide is eliminated via cation exchange (secretion). Agents that interfere with the renal cation exchange system, such as verapamil
Verapamil
Verapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...
, cimetidine
Cimetidine
Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...
, hydrochlorothiazide
Hydrochlorothiazide
Hydrochlorothiazide, abbreviated HCTZ, HCT, or HZT, is a first-line diuretic drug of the thiazide class that acts by inhibiting the kidneys' ability to retain water. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is...
, itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
, ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, prochlorperazine
Prochlorperazine
Prochlorperazine is a dopamine receptor antagonist that belongs to the phenothiazine class of antipsychotic agents that are used for the antiemetic treatment of nausea and vertigo. It is also a highly-potent typical antipsychotic, 10-20x more potent than chlorpromazine...
, and trimethoprim
Trimethoprim
Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections.It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors...
should not be administered to individuals taking dofetilide.
About 20 percent of dofetilide is metabolized in the liver via the CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
isoenzyme of the cytochrome P450 enzyme system. Drugs that interfere with the activity of the CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
isoenzyme can increase serum dofetilide levels. If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via the CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
isoenzyme system.
Side effects
Torsade de pointes is the most serious side effect of dofetilide therapy. The incidence of torsade de pointes is dose-related, and is 0.3-10.5%. The risk appears to be dose-dependent, with an increased incidence of torsades de pointes associated with higher doses of dofetilide administered.The risk of inducing torsade de pointes can be decreased by taking precautions when initiating therapy, such as hospitalizing individuals for a minimum of three days for serial creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
measurement, continuous telemetry
Telemetry
Telemetry is a technology that allows measurements to be made at a distance, usually via radio wave transmission and reception of the information. The word is derived from Greek roots: tele = remote, and metron = measure...
monitoring and availability of cardiac resuscitation .
Clinical use
Based on the results of the Danish Investigations of Arrhythmias and Mortality on Dofetilide (DIAMOND) study, dofetilide does not affect mortality in the treatment of patients post-myocardial infarctionMyocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
with left ventricular
Left ventricle
The left ventricle is one of four chambers in the human heart. It receives oxygenated blood from the left atrium via the mitral valve, and pumps it into the aorta via the aortic valve.-Shape:...
dysfunction. Because of the results of the DIAMOND study, many physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction.