Dronedarona
Dronedarona Uses, Dosage, Side Effects, Food Interaction and all others data.
Dronedarona is a Class III antiarrhythmic drug that works to restore the normal sinus rhythm in patients with paroxysmal or persistent atrial fibrillation. Atrial fibrillation is a common sustained arrhythmia where the treatment primarily focuses on stroke prevention and symptom management. It is managed by rate control, rhythm control, prevention of thromboembolic events, and treatment of the underlying disease. Similar to amiodarone, dronedarone is a multichannel blocker that works to control rhythm and rate in atrial fibrillation. It meets criteria of all four Vaughan Williams antiarrhythmic drug classes by blocking sodium, potassium, and calcium ion channels and inhibiting β-adrenergic receptors.
Dronedarona is a related benzofuran compound to amiodarone but its chemical structure lacks iodine moieties which are associated with amiodarone-induced thyroid problems. Additionally, the methyl sulfonyl group in its structure renders dronedarone to be more lipophilic with a shorter half-life than amiodarone. This ultimately leads to reduced tissue accumulation of the drug and decreased risk for organ toxicities, such as thyroid and pulmonary toxicities. Commonly marketed as Multaq®, dronedarone was approved by the FDA in July 2009 and Health Canada in August 2009. A safety concern for the risk of drug-induced hepatocellular injury has been issued following marketing of dronedarone.
Dronedarona is an antiarrhythmic agent that restores normal sinus rhythm and reduces heart rate in atrial fibrillation. In another model, it prevents ventricular tachycardia and ventricular fibrillation. Dronedarona moderately prolongs the QTc interval by about 10 ms on average. Dronedarona decreases arterial blood pressure and reduces oxygen consumption. It reduces myocardial contractility with no change in left ventricular ejection fraction. Dronedarona vasodilates coronary arteries through activation of the nitric oxide pathway. In clinical studies, dronedarone reduced incidence of hospitalizations for acute coronary syndromes and reduced incidence of stroke. Dronedarona exhibits antiadrenergic effects by reducing alpha-adrenergic blood pressure response to epinephrine and beta 1 and beta 2 responses to isoproterenol.
| Trade Name | Dronedarona |
| Availability | Prescription only |
| Generic | Dronedarone |
| Dronedarone Other Names | Dronedarona, Dronedarone |
| Related Drugs | propranolol, Xarelto, diltiazem, digoxin, rivaroxaban, sotalol, flecainide, propafenone, Multaq, esmolol |
| Type | |
| Formula | C31H44N2O5S |
| Weight | Average: 556.756 Monoisotopic: 556.297093218 |
| Protein binding | The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is 99.7% and 98.5%, respectively. Both mainly bind to albumin and are not capable of saturation. |
| Groups | Approved |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Dronedarona is an antiarrhythmic agent used in the reduce the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation.
Dronedarona is indicated for the management of atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF to reduce the risk of hospitalization.
Dronedarona is also used to associated treatment for these conditions: Atrial Fibrillation
How Dronedarona works
Atrial fibrillation is the most common type of arrhythmia that is caused by abnormal electrical activity in the atria. In atrial fibrillation, tachyarrhythmia, or fast heart rate, can either be paroxysmal (less than 7 days) or persistent (more than 7 days). Atrial fibrillation causes turbulent and abnormal blood flow through the heart chambers, leading to decreased the effectiveness of the heart to pump blood and an increased likelihood of thrombus formation within the atria which can ultimately dislodge and cause a stroke.
Dronedarona achieves heart rate and rhythm control in atrial fibrillation. In vitro, dronedarone decreased the maximum rate of the rise of an action potential in a concentration- and frequency-dependent manner. Cardiac action potentials are generated by ionic currents of multiple voltage-gated ion channels, including potassium, sodium, and calcium channels. Dronedarona is a multichannel blocker that meets the criteria of all four Vaughan Williams antiarrhythmic drug classes but the contribution of each of these activities to the drug's antiarrhythmic effect is unknown. Dronedarona inhibits rapid Na+ currents rate-dependently (class Ib), non-competitively antagonizes α– and β-adrenergic receptors (class II), blocks K+ outward currents (class III) and blocks slow Ca2+ inward currents (class IV). More specifically, it decreases delayed-rectifier K+ current (IKr), slowly activating delayed-rectifier K+ current (IKs), inward rectifier potassium current (IK1), peak Na+ current (INa) and L-type Ca2+ current (ICa (L)). Dronedarona ultimately increases refractory periods, decelerates cardiac conduction, and prolongs cardiac action potential and refractory periods.
Toxicity
In an acute toxicity study, the oral LD50 in rat was >2,000 mg/kg.
In oral studies, dronedarone showed a limited potential for toxicity in humans in acute overdose situations. However, it is recommended that the patient's cardiac rhythm and blood pressure is monitored in the event of overdose. Symptomatic and supportive treatments should be initiated.
Food Interaction
- Avoid grapefruit products. Co-administration with grapefruit may increase drug concentrations by 3-fold.
- Avoid St. John's Wort. This herb induces CYP3A4 and may increase the serum concentration of dronedarone.
- Take with food. Food, especially high-fat food, increases drug absorption.
[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of dronedarone.
The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.
According to the product labeling, administration with grapefruit juice resulted in a 2.5-fold increase in dronedarone peak plasma concentration and a 3-fold increase in systemic exposure.
Because dronedarone is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.
ADJUST DOSING INTERVAL: Food increases the oral bioavailability of dronedarone.
The mechanism of interaction is unknown.
According to the product labeling, the absolute bioavailability of dronedarone increases from about 4% when administered in the fasted state to approximately 15% when administered with a high-fat meal.
MANAGEMENT: Patients treated with dronedarone should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract.
Dronedarona should be taken twice daily with the morning and evening meals.
Dronedarona Drug Interaction
Major: furosemide, dabigatranModerate: fluticasone / salmeterol, warfarin, apixaban, atorvastatin, metoprolol, metoprolol, budesonide / formoterol, rivaroxabanUnknown: aspirin, rosuvastatin, omega-3 polyunsaturated fatty acids, esomeprazole, acetaminophen, clopidogrel, levothyroxine, cyanocobalamin, ascorbic acid, cholecalciferol
Dronedarona Disease Interaction
Volume of Distribution
The volume of distribution at steady-state ranges from 1200 to 1400 L following intravenous administration.
Elimination Route
Dronedarona is well absorbed after oral administration (>70%). It displays low systemic bioavailability due to extensive first-pass metabolism. The absolute bioavailability of dronedarone without and with a high-fat meal is 4% and 15%, respectively. The peak plasma concentrations of dronedarone and its main circulating N-debutyl metabolite are reached within 3 to 6 hours after administration with food.
Following repeated administration of 400 mg dronedarone twice daily, the steady-state was reached within 4 to 8 days of initial treatment. The steady-state Cmax and systemic exposure to the N-debutyl metabolite are similar to that of the parent compound.
Half Life
The elimination half life ranges from 13 to 19 hours.
Clearance
Following intravenous administration, the clearance ranged from 130 to 150 L/h.
Elimination Route
Following oral administration, about 84% of the labeled dose is excreted in feces and 6% is excreted in urine, mainly as metabolites. Unchanged parent compound and the N-debutyl metabolite accounted for less than 15% of the total radioactivity in the plasma.
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