Page 258 - Basic _ Clinical Pharmacology ( PDFDrive )

244 SECTION III Cardiovascular-Renal Drugs

less, fatal pulmonary fibrosis may be observed in 1% of patients. cardioverter-defibrillator discharges. The drug increases the pacing
Abnormal liver function tests and hypersensitivity hepatitis may and defibrillation threshold, and these devices require retesting
develop during amiodarone treatment and liver function tests after a maintenance dose has been achieved.
should be monitored regularly. The skin deposits result in a pho-
todermatitis and a gray-blue skin discoloration in sun-exposed
areas, eg, the malar regions. After a few weeks of treatment, DRONEDARONE
asymptomatic corneal microdeposits are present in virtually all
patients treated with amiodarone. Halos develop in the peripheral Dronedarone is a structural analog of amiodarone in which the
visual fields of some patients. Drug discontinuation is usually not iodine atoms have been removed from the phenyl ring and a
required. Rarely, an optic neuritis may progress to blindness. methanesulfonyl group has been added to the benzofuran ring.
Amiodarone blocks the peripheral conversion of thyroxine The design was intended to eliminate action of the parent drug
(T ) to triiodothyronine (T ). It is also a potential source of on thyroxine metabolism and to modify the half-life of the drug.
3
4
large amounts of inorganic iodine. Amiodarone may result in No thyroid dysfunction or pulmonary toxicity has been reported
hypothyroidism or hyperthyroidism. Thyroid function should be in short-term studies. However, liver toxicity, including two severe
evaluated before initiating treatment and should be monitored cases requiring liver transplantation, has been reported. Like
periodically. Because effects have been described in virtually every amiodarone, dronedarone has multichannel actions, including
organ system, amiodarone treatment should be reevaluated when- blocking I , I , I , and I . It also has β-adrenergic-blocking
Kr
Na
Ca
Ks
ever new symptoms develop in a patient, including arrhythmia action. The drug has a half-life of 24 hours and can be administered
aggravation. twice daily at a fixed dose of 400 mg. Dronedarone absorption
increases twofold to threefold when taken with food, and this infor-
Pharmacokinetics mation should be communicated to patients as a part of the dos-
ing instructions. Dronedarone elimination is primarily nonrenal.
Amiodarone is variably absorbed with a bioavailability of 35–65%. It inhibits tubular secretion of creatinine, resulting in a 10–20%
It undergoes hepatic metabolism, and the major metabolite, increase in serum creatinine; however, because the glomerular filtra-
desethylamiodarone, is bioactive. The elimination half-life is com- tion rate is unchanged, no adjustments are required. Dronedarone
plex, with a rapid component of 3–10 days (50% of the drug) and is both a substrate and an inhibitor of CY3A4 and should not be
a slower component of several weeks. After discontinuation of the co-administered with potent inhibitors of this enzyme, such as the
drug, effects are maintained for 1–3 months. Measurable tissue azole and similar antifungal agents, and protease inhibitors.
levels may be observed up to 1 year after discontinuation. A total Dronedarone restores sinus rhythm in a small percentage of
loading dose of 10 g is usually achieved with 0.8–1.2 g daily doses. patients (< 15%) with atrial fibrillation. It produces a 10- to
The maintenance dose is 200–400 mg daily. Pharmacologic effects 15-bpm reduction of the ventricular rate compared to placebo. In
may be achieved rapidly by intravenous loading. QT-prolonging one report, dronedarone doubled the interval between episodes
effect is modest with this route of administration, whereas brady- of atrial fibrillation recurrence in patients with paroxysmal atrial
cardia and AV block may be significant. fibrillation. Initial studies suggested a reduction in mortality or
Amiodarone has many important drug interactions, and all hospitalization in patients with atrial fibrillation. However, a
medications should be reviewed when the drug is initiated and study of dronedarone’s effects in permanent atrial fibrillation was
when the dose is adjusted. Amiodarone is a substrate for liver cyto- terminated in 2011 because of increased risk of death, stroke,
chrome CYP3A4, and its levels are increased by drugs that inhibit and heart failure. Similarly, a trial of dronedarone in advanced
this enzyme, eg, the histamine H blocker cimetidine. Drugs that heart failure was terminated prematurely because of an increase in
2
induce CYP3A4, eg, rifampin, decrease amiodarone concentration mortality. The drug carries a “black box” warning against its use in
when coadministered. Amiodarone inhibits several cytochrome acute decompensated or advanced (class IV) heart failure.
P450 enzymes and may result in high levels of many drugs,
including statins, digoxin, and warfarin. The dose of warfarin SOTALOL
should be reduced by one third to one half following initiation of
amiodarone, and prothrombin times should be closely monitored.
Sotalol has both β-adrenergic receptor-blocking (class 2) and action
Therapeutic Use potential-prolonging (class 3) actions. The drug is formulated as a
racemic mixture of d- and l-sotalol. All the β-adrenergic-blocking
Low doses (100–200 mg/d) of amiodarone are effective in main- activity resides in the l-isomer; the d- and l-isomers share action
taining normal sinus rhythm in patients with atrial fibrillation. potential prolonging effects. Beta-adrenergic-blocking action is
The drug is effective in the prevention of recurrent ventricular not cardioselective and is maximal at doses below those required
tachycardia. It is not associated with an increase in mortality in for action potential prolongation.
patients with coronary artery disease or heart failure. In many cen-
ters, the implanted cardioverter-defibrillator (ICD) has succeeded OH
drug therapy as the primary treatment modality for ventricular CH SO NH CHCH NHCH(CH )
3 2
2
3
2
tachycardia, but amiodarone may be used for ventricular tachycar-
dia as adjuvant therapy to decrease the frequency of uncomfortable Sotalol