Page 261 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 14 Agents Used in Cardiac Arrhythmias 247

Toxicity ventricular myocytes, the net effect is prolongation of the APD
and the QT interval. In myocytes isolated from mice bearing long
Adenosine causes flushing in about 20% of patients and shortness QT-associated mutations, the net effect is APD shortening. In
of breath or chest burning (perhaps related to bronchospasm) normal atrial myocytes, the net effect is prolongation of the APD.
in over 10%. Induction of high-grade AV block may occur but At rapid rates, eg, during tachycardia, the atrial action potential
is very short-lived. Atrial fibrillation may occur. Less common arises from the incompletely repolarized membrane and results
toxicities include headache, hypotension, nausea, and paresthesias.
in voltage-dependent reduction of I . Ranolazine has relatively
Na
+
little effect on I and the remaining K currents at therapeutic
Ca
IVABRADINE concentrations.
Ranolazine had been shown to have antiarrhythmic proper-
The localized expression of the “funny” current I in the SA node ties in both atrial and ventricular arrhythmias. It prevents the
f
and its important role in pacemaker activity provide an attractive induction of and may terminate atrial fibrillation. It is currently
therapeutic target for heart rate control. Ivabradine is a selective undergoing clinical trials in combination with dronedarone for
blocker of I. It slows pacemaker activity by decreasing diastolic the suppression of atrial fibrillation. Ranolazine has been shown to
f
depolarization of sinus node cells. It is an open channel blocker that suppress ventricular tachycardia in ischemic models and in a major
shows use-dependent block. Unlike other heart rate-lowering agents clinical trial of its effects in coronary artery disease. The drug has
such as β blockers, it reduces heart rate without affecting myocardial not yet received FDA approval as an antiarrhythmic drug.
contractility, ventricular repolarization, or intracardiac conduction.
At therapeutic concentrations, block of I is not complete. As a result, VERNAKALANT
f
autonomic control of the sinus node pacemaker rate is retained.
Elevated heart rate is an important determinant of the isch- Vernakalant is a multi-ion channel blocker, placing it in several
emic threshold in patients with coronary artery disease and a classes of antiarrhythmic action. It causes frequency- and voltage-
prognostic indicator in patients with congestive heart failure. dependent block of the early and late components of the sodium
Antianginal and anti-ischemic effects of ivabradine have been current. The muscarinic potassium current I , which is con-
KACh
demonstrated in patients with coronary artery disease and chronic stitutively activated in atrial fibrillation, is blocked by vernaka-
stable angina. In controlled clinical trials, ivabradine proved as lant. The early-activating potassium channels I and I are also
kur
to
effective as β blockers in the control of angina. In patients with blocked by the drug. These potassium channel currents play a more
left ventricular dysfunction and heart rates greater than 70 bpm, prominent role in atrial than ventricular repolarization. As a result,
ivabradine reduced mean heart rate and the composite end points vernakalant produces only mild QT-interval prolongation. It does
of cardiovascular mortality and hospitalization. not produce torsades de pointes. Though not yet approved by the
Inappropriate sinus tachycardia is an uncommon disorder char- FDA, vernakalant can be administered intravenously for the rapid
acterized by multiple symptoms, including palpitations, dizziness, termination of atrial fibrillation in patients with no or minimal
orthostatic intolerance, and elevated heart rates. Conventional structural heart disease. In a direct comparison trial, vernakalant
treatment includes β blockers and nondihydropyridine calcium proved more effective than placebo or amiodarone in terminating
channel blockers. Recent case reports and one clinical trial have atrial fibrillation in a 90-minute period. This relatively rapid action
shown that ivabradine provides an effective alternative to slow the decreases the required observation period for untoward side effects
heart rate in patients with inappropriate sinus tachycardia. The drug following drug administration. Sinus bradycardia and hypotension
is administered in doses of 5–10 mg as needed. Visual disturbances are the only noticeable cardiovascular adverse effects.
attributable to the block of the I channels in the retina have been
f
described. This side effect is limited by the low permeability of
ivabradine in the blood-brain barrier. Ivabradine is in use elsewhere MAGNESIUM
but is currently approved only for use in heart failure in the USA.
Originally used for patients with digitalis-induced arrhythmias
who were hypomagnesemic, magnesium infusion has been found
RANOLAZINE to have antiarrhythmic effects in some patients with normal
serum magnesium levels. The mechanisms of these effects are
+
Ranolazine was originally developed as an antianginal agent. Sub- not known, but magnesium is recognized to influence Na /
+
sequent studies have demonstrated antiarrhythmic properties that K -ATPase, sodium channels, certain potassium channels, and
are dependent on the blockade of multiple ion channels. The drug calcium channels. Magnesium therapy appears to be indicated in
+
blocks the early I and the late component of the Na current, patients with digitalis-induced arrhythmias if hypomagnesemia
Na
I NaL , the latter having a tenfold higher sensitivity to the drug. The is present; it is also indicated in some patients with torsades de
block of both components of the sodium current is frequency- and pointes even if serum magnesium is normal. The usual dosage is
voltage-dependent. Ranolazine also blocks the rapid component of 1 g (as sulfate) given intravenously over 20 minutes and repeated
+
the delayed rectifier K current I . The blockade of both I NaL and once if necessary. A full understanding of the action and indica-
Kr
I results in opposing effects on the APD; the net effect depends tions for the use of magnesium as an antiarrhythmic drug awaits
Kr
on the relative contribution of I NaL and I to the APD. In normal further investigation.
Kr