Page 262 - Basic _ Clinical Pharmacology ( PDFDrive )

248 SECTION III Cardiovascular-Renal Drugs

POTASSIUM Pretreatment Evaluation
Several important steps must be taken before initiation of any
The significance of the potassium ion concentrations inside and antiarrhythmic therapy:
outside the cardiac cell membrane was discussed earlier in this
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chapter. The effects of increasing serum K can be summarized 1. Eliminate the cause. Precipitating factors must be recognized
as (1) a resting potential depolarizing action and (2) a membrane and eliminated if possible. These include not only abnormali-
potential stabilizing action, the latter caused by increased potas- ties of internal homeostasis, such as hypoxia or electrolyte
sium permeability. Hypokalemia results in an increased risk of abnormalities (especially hypokalemia or hypomagnesemia),
early and delayed afterdepolarizations, and ectopic pacemaker but also drug therapy and underlying disease states such as
activity, especially in the presence of digitalis. Hyperkalemia hyperthyroidism or cardiac disease. It is important to separate
depresses ectopic pacemakers (severe hyperkalemia is required this abnormal substrate from triggering factors, such as
to suppress the SA node) and slows conduction. Because both myocardial ischemia or acute cardiac dilation, which may be
insufficient and excess potassium are potentially arrhythmogenic, treatable and reversible by different means.
potassium therapy is directed toward normalizing potassium gra- 2. Make a firm diagnosis. A firm arrhythmia diagnosis should be
dients and pools in the body. established. For example, the misuse of verapamil in patients
with ventricular tachycardia mistakenly diagnosed as supraven-
DRUGS THAT ACT ON CHLORIDE tricular tachycardia can lead to catastrophic hypotension and
CHANNELS cardiac arrest. As increasingly sophisticated methods to charac-
terize underlying arrhythmia mechanisms become available and
are validated, it may be possible to direct certain drugs toward
Several types of chloride channels have been identified. At present, specific arrhythmia mechanisms.
no drugs acting on chloride channels are in clinical use for cardiac
indications. However, the chloride channels involved in cystic 3. Determine the baseline condition. Underlying heart disease is
fibrosis and other conditions are of great clinical importance a critical determinant of drug selection for a particular arrhyth-
and have been the subject of intensive research (see Box: A Cystic mia in a particular patient. A key question is whether the heart
Fibrosis Link in the Heart?). is structurally abnormal. Few antiarrhythmic drugs have
documented safety in patients with congestive heart failure or
ischemic heart disease. In fact, some drugs pose a documented
■ PRINCIPLES IN THE CLINICAL proarrhythmic risk in certain disease states, eg, class 1C drugs in
USE OF ANTIARRHYTHMIC patients with ischemic heart disease. A reliable baseline should
be established against which to judge the efficacy of any subse-
AGENTS quent antiarrhythmic intervention. Several methods are now
available for such baseline quantification. These include pro-
The margin between efficacy and toxicity is particularly narrow longed ambulatory monitoring, electrophysiologic studies that
for antiarrhythmic drugs. Risks and benefits must be carefully reproduce a target arrhythmia, reproduction of a target arrhyth-
considered (see Box: Antiarrhythmic Drug-Use Principles Applied mia by treadmill exercise, or the use of transtelephonic monitor-
to Atrial Fibrillation). ing for recording of sporadic but symptomatic arrhythmias.

A Cystic Fibrosis Link in the Heart?

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Cystic fibrosis is a serious autosomal-recessive inherited disease CFTR Cl channels, has recently been approved by the FDA for
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that causes defective Cl secretion in the lung. The defective the treatment of diarrhea induced by antiviral drugs.
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Cl secretion is caused by mutations of the CFTR (cystic fibrosis Surprisingly, recent studies have demonstrated the expression
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transmembrane conductance regulator) Cl channel, resulting of CFTR Cl channels in the heart, where they appear to modulate
in the generation of thick and dehydrated mucus and chronic action potential duration and membrane potential during sym-
bacterial infections. Although more than 1600 types of muta- pathetic stimulation. Various animal models of cardiac disease
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tions have been identified in the CFTR gene, most current have suggested that CFTR Cl channels may play a role in hyper-
therapies to treat cystic fibrosis lung disease target downstream trophy and heart failure and may be cardioprotective against
consequences of the disease that are secondary to loss of CFTR ischemia and reperfusion damage. The physiologic and patho-
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Cl channel function. Recently, the FDA approved the use of a physiologic roles of CFTR Cl channels in human heart remain to
new CFTR potentiator drug, ivacaftor, for treatment of a subset be defined clearly. It is not known if there are significant cardiac
of cystic fibrosis patients (4%) with a specific (G551D) mutation. alterations in cystic fibrosis patients, and the possible effects of
Ivacaftor improves CFTR channel function, resulting in better lung the two new CFTR channel modulators, ivacaftor and crofelemer,
function. Another CFTR modulator, crofelemer, which inhibits on heart function remain to be determined.