DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 29–4
Patient-Specific Anti-Arrhythmic Drug
Contraindications
CONDITION
EXCLUDE/USE WITH CAUTION
Cardiac
Heart failure
Disopyramide, flecainide
Sinus or AV node Digoxin, verapamil,
dysfunction
diltiazem, β receptor
antagonists, amiodarone
Wolff–Parkinson–White Digoxin, verapamil,
syndrome (risk of diltiazem
extremely rapid rate if
atrial fibrillation
develops)
Infranodal conduction Na + channel blockers,
disease
amiodarone
Aortic/subaortic stenosis Bretylium
History of myocardial Flecainide
infarction
Prolonged QT interval Quinidine, procainamide,
disopyramide, sotalol,
dofetilide, ibutilide,
amiodarone
Cardiac transplant Adenosine
Noncardiac
Diarrhea
Prostatism, glaucoma
Arthritis
Lung disease
Tremor
Constipation
Asthma, peripheral
vascular disease,
hypoglycemia
Quinidine
Disopyramide
Chronic procainamide
Amiodarone
Mexiletine
Verapamil
β blockers, propafenone
atrial fibrillation, the ventricular response can be extremely rapid
and can be accelerated paradoxically by AV nodal blocking drugs
such as digitalis or Ca 2+ channel blockers; deaths owing to drug
therapy have been reported under these circumstances.
The frequency and reproducibility of arrhythmia should be
established prior to initiating therapy because inherent variability in
the occurrence of arrhythmias can be confused with a beneficial or
adverse drug effect. Techniques for this assessment include recording
cardiac rhythm for prolonged periods or evaluating the response
of the heart to artificially induced premature beats. It is important to
recognize that drug therapy may be only partially effective. A
marked decrease in the duration of paroxysms of atrial fibrillation
may be sufficient to render a patient asymptomatic even if an occasional
episode still can be detected.
3. Minimize Risks
Anti-Arrhythmic Drugs Can Cause Arrhythmias. One well-recognized
risk of anti-arrhythmic therapy is the possibility of provoking
new arrhythmias, with potentially life-threatening consequences.
Anti-arrhythmic drugs can provoke arrhythmias by different mechanisms
(Table 29–1). These drug-provoked arrhythmias must be recognized
because further treatment with anti-arrhythmic drugs often
exacerbates the problem, whereas withdrawal of the causative agent
often is curative. Thus, establishing a precise diagnosis is critical,
and targeting therapies at underlying mechanisms of the arrhythmias
may be required. For example, treating a ventricular tachycardia with
verapamil not only may be ineffective but also can cause catastrophic
cardiovascular collapse (Stewart et al., 1986).
Monitoring of Plasma Concentration. Some adverse effects of antiarrhythmic
drugs result from excessive plasma drug concentrations.
Measuring plasma concentration and adjusting the dose to maintain the
concentration within a prescribed therapeutic range may minimize some
adverse effects. In many patients, serious adverse reactions relate to
interactions involving anti-arrhythmic drugs (often at usual plasma concentrations),
transient factors such as electrolyte disturbances or myocardial
ischemia, and the type and extent of the underlying heart disease
(Ruskin, 1989; Roden, 1994). Factors such as generation of unmeasured
active metabolites, variability in elimination of enantiomers (which may
exert differing pharmacologic effects), and disease- or enantiomer-specific
abnormalities in drug binding to plasma proteins can complicate the
interpretation of plasma drug concentrations.
Patient-Specific Contraindications. Another way to minimize the
adverse effects of anti-arrhythmic drugs is to avoid certain drugs in
certain patient subsets altogether. For example, patients with a history
of congestive heart failure are particularly prone to develop heart failure
during disopyramide therapy. In other cases, adverse effects of
drugs may be difficult to distinguish from exacerbations of underlying
disease. Amiodarone may cause interstitial lung disease; its use therefore
is undesirable in a patient with advanced pulmonary disease in
whom the development of this potentially fatal adverse effect would
be difficult to detect. Specific diseases that constitute relative or
absolute contraindications to specific drugs are listed in Table 29–4.
4. Consider the Electrophysiology
of the Heart as a “Moving Target”
Cardiac electrophysiology varies dynamically in response to
external influences such as changing autonomic tone, myocardial
ischemia, and myocardial stretch (Priori et al., 1999). For example,
myocardial ischemia results in changes in extracellular K +
that make the resting potential less negative, inactivate Na + channels,
decrease Na + current, and slow conduction (Weiss et al.,
1991). In addition, myocardial ischemia can result in the formation
and release of metabolites such as lysophosphatidylcholine,
which can alter ion channel function; ischemia also may activate
channels that otherwise are quiescent, such as the ATP-inhibited
K + channels. Thus, in response to myocardial ischemia, a normal
heart may display changes in resting potential, conduction velocity,
intracellular Ca 2+ concentrations, and repolarization, any one of
which then may create arrhythmias or alter response to antiarrhythmic
therapy.
833
CHAPTER 29
ANTI-ARRHYTHMIC DRUGS