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

804 recognition of digoxin toxicity remains an important consideration
in the differential diagnosis of arrhythmias, and
neurologic or gastrointestinal symptoms in patients receiving
cardiac glycosides. An antidote, digoxin immune Fab
(DIGIBIND, DIGIFAB), is available to treat toxicity.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Among the more common electrophysiologic manifestations
of digoxin toxicity are ectopic beats originating from the AV junction
or ventricle, first- degree AV block, abnormally slow ventricular
rate response to atrial fibrillation, or an accelerated AV junctional
pacemaker. When present, only dosage adjustment and appropriate
monitoring are usually necessary. Sinus bradycardia, sinoatrial arrest
or exit block, and second- or third- degree AV conduction delay
requiring atropine or temporary ventricular pacing are uncommon.
Unless in the setting of high- degree AV block, potassium administration
should be considered for patients with evidence of increased
AV junctional or ventricular automaticity even if serum K + levels are
in the normal range. Lidocaine or phenytoin, which have minimal
effects on AV conduction, may be used for the treatment of digoxininduced
ventricular arrhythmias that threaten hemodynamic compromise
(see Chapter 29). Electrical cardioversion carries an
increased risk of inducing severe rhythm disturbances in patients
with overt digitalis toxicity and should be used with particular caution.
Note, too, that inhibition of the Na + ,K + -ATPase activity of
skeletal muscle can cause hyperkalemia. An effective antidote for
life- threatening digoxin (or digitoxin) toxicity is available in the
form of anti- digoxin immunotherapy. Purified Fab fragments from
ovine anti- digoxin antisera (DIGIBIND) are usually dosed by the estimated
total dose of digoxin ingested in order to achieve a fully neutralizing
effect. For a more comprehensive review of the treatment of
digitalis toxicity, see Kelly and Smith (1992).
β Adrenergic and Dopaminergic Agonists
In the setting of severely decompensated CHF from
reduced cardiac output, the principal focus of initial therapy
is to increase myocardial contractility. Dopamine and
dobutamine are positive inotropic agents most often
used to accomplish this. These drugs provide short- term
circulatory support in advanced CHF via stimulation of
cardiac myocyte dopamine (D 1
) and βadrenergic receptors
that stimulate the G s
- adenylyl cyclase- cyclic
AMP–PKA pathway. The catalytic subunit of PKA
phosphorylates a number of substrates that enhance
Ca +2 -dependent myocardial contraction and accelerate
relaxation (Figure 28–5). Isoproterenol, epinephrine,
and norepinephrine are useful in certain circumstances
but have little role in routine CHF management. Indeed,
inotropic agents that elevate cardiac cell cyclic AMP are
consistently associated with increased risks of hospitalization
and death, particularly in patients with NYHA
class IV. At the cellular level, enhanced cyclic AMP levels
have been associated with apoptosis (Brunton, 2005;
Yan et al., 2007). The basic pharmacology of adrenergic
agonists is discussed in Chapter 12.
Dopamine. Dopamine is an endogenous catecholamine
with only limited utility in the treatment of most patients
with cardiogenic circulatory failure. The pharmacologic
and hemodynamic effects of dopamine are concentration
dependent. Low doses (≤2 μg/kg lean body
mass/min) induces cyclic AMP–dependent vascular
smooth muscle vasodilation. In addition, activation of
D 2
receptors on sympathetic nerves in the peripheral circulation
at these concentrations also inhibits NE release
and reduces α adrenergic stimulation of vascular smooth
muscle, particularly in splanchnic and renal arterial
beds. Therefore, low- dose dopamine infusion often is
used to increase renal blood flow and thereby maintain
an adequate glomerular filtration rate in hospitalized
CHF patients with impaired renal function refractory to
diuretics. Dopamine also exhibits a pro- diuretic effect
directly on renal tubular epithelial cells that contributes
to volume reduction.
At intermediate infusion rates (2-5 μg/kg/min),
dopamine directly stimulates cardiac α receptors and
vascular sympathetic neurons that enhance myocardial
contractility and neural NE release. At higher infusion
rates (5-15 μg/kg/min), α adrenergic receptor stimulation–mediated
peripheral arterial and venous constriction
occurs. This may be desirable in patients with
critically reduced arterial pressure or in those with circulatory
failure from severe vasodilation (e.g., sepsis,
anaphylaxis). However, high- dose dopamine infusion
has little role in the treatment of patients with primary
cardiac contractile dysfunction; in this setting,
increased vasoconstriction will lead to increased afterload
and worsening of LV performance. Tachycardia,
which is more pronounced with dopamine than with
dobutamine, may actually provoke ischemia (and
ischemia- induced malignant arrhythmias) in patients
with coronary artery disease.
Dobutamine. Dobutamine is the β agonist of choice for
the management of CHF patients with systolic dysfunction.
In the formulation available for clinical use, dobutamine
is a racemic mixture that stimulates both β 1
and
β 2
receptor subtypes. In addition, the (–) enantiomer is
an agonist for α adrenergic receptors, whereas the (+)
enantiomer is a weak, partial agonist. At infusion rates
that result in a positive inotropic effect in humans, the
β 1
adrenergic effect in the myocardium predominates.
In the vasculature, the α adrenergic agonist effect of the
(–) enantiomer appears to be offset by the (+) enantiomer
and vasodilating effects of β 2
receptor stimulation.
Thus, the principal hemodynamic effect of
dobutamine is an increase in stroke volume from