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

288 Therapeutic Uses and Status. NE (LEVOPHED, others) is used as a
vasoconstrictor to raise or support blood pressure under certain intensive
care conditions. The use of it and other sympathomimetic
amines in shock is discussed later in this chapter. In the treatment of
low blood pressure, the dose is titrated to the desired pressor
response.
Dopamine
Dopamine (3,4-dihydroxyphenylethylamine, DA)
(Table 12–1) is the immediate metabolic precursor of
SECTION II
NEUROPHARMACOLOGY
NE and epinephrine; it is a central neurotransmitter
particularly important in the regulation of movement
(Chapters 14, 16, and 22) and possesses important intrinsic
pharmacological properties. In the periphery, it is synthesized
in epithelial cells of the proximal tubule and is
thought to exert local diuretic and natriuretic effects. DA
is a substrate for both MAO and COMT and thus is ineffective
when administered orally. Classification of DA
receptors is described in Chapter 13.
Pharmacological Properties.
Cardiovascular Effects. The cardiovascular effects of DA
are mediated by several distinct types of receptors that
vary in their affinity for DA (Chapter 13). At low concentrations,
the primary interaction of DA is with vascular
D 1
receptors, especially in the renal, mesenteric,
and coronary beds. By activating adenylyl cyclase and
raising intra-cellular concentrations of cyclic AMP, D 1
receptor stimulation leads to vasodilation. Infusion of
low doses of DA causes an increase in glomerular filtration
rate, renal blood flow, and Na + excretion.
Activation of D 1
receptors on renal tubular cells
decreases Na + transport by cAMP-dependent and
cAMP-independent mechanisms. Increasing cAMP
production in the proximal tubular cells and the
medullary part of the thick ascending limb of the loop
of Henle inhibits the Na + -H + exchanger and the Na + ,K + -
ATPase pump. The renal tubular actions of DA that
cause natriuresis may be augmented by the increase in
renal blood flow and the small increase in the glomerular
filtration rate that follow its administration. The
resulting increase in hydrostatic pressure in the peritubular
capillaries and reduction in oncotic pressure
may contribute to diminished reabsorption of Na + by
the proximal tubular cells. As a consequence, DA has
pharmacologically appropriate effects in the management
of states of low cardiac output associated with
compromised renal function, such as severe congestive
heart failure.
At somewhat higher concentrations, DA exerts a positive
inotropic effect on the myocardium, acting on β 1
adrenergic receptors.
DA also causes the release of NE from nerve terminals, which
contributes to its effects on the heart. Tachycardia is less prominent
during infusion of DA than of isoproterenol (discussed later). DA
usually increases systolic blood pressure and pulse pressure and
either has no effect on diastolic blood pressure or increases it
slightly. Total peripheral resistance usually is unchanged when low
or intermediate doses of DA are given, probably because of the ability
of DA to reduce regional arterial resistance in some vascular beds,
such as mesenteric and renal, while causing only minor increases in
others. At high concentrations, DA activates vascular α 1
receptors,
leading to more general vasoconstriction.
Other Effects. Although there are specific DA receptors in the CNS,
injected DA usually has no central effects because it does not readily
cross the blood-brain barrier.
Precautions, Adverse Reactions, and Contraindications.
Before DA is administered to patients in shock, hypovolemia
should be corrected by transfusion of whole blood,
plasma, or other appropriate fluid. Untoward effects due to
overdosage generally are attributable to excessive sympathomimetic
activity (although this also may be the
response to worsening shock). Nausea, vomiting, tachycardia,
anginal pain, arrhythmias, headache, hypertension,
and peripheral vasoconstriction may be encountered during
dopamine infusion. Extravasation of large amounts of
DA during infusion may cause ischemic necrosis and
sloughing. Rarely, gangrene of the fingers or toes has followed
prolonged infusion of the drug.
DA should be avoided or used at a much reduced
dosage (one-tenth or less) if the patient has received a
MAO inhibitor. Careful adjustment of dosage also is
necessary in patients who are taking tricyclic antidepressants.
Therapeutic Uses. DA is used in the treatment of severe
congestive heart failure, particularly in patients with
oliguria and low or normal peripheral vascular resistance.
The drug also may improve physiological parameters
in the treatment of cardiogenic and septic shock.
While DA may acutely improve cardiac and renal function
in severely ill patients with chronic heart disease or
renal failure, there is relatively little evidence supporting
long-term benefit in clinical outcome (Marik and
Iglesias, 1999). The management of shock is discussed
later.
Dopamine hydrochloride is used only intravenously, preferably
into a large vein to prevent perivasular infiltration; extravasation
may cause necrosis and sloughing of the surrounding tissue. The use
of a calibrated infusion pump or other device capable of controlling
the rate of flow is necessary. The drug initially is administered at a
rate of 2-5 μg/kg per minute; this rate may be increased gradually up
to 20-50 μg/kg per minute or more as the clinical situation dictates.
During the infusion, patients require clinical assessment of myocardial
function, perfusion of vital organs such as the brain, and the production
of urine. Most patients should receive intensive care, with