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

binds to the cytoplasmic bridge between domain III (IIIS) and
domain IV (IVS), and the dihydropyridine Ca 2+ channel blockers
(nifedipine and several others) bind to transmembrane segments of
both domains III and IV. These three separate receptor sites are
linked allosterically.
Pharmacological Properties
Cardiovascular Effects. Actions in Vascular Tissue. Although
there is some involvement of Na + currents, depolarization
of vascular smooth muscle cells depends primarily
on the influx of Ca 2+ . At least three distinct mechanisms
may be responsible for contraction of vascular smooth
muscle cells. First, voltage-sensitive Ca 2+ channels open
in response to depolarization of the membrane, and
extracellular Ca 2+ moves down its electrochemical gradient
into the cell. After closure of Ca 2+ channels, a finite
period of time is required before the channels can open
again in response to a stimulus. Second, agonist-induced
contractions that occur without depolarization of the
membrane result from stimulation of the G q
–PLC–IP 3
pathway, resulting in the release of intracellular Ca 2+
from the sarcoplasmic reticulum (Chapter 3). This
receptor-mediated release of intracellular Ca 2+ may trigger
further influx of extracellular Ca 2+ . Third, receptoroperated
Ca 2+ channels allow the entry of extracellular
Ca 2+ in response to receptor occupancy.
An increase in cytosolic Ca 2+ results in enhanced
binding of Ca 2+ to calmodulin. The Ca 2+ –calmodulin
complex in turn activates myosin light-chain kinase,
with resulting phosphorylation of the myosin light
chain. Such phosphorylation promotes interaction
between actin and myosin and leads to contraction of
smooth muscle. Ca 2+ channel antagonists inhibit the
voltage-dependent Ca 2+ channels in vascular smooth
muscle at significantly lower concentrations than are
required to interfere with the release of intracellular
Ca 2+ or to block receptor-operated Ca 2+ channels. All
Ca 2+ channel blockers relax arterial smooth muscle, but
they have a less pronounced effect on most venous beds
and hence do not affect cardiac preload significantly.
Actions in Cardiac Cells. The mechanisms involved in
excitation–contraction coupling in the cardiac muscle
differ from those in vascular smooth muscle in that a
portion of the two inward currents is carried by Na +
through the fast channel in addition to that carried by
Ca 2+ through the slow channel. Within the cardiac
myocyte, Ca 2+ binds to troponin, relieving the inhibitory
effect of troponin on the contractile apparatus and permitting
a productive interaction of actin and myosin,
leading to contraction. Thus, Ca 2+ channel blockers can
produce a negative inotropic effect. Although this is true
of all classes of Ca 2+ channel blockers, the greater
degree of peripheral vasodilation seen with the dihydropyridines
is accompanied by a sufficient baroreflexmediated
increase in sympathetic tone to overcome the
negative inotropic effect. Diltiazem also may inhibit
mitochondrial Na + –Ca 2+ exchange (Schwartz, 1992).
In the SA and AV nodes, depolarization largely depends on
the movement of Ca 2+ through the slow channel. The effect of a Ca 2+
channel blocker on AV conduction and on the rate of the sinus node
pacemaker depends on whether or not the agent delays the recovery
of the slow channel (Schwarz, 1992). Although nifedipine reduces
the slow inward current in a dose-dependent manner, it does not
affect the rate of recovery of the slow Ca 2+ channel. The channel
blockade caused by nifedipine and related dihydropyridines also
shows little dependence on the frequency of stimulation. At doses
used clinically, nifedipine does not affect conduction through the AV
node. In contrast, verapamil not only reduces the magnitude of the
Ca 2+ current through the slow channel but also decreases the rate of
recovery of the channel. In addition, channel blockade caused by
verapamil (and to a lesser extent by diltiazem) is enhanced as the
frequency of stimulation increases, a phenomenon known as frequency
dependence or use dependence. Verapamil and diltiazem
depress the rate of the sinus node pacemaker and slow AV conduction;
the latter effect is the basis for their use in the treatment of
supraventricular tachyarrhythmias (see Chapter 29). Bepridil, like
verapamil, inhibits both slow inward Ca 2+ current and fast inward
Na + current. It has a direct negative inotropic effect. Its electrophysiological
properties lead to slowing of the heart rate, prolongation
of the AV nodal effective refractory period, and importantly, prolongation
of the QTc interval. Particularly in the setting of hypokalemia,
the last effect can be associated with torsades de pointes, a potentially
lethal ventricular arrhythmia (see Chapter 29).
Hemodynamic Effects. All the Ca 2+ channel blockers
approved for clinical use decrease coronary vascular
resistance and can lead to an increase in coronary blood
flow. The dihydropyridines are more potent vasodilators
in vivo and in vitro than verapamil, which is more
potent than diltiazem. The hemodynamic effects of
these agents vary depending on the route of administration
and the extent of left ventricular dysfunction.
Nifedipine given intravenously increases forearm
blood flow with little effect on venous pooling; this indicates
a selective dilation of arterial resistance vessels.
The decrease in arterial blood pressure elicits sympathetic
reflexes, with resulting tachycardia and positive
inotropy. Nifedipine also has direct negative inotropic
effects in vitro. However, nifedipine relaxes vascular
smooth muscle at significantly lower concentrations
than those required for prominent direct effects on the
heart. Thus, arteriolar resistance and blood pressure are
lowered, contractility and segmental ventricular function
are improved, and heart rate and cardiac output are
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION