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

Absorption, Fate, and Excretion. Although the absorption
of these agents is nearly complete after oral administration,
their bioavailability is reduced, in some cases
markedly, by first-pass hepatic metabolism. The effects
of these drugs are evident within 30-60 minutes of an
oral dose, with the exception of the more slowly
absorbed and longer-acting agents amlodipine, isradipine,
and felodipine. Sustained-release forms of the Ca 2+
channel blockers are used clinically to reduce the number
of daily doses needed to maintain therapeutic drug
levels, and in the case of nifedipine, sustained-release
forms of the drug appear to mitigate the reflex tachycardia
sometimes seen following oral administration.
Intravenous administration of diltiazem or verapamil
leads to a rapid therapeutic response.
These agents all are bound extensively to plasma proteins
(70-98%); their elimination half-lives vary widely and range from
1.3-64 hours. During repeated oral administration, bioavailability
and t 1/2
may increase because of saturation of hepatic metabolism.
The bioavailability of some of these drugs may be increased by
grapefruit juice, likely through inhibition of enzyme CYP3A4
expressed in the small bowel. A major metabolite of diltiazem is
desacetyldiltiazem, which has about one-half of diltiazem’s potency
as a vasodilator. N-Demethylation of verapamil results in production
of norverapamil, which is biologically active but much less
potent than the parent compound. The t 1/2
of norverapamil is ~10
hours. The metabolites of the dihydropyridines are inactive or
weakly active. In patients with hepatic cirrhosis, the bioavailabilities
and half-lives of the Ca 2+ channel blockers may be increased,
and dosage should be decreased accordingly. The half-lives of these
agents also may be longer in older patients. Except for diltiazem and
nifedipine, all the Ca 2+ channel blockers are administered as racemic
mixtures (Abernethy and Schwartz, 1999).
Toxicity and Untoward Responses. The profile of adverse reactions to
the Ca 2+ channel blockers varies among the drugs in this class. Patients
receiving immediate-release capsules of nifedipine develop headache,
flushing, dizziness, and peripheral edema. However, short-acting
formulations of nifedipine are not appropriate in the long-term treatment
of angina or hypertension. Dizziness and flushing are much
less of a problem with the sustained-release formulations and with
the dihydropyridines having a long t 1/2
and relatively constant concentrations
of drug in plasma. Peripheral edema may occur in some
patients with Ca 2+ channel blockers but is not the result of generalized
fluid retention; it most likely results from increased hydrostatic
pressure in the lower extremities owing to precapillary dilation and
reflex postcapillary constriction (Epstein and Roberts, 2009). Some
other adverse effects of these drugs are due to actions in nonvascular
smooth muscle. Contraction of the lower esophageal sphincter is
inhibited by the Ca 2+ channel blockers. For example, Ca 2+ channel
blockers can cause or aggravate gastroesophageal reflux.
Constipation is a common side effect of verapamil, but it occurs less
frequently with other Ca 2+ channel blockers. Urinary retention is a
rare adverse effect. Uncommon adverse effects include rash and elevations
of liver enzymes. Worsened myocardial ischemia has been
observed with nifedipine (Egstrup and Andersen, 1993). Worsening
of angina was observed in patients with an angiographically demonstrable
coronary collateral circulation. The worsening of angina may
have resulted from excessive hypotension and decreased coronary
perfusion, selective coronary vasodilation in nonischemic regions of
the myocardium in a setting where vessels perfusing ischemic
regions were already maximally dilated (i.e., coronary steal), or an
increase in O 2
demand owing to increased sympathetic tone and
excessive tachycardia. In a study of monotherapy with an immediate-release
formulation of nisoldipine, the dihydropyridine was not
superior to placebo and was associated with a trend toward an
increased incidence of serious adverse events, a process termed
proischemia (Waters, 1991).
Although bradycardia, transient asystole, and exacerbation
of heart failure have been reported with verapamil, these responses
usually have occurred after intravenous administration of verapamil
in patients with disease of the SA node or AV nodal conduction disturbances
or in the presence of β blockade. The use of intravenous
verapamil with an intravenous β adrenergic receptor antagonist is
contraindicated because of the increased propensity for AV block
and/or severe depression of ventricular function. Patients with ventricular
dysfunction, SA or AV nodal conduction disturbances, and
systolic blood pressures below 90 mm Hg should not be treated with
verapamil or diltiazem, particularly intravenously. Some Ca 2+ channel
antagonists can cause an increase in the concentration of digoxin
in plasma, although toxicity from the cardiac glycoside rarely develops.
The use of verapamil to treat digitalis toxicity thus is contraindicated;
AV nodal conduction disturbances may be exacerbated.
Several studies have raised concerns about the long-term
safety of short-acting nifedipine (Opie et al., 2000). The proposed
mechanism for this adverse effect lies in abrupt vasodilation with
reflex sympathetic activation. There does not appear to be either significant
reflex tachycardia or long-term adverse outcomes from treatment
with sustained-release forms of nifedipine or with the
dihydropyridine Ca 2+ blockers such as amlodipine or felodipine,
which have more favorable (slower) pharmacokinetics.
Important drug–drug interactions may be encountered with
Ca 2+ channel blockers. Verapamil blocks the P-glycoprotein drug
transporter. Both the renal and hepatic disposition of digoxin occurs
via this transporter. Accordingly, verapamil inhibits the elimination
of digoxin and other drugs that are cleared from the body by the
P-glycoprotein (see Chapter 5). When used with quinidine, Ca 2+
channel blockers may cause excessive hypotension, particularly in
patients with idiopathic hypertrophic subaortic stenosis.
Therapeutic Uses
Variant Angina. Variant angina results from reduced
blood flow (a consequence of transient localized vasoconstriction)
rather than increased oxygen demand.
Controlled clinical trials have demonstrated efficacy of
the Ca 2+ channel blocking agents for the treatment of
variant angina (Gibbons et al., 2003). These drugs can
attenuate ergonovine-induced vasospasm in patients
with variant angina, which suggests that protection in
variant angina is due to coronary dilation rather than to
alterations in peripheral hemodynamics.
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION