The defect that causes anginal pain is inadequate coronary oxygen
delivery relative to the myocardial oxygen requirement. At present,
this defect is corrected by either increasing oxygen delivery or
by reducing the oxygen requirement (Figure 8–3).
Currently popular pharmacologic therapies include the nitrates,
the calcium channel blockers, and the β-receptor antagonists. These drug classes all reduce the oxygen requirement
in atherosclerotic angina. Nitrates and calcium channel blockers,
but not β-receptor antagonists, can also increase
oxygen delivery by reducing vasospasm, a useful effect only in vasospastic
angina. Myocardial revascularization corrects coronary obstruction
either by bypass grafting or by angioplasty (enlargement of the
coronary lumen by means of a special catheter).
The therapy for unstable angina differs from that of exertional
or vasospastic angina. Urgent angioplasty is the treatment of choice
in most patients with unstable angina, and platelet clotting is
the major target of drug therapy. The antithrombotics, eptifibatide and tirofiban, are
used in this condition (Chapter 11). Intravenous nitroglycerin is
sometimes of value.
The drugs of this pharmacologic class are sometimes referred
to as “organic nitrates.” Nitroglycerin is the prototypical
agent of this class and is the most important of the therapeutic
nitrates. Nitroglycerin, also known as glyceryl trinitrate, is available
in several forms (Table 8–1). Because treatment of acute
attacks and prevention of attacks are both important aspects of
therapy, the pharmacokinetics of these different dosage forms are
Table 8–1. Pharmacokinetically
Distinct Forms of Nitrate Drugs Used in Angina ||Download (.pdf)
Table 8–1. Pharmacokinetically
Distinct Forms of Nitrate Drugs Used in Angina
|Category||Example||Duration of Action|
|Short||Sublingual nitroglycerin or isosorbide dinitrate||10–30 min (isosorbide dinitrate has a somewhat longer
half-life than nitroglycerin)|
|Intermediate||Oral regular or sustained-release nitroglycerin or isosorbide dinitrate
or mononitrate||4–8 h (much of the effect is due to active metabolites)|
|Long||Transdermal nitroglycerin patch|| 8–10 h (blood levels may persist for 24 h, but
tolerance limits the duration of action)|
Glyceryl trinitrate is rapidly denitrated in the liver and in
smooth muscle, first to glyceryl dinitrate and more slowly to glyceryl
mononitrate. The dinitrate retains a significant vasodilating effect; the
mononitrate is much less active. Because of the high enzyme activity
in the liver, the first-pass effect for nitroglycerin is large—about
90%. The efficacy of swallowed nitroglycerin probably results
from the high levels of glyceryl dinitrate in the blood. The effects
of sublingual nitroglycerin are mainly the result of the unchanged
drug because this route avoids the first-pass effect (Chapter 3).
Other nitrates are similar to nitroglycerin in their pharmacokinetics
and pharmacodynamics. Isosorbide dinitrate is
another commonly used nitrate, and is available in sublingual and
oral forms. Isosorbide dinitrate is rapidly denitrated in the liver
and smooth muscle to isosorbide mononitrate, which is also active. Isosorbide mononitrate is available
as a separate drug for oral use. Several other nitrates are available
for oral use and, like the oral nitroglycerin preparation, have
an intermediate duration of action of 4 to 6 hours. Parenteral passive
transdermal delivery is also available. Patches or ointment containing
nitroglycerin provide maintenance therapy by providing consistent
blood levels for hours at a time.
Denitration of the nitrates within smooth muscle cells releases nitric oxide (NO), which stimulates
guanylyl cyclase. Increased guanylyl cyclase activity increases
the second messenger cyclic guanosine monophosphate (cGMP) and leads
to smooth muscle relaxation by dephosphorylation of myosin light
chain phosphate (Figure 8–4). This mechanism is identical to
that of the direct-acting vasodilator nitroprusside (Chapter 7).
Mechanism of vasodilation by nitrates and drugs used
in erectile dysfunction. Nitrate-stimulated guanylyl cyclase activity
increases cyclic guanosine monophosphate (cGMP) resulting in smooth muscle
relaxation and vasodilation. Sildenafil and similar drugs used in
erectile dysfunction inhibit a phosphodiesterase isoform (PDE-5)
that metabolizes cGMP in smooth muscle of the corpora cavernosa.
The increased cGMP relaxes the erectile smooth muscle, allowing
for greater inflow of blood and a more effective and prolonged erection.
This effect also occurs to a lesser extent in the smooth muscle
of other tissues, especially the vessels. Because nitrates and PDE-5 inhibitors
both increase cGMP by complementary mechanisms, they can have a
synergistic effect on decreasing blood pressure.
The main beneficial
effects of these drugs in the treatment of angina are on the cardiovascular
system (Table 8–2); however, additional effects in other
tissues are also observed. In the cardiovascular system, smooth
muscle relaxation leads to peripheral venodilation, which results
in reduced cardiac size and cardiac output through reduced preload. Reduced
afterload, from arteriolar dilation, may contribute to an increase
in ejection volume and a further decrease in cardiac size. The veins
are the most sensitive to the action of nitrates, arteries less
so, and arterioles are least sensitive. Venodilation leads to a
decrease in venous return to the heart (preload) and subsequent
reduction of intracardiac volume during diastole. The decrease in
diastolic dilation reduces myocardial fiber tension. This decrease
in fiber tension reduces myocardial oxygen demand. Arteriolar dilation
leads to reduced peripheral resistance and blood pressure. These
changes contribute to an overall reduction in myocardial fiber tension,
oxygen consumption, and the double product. Thus, the primary mechanism
for therapeutic benefit in atherosclerotic angina is reduction of
the oxygen requirement. An increase in coronary flow via collateral
vessels in ischemic areas has also been proposed. In vasospastic
angina, a reversal of coronary spasm and increased flow can be demonstrated.
Nitrates have no direct effects on cardiac muscle, but a significant
reflex tachycardia and increased force of contraction are predictable
when nitroglycerin reduces the blood pressure. In other organs,
nitrates relax the smooth muscle of the bronchi, gastrointestinal
tract, and genitourinary tract, but these effects are too small
to be clinically useful. Intravenous nitroglycerin is sometimes
used in unstable angina and has been demonstrated to reduce platelet
aggregation. There are no significant effects on other tissues.
Table 8–2. Beneficial
and Deleterious Cardiovascular Effects of Nitrates in the Treatment
of Angina ||Download (.pdf)
Table 8–2. Beneficial
and Deleterious Cardiovascular Effects of Nitrates in the Treatment
|Potential Beneficial Effects|
|Decreased ventricular volume||Decreased myocardial oxygen requirement|
|Decreased arterial pressure|
|Decreased ejection time|
|Vasodilation of epicardial coronary arteries||Relief of coronary artery spasm|
|Increased collateral flow||Improved perfusion to ischemic myocardium|
|Decreased left ventricular diastolic pressure||Improved subendocardial perfusion|
|Potential Deleterious Effects|
|Reflex tachycardia||Increased myocardial oxygen requirement|
|Reflex increase in contractility|
|Decreased diastolic perfusion time due to tachycardia||Decreased myocardial perfusion|
As previously stated, vasodilators used in hypertension such
as nitroprusside and nitrates used
in angina act by releasing nitric oxide. Nitroprusside and other
drugs in this class are strong arteriolar vasodilators, in contrast
to nitrates, which are relatively less effective dilators of arterioles.
The more limited arteriolar vasodilation caused by nitrates ensures
that excessive dilation will not occur in normal vessels to the
detriment of flow through partially obstructed ones. Drugs such
as nitroprusside would vasodilate both partially obstructed and
normal coronary arterioles, and more so in the latter. Blood flow
in the unobstructed arteriole then would increase disproportionately
compared to the partially obstructed coronary arteriole, ultimately
decreasing blood flow through the partially obstructed coronary
arteriole and potentially exacerbating the tissue ischemia (coronary steal). For this reason,
drugs such as nitrates that act primarily on veins are very useful
in angina because they demonstrate minimal coronary steal.
As previously noted, nitroglycerin
is available in several formulations (Table 8–1). The standard
form for treatment of acute exertional anginal pain is the sublingual
tablet, which has a duration of action of 10 to 20 minutes. Isosorbide dinitrate
is similar or slightly longer in duration of action. Swallowed normal-release
nitroglycerin has a duration of action of 4 to 6 hours. Sustained-release
oral forms have a somewhat longer duration of action. Transdermal
formulations, in ointment or patch, can maintain blood levels for
up to 24 hours. Tolerance develops after 8 to 10 hours, however,
with rapidly diminishing effectiveness thereafter. Therefore, conventional
medical practice is to recommend that nitroglycerin patches be removed
after 10 to 12 hours to allow recovery of sensitivity to the drug.
The most common adverse effects
of nitrates are the responses evoked by vasodilation (Table 8–2).
These include tachycardia from the baroreceptor reflex, orthostatic
hypotension as a direct extension of the venodilator effect, and throbbing
headache from meningeal artery vasodilation. Nitrates interact with
sildenafil and similar drugs promoted for erectile dysfunction.
Both classes of drugs increase cGMP in vascular smooth muscle causing
a synergistic relaxation of vascular smooth muscle with potentially
dangerous hypotension and hypoperfusion of critical organs (Figure 8–4).
These drugs are described in detail in Chapter 6. All β-receptor antagonists are effective in the prophylaxis of atherosclerotic
Beneficial effects include decreases
in heart rate, cardiac contractility, and blood pressure. Like the
nitrates and calcium channel blockers, the β-receptor antagonists reduce the double product.
are used only for prophylactic therapy of angina, but are extremely
important in this application. They are of no value in an acute
attack. These drugs are effective in preventing exertional angina,
but are ineffective against the vasospastic form. The combination
of β-receptor antagonists with nitrates is useful
in the treatment of angina because the adverse compensatory effects
discussed below are minimized.
Adverse cardiac effects caused
by β-receptorantagonists include increased end
diastolic pressure and increased ejection time. For additional adverse effects,
see Chapter 6.
These drugs were discussed in the treatment of hypertension (Chapter 7). Several of the calcium channel blockers are approved for use
in angina (Table 8–3). These drugs may be divided into
two main classes: dihydropyridines and miscellaneous agents. Nifedipine is the prototypical dihydropyridine,
whereas diltiazem and verapamil are familiar examples of
the miscellaneous class. Although calcium channel blockers differ markedly
in structure, all are orally active and most have half-lives of
3 to 6 hours.
Table 8–3. Clinical
Indications and Toxicities of Some Calcium Channel Blocking Drugs ||Download (.pdf)
Table 8–3. Clinical
Indications and Toxicities of Some Calcium Channel Blocking Drugs
|Amlodipine||Angina, hypertension||Headache, peripheral edema|
|Felodipine||Hypertension, Raynaud’s phenomenon, congestive heart
|Nicardipine||Angina, hypertension, congestive heart failure||Peripheral edema, dizziness, headache, flushing|
|Nifedipine||Angina, hypertension, migraine, cardiomyopathy, Raynaud’s phenomenon||Hypotension, dizziness, flushing, nausea, constipation, dependent edema|
|Nimodipine||Subarachnoid hemorrhage, migraine||Headache|
|Nisoldipine||Hypertension||Probably similar to nifedipine|
|Nitrendipine||Investigational for angina, hypertension||Probably similar to nifedipine|
|Diltiazem||Angina, hypertension, Raynaud’s phenomenon||Hypotension, dizziness, flushing, bradycardia|
|Verapamil||Angina, hypertension, arrhythmias, migraine, cardiomyopathy||Hypotension, myocardial depression, constipation, dependent
These drugs block voltage-gated L-type calcium channels, which
are the calcium channels most important in cardiac and smooth muscle.
These agents decrease calcium influx during action potentials in
a frequency- and voltage-dependent manner. As a result of the reduced
intracellular calcium, cardiac and vascular smooth muscle contractility
is decreased. None of these L-type channel blockers interfere with
calcium-dependent neurotransmission or hormone release because those
processes do not utilize L-type channels.
Calcium channel blockers decrease
cardiac contractility, relax blood vessels, and, to a lesser extent,
relax the uterus, bronchi, and gut. The physiologic response to
these drugs varies with the specific agent (Table 8–3).
Diltiazem and verapamil have a greater inhibitory effect on cardiac
rate and contraction compared to their vasodilatory effect. Because
they block calcium-dependent conduction in the atrioventricular
(AV) node, verapamil and diltiazem may be used to treat AV nodal
arrhythmias (Chapter 10). Nifedipine and other dihydropyridines
evoke greater vasodilation, and the resulting sympathetic reflex
prevents bradycardia and may actually increase the heart rate. All
the calcium channel blockers reduce blood pressure and reduce the
double product in patients with angina.
Calcium channel blockers are effective
as prophylactic therapy in both exertional and vasospastic angina.
Nifedipine has also been used to abort acute anginal attacks. In
atherosclerotic angina, these drugs are particularly valuable when combined
with nitrates. In addition to well-established uses in angina, hypertension,
and supraventricular tachycardia, some of these agents are used
in the treatment of migraine headaches, preterm labor, and Raynaud’s
phenomenon (Table 8–3). Finally, nimodipine, another
dihydropyridine, is approved only for the management of stroke associated
with subarachnoid hemorrhage.
A summary of the adverse events
related to calcium channel blockers when used alone is presented
in Table 8–3. These drugs cause constipation, pretibial
edema, nausea, flushing, and dizziness. More serious adverse effects include
heart failure, atrioventricular blockade, and sinoatrial node depression;
these are more common with verapamil than with the dihydropyridines.