1. Drugs Used in the Treatment of Angina Pectoris
Drugs Used in the Treatment of Angina Pectoris: Introduction
Angina pectoris refers to a strangling or pressure-like pain caused by cardiac
ischemia. The pain is usually located substernally but is sometimes
perceived in the neck, shoulder and arm, or epigastrium. Women are less
likely than men to have classic substernal pain. Drugs used in angina exploit
two main strategies: reduction of oxygen demand and increase of the
oxygen delivery to the myocardium.
High-Yield Terms to Learn
Angina of effort, classic angina, atherosclerotic angina Angina pectoris
(crushing, strangling chest pain) that is precipitated by exertion, that is,
increased O2 demand that cannot be met because of relatively irreversible
atherosclerotic obstruction of coronary arteries
Vasospastic angina, variant angina, Prinzmetal's angina Angina
precipitated by reversible spasm of coronary vessels Coronary
vasodilator Older, incorrect name for drugs useful in angina; drugs that
relieve angina of effort do not usually act primarily through coronary
vasodilation; some potent coronary vasodilators are ineffective in
angina "Monday disease" Industrial disease caused by chronic exposure to
vasodilating concentrations of organic nitrates in the workplace;
characterized by headache, dizziness, and tachycardia on return to work
after 2 days absence Nitrate tolerance, tachyphylaxisLoss of effect of a
nitrate vasodilator when exposure is prolonged beyond 10-12 h Unstable
angina Rapidly progressing increase in frequency and severity of anginal
attacks, especially pain at rest; an acute coronary syndrome and often
heralds imminent myocardial infarction Preload Filling pressure of the heart,
dependent on venous tone and blood volume; determines end-diastolic fiber
length and tension Afterload Resistance to ejection of stroke volume;
determined by arterial blood pressure and arterial stiffness; afterload
determines systolic fiber tension Intramyocardial fiber tension Force
exerted by myocardial fibers, especially ventricular fibers at any given time;
a primary determinant of O2 requirement
2. Double product The product of heart rate and systolic blood pressure; an
estimate of cardiac work Myocardial revascularization Mechanical
intervention to improve O2 delivery to the myocardium by angioplasty or
bypass grafting
Pathophysiology of Angina
Types of Angina
Atherosclerotic Angina
Atherosclerotic angina is also known as angina of effort or classic angina. It
is associated with atheromatous plaques that partially occlude 1 or more
coronary arteries. When cardiac work increases (eg, in exercise), the
obstruction of flow and inadequate oxygen delivery results in the
accumulation of acidic metabolites and ischemic changes that stimulate
myocardial pain endings. Rest usually leads to complete relief of the pain
within 15 min. Atherosclerotic angina constitutes about 90% of angina
cases.
Vasospastic Angina
Vasospastic angina, also known as rest angina, variant angina, or
Prinzmetal's angina, is responsible for less than 10% of cases. It involves
reversible spasm of coronaries, usually at the site of an atherosclerotic
plaque. Spasm may occur at any time, even during sleep. Vasospastic
angina may deteriorate into unstable angina.
Unstable Angina
A third type of angina—unstable or crescendo angina, also known as acute
coronary syndrome —is characterized by increased frequency and severity
of attacks that result from a combination of atherosclerotic plaques, platelet
aggregation at fractured plaques, and vasospasm. Unstable angina is
thought to be the immediate precursor of a myocardial infarction and is
treated as a medical emergency.
Determinants of Cardiac Oxygen Requirement
The pharmacologic treatment of coronary insufficiency is based on the
physiologic factors that control myocardial oxygen requirement. A major
determinant is myocardial fiber tension (the higher the tension, the
greater the oxygen requirement).
Several variables contribute to fiber tension (Figure 12-1), as discussed
next.
FIGURE 12-1
3. Determinants of the volume of oxygen required by the heart. Both diastolic
and systolic factors contribute to the oxygen requirement; most of these
factors are directly influenced by sympathetic discharge (venous tone,
peripheral resistance, heart rate, and heart force).
Preload and Afterload
Preload (diastolic filling pressure) is a function of blood volume and venous
tone. Venous tone is mainly controlled by sympathetic outflow. Afterload is
determined by arterial blood pressure and large artery stiffness. It is one of
the systolic determinants of oxygen requirement.
Heart Rate
Heart rate contributes to total fiber tension because at fast heart rates,
fibers spend more time at systolic tension levels. Furthermore, at faster
rates, diastole is abbreviated, and diastole constitutes the time available for
coronary flow (coronary blood flow is low or nil during systole).
Heart rate and systolic blood pressure may be multiplied to yield the double
product, a measure of cardiac work and therefore of oxygen requirement.
As intensity of exercise (eg, running on a treadmill) increases, demand for
cardiac output increases, so the double product also increases. However, the
double product is sensitive to sympathetic tone, as is cardiac oxygen
demand (Figure 12-1). In patients with atherosclerotic angina, effective
drugs reduce the double product by reducing cardiac work without reducing
exercise capacity.
Cardiac Contractility
Force of cardiac contraction is another systolic factor controlled mainly by
sympathetic outflow to the heart. Ejection time for ventricular contraction
is inversely related to force of contraction but is also influenced by
impedance to outflow. Increased ejection time (prolonged systole) increases
oxygen requirement.
Therapeutic Strategies
The defect that causes anginal pain is inadequate coronary oxygen delivery
relative to the myocardial oxygen requirement. This defect can be
corrected—at present—in 2 ways: by increasing oxygen deliveryand
by reducing oxygen requirement (Figure 12-2). Traditional pharmacologic
4. therapies include the nitrates, the calcium channel blockers, and
the blockers.
FIGURE 12-2
Strategies for the treatment of angina pectoris. When coronary flow is
adequate, O2 delivery is equal to O2 requirement (horizontal black line).
Angina is characterized by reduced coronary oxygen delivery versus oxygen
requirement (oblique solid blue line). In some cases, this can be corrected
by increasing oxygen delivery (box on left: revascularization or, in the case
of reversible vasospasm, nitrates and calcium channel blockers). More often,
drugs are used to reduce oxygen requirement (box on right:
nitrates, blockers, and calcium channel blockers) and cause a shift to the
dashed blue line.
A newer strategy attempts to increase the efficiency of oxygen
utilization by shifting the energy substrate preference of the heart from
fatty acids to glucose. Drugs that may act by this mechanism are termed
partial fatty acid oxidation inhibitors (pFOX inhibitors) and
include ranolazine and trimetazidine. However, more recent evidence
suggests that the major mechanism of action of ranolazine is inhibition of
late sodium current (see below). Another new group of antianginal drugs
selectively reduces heart rate with no other detectable hemodynamic effects.
These investigational drugs (ivabradine is the prototype) act by inhibition
of the sinoatrial pacemaker current, If.
The nitrates, calcium blockers, and blockers all reduce the oxygen
requirement in atherosclerotic angina. Nitrates and calcium channel blockers
(but not blockers) can also increase oxygen delivery by reducing spasm in
vasospastic angina. Myocardial revascularization corrects coronary
obstruction either by bypass grafting or by angioplasty (enlargement of the
lumen by means of a special catheter). Therapy of unstable angina differs
from that of stable angina in that urgent angioplasty is the treatment of
choice in most patients and platelet clotting is the major target of drug
therapy. The platelet glycoprotein IIb/IIIa inhibitors—abciximab, eptifibatide,
and tirofiban—are used in this condition (see Chapter 34). Intravenous
nitroglycerin is sometimes of value.
Nitrates
Classification and Pharmacokinetics
5. Nitroglycerin (the active ingredient in dynamite) is the most important of
the therapeutic nitrates and is available in forms that provide a range of
durations of action from 10-20 min (sublingual) to 8-10 h (transdermal) (see
the Drug Summary Table at the end of the chapter). Because treatment of
acute attacks and prevention of attacks are both important aspects of
therapy, the pharmacokinetics of these different dosage forms are clinically
significant.
Nitroglycerin (glyceryl trinitrate) is rapidly denitrated in the liver and in
smooth muscle—first to the dinitrate (glyceryl dinitrate), which retains a
significant vasodilating effect; and more slowly to the mononitrate, which 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 oral
(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
(see Chapters 1 and 3).
Other nitrates are similar to nitroglycerin in their pharmacokinetics and
pharmacodynamics. Isosorbide dinitrate is another commonly used nitrate;
it 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 (4-6 h).
Amyl nitrite is a volatile and rapid-acting vasodilator that was used for
angina by the inhalational route but is now rarely prescribed.
Mechanism of Action
Denitration of the nitrates within smooth muscle cells releases nitric oxide
(NO), which stimulates guanylyl cyclase, and causes an increase of the
second messenger cGMP (cyclic guanosine monophosphate); the latter
results in smooth muscle relaxation by dephosphorylation of myosin light
chain phosphate (Figure 12-3). Note that this mechanism is identical to that
of nitroprusside (see Chapter 11).
6. Mechanisms of smooth muscle relaxation by calcium channel blockers and
nitrates. Contraction results from phosphorylation of myosin light chains
(MLC) by myosin light-chain kinase (MLCK). MLCK is activated by Ca2+
, so
calcium channel blockers reduce this step. Relaxation follows when the
phosphorylated light chains are dephosphorylated, a process facilitated by
cyclic guanosine monophosphate (cGMP). Nitrates and other sources of nitric
oxide (NO) increase cGMP synthesis, and phosphodiesterase (PDE) inhibitors
reduce cGMP metabolism. eNOS, endothelial nitric oxide synthase; GTP,
guanosine triphosphate.
Organ System Effects
Cardiovascular
Smooth muscle relaxation by nitrates leads to an important degree of
venodilation, which results in reduced cardiac size and cardiac output
through reduced preload. Relaxation of arterial smooth muscle may increase
flow through partially occluded epicardial coronary vessels. Reduced
afterload, from arteriolar dilation, may contribute to an increase in ejection
and a further decrease in cardiac size. Some studies suggest that of the
vascular beds, the veins are the most sensitive, arteries less so, and
arterioles least sensitive. Venodilation leads to decreased diastolic heart size
and fiber tension. 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 of therapeutic benefit in atherosclerotic angina
is reduction of the oxygen requirement. A secondary mechanism—namely,
an increase in coronary flow via collateral vessels in ischemic areas—has
7. 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 significant reflex
tachycardia and increased force of contraction are common results when
nitroglycerin reduces the blood pressure. These compensatory effects result
from the baroreceptor mechanism shown in Figure 6-4.
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 (sometimes used in unstable angina) reduces
platelet aggregation. There are no significant effects on other tissues.
Clinical Uses
As previously noted, nitroglycerin is available in several formulations (Drug
Summary Table). The standard form for treatment of acute anginal pain is
the sublingual tablet or spray, which has a duration of action of 10-20 min.
Isosorbide dinitrate is similar with a duration of 30 min. Oral (swallowed)
normal-release nitroglycerin has a duration of action of 4-6 h, largely owing
to circulating glyceryl dinitrate. Sustained-release oral forms have a
somewhat longer duration of action. Transdermal formulations (ointment or
patch) can maintain blood levels for up to 24 h. Tolerance develops after 8-
10 h, however, with rapidly diminishing effectiveness thereafter. It is
therefore recommended that nitroglycerin patches be removed after 10-12 h
to allow recovery of sensitivity to the drug.
Toxicity of Nitrates and Nitrites
The most common toxic effects of nitrates are the responses evoked by
vasodilation. These include tachycardia (from the baroreceptor reflex),
orthostatic hypotension (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. These agents inhibit a phosphodiesterase isoform (PDE5) that
metabolizes cGMP in smooth muscle (Figure 12-4). The increased cGMP in
erectile smooth muscle relaxes it, allowing for greater inflow of blood and
more effective and prolonged erection. This effect also occurs in vascular
smooth muscle. As a result, the combination of nitrates (through increased
production of cGMP) and a PDE5 inhibitor (through decreased breakdown of
cGMP) causes a synergistic relaxation of vascular smooth muscle with
potentially dangerous hypotension and inadequate perfusion of critical
organs.
FIGURE 12-4
8. Mechanism of the interaction between nitrates and drugs used in erectile
dysfunction. Because these drug groups increase cyclic guanosine
monophosphate (cGMP) by complementary mechanisms, they can have a
synergistic effect on blood pressure resulting in dangerous hypotension.
GTP, guanosine triphosphate.
Nitrites are of significant toxicologic importance because they cause
methemoglobinemia at high blood concentrations. This same effect has a
potential antidotal action in cyanide poisoning (see later discussion). The
nitrates do not cause methemoglobinemia. In the past, the nitrates were
responsible for several occupational diseases in munitions factories in which
work-place contamination by these volatile chemicals was severe. The most
common of these diseases was "Monday disease," that is, the alternating
development of tolerance (during the work week) and loss of tolerance (over
the weekend) for the vasodilating action and its associated tachycardia and
resulting in headache (from cranial vasodilation), tachycardia, and dizziness
(from orthostatic hypotension) every Monday.
Nitrites in the Treatment of Cyanide Poisoning
Cyanide ion rapidly complexes with the iron in cytochrome oxidase, resulting
in a block of oxidative metabolism and cell death. Fortunately, the iron in
methemoglobin has a higher affinity for cyanide than does the iron in
cytochrome oxidase. Nitrites convert the ferrous iron in hemoglobin to the
ferric form, yielding methemoglobin. Therefore, cyanide poisoning can be
treated by a 3-step procedure: (1) immediate exposure to amyl nitrite,
followed by (2) intravenous administration of sodium nitrite, which rapidly
increases the methemoglobin level to the degree necessary to remove a
significant amount of cyanide from cytochrome oxidase.
This is followed by (3) intravenous sodium thiosulfate, which converts
cyanomethemoglobin resulting from step 2 to thiocyanate and
methemoglobin. Thiocyanate is much less toxic than cyanide and is excreted
by the kidney. (It should be noted that excessive methemoglobinemia is
fatal because methemoglobin is a very poor oxygen carrier.) Recently,
9. hydroxocobalamin, a form of vitamin B12 , has become the preferred
method of treating cyanide poisoning (see Chapter 58).
Calcium Channel-Blocking Drugs
Classification and Pharmacokinetics
Several types of calcium channel blockers are approved for use in angina;
these drugs are typified by nifedipine, a dihydropyridine, and several
other dihydropyridines; diltiazem ; and verapamil. Although calcium
channel blockers differ markedly in structure, all are orally active and most
have half-lives of 3-6 h.
Mechanism of Action
Calcium channel blockers block voltage-gated L-type calcium channels, the
calcium channels most important in cardiac and smooth muscle. By
decreasing calcium influx during action potentials in a frequency- and
voltage-dependent manner, these agents reduce intracellular calcium
concentration and muscle contractility. None of these channel blockers
interferes with calcium-dependent neurotransmission or hormone release
because these processes use different types of calcium channels that are not
blocked by these agents. Nerve ending calcium channels are of the N-, P-,
and R-types. Secretory cells use L-type channels, but these channels are
less sensitive to the calcium blockers than are cardiac and smooth muscle L-
type channels.
Effects and Clinical Use
Calcium blockers relax blood vessels and, to a lesser extent, the uterus,
bronchi, and gut. The rate and contractility of the heart are reduced by
diltiazem and verapamil. Because they block calcium-dependent conduction
in the atrioventricular (AV) node, verapamil and diltiazem may be used to
treat AV nodal arrhythmias (see Chapter 14). 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 blockers are effective as prophylactic therapy in both effort and
vasospastic angina; nifedipine has also been used to abort acute anginal
attacks but use of the prompt-release form is discouraged (see Skill Keeper).
In severe atherosclerotic angina, these drugs are particularly valuable when
combined with nitrates (Table 12-1). In addition to well-established uses in
angina, hypertension, and supraventricular tachycardia, some of these
agents are used in migraine, preterm labor, stroke, and Raynaud's
phenomenon.
TABLE 12-1 Effects of nitrates alone or with beta blockers or calcium channel
blockers in angina pectoris.a
Nitrates Alone Beta Blockers or Calcium Channel Blockers
Alone Combined Nitrate and Beta Blocker or Calcium Channel
Blocker Heart rate Reflex increase Decrease Decrease Arterial pressure
10. Decrease DecreaseDecrease End-diastolic
pressure Decrease Increase Decrease Contractility Reflex
increase Decrease No effect or decrease Ejection time Reflex
decrease Increase No effect Net myocardial oxygen
requirement Decrease DecreaseDecrease
a
Undesirable effects (effects that increase oxygen requirement) are shown
in italics; major beneficial effects are shown in bold.
Toxicity
The calcium channel blockers cause constipation, pretibial edema, nausea,
flushing, and dizziness. More serious adverse effects include heart failure, AV
blockade, and sinus node depression; these are most common with
verapamil and least common with the dihydropyridines.
