Page 209 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 195

Unstable angina, an acute coronary syndrome, is said to Drugs that reduce cardiac size, rate, or force reduce cardiac
be present when episodes of angina occur at rest and there is an oxygen demand. Thus, vasodilators, β blockers, and calcium
increase in the severity, frequency, and duration of chest pain in blockers have predictable benefits in angina. A small, late com-
patients with previously stable angina. Unstable angina is caused ponent of sodium current helps to maintain the long plateau
by episodes of increased epicardial coronary artery resistance or and prolong the calcium current of myocardial action potentials.
small platelet clots occurring in the vicinity of an atherosclerotic Drugs that block this late sodium current can indirectly reduce
plaque. In most cases, formation of labile partially occlusive calcium influx and consequently reduce cardiac contractile force.
thrombi at the site of a fissured or ulcerated plaque is the mecha- The heart favors fatty acids as a substrate for energy production.
nism for reduction in flow. Inflammation may be a risk factor, However, oxidation of fatty acids requires more oxygen per unit of
because patients taking tumor necrosis factor inhibitors appear ATP generated than oxidation of carbohydrates. Therefore, drugs
to have a lower risk of myocardial infarction. The course and the that shift myocardial metabolism toward greater use of glucose
prognosis of unstable angina are variable, but this subset of acute (fatty acid oxidation inhibitors), at least in theory, may reduce the
coronary syndrome is associated with a high risk of myocardial oxygen demand without altering hemodynamics.
infarction and death and is considered a medical emergency.
In theory, the imbalance between oxygen delivery and myo- Determinants of Coronary Blood Flow &
cardial oxygen demand can be corrected by decreasing oxygen Myocardial Oxygen Supply
demand or by increasing delivery (by increasing coronary flow).
In effort angina, oxygen demand can be reduced by decreasing In the normal heart, increased demand for oxygen is met by
cardiac work or, according to some studies, by shifting myocar- augmenting coronary blood flow. Because coronary flow drops to
dial metabolism to substrates that require less oxygen per unit of near zero during systole, coronary blood flow is directly related
adenosine triphosphate (ATP) produced. In variant angina, on the to the aortic diastolic pressure and the duration of diastole.
other hand, spasm of coronary vessels can be reversed by nitrate Therefore, the duration of diastole becomes a limiting factor for
or calcium channel-blocking vasodilators. In unstable angina, myocardial perfusion during tachycardia. Coronary blood flow is
vigorous measures are taken to achieve both—increase oxygen inversely proportional to coronary vascular resistance. Resistance
delivery (by medical or physical interventions) and decrease is determined mainly by intrinsic factors, including metabolic
oxygen demand. Lipid-lowering drugs have become extremely products and autonomic activity, and can be modified—in normal
important in the long-term treatment of atherosclerotic disease coronary vessels—by various pharmacologic agents. Damage to
(see Chapter 35). the endothelium of coronary vessels has been shown to alter their
ability to dilate and to increase coronary vascular resistance.
PATHOPHYSIOLOGY OF ANGINA
Determinants of Vascular Tone
Determinants of Myocardial Oxygen Peripheral arteriolar and venous tone (smooth muscle tension) both
Demand play a role in determining myocardial wall stress (Table 12–1).
Arteriolar tone directly controls peripheral vascular resistance and
The major determinants of myocardial oxygen requirement are thus arterial blood pressure. In systole, intraventricular pressure
listed in Table 12–1. The effects of arterial blood pressure and must exceed aortic pressure to eject blood; arterial blood pressure
venous pressure are mediated through their effects on myocardial thus determines the left ventricular systolic wall stress in an important
wall stress. As a consequence of its continuous activity, the heart’s way. Venous tone determines the capacity of the venous circulation
oxygen needs are relatively high, and it extracts approximately and controls the amount of blood sequestered in the venous system
75% of the available oxygen even in the absence of stress. The versus the amount returned to the heart. Venous tone thereby deter-
myocardial oxygen requirement increases when there is an increase mines the right ventricular diastolic wall stress.
in heart rate, contractility, arterial pressure, or ventricular volume. The regulation of smooth muscle contraction and relaxation is
These hemodynamic alterations occur during physical exercise shown schematically in Figure 12–1. The mechanisms of action of
and sympathetic discharge, which often precipitate angina in the major types of vasodilators are listed in Table 11–3. As shown
patients with obstructive coronary artery disease.
in Figures 12–1 and 12–2, drugs may relax vascular smooth
muscle in several ways:
TABLE 12–1 Hemodynamic determinants of
myocardial oxygen consumption. 1. Increasing cGMP: cGMP facilitates the dephosphorylation of
myosin light chains, preventing the interaction of myosin with
Wall stress actin. Nitric oxide (NO) is an effective activator of soluble
Intraventricular pressure guanylyl cyclase and acts mainly through this mechanism.
Ventricular radius (volume) Important molecular donors of nitric oxide include nitroprus-
side (see Chapters 11 and 19) and the organic nitrates used in
Wall thickness
angina. Atherosclerotic disease may diminish endogenous
Heart rate
endothelial NO synthesis, thus making the vascular smooth
Contractility muscle more dependent upon exogenous sources of NO.