Page 221 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 207

both of which tend to increase myocardial oxygen requirement. relevant concentrations.) Trimetazidine does inhibit LC-3KAT at
These deleterious effects of β-blocking agents can be balanced by achievable concentrations and has demonstrated efficacy in stable
the concomitant use of nitrates as described below. angina. However, it is not approved for use in the USA.
Contraindications to the use of β blockers are asthma and Perhexiline was found to benefit some patients with angina
other bronchospastic conditions, severe bradycardia, atrioven- decades ago but was abandoned because of reports of hepatotoxic-
tricular blockade, bradycardia-tachycardia syndrome, and severe ity and peripheral neuropathy. However, pharmacokinetic studies
unstable left ventricular failure. Potential complications include suggested that toxicity was due to variable clearance of the drug,
fatigue, impaired exercise tolerance, insomnia, unpleasant dreams, with extremely high plasma concentrations in patients with defi-
worsening of claudication, and erectile dysfunction. cient CYP2D6 activity. This drug may shift myocardial metabo-
lism from fatty acid oxidation to more efficient glucose oxidation
NEWER ANTIANGINAL DRUGS (compared with trimetazidine). Because it does not involve vaso-
dilation, it may be useful in patients refractory to ordinary medical
Because of the high prevalence of angina, new drugs are actively therapy if plasma concentration is carefully controlled. Perhexiline
sought for its treatment. Some of the drugs or drug groups is currently approved in only a few countries (not the USA).
currently under investigation are listed in Table 12–6. So-called bradycardic drugs, relatively selective I sodium chan-
f
Ranolazine appears to act by reducing a late sodium cur- nel blockers (eg, ivabradine), reduce cardiac rate by inhibiting the
rent (I ) that facilitates calcium entry via the sodium-calcium hyperpolarization-activated sodium channel in the sinoatrial node.
Na
exchanger (see Chapter 13). The reduction in intracellular cal- No other significant hemodynamic effects have been reported.
cium concentration that results from ranolazine reduces diastolic Ivabradine appears to reduce anginal attacks with an efficacy simi-
tension, cardiac contractility, and work. Ranolazine is approved lar to that of calcium channel blockers and β blockers. The lack of
for use in angina in the USA. Several studies demonstrate its effect on gastrointestinal and bronchial smooth muscle is an advan-
effectiveness in stable angina, but it does not reduce the incidence tage of ivabradine, and it is approved for use in angina and heart
of death in acute coronary syndromes. Ranolazine prolongs the failure outside the USA. In the USA, it is approved for heart failure
QT interval in patients with coronary artery disease (but shortens and is used off-label for angina in combination with β blockers.
it in patients with long QT syndrome, LQT3). It has not been The Rho kinases (ROCK) comprise a family of enzymes that
associated with torsades de pointes arrhythmia and may inhibit inhibit vascular relaxation and diverse functions of several other
the metabolism of digoxin and simvastatin. cell types. Excessive activity of these enzymes has been implicated
Certain metabolic modulators (eg, trimetazidine) are known in coronary spasm, pulmonary hypertension, apoptosis, and other
as pFOX inhibitors because they partially inhibit the fatty acid conditions. Drugs targeting the enzyme have therefore been sought
oxidation pathway in myocardium. Because metabolism shifts to for possible clinical applications. Fasudil is an inhibitor of smooth
oxidation of fatty acids in ischemic myocardium, the oxygen muscle Rho kinase and reduces coronary vasospasm in experimen-
requirement per unit of ATP produced increases. Partial inhibi- tal animals. In clinical trials in patients with CAD, it has improved
tion of the enzyme required for fatty acid oxidation (long-chain performance in stress tests. It is investigational in angina.
3-ketoacyl thiolase, LC-3KAT) appears to improve the meta- Allopurinol represents another type of metabolic modifier.
bolic status of ischemic tissue. (Ranolazine was initially assigned Allopurinol inhibits xanthine oxidase (see Chapter 36), an enzyme
to this group of agents, but it lacks this action at clinically that contributes to oxidative stress and endothelial dysfunction in
addition to reducing uric acid synthesis, its mechanism of action
in gout. Studies suggest that high-dose allopurinol (eg, 600 mg/d)
TABLE 12–6 New drugs or drug groups under prolongs exercise time in patients with atherosclerotic angina.
investigation for use in angina. The mechanism is uncertain, but the drug appears to improve
endothelium-dependent vasodilation. Allopurinol is not currently
Drugs
approved for use in angina.
Amiloride
Capsaicin
Direct bradycardic agents, eg, ivabradine ■ CLINICAL PHARMACOLOGY OF
Inhibitors of slowly inactivating sodium current, eg, ranolazine DRUGS USED TO TREAT ANGINA
Metabolic modulators, eg, trimetazidine
Therapy of coronary artery disease (CAD) is important because
Nitric oxide donors, eg, l-arginine
angina and other manifestations of CAD severely impact quality of
Potassium channel activators, eg, nicorandil life and even life itself. Several grading systems have been devised to
Protein kinase G facilitators, eg, detanonoate rate the severity of disease based on the limitation of the patient’s
Rho-kinase inhibitors, eg, fasudil physical activity and to guide therapy (see Goldman reference).
Sulfonylureas, eg, glibenclamide Treatment includes both medical and surgical methods. Refrac-
tory angina and acute coronary syndromes are best treated with
Thiazolidinediones
physical revascularization, ie, percutaneous coronary intervention
Vasopeptidase inhibitors
(PCI), with insertion of stents, or coronary artery bypass grafting
Xanthine oxidase inhibitors, eg, allopurinol (CABG). The standard of care for acute coronary syndrome (ACS)