Page 182 - Basic _ Clinical Pharmacology ( PDFDrive )

168 SECTION II Autonomic Drugs

Other Cardiovascular Disorders
.30 Beta-receptor antagonists have been found to increase stroke
Cumulative mortality rate .20 Placebo beneficial effect is thought to result from the slowing of ventricu-
.25
volume in some patients with obstructive cardiomyopathy. This

lar ejection and decreased outflow resistance. Beta antagonists are
.15
useful in dissecting aortic aneurysm to decrease the rate of devel-
.10
opment of systolic pressure. Beta antagonists have been claimed
Timolol
.05
p = 0.0028 to prevent adverse cardiovascular outcomes resulting from non-
cardiac surgery, but this is controversial.
.00
0 12 24 36 48 60 72 Glaucoma (See Box: The Treatment of
Time (mo) Glaucoma)
FIGURE 10–8 Effects of β-blocker therapy on life-table cumu- Systemic administration of β-blocking drugs for other indica-
lated rates of mortality from all causes over 6 years among 1884 tions was found serendipitously to reduce intraocular pressure in
patients surviving myocardial infarctions. Patients were randomly patients with glaucoma. Subsequently, it was found that topical
assigned to treatment with placebo (dashed red line) or timolol (solid administration also reduces intraocular pressure. The mechanism
blue line). (Reproduced, with permission, from Pedersen TR: Six-year follow-up of appears to involve reduced production of aqueous humor by the
the Norwegian multicenter study on timolol after acute myocardial infarction. N ciliary body, which is physiologically activated by cAMP. Timo-
Engl J Med 1985;313:1055. Copyright © 1985 Massachusetts Medical Society.)
lol and related β antagonists are suitable for local use in the eye
because they lack local anesthetic properties. Beta antagonists
appear to have an efficacy comparable to that of epinephrine or
moderate or severe left ventricular failure, shock, heart block, and pilocarpine in open-angle glaucoma and are far better tolerated
active airways disease. It has been suggested that certain polymor- by most patients. While the maximal daily dose applied locally
phisms in β -adrenoceptor genes may influence survival among (1 mg) is small compared with the systemic doses commonly used
2
patients receiving antagonists after acute coronary syndromes. in the treatment of hypertension or angina (10–60 mg), sufficient
timolol may be absorbed from the eye to cause serious adverse
effects on the heart and airways in susceptible individuals. Topi-
Cardiac Arrhythmias cal timolol may interact with orally administered verapamil and

Beta antagonists are often effective in the treatment of both increase the risk of heart block.
supraventricular and ventricular arrhythmias (see Chapter 14). Betaxolol, carteolol, levobunolol, and metipranolol are also
It has been suggested that the improved survival following myo- approved for the treatment of glaucoma. Betaxolol has the poten-
cardial infarction in patients using β antagonists (Figure 10–8) is tial advantage of being β -selective; to what extent this potential
1
due to suppression of arrhythmias, but this has not been proved. advantage might diminish systemic adverse effects remains to be
By increasing the atrioventricular nodal refractory period, β determined. The drug apparently has caused worsening of pulmo-
antagonists slow ventricular response rates in atrial flutter and nary symptoms in some patients.
fibrillation. These drugs can also reduce ventricular ectopic beats,
particularly if the ectopic activity has been precipitated by cate- Hyperthyroidism
cholamines. Esmolol is particularly useful against acute periopera- Excessive catecholamine action is an important aspect of the
tive arrhythmias because it has a short duration of action and can pathophysiology of hyperthyroidism, especially in relation to
be given parenterally. Sotalol has antiarrhythmic effects involving the heart (see Chapter 38). The β antagonists are beneficial in
ion channel blockade in addition to its β-blocking action; these this condition. The effects presumably relate to blockade of
are discussed in Chapter 14.
adrenoceptors and perhaps in part to the inhibition of peripheral
conversion of thyroxine to triiodothyronine. The latter action may
Heart Failure vary from one β antagonist to another. Propranolol has been used
extensively in patients with thyroid storm (severe hyperthyroid-
Clinical trials have demonstrated that at least three β antagonists— ism); it is used cautiously in patients with this condition to control
metoprolol, bisoprolol, and carvedilol—are effective in reducing supraventricular tachycardias that often precipitate heart failure.
mortality in selected patients with chronic heart failure. Although
administration of these drugs may worsen acute congestive heart Neurologic Diseases
failure, cautious long-term use with gradual dose increments in
patients who tolerate them may prolong life. Although mecha- Propranolol reduces the frequency and intensity of migraine
nisms are uncertain, there appear to be beneficial effects on myo- headache. Other β-receptor antagonists with preventive effi-
cardial remodeling and in decreasing the risk of sudden death cacy include metoprolol and probably also atenolol, timolol,
(see Chapter 13). and nadolol. The mechanism is not known. Since sympathetic