Page 179 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 10 Adrenoceptor Antagonist Drugs 165

Glucagon is the primary hormone used to combat hypoglycemia;
it is unclear to what extent β antagonists impair recovery from The Treatment of Glaucoma
hypoglycemia, but they should be used with caution in insulin-
dependent diabetic patients. This may be particularly important Glaucoma is a major cause of blindness and of great pharmaco-
in diabetic patients with inadequate glucagon reserve and in pan- logic interest because the chronic form often responds to drug
createctomized patients since catecholamines may be the major therapy. The primary manifestation is increased intraocular
factors in stimulating glucose release from the liver in response to pressure not initially associated with symptoms. Without treat-
hypoglycemia. Beta -receptor–selective drugs may be less prone ment, increased intraocular pressure results in damage to the
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to inhibit recovery from hypoglycemia. Beta-receptor antagonists retina and optic nerve, with restriction of visual fields and,
are much safer in those type 2 diabetic patients who do not have eventually, blindness. Intraocular pressure is easily measured
hypoglycemic episodes. as part of the routine ophthalmologic examination. Two major
The chronic use of β-adrenoceptor antagonists has been asso- types of glaucoma are recognized: open-angle and closed-
ciated with increased plasma concentrations of very-low-density angle (also called narrow-angle). The closed-angle form is
lipoproteins (VLDL) and decreased concentrations of HDL cho- associated with a shallow anterior chamber, in which a dilated
lesterol. Both of these changes are potentially unfavorable in terms iris can occlude the outflow drainage pathway at the angle
of risk of cardiovascular disease. Although low-density lipoprotein between the cornea and the ciliary body (see Figure 6–9). This
(LDL) concentrations generally do not change, there is a variable form is associated with acute and painful increases of pressure,
decline in the HDL cholesterol/LDL cholesterol ratio that may which must be controlled on an emergency basis with drugs or
increase the risk of coronary artery disease. These changes tend to prevented by surgical removal of part of the iris (iridectomy).
occur with both selective and nonselective β blockers, although The open-angle form of glaucoma is a chronic condition,
they may be less likely to occur with β blockers possessing intrin- and treatment is largely pharmacologic. Because intraocular
sic sympathomimetic activity (partial agonists). The mechanisms pressure is a function of the balance between fluid input and
by which β-receptor antagonists cause these changes are not drainage out of the globe, the strategies for the treatment of
understood, although changes in sensitivity to insulin action may open-angle glaucoma fall into two classes: reduction of aque-
contribute. ous humor secretion and enhancement of aqueous outflow.
Five general groups of drugs—cholinomimetics, α agonists,
β blockers, prostaglandin F 2α analogs, and diuretics—have
E. Effects Not Related to Beta-Blockade been found to be useful in reducing intraocular pressure and
Partial β-agonist activity may have been considered desirable to can be related to these strategies as shown in Table 10–3. Of
prevent untoward effects such as precipitation of asthma or exces- the five drug groups listed in Table 10–3, the prostaglandin
sive bradycardia. Pindolol and other partial agonists are noted in analogs and the β blockers are the most popular. This popu-
Table 10–2. However, these drugs may not be as effective as the larity results from convenience (once- or twice-daily dosing)
pure antagonists in secondary prevention of myocardial infarction. and relative lack of adverse effects (except, in the case of β
Clinical trials of partial β-agonist drugs in hypertension have not blockers, in patients with asthma or cardiac pacemaker or
confirmed increased benefit. conduction pathway disease). Other drugs that have been
Local anesthetic action, also known as “membrane-stabilizing” reported to reduce intraocular pressure include prostaglan-
action, is a prominent effect of several β blockers (Table 10–2). din E 2 and marijuana. The use of drugs in acute closed-angle
This action is the result of typical local anesthetic blockade of glaucoma is limited to cholinomimetics, acetazolamide, and
sodium channels (see Chapter 26) and can be demonstrated osmotic agents preceding surgery. The onset of action of the
experimentally in isolated neurons, heart muscle, and skel- other agents is too slow in this situation.
etal muscle membrane. However, it is unlikely that this effect
is important after systemic administration of these drugs, since
the concentration in plasma usually achieved by these routes is
too low for the anesthetic effects to be evident. The membrane-
stabilizing β blockers are not used topically on the eye, because occur over a 24-hour period. The drug has negligible effects at α
local anesthesia of the cornea, eliminating its protective reflexes, and muscarinic receptors; however, it may block some serotonin
would be highly undesirable. Sotalol is a nonselective β-receptor receptors in the brain, although the clinical significance is unclear.
antagonist that lacks local anesthetic action but has marked It has no detectable partial agonist action at β receptors.
class III antiarrhythmic effects, reflecting potassium channel Metoprolol, atenolol, and several other drugs (Table 10–2)
blockade (see Chapter 14). are members of the β -selective group. These agents may be safer
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in patients who experience bronchoconstriction in response to pro-
pranolol. Since their β selectivity is rather modest, they should be
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SPECIFIC AGENTS (SEE TABLE 10–2) used with great caution, if at all, in patients with a history of asthma.
However, in selected patients with COPD, the benefits may exceed
Propranolol is the prototypical β-blocking drug. As noted above, the risks, eg, in patients with myocardial infarction. Beta 1 -selective
it has low and dose-dependent bioavailability. A long-acting form antagonists may be preferable in patients with diabetes or peripheral
of propranolol is available; prolonged absorption of the drug may vascular disease when therapy with a β blocker is required, since