Page 175 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 10 Adrenoceptor Antagonist Drugs 161

240 pressure reflects excess circulating concentrations of α agonists,
eg, in pheochromocytoma, overdosage of sympathomimetic
220 Supine drugs, or clonidine withdrawal. However, other drugs are gener-
Standing
ally preferable, since considerable experience is necessary to use
200
α-adrenoceptor antagonist drugs safely in these settings.
180
Chronic Hypertension
160 Members of the prazosin family of α -selective antagonists are
Blood pressure (mm Hg) 120 hypertension (see Chapter 11). They are generally well toler-
1
efficacious drugs in the treatment of mild to moderate systemic
140
ated, but they are not usually recommended as monotherapy for
hypertension because other classes of antihypertensives are more
100
effective in preventing heart failure. Their major adverse effect is
orthostatic hypotension, which may be severe after the first few
80
doses but is otherwise uncommon. Prazosin and related drugs
60 may also be associated with dizziness. Orthostatic changes in
blood pressure should be checked routinely in any patient being
Dibenzyline
40 80 treated for hypertension. Nonselective α antagonists are not used
mg/d 40 in primary systemic hypertension.
20 0 It is interesting that the use of α-adrenoceptor antagonists such
as prazosin has been found to be associated with either no changes
0
1 2345678 9101112131415 in plasma lipids or increased concentrations of high-density
Weeks lipoproteins (HDL), which could be a favorable alteration. The
mechanism for this effect is not known.
FIGURE 10–4 Effects of phenoxybenzamine (Dibenzyline) on
blood pressure in a patient with pheochromocytoma. Dosage of the Peripheral Vascular Disease
drug was begun in the fourth week as shown by the shaded bar.
Supine systolic and diastolic pressures are indicated by the circles, Alpha-receptor–blocking drugs do not seem to be effective in the
and the standing pressures by triangles and the hatched area. Note treatment of peripheral vascular occlusive disease characterized by
that the α-blocking drug dramatically reduced blood pressure. The morphologic changes that limit flow in the vessels. Occasionally,
reduction in orthostatic hypotension, which was marked before individuals with Raynaud’s phenomenon and other conditions
treatment, is probably due to normalization of blood volume, a involving excessive reversible vasospasm in the peripheral circula-
variable that is sometimes markedly reduced in patients with long- tion do benefit from prazosin or phenoxybenzamine, although
standing pheochromocytoma-induced hypertension. (Adapted, with calcium channel blockers may be preferable for most patients.
permission, from Engelman E, Sjoerdsma A: Chronic medical therapy for pheochro-
mocytoma. Ann Intern Med 1964;61:229.)
Urinary Obstruction
Benign prostatic hyperplasia is common in elderly men. Various
to establishing effective α-receptor blockade, since unopposed surgical treatments are effective in relieving the urinary symptoms
β-receptor blockade could theoretically cause blood pressure eleva- of BPH; however, drug therapy is efficacious in many patients.
tion from increased vasoconstriction. The mechanism of action in improving urine flow involves partial
Pheochromocytoma is sometimes treated with metyrosine
(α-methyltyrosine), the α-methyl analog of tyrosine. This agent is reversal of smooth muscle contraction in the enlarged prostate and
-receptor
a competitive inhibitor of tyrosine hydroxylase, the rate-limiting in the bladder base. It has been suggested that some α 1
antagonists may have additional effects on cells in the prostate that
step in the synthesis of dopamine, norepinephrine, and epineph- help improve symptoms.
rine (see Figure 6–5). Metyrosine is especially useful in symptom- Prazosin, doxazosin, and terazosin are all efficacious in patients
atic patients with inoperable or metastatic pheochromocytoma. with BPH. These drugs are particularly useful in patients who also
Because it has access to the CNS, metyrosine can cause extrapyra- have hypertension. Considerable interest has focused on which
midal effects due to reduced dopamine levels.
α 1 -receptor subtype is most important for smooth muscle con-
traction in the prostate: subtype-selective α -receptor antagonists
Hypertensive Emergencies like tamsulosin may have improved efficacy and safety in treating
1A
The α-adrenoceptor antagonist drugs have limited application this disease. As indicated above, even though tamsulosin has less
in the management of hypertensive emergencies, but labet- blood pressure–lowering effect, it should be used with caution in
alol has been used in this setting (see Chapter 11). In theory, patients susceptible to orthostatic hypotension and should not be
α-adrenoceptor antagonists are most useful when increased blood used in patients undergoing eye surgery.