Page 174 - Basic _ Clinical Pharmacology ( PDFDrive )

160 SECTION II Autonomic Drugs

α subtype mediating prostate smooth muscle contraction. Fur- ■ CLINICAL PHARMACOLOGY
thermore, compared with other antagonists, tamsulosin has less OF THE ALPHA-RECEPTOR–
effect on standing blood pressure in patients. Nevertheless, cau-
tion is appropriate in using any α antagonist in patients with BLOCKING DRUGS
diminished sympathetic nervous system function (see http://www
.bmj.com/content/347/bmj.f6320). Recent epidemiologic studies Pheochromocytoma
suggest an increased risk of orthostatic hypotension shortly after
initiation of treatment. A recently recognized and potentially Pheochromocytoma is a tumor of the adrenal medulla or sym-
serious adverse effect of oral tamsulosin in patients undergoing pathetic ganglion cells. The tumor secretes catecholamines,
cataract surgery is that they are at increased risk of the intraopera- especially norepinephrine and epinephrine. The patient in the
tive floppy iris syndrome (IFIS), characterized by the billowing of case study at the beginning of this chapter had a left adrenal
a flaccid iris, propensity for iris prolapse, and progressive intra- pheochromocytoma that was identified by imaging. In addition,
operative pupillary constriction. These effects increase the risk of he had elevated plasma and urinary norepinephrine, epinephrine,
cataract surgery, and complications are more likely in the ensuing and their metabolites, normetanephrine and metanephrine.
14 days if patients are taking these agents. The diagnosis of pheochromocytoma is confirmed on the basis
of elevated plasma or urinary levels of norepinephrine, epinephrine,
metanephrine, and normetanephrine (see Chapter 6). Once diag-
OTHER ALPHA-ADRENOCEPTOR nosed biochemically, techniques to localize a pheochromocytoma
ANTAGONISTS include computed tomography and magnetic resonance imaging
131
scans and scanning with radiomarkers such as I-meta-iodoben-
Alfuzosin is an α -selective quinazoline derivative that is approved zylguanidine (MIBG), a norepinephrine transporter substrate that
1
for use in BPH. It has a bioavailability of about 60%, is extensively is taken up by tumor cells and is therefore a useful imaging agent
metabolized, and has an elimination half-life of about 5 hours. It to identify the site of pheochromocytoma.
may increase risk of QT prolongation in susceptible individuals. The major clinical use of phenoxybenzamine is in the man-
Silodosin resembles tamsulosin in blocking the α receptor and agement of pheochromocytoma. Patients with this tumor have
1A
is also used in the treatment of BPH. Indoramin is another α - many symptoms and signs of catecholamine excess, including
1
selective antagonist that also has efficacy as an antihypertensive. intermittent or sustained hypertension, headaches, palpitations,
It is not available in the USA. Urapidil is an α antagonist (its and increased sweating.
1
primary effect) that also has weak α -agonist and 5-HT -agonist Release of stored catecholamines from pheochromocytomas
1A
2
actions and weak antagonist action at β receptors. It is used in may occur in response to physical pressure, chemical stimulation,
1
Europe as an antihypertensive agent and for BPH. Labetalol and or spontaneously. When it occurs during operative manipulation
carvedilol have both α -selective and β-antagonistic effects; they of pheochromocytoma, the resulting hypertension may be con-
1
are discussed below. Neuroleptic drugs such as chlorpromazine trolled with α-receptor blockade or the vasodilator nitroprusside.
and haloperidol are potent dopamine receptor antagonists but are Nitroprusside is preferred because its effects can be more readily
also antagonists at α receptors. Their antagonism of α receptors titrated and it has a shorter duration of action.
probably contributes to some of their adverse effects, particularly Alpha-receptor antagonists are most useful in the preoperative
hypotension. Similarly, the antidepressant trazodone has the management of patients with pheochromocytoma (Figure 10–4).
capacity to block α receptors. Ergot derivatives, eg, ergotamine Administration of phenoxybenzamine in the preoperative period
1
and dihydroergotamine, cause reversible α-receptor blockade, helps to control hypertension and tends to reverse chronic
probably via a partial agonist action (see Chapter 16). changes resulting from excessive catecholamine secretion such as
Yohimbine is an α -selective antagonist. It is sometimes used plasma volume contraction, if present. Furthermore, the patient’s
2
in the treatment of orthostatic hypotension because it promotes operative course may be simplified. Oral doses of 10 mg/d can
norepinephrine release through blockade of α receptors in both be increased at intervals of several days until hypertension is
2
the CNS and the periphery. This increases central sympathetic controlled. Some physicians give phenoxybenzamine to patients
activation and also promotes increased norepinephrine release with pheochromocytoma for 1–3 weeks before surgery. Other
in the periphery. It was once widely used to treat male erectile surgeons prefer to operate on patients in the absence of treatment
dysfunction but has been superseded by phosphodiesterase-5 with phenoxybenzamine, counting on modern anesthetic tech-
inhibitors like sildenafil (see Chapter 12). Yohimbine can greatly niques to control blood pressure and heart rate during surgery.
elevate blood pressure if administered to patients receiving norepi- Phenoxybenzamine can be very useful in the chronic treatment
nephrine transport-blocking drugs. Yohimbine reverses the anti- of inoperable or metastatic pheochromocytoma. Although there
hypertensive effects of α -adrenoceptor agonists such as clonidine. is less experience with alternative drugs, hypertension in patients
2
It is used in veterinary medicine to reverse anesthesia produced by with pheochromocytoma may also respond to reversible α 1 -
xylazine, an α agonist used to calm animals. Although yohim- selective antagonists or to conventional calcium channel antago-
2
bine has been taken off the market in the USA solely for financial nists. Beta-receptor antagonists may be required after α-receptor
reasons, it is available as a “nutritional” supplement and through blockade has been instituted to reverse the cardiac effects of exces-
compounding pharmacies. sive catecholamines. Beta antagonists should not be used prior