Page 196 - Basic _ Clinical Pharmacology ( PDFDrive )

182 SECTION III Cardiovascular-Renal Drugs

Interactions with other drugs may complicate guanethidine ADRENOCEPTOR ANTAGONISTS
therapy. Sympathomimetic agents, at doses available in over-the-
counter cold preparations, can produce hypertension in patients The detailed pharmacology of α- and β-adrenoceptor blockers is
taking guanethidine. Similarly, guanethidine can produce hyper- presented in Chapter 10.
tensive crisis by releasing catecholamines in patients with pheo-
chromocytoma. When tricyclic antidepressants are administered BETA-ADRENOCEPTOR-BLOCKING
to patients taking guanethidine, the drug’s antihypertensive effect AGENTS
is attenuated, and severe hypertension may follow.

Of the large number of β blockers tested, most have been shown
Reserpine to be effective in lowering blood pressure. The pharmacologic
Reserpine, an alkaloid extracted from the roots of an Indian plant, properties of several of these agents differ in ways that may confer
Rauwolfia serpentina, was one of the first effective drugs used on a therapeutic benefits in certain clinical situations.
large scale in the treatment of hypertension. At present, it is rarely
used owing to its adverse effects. Propranolol
Propranolol was the first β blocker shown to be effective in hyper-
A. Mechanism and Sites of Action tension and ischemic heart disease. Propranolol has now been
Reserpine blocks the ability of aminergic transmitter vesicles to largely replaced by cardioselective β blockers such as metoprolol
take up and store biogenic amines, probably by interfering with the and atenolol. All β-adrenoceptor-blocking agents are useful for
vesicular membrane-associated transporter (VMAT, see Figure 6–4). lowering blood pressure in mild to moderate hypertension. In severe
This effect occurs throughout the body, resulting in depletion of nor- hypertension, β blockers are especially useful in preventing the
epinephrine, dopamine, and serotonin in both central and periph- reflex tachycardia that often results from treatment with direct vaso-
eral neurons. Chromaffin granules of the adrenal medulla are also dilators. Beta blockers have been shown to reduce mortality after a
depleted of catecholamines, although to a lesser extent than are the myocardial infarction and some also reduce mortality in patients
vesicles of neurons. Reserpine’s effects on adrenergic vesicles appear with heart failure; they are particularly advantageous for treating
irreversible; trace amounts of the drug remain bound to vesicular hypertension in patients with these conditions (see Chapter 13).
membranes for many days.
Depletion of peripheral amines probably accounts for much A. Mechanism and Sites of Action
of the beneficial antihypertensive effect of reserpine, but a central Propranolol’s efficacy in treating hypertension as well as most of
component cannot be ruled out. Reserpine readily enters the its toxic effects result from nonselective β blockade. Propranolol
brain, and depletion of cerebral amine stores causes sedation, decreases blood pressure primarily as a result of a decrease in
mental depression, and parkinsonism symptoms. cardiac output. Other β blockers may decrease cardiac output or
At lower doses used for treatment of mild hypertension, reser- decrease peripheral vascular resistance to various degrees, depend-
pine lowers blood pressure by a combination of decreased cardiac ing on cardioselectivity and partial agonist activities.
output and decreased peripheral vascular resistance. Propranolol inhibits the stimulation of renin production by
catecholamines (mediated by β receptors). It is likely that propran-
1
B. Pharmacokinetics and Dosage olol’s effect is due in part to depression of the renin-angiotensin-
See Table 11–2. aldosterone system. Although most effective in patients with high
plasma renin activity, propranolol also reduces blood pressure in
C. Toxicity hypertensive patients with normal or even low renin activity. Beta
blockers might also act on peripheral presynaptic β adrenoceptors
At the low doses usually administered, reserpine produces little to reduce sympathetic vasoconstrictor nerve activity.
postural hypotension. Most of the unwanted effects of reserpine In mild to moderate hypertension, propranolol produces a
result from actions on the brain or gastrointestinal tract. significant reduction in blood pressure without prominent pos-
High doses of reserpine characteristically produce sedation, tural hypotension.
lassitude, nightmares, and severe mental depression; occasionally,
these occur even in patients receiving low doses (0.25 mg/d). B. Pharmacokinetics and Dosage
Much less frequently, ordinary low doses of reserpine produce See Table 11–2. Resting bradycardia and a reduction in the heart
extrapyramidal effects resembling Parkinson’s disease, probably as rate during exercise are indicators of propranolol’s β-blocking
a result of dopamine depletion in the corpus striatum. Although effect, and changes in these parameters may be used as guides for
these central effects are uncommon, it should be stressed that they regulating dosage. Propranolol can be administered twice daily,
may occur at any time, even after months of uneventful treatment. and slow-release once-daily preparations are available.
Patients with a history of mental depression should not receive
reserpine, and the drug should be stopped if depression appears. C. Toxicity
Reserpine rather often produces mild diarrhea and gastrointes- The principal toxicities of propranolol result from blockade
tinal cramps and increases gastric acid secretion. The drug should of cardiac, vascular, or bronchial β receptors and are described
not be given to patients with a history of peptic ulcer. in more detail in Chapter 10. The most important of these