DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

furosemide and bumetanide, in patients who have normal
renal function. This differential effect is most likely
related to the short duration of action of loop diuretics,
such that a single daily dose does not cause a significant
net loss of Na + for an entire 24-hour period. Indeed,
loop diuretics are frequently and inappropriately prescribed
as a once-a-day medication in the treatment not
only of hypertension, but also of congestive heart failure
and ascites. The spectacular efficacy of the loop
diuretics in producing a rapid and profound natriuresis
can be detrimental for the treatment of hypertension.
When a loop diuretic is given twice daily, the acute
diuresis can be excessive and lead to more side effects
than occur with a slower-acting, milder thiazide diuretic.
Loop diuretics may be particularly useful in patients
with azotemia or with severe edema associated with a
vasodilator such as minoxidil.
Amiloride is a K + -sparing diuretic that has some
efficacy in lowering blood pressure in patients with
hypertension. Another K + -sparing diuretic, spironolactone,
also lowers blood pressure but has some significant
adverse effects, especially in men (e.g., erectile dysfunction,
gynecomastia, benign prostatic hyperplasia).
Eplerenone is a newer aldosterone receptor antagonist
that does not have the sexually related adverse effects
induced by spironolactone. As a result of their capacity
to inhibit loss of K + in the urine, these drugs are used
in the medical treatment of patients with hyperaldosteronism,
a syndrome that can lead to hypokalemia.
Triamterene is a K + -sparing diuretic that decreases the
risk of hypokalemia in patients treated with a thiazide
diuretic but does not have efficacy in lowering blood
pressure by itself. These agents should be used cautiously
with frequent measurements of K + concentrations in
plasma in patients predisposed to hyperkalemia. Patients
taking spironolactone, amiloride, or triamterene should
be cautioned regarding the possibility that concurrent use
of K + -containing salt substitutes could produce hyperkalemia.
Renal insufficiency is a relative contraindication
to the use of K + -sparing diuretics. Concomitant use
of an ACE inhibitor or an angiotensin receptor antagonist
magnifies the risk of hyperkalemia with these agents.
Diuretic-Associated Drug Interactions
Because the antihypertensive effects of diuretics are frequently
additive with those of other antihypertensive
agents, a diuretic commonly is used in combination with
other drugs. The K + - and Mg 2+ -depleting effects of the
thiazides and loop diuretics also can potentiate arrhythmias
that arise from digitalis toxicity. Corticosteroids can
amplify the hypokalemia produced by the diuretics. All
diuretics can decrease the clearance of Li + , resulting in
increased plasma concentrations of Li + and potential toxicity.
Nonsteroidal anti-inflammatory drugs (NSAIDs; see
Chapter 34) that inhibit the synthesis of prostaglandins
reduce the antihypertensive effects of diuretics. The
effects of selective cyclooxygenase-2 (COX-2) inhibitors
on renal prostaglandin synthesis and function are similar
to those of the traditional NSAIDs. NSAIDs, β receptor
antagonists, and ACE inhibitors reduce plasma concentrations
of aldosterone and can potentiate the hyperkalemic
effects of a K + -sparing diuretic.
SYMPATHOLYTIC AGENTS
With the demonstration in 1940 that bilateral excision
of the thoracic sympathetic chain could lower blood
pressure, there was a search for effective chemical
sympatholytic agents. Many of the early sympathetic
drugs were poorly tolerated and had adverse side effects.
A number of sympathetic agents are currently in use
(Table 27–5). Antagonists of α and β adrenergic receptors
have been mainstays of antihypertensive therapy.
β Adrenergic Receptor Antagonists
β Adrenergic receptor antagonists were not expected to
have antihypertensive effects when they were first
investigated in patients with angina, their primary indication.
However, pronethalol, a drug that was never
marketed, was found to reduce arterial blood pressure
in hypertensive patients with angina pectoris. This antihypertensive
effect was subsequently demonstrated for
propranolol and all other β adrenergic receptor antagonists.
The pharmacology of these drugs is discussed
in Chapter 12; characteristics relevant to their use in
hypertension are described here.
Locus and Mechanism of Action. Antagonism of β adrenergic
receptors affects the regulation of the circulation
through a number of mechanisms, including a reduction
in myocardial contractility, heart rate, and cardiac
output (see Chapter 26). An important consequence is
blockade of the β receptors of the juxtaglomerular complex,
reducing renin secretion and thereby diminishing
production of circulating AngII. This action likely contributes
to the antihypertensive action of this class of
drugs, in concert with the cardiac effects. β receptor
antagonists may lower blood pressure by other mechanisms.
Some members of this large, heterogeneous class
of drugs have additional effects unrelated to their capacity
to bind to β adrenergic receptors. For example,
labetalol is an α receptor antagonist, and nebivolol
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION