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

Table 27–6
Hemodynamic Effects of Long-Term Administration of Antihypertensive Agents
TOTAL
PLASMA
HEART CARDIAC PERIPHERAL PLASMA RENIN
RATE OUTPUT RESISTANCE VOLUME ACTIVITY
Diuretics i i b –b a
Sympatholytic agents
Centrally acting –b –b b –a –b
Adrenergic neuron –b b b a –a
blockers
α receptor antagonists –a –a b –a i
β receptor antagonists
No ISA b b –b –a b
ISA i i b –a –↓
Arteriolar vasodilators a a b a a
Ca 2+ channel blockers b or a bor a b –a –a
ACE inhibitors i i b i a
AT 1
receptor antagonists i i b i a
Renin inhibitor i i b i b(but [renin] a)
a, increased; b, decreased; –a, increased or no change; –b, decreased or no change; i, unchanged. ACE, angiotensin-converting enzyme; AT 1
, the
type 1 receptor for angiotensin II; ISA, intrinsic sympathomimetic activity.
alone, and they enhance the efficacy of virtually all
other antihypertensive drugs. On account of these considerations,
coupled with the very large favorable experience
with diuretics in randomized trials in patients
with hypertension, this class of drugs remains very
important in the treatment of hypertension.
The exact mechanism for reduction of arterial
blood pressure by diuretics is not certain. The initial
action of these drugs decreases extracellular volume by
interacting with a thiazide-sensitive NaCl co-transporter
(NCC; gene symbol SLC12A3) expressed in the distal
convoluted tubule in the kidney, enhancing Na + excretion
in the urine, and leading to a fall in cardiac output.
However, the hypotensive effect is maintained during
long-term therapy due to decreased vascular resistance;
cardiac output returns to pretreatment values and extracellular
volume returns almost to normal due to compensatory
responses such as activation of the RAS. The
explanation for the long-term vasodilation induced by
these drugs is unknown. Thiazides directly promote
vasodilation in isolated arteries in vitro. On the other
hand, there is suggestive evidence that vasodilation may
occur as an indirect consequence of action of the drugs
on the kidneys (Ellison and Loffing, 2009).
Hydrochlorothiazide may open Ca 2+ -activated K + channels,
leading to hyperpolarization of vascular smooth muscle cells, which
leads in turn to closing of L-type Ca 2+ channels and lower probability
of opening, resulting in decreased Ca 2+ entry and reduced vasoconstriction.
Hydrochlorothiazide also inhibits vascular carbonic
anhydrase, which hypothetically may alter smooth-cell systolic pH
and thereby cause opening of Ca 2+ -activated K + channels with the
consequences noted above (Pickkers et al., 1999). The relevance of
these findings—largely assessed in vitro—to the observed antihypertensive
effects of thiazides is speculative. The major action of
these drugs on SLC12A3—expressed predominantly in the distal
convoluted tubules and not in vascular smooth muscle or the heart—
has contributed to repeated suggestions that these drugs decrease
peripheral resistance as an indirect effect of negative sodium balance.
That thiazides lose efficacy in treating hypertension in patients
with co-existing renal insufficiency is compatible with this hypothesis.
Moreover, carriers of rare functional mutations in SLC12A3
that decrease renal Na + reabsorption have lower blood pressure than
appropriate controls (Ji et al., 2008); in a sense, this is an experiment
of nature that may mimic the therapeutic effect of thiazides.
Nonetheless, sorting out direct versus indirect actions of thiazides
in promoting decreased peripheral resistance requires further experimental
testing (Ellison and Loffing, 2009).
Benzothiadiazines and Related
Compounds
Benzothiadiazines (“thiazides”) and related diuretics are
the most frequently used class of antihypertensive
agents in the U.S. Following the discovery of chlorothiazide,
a number of oral diuretics were developed that