Page 191 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 11 Antihypertensive Agents 177

Resistant Hypertension & Polypharmacy

Monotherapy of hypertension (treatment with a single drug) is inhibitors report a maximal lowering of blood pressure of less
desirable because compliance is likely to be better and the cost than 10 mm Hg. In patients with more severe hypertension
is lower, and because in some cases adverse effects are fewer. (pressure > 160/100 mm Hg), this is inadequate to prevent all
However, most patients with hypertension require two or more the sequelae of hypertension, but ACE inhibitors have important
drugs acting by different mechanisms (polypharmacy). Accord- long-term benefits in preventing or reducing renal disease in
ing to some estimates, up to 40% of patients may respond inad- diabetic persons and in reduction of heart failure. Finally, the
equately even to two agents and are considered to have “resistant toxicity of some effective drugs prevents their use at maximally
hypertension.” Some of these patients have treatable secondary effective doses.
hypertension that has been missed, but most do not, and three In practice, when hypertension does not respond adequately
or more drugs are required. to a regimen of one drug, a second drug from a different class
One rationale for polypharmacy in hypertension is that most with a different mechanism of action and different pattern of
drugs evoke compensatory regulatory mechanisms for main- toxicity is added. If the response is still inadequate and com-
taining blood pressure (see Figures 6–7 and 11–1), which may pliance is known to be good, a third drug should be added. If
markedly limit their effect. For example, vasodilators such as three drugs (usually including a diuretic) are inadequate, other
hydralazine cause a significant decrease in peripheral vascular causes of resistant hypertension such as excessive dietary
resistance, but evoke a strong compensatory tachycardia and sodium intake, use of nonsteroidal anti-inflammatory or stimu-
salt and water retention (Figure 11–4) that are capable of almost lant drugs, or the presence of secondary hypertension should be
completely reversing their effect. The addition of a β blocker considered. In some instances, an additional drug may be neces-
prevents the tachycardia; addition of a diuretic (eg, hydrochloro- sary, and mineralocorticoid antagonists, such as spironolactone,
thiazide) prevents the salt and water retention. In effect, all three have been found to be particularly useful. Occasionally patients
drugs increase the sensitivity of the cardiovascular system to each are resistant to four or more drugs, and nonpharmacologic
other’s actions. approaches have been considered. Two promising treatments
A second reason is that some drugs have only modest maxi- that are still under investigation, particularly for patients with
mum efficacy but reduction of long-term morbidity mandates advanced kidney disease, are renal denervation and carotid
their use. Many studies of angiotensin-converting enzyme (ACE) barostimulation.

Mechanisms of Action & Hemodynamic Use of Diuretics
Effects of Diuretics The sites of action within the kidney and the pharmacokinetics
Diuretics lower blood pressure primarily by depleting body sodium of various diuretic drugs are discussed in Chapter 15. Thiazide
stores. Initially, diuretics reduce blood pressure by reducing blood diuretics are appropriate for most patients with mild or moder-
volume and cardiac output; peripheral vascular resistance may ate hypertension and normal renal and cardiac function. While
increase. After 6–8 weeks, cardiac output returns toward normal all thiazides lower blood pressure, the use of chlorthalidone in
while peripheral vascular resistance declines. Sodium is believed to preference to others is supported by evidence of improved 24-hour
contribute to vascular resistance by increasing vessel stiffness and blood pressure control and reduced cardiovascular events in large
neural reactivity, possibly related to altered sodium-calcium exchange clinical trials. Chlorthalidone is likely to be more effective than
with a resultant increase in intracellular calcium. These effects are hydrochlorothiazide because it has a longer duration of action.
reversed by diuretics or dietary sodium restriction. More powerful diuretics (eg, those acting on the loop of Henle)
Diuretics are effective in lowering blood pressure by 10–15 mm Hg such as furosemide are necessary in severe hypertension, when
in most patients, and diuretics alone often provide adequate treat- multiple drugs with sodium-retaining properties are used;
ment for mild or moderate essential hypertension. In more severe in renal insufficiency, when glomerular filtration rate is less
hypertension, diuretics are used in combination with sympathople- than 30–40 mL/min; and in cardiac failure or cirrhosis, in which
gic and vasodilator drugs to control the tendency toward sodium sodium retention is marked.
retention caused by these agents. Vascular responsiveness—ie, Potassium-sparing diuretics are useful both to avoid excessive
the ability to either constrict or dilate—is diminished by sympa- potassium depletion and to enhance the natriuretic effects of
thoplegic and vasodilator drugs, so that the vasculature behaves other diuretics. Aldosterone receptor antagonists in particular also
like an inflexible tube. As a consequence, blood pressure becomes have a favorable effect on cardiac function in people with heart
exquisitely sensitive to blood volume. Thus, in severe hyperten- failure.
sion, when multiple drugs are used, blood pressure may be well Some pharmacokinetic characteristics and the initial and
controlled when blood volume is 95% of normal but much too usual maintenance dosages of diuretics are listed in Table 11–2.
high when blood volume is 105% of normal. Although thiazide diuretics are more natriuretic at higher doses