Page 193 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 11 Antihypertensive Agents 179

TABLE 11–2 Pharmacokinetic characteristics and dosage of selected oral antihypertensive drugs.

Bioavailability Suggested Initial Usual Maintenance Reduction of Dosage Required
Drug Half-life (h) (percent) Dose Dose Range in Moderate Renal Insufficiency 1
Amlodipine 35 65 2.5 mg/d 5–10 mg/d No
Atenolol 6 60 50 mg/d 50–100 mg/d Yes
Benazepril 0.6 2 35 5–10 mg/d 20–40 mg/d Yes
Captopril 2.2 65 50–75 mg/d 75–150 mg/d Yes
Chlorthalidone 40–60 65 25 mg/d 25–50 mg/d No
Clonidine 8–12 95 0.2 mg/d 0.2–1.2 mg/d Yes
Diltiazem 3.5 40 120–140 mg/d 240–360 mg/d No
Hydralazine 1.5–3 25 40 mg/d 40–200 mg/d No
Hydrochlorothiazide 12 70 25 mg/d 25–50 mg/d No
Lisinopril 12 25 10 mg/d 10–80 mg/d Yes
Losartan 1–2 3 36 50 mg/d 25–100 mg/d No
Methyldopa 2 25 1 g/d 1–2 g/d No
Metoprolol 3–7 40 50–100 mg/d 200–400 mg/d No
Minoxidil 4 90 5–10 mg/d 40 mg/d No
Nebivolol 12 Nd 4 5 mg/d 10–40 mg/d No
Nifedipine 2 50 30 mg/d 30–60 mg/d No
Prazosin 3–4 70 3 mg/d 10–30 mg/d No
Propranolol 3–5 25 80 mg/d 80–480 mg/d No
Reserpine 24–48 50 0.25 mg/d 0.25 mg/d No
Verapamil 4–6 22 180 mg/d 240–480 mg/d No
1 Creatinine clearance ≥ 30 mL/min. Many of these drugs do require dosage adjustment if creatinine clearance falls below 30 mL/min.
2
The active metabolite of benazepril has a half-life of 10 hours.
3 The active metabolite of losartan has a half-life of 3–4 hours.
4
Nd, not determined.

of parasympathetic regulation, in addition to profound sympathetic Mechanisms & Sites of Action
blockade and are no longer used. Drugs that act chiefly by reducing
release of norepinephrine from sympathetic nerve endings cause These agents reduce sympathetic outflow from vasomotor centers
effects that are similar to those of surgical sympathectomy, includ- in the brain stem but allow these centers to retain or even increase
ing inhibition of ejaculation, and hypotension that is increased by their sensitivity to baroreceptor control. Accordingly, the anti-
upright posture and after exercise. Drugs that block postsynaptic hypertensive and toxic actions of these drugs are generally less
adrenoceptors produce a more selective spectrum of effects depend- dependent on posture than are the effects of drugs that act directly
ing on the class of receptor to which they bind. on peripheral sympathetic neurons.
Finally, one should note that all of the agents that lower blood Methyldopa (l-α-methyl-3,4-dihydroxyphenylalanine) is an
pressure by altering sympathetic function can elicit compensatory analog of l-dopa and is converted to α-methyldopamine and
effects through mechanisms that are not dependent on adrenergic α-methylnorepinephrine; this pathway directly parallels the synthe-
nerves. Thus, the antihypertensive effect of any of these agents sis of norepinephrine from dopa illustrated in Figure 6–5. Alpha-
used alone may be limited by retention of sodium by the kidney methylnorepinephrine is stored in adrenergic nerve vesicles, where it
and expansion of blood volume. For this reason, sympathoplegic stoichiometrically replaces norepinephrine, and is released by nerve
antihypertensive drugs are most effective when used concomitantly stimulation to interact with postsynaptic adrenoceptors. However,
with a diuretic. this replacement of norepinephrine by a false transmitter in periph-
eral neurons is not responsible for methyldopa’s antihypertensive
effect, because the α-methylnorepinephrine released is an effective
CENTRALLY ACTING agonist at the α adrenoceptors that mediate peripheral sympathetic
SYMPATHOPLEGIC DRUGS constriction of arterioles and venules. In fact, methyldopa’s anti-
hypertensive action appears to be due to stimulation of central α
Centrally acting sympathoplegic drugs were once widely used in adrenoceptors by α-methylnorepinephrine or α-methyldopamine.
the treatment of hypertension. With the exception of clonidine, The antihypertensive action of clonidine, a 2-imidazoline deriv-
these drugs are rarely used today. ative, was discovered in the course of testing the drug for use as a