Page 216 - Basic _ Clinical Pharmacology ( PDFDrive )

202 SECTION III Cardiovascular-Renal Drugs

TABLE 12–3 Nitrate and nitrite drugs used in the treatment of angina.

Drug Dose Duration of Action
Short-acting
Nitroglycerin, sublingual 0.15–1.2 mg 10–30 minutes
Isosorbide dinitrate, sublingual 2.5–5 mg 10–60 minutes
Amyl nitrite, inhalant (obsolete) 0.18–0.3 mL 3–5 minutes
Long-acting
Nitroglycerin, oral sustained-action 6.5–13 mg per 6–8 hours 6–8 hours
Nitroglycerin, 2% ointment, transdermal 1–1.5 inches per 4 hours 3–6 hours
Nitroglycerin, slow-release, buccal 1–2 mg per 4 hours 3–6 hours
Nitroglycerin, slow-release patch, transdermal 10–25 mg per 24 hours (one patch per day) 8–10 hours
Isosorbide dinitrate, sublingual 2.5–10 mg per 2 hours 1.5–2 hours
Isosorbide dinitrate, oral 10–60 mg per 4–6 hours 4–6 hours
Isosorbide dinitrate, chewable oral 5–10 mg per 2–4 hours 2–3 hours
Isosorbide mononitrate, oral 20 mg per 12 hours 6–10 hours
Pentaerythritol tetranitrate (PETN) 50 mg per 12 hours 10–12 hours

effects are quickly reversed when the infusion is stopped. Clinical and is not subject to tolerance. Recent studies suggest that it may
use of intravenous nitroglycerin is therefore restricted to the treat- reduce cerebral vasospasm in stroke. It is not available in the USA.
ment of severe, recurrent rest angina. Slowly absorbed prepara-
tions of nitroglycerin include a buccal form, oral preparations, and
several transdermal forms. These formulations have been shown to CALCIUM CHANNEL-BLOCKING DRUGS
provide blood concentrations for long periods but, as noted above,
this leads to the development of tolerance. It has been known since the late 1800s that transmembrane
The hemodynamic effects of sublingual or chewable isosorbide calcium influx is necessary for the contraction of smooth and car-
dinitrate and the oral organic nitrates are similar to those of nitro- diac muscle. The discovery of a calcium channel in cardiac muscle
glycerin given by the same routes. Although transdermal admin- was followed by the finding of several different types of calcium
istration may provide blood levels of nitroglycerin for 24 hours channels in different tissues (Table 12–4). The discovery of these
or more, the full hemodynamic effects usually do not persist for channels made possible the measurement of the calcium current,
more than 8–10 hours. The clinical efficacy of slow-release forms I , and subsequently, the development of clinically useful block-
Ca
of nitroglycerin in maintenance therapy of angina is thus limited ing drugs. Although the blockers currently available for clinical
by the development of tolerance. Therefore, a nitrate-free period use in cardiovascular conditions are exclusively L-type calcium
of at least 8 hours between doses of long-acting and slow-release channel blockers, selective blockers of other types of calcium
forms should be observed to reduce or prevent tolerance. channels are under intensive investigation. Certain antiseizure
drugs are thought to act, at least in part, through calcium channel
(especially T-type) blockade in neurons (see Chapter 24).
OTHER NITRO-VASODILATORS

Chemistry & Pharmacokinetics
Nicorandil is a nicotinamide nitrate ester that has vasodilating
properties in normal coronary arteries but more complex effects in Verapamil, the first clinically useful member of this group, was
patients with angina. Recent studies in isolated myocytes indicate the result of attempts to synthesize more active analogs of papav-
+
2+
that the drug activates an Na /Ca exchanger and reduces intra- erine, a vasodilator alkaloid found in the opium poppy. Since
2+
cellular Ca overload. Clinical studies suggest that it reduces both then, dozens of agents of varying structure have been found to
preload and afterload. It also provides some myocardial protection have the same fundamental pharmacologic action (Table 12–5).
via preconditioning by activation of cardiac K ATP channels. One Three chemically dissimilar calcium channel blockers are shown
large trial showed a significant reduction in relative risk of fatal and in Figure 12–4. Nifedipine is the prototype of the dihydropyridine
nonfatal coronary events in patients receiving the drug. Nicorandil family of calcium channel blockers; dozens of molecules in this
is currently approved for use in the treatment of angina in Europe family have been investigated, and several are currently approved
and Japan but has not been approved in the USA. Molsidomine is in the USA for angina, hypertension, and other indications.
a prodrug that is converted to a nitric oxide–releasing metabolite. The calcium channel blockers are orally active agents and
It is said to have efficacy comparable to that of the organic nitrates are characterized by high first-pass effect, high plasma protein