ORGANICNITRATES Chemische Eigenschaften,Einsatz,Produktion Methoden
Biologische Funktion
The oxygen requirements of the myocardial tissues are related to the workload (oxygen demand) of
the heart, which is, in part, a function of the heart rate, the systolic pressure, and the peripheral
resistance of the blood flow (oxygen supply). Myocardial ischemia occurs when the oxygen supply is
insufficient to meet the myocardial oxygen demand. This can occur, as explained previously,
because of atherosclerotic narrowing of the coronary circulation (typical) or vasospasm of the
coronary artery (variant). The nitrates have been shown to be effective in treating angina resulting
from either cause. The vasodilating effect of organic nitrates on the veins leads to pooling of the
blood in the veins and decreased venous return to the heart (decreased preload), whereas
vasodilation of the coronary arterioles decreases the resistance of the peripheral tissues (decreased
afterload). The decrease in both preload and afterload results in a generalized decrease in the
myocardial workload, which translates into a reduced oxygen demand by the myocardium. Organic
nitrates restore the balance between oxygen supply by venous dilation and oxygen demand by
decreasing the myocardial workload.
Mechanism of action
The organic nitrates are pharmacological sources of nitric oxide (NO) for the body. In the
cardiovascular system, NO is naturally produced by vascular endothelial cells. This endothelialderived NO has several important functions, including relaxation of vascular smooth muscle,
inhibiting platelet aggregation (antithrombotic), and inhibiting leukocyte-endothelial interactions
(anti-inflammatory). These actions involve NO-stimulated formation of cyclic guanosine
monophosphate (cGMP). Nitrodilators are drugs that mimic the actions of
endogenous NO by releasing NO or forming NO within tissues. Free tissue sulfhydryl groups play a
key role in the venodilation effect of nitroglycerin, which is supported by experimental evidence
showing that prior administration of N-acetylcysteine, which should increase the availability of free
sulfhydryl groups, resulted in an increase in the venodilating effect of organic nitrates. Similarly,
pretreatment with reagents that react with free sulfhydryl groups, such as ethacrynic acid, blocked
glyceryl trinitrate venodilation in vitro. A more complex mechanism for nitrate venodilation,
however, was proposed
by Ignarro et al.. They suggested that the nitrates act indirectly, by stimulating the enzyme
guanylate (also known as guanylyl) cyclase and, thereby, producing elevated levels of cGMP, which
in turn leads to venodilation. The initial stimulation of soluble guanylate cyclase is believed to be mediated by a nitrate-derived nitrosothiol metabolite produced intracellularly.
Clinical Use
Organic nitrates are used for both treatment and prevention of painful anginal attacks. The
therapeutic approaches to achieve these two goals, however, are distinctly different. For the
treatment of acute anginal attacks (i.e., attacks that have already begun), a rapid-acting preparation
is required. In contrast, preventative therapy requires a long-acting preparation with more emphasis
on duration and less emphasis on onset. The onset of organic nitrate action is influenced not only by
the specific agent chosen but also by the route of administration. Sublingual administration is used
predominantly for a rapid onset of action. The duration of nitrate action is strongly influenced by rate
of metabolism. All of the organic nitrates are subject to rapid first-pass metabolism not only by the
action of glutathione-nitrate reductase in the liver, but also in extrahepatic tissues, such as the
blood vessel walls themselves. In addition, rapid uptake into the vessel walls plays a
significant role in the rapid disappearance of organic nitrates from the bloodstream. Sublingual,
transdermal, and buccal administration routes have been used in an attempt to avoid at least some
of the hepatic metabolism.
Nebenwirkungen
Most patients tolerate the nitrates fairly well. Headache and postural hypotension are the most
common side effects of organic nitrates. Dizziness, nausea, vomiting, rapid pulse, and restlessness
are among the additional side effects reported. These symptoms may be controlled by administering
low doses initially and then gradually increasing the dose. Fortunately, tolerance to nitrate-induced headache develops
after a few days of therapy. Because postural hypotension may occur in some individuals, advise the
patient to sit down when taking a rapid-acting nitrate preparation for the first time. An effective dose
of nitrate usually produces a fall in upright systolic pressure of 10 mm Hg and a reflex rise in heart
rate of 10 beats per minute.
Another concern associated with prophylactic nitrate use is the development of tolerance.
Tolerance, usually in the form of shortened duration of action, is commonly observed with chronic
nitrate use. The clinical importance of this tolerance is, however, a matter of controversy. Because
tolerance to nitrates has not been reported to lead to a total loss of activity, some physicians feel
that it is not clinically relevant. In addition, an adjustment in dosage can compensate for the reduced
response. It also has been reported that intermittent use of long-acting and sustained-release
preparations may limit the extent of tolerance development.
Arzneimittelwechselwirkung
The most significant interactions of organic nitrates are with those agents that cause hypotension,
such as other vasodilators, alcohol, and tricyclic antidepressants, in which the potential for
orthostatic hypotension may arise. On the other hand, concurrent administration with
sympathomimetic amines, such as ephedrine and norepinephrine, may lead to a decrease in the
antianginal efficacy of the organic nitrates.
Stoffwechsel
Acute angina most frequently is treated with sublingual glyceryl trinitrate. This sublingual
preparation is rapidly absorbed from the sublingual, lingual, and buccal mucosa and usually provides
relief within 2 minutes. The duration of action also is short (~30 minutes). Other treatments include
amyl nitrite by inhalation and sublingual isosorbide dinitrate. Amyl nitrite is by far the fastest-acting
preparation, with an onset of action in approximately 15 to 30 seconds, but the duration of action is
only approximately 1 minute. Isosorbide dinitrate, although usually used as a long-acting agent, may
be used to treat acute angina. Sublingually administered isosorbide dinitrate has a somewhat slower
onset than glyceryl trinitrate (~3 minutes), but its action may last for 4 to 6 hours. Although the
onset appears to be almost as rapid as that of glyceryl trinitrate, waiting an additional minute for
relief may be deemed unacceptable by some patients.
ORGANICNITRATES Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
