Organic Nitrates

Various esters of nitric acid (HNO3) and polyvalent alcohols relax vascular smooth muscle, e.g., nitroglycerin (gly-ceryltrinitrate) and isosorbide dinitrate. The effect is more pronounced in venous than in arterial beds.

These vasodilator effects produce hemodynamic consequences that can be put to therapeutic use. Due to a decrease in both venous return (preload) and arterial afterload, cardiac work is decreased (p. 308). As a result, the cardiac oxygen balance improves. Spasmodic constriction of larger coronary vessels (coronary spasm) is prevented.

Uses. Organic nitrates are used chiefly in angina pectoris (p. 308, 310), less frequently in severe forms of chronic and acute congestive heart failure. Continuous intake of higher doses with maintenance of steady plasma levels leads to loss of efficacy, inasmuch as the organism becomes refractory (tachy-phylactic). This "nitrate tolerance" can be avoided if a daily "nitrate-free interval" is maintained, e.g., overnight.

At the start of therapy, unwanted reactions occur frequently in the form of a throbbing headache, probably caused by dilation of cephalic vessels. This effect also exhibits tolerance, even when daily "nitrate pauses" are kept. Excessive dosages give rise to hypotension, reflex tachycardia, and circulatory collapse.

Mechanism of action. The reduction in vascular smooth muscle tone is presumably due to activation of guany-late cyclase and elevation of cyclic GMP levels. The causative agent is most likely nitric oxide (NO) generated from the organic nitrate. NO is a physiological messenger molecule that endothelial cells release onto subjacent smooth muscle cells ("endothelium-derived relaxing factor," EDRF). Organic nitrates would thus utilize a pre-existing pathway, hence their high efficacy. The generation of NO within the smooth muscle cell depends on a supply of free sulfhy-dryl (-SH) groups; "nitrate-tolerance" Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

has been attributed to a cellular exhaustion of SH-donors but this may be not the only reason.

Nitroglycerin (NTG) is distinguished by high membrane penetrability and very low stability. It is the drug of choice in the treatment of angina pec-toris attacks. For this purpose, it is administered as a spray, or in sublingual or buccal tablets for transmucosal delivery. The onset of action is between 1 and 3 min. Due to a nearly complete pre-systemic elimination, it is poorly suited for oral administration. Transdermal delivery (nitroglycerin patch) also avoids presystemic elimination. Isosorbide dinitrate (ISDN) penetrates well through membranes, is more stable than NTG, and is partly degraded into the weaker, but much longer acting, 5-isosorbide mononitrate (ISMN). ISDN can also be applied sublingually; however, it is mainly administered orally in order to achieve a prolonged effect. ISMN is not suitable for sublingual use because of its higher polarity and slower rate of absorption. Taken orally, it is absorbed and is not subject to first-pass elimination.

Molsidomine itself is inactive. After oral intake, it is slowly converted into an active metabolite. Apparently, there is little likelihood of "nitrate tolerance".

Sodium nitroprusside contains a nitroso (-NO) group, but is not an ester. It dilates venous and arterial beds equally. It is administered by infusion to achieve controlled hypotension under continuous close monitoring. Cyanide ions liberated from nitroprusside can be inactivated with sodium thiosulfate (Na2S2O3) (p. 304).

Preload I O2"Supply t

Venous blood return to heart j

I Blood pressure!

Preload I O2"Supply t

Venous blood return to heart j

I Blood pressure!

Route:

e.g., sublingual, transdermal

Glyceryl trinitrate Nitroglycerin

Edrf Nitrates

5-Isosorbide mononitrate, an active metabolite tv~ 240 min

Route:

e.g., sublingual, transdermal

Glyceryl trinitrate Nitroglycerin

O-NO2 Isosorbide dinitrate t>2

Inactivation

SH-donors e.g., glutathione

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