Organic nitrates
The term nitrites applies to salts of nitrous acid such as sodium nitrite or their esters such as amyl nitrite . Organic nitrates are esters of nitric acid . These include, for example, glycerol trinitrate ( nitroglycerin ), isosorbide dinitrate , isosorbide mononitrate and molsidomine , which are also known as NO donors .
Organic nitrates have a characteristic spectrum of activity on the vascular muscles, as it is mainly the capacity vessels and larger arteries that are widened, while the effect on the arterioles is minor. The hemodynamic (blood flow) situation resulting from this effect makes organic nitrates particularly suitable for the treatment of angina pectoris .
Substance properties
The most important substances in this group are esters of nitric acid with various alcohols (organic nitrate esters). Glycerol trinitrate - also called nitroglycerin - is an oily liquid that is only highly explosive in its pure form when it is shaken , but not in an alcoholic solution or with the addition of inert lactose molecules. In the latter forms, glycerol trinitrate is used for the manufacture of medicines . The other therapeutically used nitrate esters (isosorbide-5-mononitrate, isosorbide dinitrate, pentaerythrityl tetranitrate) are solid substances like molsidomine.
Pharmacodynamics
Nitrate esters lower the tone of the vascular muscles . The venous capacity vessels are particularly affected by this effect, the expansion of which ("venous pooling") reduces the preload on the heart. The diastolic filling volume can decrease, the wall tension is reduced and the oxygen consumption decreases. In addition, nitrates dilate large arteries. The extramural coronary arteries are also affected. However, this has little effect on the overall coronary perfusion , but can improve the peripheral blood flow to ischemic areas by increasing the perfusion pressure in collaterals. The arterioles in the face and neck area are particularly sensitive; their widening causes a characteristic reddening of the skin (“flushing symptoms”) in these areas. The vasodilation of the meningeal arteries triggers the sometimes severe headache. The arterioles are only enlarged in high doses; this is accompanied by a drop in blood pressure and a decrease in afterload. With preparations to be administered orally, venous pooling in the splanchnic area is probably decisive for the relieving effect on the heart.
It has been known since the 1980s that vascular tone can be regulated locally in an endothelial-dependent manner. Various physiological stimuli such as B. Release of acetylcholine , histamine , serotonin , noradrenaline , bradykinin , ATP , ADP , thrombin , or intravascular hypoxia lead to vasodilation, in which a labile mediator substance formed by the endothelium is involved. This was known as EDRF ("endothelium-derived relaxing factor") and chemically identified as nitrogen monoxide (NO). NO is formed from L- arginine in the endothelial cells and diffuses into the smooth muscle cells in order to relax them. Since NO is not stable and is converted to inactive nitrogen dioxide within a few seconds by reacting with oxygen, the effect only lasts for a short time. The slackening effect of NO is not limited to the vascular smooth muscles, but also includes the smooth muscles of the gastrointestinal tract as well as the bronchi, gallbladder and draining bile ducts. Furthermore, NO plays a role in physiological processes as diverse as neurotransmission, the reactivity of blood platelets or the cytotoxicity of immune cells.
Mechanism of action
Release of NO through enzymatic activation
The release of NO from nitrate esters takes place enzymatically by the thiol group-dependent nitrate reductase. From glycerol trinitrate, NO is formed in the smooth muscle cells with the help of organic nitrate reductase ( ALDH-2 ). For this enzymatic release of NO, thiol groups (cysteine) are required as cofactors for the regeneration of the enzyme.
Release of NO through non-enzymatic activation
Non-enzymatically generated NO only from the Molsidominmetaboliten Linsidomin, by intramolecular rearrangement reactions.
Effect of NO on smooth muscle cells
NO activates a soluble guanylate cyclase (sGC) in the cytosol of the smooth muscle cells and thus stimulates the formation of cGMP . With the intracellular increase in cGMP, a membrane-bound phosphokinase is activated, which stimulates the myosin phosphatase of the smooth muscles. This outweighs MLCP of MLCK and myosin is less phosphorylated. Unphosphorylated myosin cannot be made to interact with actin and as a result the blood vessel can relax.
Another described mechanism explains the relaxation of the muscle cells by activation of cGMP-dependent protein kinase G . This causes a decrease in the intracellular calcium concentration and thus a decrease in contractility. For this purpose z. B. removed a nitrate patch during the night. Tolerance is only observed with nitrate esters, from which NO is enzymatically released depending on thiol groups, but not with molsidomine.
unwanted effects
At the beginning of therapy, local vasodilation in the head and neck area often leads to headaches and reddening of the skin (flush). This reaction has been known as the "nitroglycerin headache" from Alfred Nobel's early explosives factories since 1862. These symptoms usually go away again in the further course of therapy. Dizziness and a feeling of weakness are an expression of orthostatic dysregulation. With high-dose therapy with nitrate esters, excessive dilatation of the veins can lead to severe orthostatic hypotension and even loss of consciousness (nitrate syncope). Excessive dilation of the arteries can worsen myocardial oxygen deficiency (paradoxical reaction). As a result of the sharp decrease in arterial blood pressure, the coronary perfusion pressure (= mean diastolic aortic pressure minus left ventricular end-diastolic pressure ) is reduced and the oxygen supply is restricted. In addition, reflex tachycardia triggers an increase in myocardial oxygen consumption by activating the sympathetic nervous system .
A reflex or drug-induced tachycardia has two unfavorable effects in patients with angina pectoris: on the one hand, the myocardial oxygen consumption increases due to the frequency, and on the other hand, the oxygen supply decreases because the diastole (coronary blood flow!) Becomes shorter relative to the duration of the entire contraction cycle.
Skin rashes as an expression of a hypersensitivity reaction are rare and mostly described in connection with pentarythritol tetranitrate. Furthermore, nausea and disorders in the gastrointestinal tract , and after high doses, diarrhea can occur. Methaemoglobin is mainly formed by nitrites and does not play a role in low-dose therapy with nitrate esters. Molsidomine inhibits platelet aggregation , probably also NO-mediated.
Nitrate tolerance
In long-term therapy with retarded orally applied preparation forms or with nitrate patches, a loss of effectiveness, which is referred to as tolerance, develops rapidly. The mechanism of their formation is not fully understood.
In the past, tolerance was attributed to exhaustion of the cellular content of reduced SH groups, since normal responsiveness is usually restored 1–2 days after interruption of therapy. Today it is assumed that this effect plays a subordinate role. Another, experimentally proven effect is the increased formation of oxygen radicals (ROS) with the administration of NO donors. The oxygen radicals would then (according to the theory ) intercept the nitrogen monoxide (NO) formed and thus weaken its effect. Another effect discussed is the inhibition of the nitrate reductase ALDH-2, which is necessary for bioactivation of enzymatically cleaved NO donors, by oxygen radicals and by a NO-induced negative feedback mechanism.
The development of nitrate tolerance can be avoided by introducing a nitrate-free therapy interval. For this purpose z. B. removed a nitrate patch during the night. Tolerance is only observed with nitrate esters, from which NO is enzymatically released depending on thiol groups, but not with molsidomine . People who are exposed to high workplace concentrations during the production of organic nitrates can develop a nitrate dependency. If the nitrate esters are suddenly "discontinued" in this group of people, severe withdrawal reactions can occur. Angina pectoris attacks appear as an expression of vascular spasms, and even heart attacks have been described. Any long-term exposure to high doses of nitrate esters should be carefully and gradually ended in order to avoid the threat of a seizure trigger (rebound effect).
Pharmacokinetics
Absorption and distribution: Due to their good lipid solubility, the nitrate esters are well absorbed through the mucous membranes and skin. After oral administration, they are subject to a high first-pass effect in the liver, so their bioavailability (with the exception of isorbide-5-mononitrate, see below) is low. For a rapid onset of action, glycerol trinitrate and isosorbide dinitrate must therefore be administered sublingually or buccally, bypassing the liver circulation. Resorption through the oral mucosa takes place rapidly, the maximum plasma concentration after sublingual application of glycerol trinitrate is reached after 4 minutes, of isosorbide dinitrate after 6 minutes. The nitrate esters are well distributed in all tissues, only about 1% of the total body content is in the plasma.
Elimination: The plasma half-life of glycerol trinitrate is 1–3 minutes. In the liver, the glutathione-dependent organic nitrate reductase from glycerol trinitrate releases NO, producing 1,3- or 1,2-glycerol dinitrate, which are about ten times less effective and have a plasma half-life of 4 hours. Isosorbide dinitrate produces isosorbide-2-mononitrate and isosorbide-5-mononitrate, which are additionally inactivated by glucuronidation. Their plasma half-life is 2–5 hours. Isosorbide-5-mononitrate is also used directly because of its good bioavailability. Molsidomine is converted into linsidomine in the liver, which breaks down into a labile metabolite from which NO is released without the mediation of reduced thiol groups.
Therapeutic use
Treatment goals in coronary heart disease are
- Breaking through an attack of angina and
- reducing the number of seizures (seizure prophylaxis)
Indications : Depending on the type of application, to break an angina pectoris attack (glycerol trinitrate sublingual; isosorbide dinitrate sublingual) and for prophylaxis (delayed preparations of glycerol trinitrate po or as a plaster, molsidomine). The effectiveness is independent of the pathogenesis of angina pectoris (arteriosclerosis, coronary spasms)
Contraindication : hypotonic circulatory failure, taking potency-enhancing agents within the last 24 hours ( 48 hours for Tadalafil )
Interactions : With simultaneous consumption of alcohol, the vasodilatory effect of organic nitrates is increased. This particularly applies to flushing symptoms in the face and neck area and orthostatic dysregulation.
List of active ingredients
enzymatically activated NO donors:
- Glycerol trinitrate (GTN)
- Isosorbide dinitrate (ISDN)
- Isosorbide Mononitrate (ISMN)
- Pentaerythrityl tetranitrate (PETN)
non-enzymatically activated NO donors:
literature
- AWMF guidelines on coronary heart disease ( Memento from April 20, 2008 in the Internet Archive )
Individual evidence
- ↑ Reinhard Larsen: Anesthesia and intensive medicine in cardiac, thoracic and vascular surgery. (1st edition 1986) 5th edition. Springer, Berlin / Heidelberg / New York et al. 1999, ISBN 3-540-65024-5 , p. 193 f.
- ↑ Schubert-Zsilavecz, Manfred., Roth, Hermann J .: Medicinal Chemistry: Targets - Drugs - Chemical Biology; 191 tables . 2., completely reworked. and exp. Ed. Dt. Apotheker-Verl, Stuttgart 2010, ISBN 978-3-7692-5002-2 .
