AT 1 antagonist

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AT 1 antagonists ( angiotensin II receptor subtype 1 antagonists, AT 1 receptor antagonists, AT 1 blockers, AT 1 receptor blockers, angiotensin 1 receptor blockers, " sartans ") are drugs that are used to treat high blood pressure or Heart failure can be used.

Structural formula of the AT 1 antagonist losartan

properties

AT 1 antagonists act as specific inhibitors of the angiotensin II receptor (subtype 1) , which normally causes an increase in blood pressure. Some AT 1 antagonists are also approved for chronic heart failure (valsartan, candesartan, losartan), post- heart attack conditions (valsartan) and diabetic nephropathy (as part of hypertension treatment - losartan, irbesartan). The substance group is a further development of the ACE inhibitors and has been on the market since 1995. Compared to ACE inhibitors, it essentially offers the advantage that their most common side effect , the dry, irritating cough, occurs significantly less often.

Chemical basics

The individual active ingredients are relatively closely related chemically. They are further developments of the parent substance losartan , which was the first non-peptide AT 1 antagonist. All AT 1 antagonists show a more than 10,000-fold selectivity for the AT 1 receptor compared to the AT 2 receptor. With the exception of valsartan, the AT 1 antagonists have either an imidazole or a benzimidazole backbone. In addition, with the exception of eprosartan, all AT 1 antagonists have a biphenyl system . Either a carboxy group is bound to this or a tetrazole ring, which, as a so-called bioisoster, has very similar chemical properties to a carboxylic acid, but compared to the carboxy function, due to its lower polarity, leads to better oral bioavailability .

Mechanism of action (pharmacodynamics)

The sartans act as specific inhibitors (antagonists) on subtype 1 of the angiotensin II receptor. Angiotensin II is an endogenous hormone that is produced from angiotensin I through catalysis of the angiotensin converting enzyme (ACE) . From a chemical point of view, angiotensin I is a peptide that is split off from the precursor protein angiotensinogen by renin .

The effect of angiotensin II is mediated via two different receptor subtypes (AT 1 and AT 2 ). The main blood pressure-increasing effect arises after the binding of angiotensin II to the AT 1 receptors. As a result, cells of the smooth vascular muscles in the arterioles cause the vascular muscles to contract directly and thus narrow the blood vessels. The peripheral vascular resistance increases and the blood pressure rises. This also leads to reduced blood flow in the kidneys. The increase in blood pressure is also promoted by an AT 1 -receptor-mediated increased reabsorption of sodium ions in the proximal tubular cells of the nephrons in the kidneys. This reabsorption is reinforced by the increase in aldosterone synthesis in the adrenal cortex . The reduced loss of sodium ions ultimately leads to less water being excreted via the kidneys, which increases blood volume and increases blood pressure.

The AT 1 antagonists have an advantage over the ACE inhibitors, which also prevent the blood pressure-increasing effect of angiotensin II, because they cause a dry cough as a side effect significantly less often. The reason is that the angiotensin converting enzyme also catalyzes the breakdown of pro-inflammatory bradykinins. A angioedema , which can occur as a rare side effect of ACE inhibitors, is under treatment with an AT 1 antagonist significantly less frequently. Nevertheless, patients with potentially life-threatening angioedema as a side effect of ACE inhibitors should not be treated with AT 1 antagonists.

AT 2 receptors are seen as opponents of the much more frequently encountered AT 1 subtype. They are said to have positive properties in the function of the vascular wall. After the AT 1 receptors have been blocked by AT 1 blockers, the increased angiotensin II caused by negative feedback stimulates the AT 2 receptors and could thus be responsible for the organ-protective properties of the AT 1 blockers that go beyond lowering blood pressure .

Absorption and distribution in the body (pharmacokinetics)

AT 1 antagonists are in the small intestine after oral ingestion absorbed . The excretion takes place either directly via the biliary tract into the intestine, some active substances are first metabolized in the liver. All AT 1 antagonists are only excreted to a small extent via the kidneys. This explains the fact that the dosage is largely independent of possible renal insufficiency.

Adverse effects (side effects)

Overall, AT 1 antagonists are well tolerated and have few side effects. Common side effects of AT 1 antagonists are headache, dizziness, fatigue; increased levels of potassium in the blood ( hyperkalemia ) may occur. Because of the lack of aldosterone in the collecting ducts of the kidney, ENac channels are no longer built in, which means that K + is normally secreted to compensate for Na + uptake .

Angioedema (Quincke's edema) occurs rarely, but even less frequently compared to the more common ACE inhibitors , which can lead to life-threatening conditions, especially if the base of the tongue, the floor of the mouth or the larynx swell. This occurs as a result of the excess of bradykinin , which is normally inactivated by the ACE. Bradykinin has a vasodilating and permeability-increasing effect.

Cancer risk

According to a meta-analysis of all publicly available studies on sartans published in 2010 , the risk of developing new cancer within the follow-up period (mean 4 years) increased from 6.0 to 7.2% ( significantly ), but dying from it only from 1.6 to 1.8% (not significant). In relation to individual solid tumors, only the risk of lung cancer was significantly increased (0.9% instead of 0.7%). 85% (30,014) received telmisartan as the study drug. Experimental studies indicate an influence of the renin-angiotensin system on cell growth , new blood vessels and tumor progression . Overall mortality and quality of life were not the subject of this study.

In a network meta-analysis published in 2011 , the same public studies were included as well as a few others in order to achieve better informative value. The scientists collected to recalculate data from more than 324,000 patients and examined the association between the use of anti-hypertensive agents and an increased risk of developing cancer cancer. The result was that the increased cancer risk due to ARBs (angiotensin II receptor blockers) was refuted and only in patients who had taken sartans and ACE inhibitors at the same time , this risk could not be excluded.

The Committee for Medicinal Products for Human Use ( CHMP ) of the European Medicines Agency (EMA) came to the conclusion in 2012, after evaluating all available data, that the suspicion of a slightly increased risk of developing cancer in connection with the use of angiotensin II receptor Antagonists (ARBs or sartans) has not been confirmed.

Drug interactions

The effects and side effects of other antihypertensive drugs can be increased. In particular, the combination with ACE inhibitors has not been recommended since 2011, since kidney dysfunction has increased. The combination with the renin inhibitor aliskiren was advised against in 2011, especially for diabetics and patients with known renal insufficiency.

Simultaneous intake of indomethacin or acetylsalicylic acid (ASA) can weaken the effect of AT 1 antagonists.

Contraindications and restrictions on use

Significance, advantages and disadvantages of the AT 1 antagonists

The main area of ​​application of this group of active substances is high blood pressure (all), chronic heart failure (only valsartan , candesartan and losartan ) and the condition after a heart attack (only valsartan) or a combination of these diseases and additional risk factors such as diabetes mellitus .

An advantage is the longer duration of action and the slightly better tolerability compared to the ACE inhibitors and the resulting higher compliance of the patients.

Because of their higher price, AT 1 antagonists are more likely to be prescribed when an ACE inhibitor would be indicated but not tolerated.

Proof in drinking water

The frequency of application and the persistence of the active ingredients lead to a transfer into the drinking water, since the substances cannot be sufficiently removed by the previous cleaning processes. The detection takes place by coupling the HPLC with the mass spectrometry .

Individual substances

The following representatives from the group of sartans are known:

Of these, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan are used therapeutically.

literature

  • AT1 antagonists (sartans) and cancer risk. (115 kB; PDF) In: Statement by the Drugs Commission of the German Medical Association from August 2, 2010. Accessed on August 3, 2010 (17 references): “Analysis by FDA and EMA meanwhile started; The high number of prescriptions in Germany suggests that it can be used widely even in patients for whom an ACE inhibitor would be more appropriate. There is currently no need to change the recommendations for the regulation. "
  • Heribert Schunkert, German Society for Cardiology - Heart and Circulatory Research (Ed.): Guidelines for the management of arterial hypertension . Börm Bruckmeier, Grünwald 2013, ISBN 978-3-89862-948-5 ( online [PDF]).
  • Rote Liste Service GmbH (Ed.): Rote Liste Buch 2005 . Editio Cantor Verlag, Aulendorf 2005, ISBN 3-87193-306-6 .
  • M. Bas, V. Adams, T. Suvorava, T. Niehues, TK Hoffmann, G. Kojda: Nonallergic angioedema: role of bradykinin . In: Allergy . tape 62 , no. 8 , August 2007, p. 842-856 , doi : 10.1111 / j.1398-9995.2007.01427.x , PMID 17620062 .
  • Duncan J. Campbell, Henry Krum, Murray D. Esler: Losartan Increases Bradykinin Levels in Hypertensive Humans . In: Circulation . tape 111 , no. 3 , January 2005, p. 315-320 , doi : 10.1161 / 01.CIR.0000153269.07762.3B , PMID 15655136 .
  • Stefan HG Altmannsberger, Andrea Paneitz, Werner Siegmund, Heyo K. Kroemer: Effect of the AT1 receptor antagonists: Pharmacological principles . In: Pharmacy in our time . tape 30 , no. 4 , July 2001, p. 296-302 , doi : 10.1002 / 1615-1003 (200107) 30: 43.0.CO; 2-R .

Individual evidence

  1. ↑ I. Sipahi et al .: Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomized controlled trials. In: The Lancet Oncology. 11, 7, July 2010, pp. 627-636. doi: 10.1016 / S1470-2045 (10) 70106-6 PMID 20542468 .
  2. ^ S. Bangalore et al.: Antihypertensive drugs and risk of cancer: network meta-analyzes and trial sequentialanalyses of 324 168 participants from randomized trials. In: The Lancet Oncology. 12, 1, Jan. 2011, pp. 65-82. doi: 10.1016 / S1470-2045 (10) 70260-6 . PMID 21123111 .
  3. ↑ Suspicion of a potential carcinogenicity risk was not confirmed Risk information from the BfArM dated April 12, 2012.
  4. ↑ S. Chatterjee, C Behles: Cancer Risk and Cardiovascular Mortality from Sartans? Current status of the discussion. Drug Safety Bulletin - Issue 4 - December 2011.
  5. ↑ Claudia Dellas: Pharmacology crash course: revision course with incorporation of the most important examination facts . Elsevier, Urban & Fischer, Munich a. a. 2011, ISBN 978-3-437-43182-1 .
  6. ↑ Hans-Henrik Parving, Frederik Persson, Julia B. Lewis, Edmund J. Lewis, Norman K. Hollenberg: Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy . In: New England Journal of Medicine . tape 358 , no. 23 , 2008, p. 2433-2446 , doi : 10.1056 / NEJMoa0708379 ( nejm.org [accessed February 15, 2013]).
  7. ↑ Clinical Study (Phase III): Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (Core and Extension Phases) (ALTITUDE) at Clinicaltrials.gov of the NIH .
  8. ↑ J. Giebułtowicz, A. Stankiewicz, P. Wroczyński, G. Nałęcz-Jawecki: Occurrence of cardiovascular drugs in the sewage-impacted Vistula River and in tap water in the Warsaw region (Poland). In: Environ Sci Pollut Res Int. 23 (23), Dec 2016, pp. 24337-24349. PMID 27655616
  9. ↑ T. Letzel, A. Bayer, W. Schulz, A. Heermann, T. Lucke, G. Greco, S. Grosse, W. Schüssler, M. Sengl, M. Letzel: LC-MS screening techniques for wastewater analysis and analytical data handling strategies: Sartans and their transformation products as an example. In: Chemosphere. 137, Oct 2015, pp. 198-206. PMID 26246044
  10. ↑ A. Bayer, R. Asner, W. Schüssler, W. Kopf, K. Weiß, M. Sengl, M. Letzel: Behavior of sartans (antihypertensive drugs) in wastewater treatment plants, their occurrence and risk for the aquatic environment. In: Environ Sci Pollut Res Int. 21 (18), Sep 2014, pp. 10830-10839. PMID 24898294