ACE inhibitors

from Wikipedia, the free encyclopedia

ACE inhibitors (short for angiotensin converting enzyme inhibitors ) are vasodilator , thus vascular resistance lowering, and the release of pressor catecholamines noradrenaline and adrenaline -inflammatory drugs , in particular in the treatment of high blood pressure ( hypertension ) and chronic heart failure application Find. They are inhibitors ( inhibitors ) of the angiotensin converting enzyme ( A ngiotensin C onverting E nzyme ) which substantially effects the conversion of inactive angiotensin I into the active angiotensin II and a part of the blood pressure -controlling cascade is ( renin-angiotensin Aldosterone system ). ACE-inhibiting ingredients were first found in snake venom . The most important active substances in this category used in therapy are captopril , enalapril , lisinopril , perindopril and ramipril .

chemistry

Jararaca lance viper, whose poison shows, among other things, an ACE-inhibiting effect
Structural analogy of the snake venom peptide BPP 5a and the ACE inhibitors captopril and enalapril. The tripeptide sequence of BPP 5a responsible for the action and the analogous substructures of captopril and enalapril are shown in red, the building blocks inserted to increase stability and effectiveness are shown in green.

ACE inhibitors such as captopril, enalapril and their successors are substances structurally related to from the snake venom of the Brazilian Jararaca Pitviper ( Bothrops jararaca ) isolated Penta peptide BPP 5a (from " B radykinin p otenzierendes P eptid"; sequence DKWAP, see figure) . The tripeptide sequence tryptophan - alanine - proline occurring in BPP 5a was recognized as an effective component (shown in red in the figure).

Since BPP 5a and the tripeptide are broken down very quickly in the body, numerous modifications were made to the molecule in order to extend the duration of action. For this purpose, the WAP sequence was exchanged for a similar but more stable FAP sequence. The introduction of a succinic acid - or glutarsäureanalogen structure (shown in green in Figure) brought more stability and a strengthening of the inhibitory effect on angiotensin converting enzyme.

In addition, apart from captopril and lisinopril, all ACE inhibitors used therapeutically are prodrugs that are only activated in the body. In the case of enalapril and ramipril, this is done by splitting off the ethyl group by esterases , which creates the active form, the enalaprilat or ramiprilat , with a free carboxy group that can complex the zinc of the ACE .

pharmacology

application areas

ACE inhibitors are mainly used to treat high blood pressure. For this purpose, they apply individually (monotherapy) and in combination with other antihypertensive agents (combination therapy, especially with diuretics or calcium antagonists ) as the first choice. On the other hand, ACE inhibitors are insufficiently effective in forms of high blood pressure that are associated with a reduced renin level in the blood plasma (e.g. Conn's syndrome ).

In addition, some ACE inhibitors have also been shown to prolong life in chronic heart failure in numerous large clinical studies . This is probably due to the lowering of the afterload and the decrease in the wall tension of the heart muscle due to the decrease in angiotensin II .

ACE inhibitors are also used after heart attacks and when the heart muscle is inflamed.

Another indication for ACE inhibitors is diabetic nephropathy . The Canadian ONTARGET study indicates, however, that ACE inhibitors should never be taken in combination with angiotensin II receptor blockers. While both drugs have a nephroprotective effect on their own, the combination therapy resulted in significantly impaired kidney function. There was also a trend towards an increase in the need for dialysis. Investigated were u. a. Ramipril and telmisartan .

Mechanism of action

Target of the ACE inhibitors: ACE inhibitors lead to two independent main effects by inhibiting the angiotensin converting enzyme (ACE). On the one hand, they reduce angiotensin II production from angiotensin I (left field). On the other hand, they also inhibit the breakdown of bradykinin and lead to its accumulation (right field).

The mechanism of action of ACE inhibitors is based on the inhibition of the angiotensin I-converting enzyme ACE. This enzyme has two main tasks in the organism: On the one hand, it is responsible for the synthesis of the vasoconstricting octapeptide (peptide of eight amino acids ) angiotensin II from its inactive precursor, the decapeptide (ten amino acids) angiotensin I with cleavage of the two C-terminal amino acids. On the other hand, it catalyzes the breakdown of the mediator bradykinin into inactive products.

The inhibition of the angiotensin converting enzyme leads to a decrease in the angiotensin II concentration at the angiotensin receptors (AT 1 and AT 2 ). Primarily, the tone of the blood vessels decreases and the blood pressure decreases. In terms of hemodynamics, there is therefore a reduction in the preload and the afterload . Secondly, the decrease in the angiotensin II level leads to a reduction in the release of aldosterone from the adrenal cortex and thus to an influence on the water balance (see also Renin-Angiotensin-Aldosterone System , RAAS). At the cellular level, a decrease in the mitogenic effects mediated by angiotensin II on fibroblasts and myocytes of the heart, which lead to unfavorable changes ( remodeling ), especially after a heart attack , can be observed. The extent to which the blood pressure is lowered depends on how active the RAA system is. In the case of heart failure , the activity of the RAAS is very high, so you should definitely only dose slowly in order to avoid an excessive drop in blood pressure.

In kidney diseases such as diabetic nephropathy , ACE inhibitors lead to a reduced protein excretion and prevent the disease from progressing (nephroprotection).

The inhibition of the breakdown of bradykinin , however, leads to its accumulation and the associated side effects .

Molecular mechanism of action

The molecular mechanism of action of the ACE inhibitors could also be elucidated. It is based on the similarity of the ACE inhibitor to a peptide chain end of the angiotensin I . As a result, ACE inhibitors are mistaken for the physiological substrate angiotensin I by the angiotensin converting enzyme. In contrast to the physiological substrate, however, they are not converted by the enzyme, but rather block it. Three interactions are important for the binding of the ligand:

Molecular mechanism of action of ACE inhibitors: ACE inhibitors (e.g. enalaprilat, right) bind instead of the substrate angiotensin I (left) in the binding pocket of the angiotensin converting enzyme (ACE, blue) and thereby competitively inhibit this enzyme .

Pharmacokinetics

The ACE inhibitors differ in their pharmacokinetics according to their chemical differences . The majority of the ACE inhibitors currently available are prodrugs . This means that after a 20% (ramipril) to almost 100% absorption ( resorption ) they have to be activated by enzymes in the body (see chemistry). Only captopril and lisinopril do not require this activation step. Maximum plasma levels of the active forms are reached after 1 to 8 hours. The plasma half- lives vary between 2 (captopril) and 40 hours ( spirapril ). The duration of action varies accordingly (8 to 48 hours). Most of the ACE inhibitors are eliminated via the kidneys . Fosinopril , Moexipril and Spirapril also show relevant biliary excretion (excretion via the bile ).

Side effects

The main side effects are dry cough, hypotension , acute kidney failure, hyperkalemia, and problems during pregnancy (explained individually below). These side effects are common to all ACE inhibitors. In a cohort study published in 2018 of nearly one million patients, the use of ACE inhibitors was associated with an overall 14% increased risk of lung cancer after five years of use . There was a 31% increased risk in patients who used ACE inhibitors for more than ten years.

Most of the side effects of ACE inhibitors have been associated with slower breakdown and accumulation of bradykinin by ACE inhibitors. These include skin reactions such as B. exanthema (0.1-1%) and hives (0.01-0.1%). Serious allergic skin reactions, however, are only very rarely observed (<0.01%). The side effect that is considered characteristic of ACE inhibitors, the occurrence of angioedema , can also only rarely be observed (0.01–0.1%).

The majority of side effects affecting the respiratory tract can also be associated with an accumulation of bradykinin. This primarily includes a dry cough , which occurs in 5-35% of patients in the first three months. This side effect is not dose related. In the case of a dry cough, the ACE inhibitor should be discontinued or exchanged for another drug depending on the indication.

Hoarseness and sore throat (0.1–1%) also occur. Asthma attacks and shortness of breath can also occur, albeit rarely (0.01–0.1%).

During therapy with ACE inhibitors, hypotension can occur independently of bradykinin , i. H. reduce blood pressure too much. As a result, dizziness, headache, and drowsiness may occasionally be observed (0.1–1%). Serious cardiovascular events such as angina pectoris , myocardial infarction and syncope have only been reported in isolated cases. This side effect (which occurs mainly in patients with heart failure) can be prevented by taking precautionary measures: if the patient is dehydrated, first fluid and stop taking diuretics (if the patient is taking them), then start taking ACE inhibitors; in heart failure patients, start with a lower dose than intended, then increase the dose.

Functional renal dysfunction can occasionally be observed through interference with the water and electrolyte balance (0.1–1%). A proteinuria (increased excretion of protein in the urine) to acute renal failure , however, was rarely observed (0.01-0.1%). Acute kidney failure occurs almost only in high-risk patients, i. H. in humans or animals with bilateral renal artery stenosis , with hypertonic nephrosclerosis , with heart failure , with polycystic kidney disease, or with pre-existing chronic kidney failure. Kidney failure is often reversible.

Clinically relevant hyperkalemia occurs in <10%; in almost all patients a small, clinically irrelevant increase in the potassium level can be observed. The clinically relevant hyperkalemia very often occurs in patients with pre-existing renal failure, simultaneous use of potassium-sparing diuretics (e.g. triamterene ), NSAIDs ( non-steroidal anti-inflammatory drugs ), severe heart failure and in elderly patients. Low doses of ACE inhibitors do not cause this side effect.

This further undesirable effect of ACE inhibitors can be explained by the effects on the renin-angiotensin-aldosterone system with a decrease in aldosterone secretion: Aldosterone increases the uptake of sodium and water in the kidneys while it promotes potassium excretion . If the concentration of aldosterone is reduced, the opposite effect occurs: increased sodium and water excretion by the kidneys, while more potassium remains in the body. This can lead to hyperkalemia , which is particularly dangerous for the heart . Hyponatremia is also rare .

Contraindicated during pregnancy : As ACE inhibitors can be used during pregnancy . a. ACE inhibitors should not be taken during this time and should be replaced by other therapeutic measures. See e.g. B. the aplasia cutis congenita .

Interactions

ACE inhibitors increase the side effects of immunosuppressive drugs ( immunosuppressants , cytostatics and glucocorticoid ) that change the blood count . ACE inhibitors also increase the blood sugar lowering effect of oral antidiabetic drugs and insulin .

By interfering with the water and electrolyte balance, the excretion of lithium can be slowed down. An increase in the rise in potassium levels can also be observed when combined with potassium-sparing diuretics .

When combined with other antihypertensive drugs, increased blood pressure lowering should be taken into account. Synergistic effects, which are also used therapeutically, occur in particular with diuretics and with calcium channel inhibitors. A reduced antihypertensive effect of the ACE inhibitors was observed in isolated cases after the consumption of high-salt foods.

Medicinal substances

The international non-proprietary names of the individual ACE inhibitors end in -pril . At present, in Germany the following ACE inhibitor approved as a drug (substance or prodrug):

history

Since 1980, ACE inhibitors have played an important role in the treatment of coronary heart disease . To do this, knowledge about the renin-angiotensin-aldosterone system (RAAS) first had to be gained. Research into this began in 1898 with the isolation of renin , made possible by Robert Tigerstedt and Per Gustav Bergman . Harry Goldblatt postulated the enzyme's involvement in blood pressure regulation . However, this hypothesis could only be proven in 1939. In 1946 there were reports that showed that patients with chronic heart failure show increased renin activity. For this reason, research into the RAAS in hypertension was intensified from the 1950s onwards .

The foundation for the development of ACE inhibitors was established in 1956 with the elucidation of the function of angiotensin converting enzyme (ACE) by Leonard T. Skeggs Jr. set. The importance of this enzyme for regulating blood pressure was initially underestimated.

14 years after the discovery of the angiotensin converting enzyme, the pharmacologist Sérgio Henrique Ferreira found out in 1965 that the venom of the Jararaca lance viper inhibited this enzyme in vitro. In 1970 he and, independently of him, Miguel Ondetti isolated the pentapeptide BPP 5a from snake venom , which inhibits angiotensin I conversion in a highly specific manner.

Since BPP 5a is very unstable in the body, a search for more potent and more stable inhibitors of the enzyme started almost simultaneously. A first success came in 1971 with the discovery of the ACE-inhibiting effect of the nonapeptide teprotid . However, the manufacturers discontinued clinical development of Teprotid two years later due to a lack of commercial interest. In addition, Teprotid had to be administered intravenously, which made it unsuitable for chronic diseases such as hypertension.

The first synthesis of an oral ACE inhibitor was achieved by David Cushman and Ondetti: With the help of the knowledge about the structural similarity of ACE to the carboxypeptidase A found in the pancreas , the compound succinylproline could be produced, which was by far not as effective as teprotid.

At the beginning of the 1970s, the effective partial structure of the ACE-inhibiting peptides BPP 5a and Teprotid could be elucidated. Based on these discoveries, new non-peptide ACE inhibitors have been developed. In 1974, the ACE inhibitor captopril was described for the first time as a product of a large-scale drug search ( screening ) by the pharmaceutical company Squibb . In 1981 it was introduced into therapy as the first ACE inhibitor under the trade name Lopirin . In terms of potency, captopril is the same as that of Teprotid.

In the following years attempts were made to develop structurally similar compounds to captopril. This led to compounds with SH groups , which have a higher lipophilicity . Since captopril was initially used in relatively high doses in clinical studies, numerous side effects, some of them serious, occurred. a. to the sulfyhydryl content in the molecule. For this reason, the doses were reduced, which also significantly reduced the incidence of side effects. Nevertheless, efforts continued to synthesize an ACE inhibitor without a sulfylhydryl component. This goal was achieved in 1980 when Arthur A. Patchett and Charles S. Sweet synthesized and introduced the sulfylhydryl-free ACE inhibitors enalapril and enalaprilat, respectively . The latter, however, had only a low bioavailability , which is why it came onto the market in the form of the ethyl ester as a prodrug under the trade names Pres and Xanef . The enalapril was now considered the “prototype” for other structurally similar ACE inhibitors. Due to the great therapeutic and economic success of the drugs captopril and enalapril, a second generation of ACE inhibitors was developed and has been available since the early 1990s.

Economic importance

In Germany, around 20% of the population and every second person over the age of 55 take drugs to treat high blood pressure. ACE inhibitors are the most commonly prescribed antihypertensive drugs with a share of over 50% . About 80% of high blood pressure patients treated with an ACE inhibitor use a single agent , the rest use a combination drug . The number of prescriptions, which in Germany reached around 5 billion defined daily doses (DDD) in 2009 , has increased linearly by around 200% over the past ten years. In the German market, which is dominated by generics , the drug ramipril (68%) clearly dominates ahead of enalapril (18%) and lisinopril (10%).

Alternatives

Newer substances from the group of AT 1 antagonists ( sartans ) no longer inhibit the angiotensin converting enzyme, but have an antagonistic effect on the angiotensin II receptor 1 subtype , so that side effects occur less frequently. Their better tolerance is based on the fact that they do not affect the bradykinin system. AT 1 antagonists have also been on the market as generics for a number of years (e.g. Eprosartan 2008, Losartan 2010 ), but they are still more expensive than ACE inhibitors.

Another point of attack is the inhibition of the renin enzyme that is produced in the kidneys and is responsible for the synthesis of angiotensin I. With aliskiren in 2007 a selective inhibitor of this enzyme has been approved, other renin inhibitor such. B. Remikiren and Zankiren are in clinical trials.

Vasopeptidase inhibitors such as omapatrilat are derived from the classic ACE inhibitors and were still about to be approved by the health authorities in 2010 because studies showed severe angioedema. In addition to inhibiting the angiotensin converting enzyme, the vasopeptidase inhibitors also inhibit the neutral endopeptidase , an enzyme that is responsible for inactivating the blood vessel relaxing atrial natriuretic peptide (ANP).

Intensive care aspect

Intensive care medicine has shown that patients who were treated with ACE inhibitors before entering the intensive care unit often have a higher consumption of catecholamines in order to stabilize the mean arterial pressure. The reason for this is likely to be a vasopressin deficiency , which could be traced back to the previous therapy with ACE inhibitors. By substituting vasopressin (ADH), the need for catecholamines can often be quickly reduced (provided there are no other reasons for low blood pressure) and then the vasopressin can be tapered off within 12–24 hours.

literature

  • DW Cusham, MA Ondetti: History of the design of captopril and related inhibitors of angiotensin converting enzyme. In: Hypertension. Baltimore, 17.1991, pp. 589-592. PMID 2013486 .
  • E. Mutschler, G. Geisslinger, HK Kroemer, M. Schäfer-Korting: Therapy of hypertension. In: E. Mutschler (Ed.): Drug effects. Wissenschaftliche Verlagsgesellschaft, Stuttgart 2001, ISBN 3-8047-1118-9 , pp. 571-587.

Web links

Individual evidence

  1. ^ A b S. H. Ferreira, LH Greene, VA Alabaster, YS Bakhle, JR Vane: Activity of various fractions of bradykinin potentiating factor against angiotensin I converting enzyme. In: Nature. Volume 225, Number 5230, Jan 1970, pp. 379-380, PMID 4312128 .
  2. ↑ a b K. Nemec, M. Schubert-Zsilavecz: From Teprotid to Captopril - Rational Design of ACE Inhibitors. In: Pharmacy in our time. Volume 32, number 1, 2003, pp. 11-16, doi: 10.1002 / pauz.200390001 , PMID 12577755 (review).
  3. ↑ Technical information for ACE inhibitors ratiopharm (R) as of February 2008
  4. ↑ Peter Dominiak: The role of ACE inhibitors in high pressure therapy: Established for a long time! In: Pharmacy in our time. 32, 2003, p. 24, doi: 10.1002 / pauz.200390004 .
  5. ↑ Blánaid M Hicks, Kristian B Filion, Hui Yin, Lama Sakr, Jacob A Udell, Laurent Azoulay: Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. In: BMJ. , S. k4209, doi : 10.1136 / bmj.k4209 .
  6. ↑ PV Dicpinigaitis: Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines. In: Chest. Volume 129, Number 1 Suppl, January 2006, pp. 169S-173S, doi : 10.1378 / chest.129.1_suppl.169S , PMID 16428706 (review).
  7. ^ ZH Israili, WD Hall: Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. In: Annals of internal medicine. Volume 117, Number 3, August 1992, pp. 234-242, PMID 1616218 (review).
  8. ^ JB Kostis, B. Shelton, G. Gosselin, C. Goulet, WB Hood, RM Kohn, SH Kubo, E. Schron, MB Weiss, PW Willis, JB Young, J. Probstfield: Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators. In: American Heart Journal . Volume 131, Number 2, February 1996, pp. 350-355, PMID 8579032 .
  9. ↑ George L. Bakris, Matthew R. Weir: Angiotensin-Converting Enzyme Inhibitor-Associated Elevations in Serum Creatinine. In: Archives of Internal Medicine. 160, 2000, doi: 10.1001 / archinte.160.5.685 .
  10. ^ RD Toto, HC Mitchell, HC Lee, C. Milam, WA Pettinger: Reversible renal insufficiency due to angiotensin converting enzyme inhibitors in hypertensive nephrosclerosis. In: Annals of internal medicine. Volume 115, Number 7, October 1991, pp. 513-519, PMID 1883120 .
  11. ↑ Lawrence C. Reardon, David S. Macpherson: Hyperkalemia in Outpatients Using Angiotensin-Converting Enzyme Inhibitors. In: Archives of Internal Medicine. 158, 1998, p. 26, doi: 10.1001 / archinte.158.1.26 .
  12. ↑ a b Information for professionals Lopirin ® Cor / 25/50 . Bristol-Myers Squibb. As of November 2006.
  13. ↑ a b XANEF ® specialist information . MSD. As of January 2006.
  14. ↑ Overview of the most frequently prescribed preparations / active ingredients and their allocation to active ingredient groups according to the documentation data set, taking into account the AOK discount agreements and the active ingredient agreement. General local health insurance companies , October 1, 2018
  15. ^ A b c d Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 175 f .
  16. ^ LT Skeggs, JR Kahn, NP Shumway: The preparation and function of the hypertensin-converting enzyme. In: The Journal of experimental medicine. Volume 103, Number 3, March 1956, pp. 295-299, PMID 13295487 , PMC 2136590 (free full text).
  17. ^ CG Smith, JR Vane: The discovery of captopril. (PDF) In: FASEB journal: official publication of the Federation of American Societies for Experimental Biology. Volume 17, Number 8, May 2003, pp. 788-789, doi: 10.1096 / fj.03-0093life , PMID 12724335 .
  18. ↑ Manfred Anlauf: Inhibitors of the Angiotenin-Renin-System . In: Dieter Paffrath; Ulrich Schwabe (Ed.): Drug Ordinance Report 2010: Current Data, Costs, Trends and Comments (German Edition) . Springer, Berlin 2010, ISBN 3-642-13379-7 , pp. 219-252.
  19. ^ Symposium of the Paul Martini Foundation (PMS) on October 23, 2009 in Heidelberg (PDF; 102 kB) Retrieved on August 18, 2010.
This article was added to the list of excellent articles on December 23, 2004 in this version .