ACE inhibitors are drugs, used particularly in the treatment of high blood pressure (hypertension) and chronic heart failure application. They are inhibitors of the angiotensin-converting enzyme (angiotensin converting enzyme = ACE), which is a part of a regulatory cascade is blood pressure (renin-angiotensin-aldosterone system). ACE-inhibitory substances were first found in snake poisons.

The most important in the therapy used are representative of Captopril, Enalapril, Lisinopril and Ramipril. These are also due to its great importance to the therapeutic-selling drugs ever.

Chemistry

ACE inhibitors such as Captopril, Enalapril, and their successors are substances structurally with the snake venom of the Brazilian Jararaca Notter-lance (Bothrops jararaca) isolated peptide BPP5a (from “peptide bradykinin potentiation”, see Figure). The BPP5a occurring amino acids and three existing Tripeptidsequenz tryptophan-alanine-proline has been recognized as an effective component.

Since BPP5a and Tripeptid in the body very quickly dismantled, were numerous modifications to the molecule carried out in order to prolong the duration of action. This was the tryptophan-alanine-proline sequence against a similar but more stable phenylalanine-alanine-proline sequence exchanged. The introduction of an amber-acid or glutarsäureanalogen structure brought more stability and a strengthening of the inhibitory effect on angiotensin converting enzyme.

In addition, up to Captopril and Lisinopril all therapeutically used ACE inhibitor prodrugs, which only are activated in the body. In the case of enalapril, this is done by the secession Ethylgruppe by esterases, which Wirkform the Enalaprilat, with a free carboxyl arises.

Pharmacology

Application Areas

ACE inhibitors are mainly for the treatment of hypertension used. Apply singly (monotherapy) and in combination with other blood pressure core (combination therapy, especially with diuretics or calcium antagonists) as a tool of first choice. For high blood pressure forms, with a low renin levels in plasma, accompanied (as Conn’s syndrome) show ACE inhibitors, however, insufficient efficacy.

In addition, ACE inhibitors in numerous large clinical trials, even with chronic heart failure as a life prolonging proved. This is probably due to the reduction in after load and decrease in wall tension of the myocardium by the decrease of angiotensin II

Even After Heart Attacks ACE Inhibitors Are Used.

Another indication of ACE inhibitors is diabetic nephropathy. At present only an authorization for Captopril.

Mechanism of action

The mechanism of action of ACE inhibitors is based in an inhibition of the angiotensin-converting enzyme. This enzyme in the organism has two main tasks. Firstly it is important for the synthesis of gefässverengend effective Octapeptids (from 8 amino acid peptide) angiotensin II from its inactive precursor, the Decapeptid (10 amino acids) angiotensin I under the separation of the two C-terminal amino acids responsible. Other hand, it catalyses the reduction of the mediator bradykinin into inactive products.

Inhibition of angiotensin converting enzyme, a decrease in angiotensin-II concentration of the angiotensin receptors (AT1 and AT2) result. Primary thereby decreasing the Blutgefässtonus and blood pressure decreases. Secondary leads the decrease in angiotensin II levels to a reduction of aldosterone release from the adrenal cortex and thus to influence the water (see also the renin-angiotensin-aldosterone system). At the cellular level, a decrease of angiotensin II-mediated mitogenic effects on fibroblasts and Myozyten of the heart, especially after a heart attack on unfavorable changes (remodeling) that can be observed.

In renal diseases such as diabetic nephropathy, ACE inhibitors lead to a decrease in protein excretion (proteinuria) and prevent disease progression (Nephroprotektion).

The inhibition of the degradation of bradykinin, however, leads to its accumulation and related side effects.
Angriffsort of ACE inhibitors Angriffsort of ACE inhibitors: ACE inhibitors lead through an inhibition of the angiotensin-converting enzyme (ACE) to two mutually independent main effects. One lead to a decreased angiotensin II production from angiotensin I (left field). Other hand, they also inhibit the degradation of bradykinin, leading to its accumulation (right field).

Molecular Mechanism of Action

Also, the molecular mechanism of action of ACE inhibitors could be elucidated. It is based on the similarity of the ACE inhibitor to a peptide chain at the end of angiotensin I. This ACE-inhibitors of angiotensin converting enzyme falsely for the physiological substrate angiotensin I kept. In contrast to the physiological substrate, they are not implemented by the enzyme and block it.

Pharmacokinetics

According to their chemical differences are differences between the ACE inhibitor among themselves in the pharmacokinetics. The majority of the currently available ACE inhibitors are prodrugs. This means that after a 20% (Ramipril) to almost 100% uptake (absorption) by enzymes in the body have to be activated (see Chemistry). Only Captopril and Lisinopril need this activation step is not. Maximum plasma levels of Wirkformen after 1 a.m. to 8 p.m. hours. The plasma half-life varies between 2 (Captopril) and 40 hours (Spirapril). Accordingly, the effect also varies (from 8 to 48 hours). All ACE inhibitors are predominantly excreted via the kidney. Fosinopril, Moexipril and Spirapril show beyond a relevant biliary excretion (excretion via the bile).

Side effects

Most side effects of ACE inhibitors with a slower accumulation and degradation of bradykinin by ACE inhibitors is associated. These include skin reactions, such as Eruptions (0.1 – 1%) and urticaria (0.01 – 0.1%). Serious allergic skin reactions are only rarely observed (<0.01%). The main characteristic of ACE inhibitors in force incident, the occurrence of angioneurotic edema, may also rarely be observed (0.01 -0.1%).

Also, the majority of airways may be associated with adverse accumulation of bradykinin. These include dry cough, hoarseness and neck pain (0.1 – 1%). Asthma attacks and respiratory distress may also, albeit rarely, occur (0.01 – 0.1%).

Under the therapy with ACE inhibitors may bradykininunabhängig to excessive blood pressure reduction come. As a result, may have occasional dizziness, headache and dizziness can be observed (0.1 – 1%). From serious cardiovascular events such as angina pectoris, myocardial infarction, and syncope, has only been reported in individual cases.

Due to interference in the water and electrolyte balance may occasionally renal functional disturbances observe (0.1 – 1%)? Proteinuria (excretion of protein in urine) was only rarely observed (0.01 – 0.1%). Due to the effects on the renin-angiotensin-aldosterone system with a decrease in aldosterone distribution can be a further adverse effect of ACE inhibitors explain: Aldosterone increases the Na and water recovery in the kidney, while it promotes potassium excretion. At reduced concentrations of aldosterone causes the opposite effect: increased sodium and water excretion of the kidneys, while increasing potassium in the body remains. So there may be one, especially for the heart, dangerous hyperkalaemia come. Rarely, it is to hyponatremia.

Since ACE inhibitors during pregnancy including Growth and bone formation disorders in children associated with an increased mortality rate may cause, may ACE inhibitors during this time not to be and should be supported by other appropriate therapeutic measures to be replaced.

Interaction

ACE inhibitors increase the blood-changing effects acting immunosuppressive drugs (immuno suppressants, cytostatics, and Glucocorticoids). Similarly, ACE inhibitors increase the blood glucose lowering effect of oral antidiabetic agents and insulin.

Due to interference in the water and electrolyte balance, the excretion of lithium slowed. Similarly, a strengthening of the increase in potassium levels when combined with application of potassium-sparing diuretics can be observed.

In combination with other antihypertensive drugs should be increased blood pressure into account. Synergistic effects, which are also exploited therapeutically, occur particularly with diuretics and calcium channel inhibitors. A reduction in blood pressure lowering effect of ACE inhibitors was isolated after salt-rich diet ingestion can be observed.

Arzneistoffe

Currently, the following ACE inhibitors as drug approved:

* Benazepril (Cibacen ®)
* Captopril (Lopirin ®, Tensobon ®, and many generics)
* Cilazapril (Dynorm ®)
* Enalapril (Xanef ®, Pres ®, and many generics)
* Fosinopril (Fosinorm ®, Dynacil ®)
* Imidapril (Tanatril ®)
* Lisinopril (Acerbon ®, Coric ®, generics)
* Moexipril (Fempress ®)
* Perindopril (Coversum ®, Preterax ®)
* Quinapril (Accupro ®, generics)
* Ramipril (Delix ®, Vesdil ®, generics)
* Spirapril (Quadropril ®)
* Trandolapril (Gopten ®, Udrik ®)

History

The foundation for the development of ACE inhibitors was established in 1956 with the elucidation of the role of the angiotensin converting enzyme (ACE), by Leonard T. Skeggs laid. The importance of this enzyme for the regulation of blood pressure was initially underestimated.

14 years after the discovery of the angiotensin converting enzyme (1970) was amended by Sergio H. Ferreira pharmacologists have discovered that the venom of the spear-Jararaca Notter in-vitro inhibition of this enzyme leads. By this snake venom peptide contained Pentaplast BPP5a was once one of the active components isolated.

Since BPP5a in the body is very unstable, started almost simultaneously with a search for more potent and stable inhibitors of the enzyme. A first success was in 1971 with the discovery of the ACE-inhibitory activity of Nonapeptids Teprotid. The clinical development of Teprotid but was two years later from a lack of commercial interest from the manufacturer terminated.

Also at the beginning of the 1970s was part of the effective structure of the ACE-inhibitory peptides BPP5a and Teprotid are elucidated. Based on these discoveries, new nichtpeptidische ACE inhibitors developed. In 1974, the first ACE inhibitor Captopril describes the product of a large-scale drug discovery (screening) of the pharmaceutical company Squibb was. In 1981 he was the first ACE inhibitors in the therapy was introduced. Two years later followed with enalapril the launch of a second ACE inhibitor.

Because of the great therapeutic and commercial success of the drugs Enalapril and Captopril was a 2 nd Generation of ACE inhibitors, which since the early 1990s are available (eg, Lisinopril and Ramipril).

Economic Significance

Approximately 20% of the population and every second over 55 medicines for the treatment of hypertension A. Approximately 35% of hypertension patients are treated with an ACE-inhibitor monotherapy and in about 55% in combination with another blood pressure-lowering medicine.

In the USA in the year 2001 114 million packs prescribed ACE inhibitors. This corresponds to a turnover of approximately 4.3 billion U.S. Dollar. The main share of it borne by the ACE inhibitor Lisinopril (47%) followed by enalapril (17%), Captopril and Ramipril (each 9%). On the influence of the German generics market is dominated, however, the drug Enalapril.

Alternatives

Newer agents from the group of AT1 antagonists no longer inhibit the angiotensin converting enzyme, but antagonistic effects on the angiotensin II receptor subtype-1, so that rare side effects may occur. AT1 antagonists but are still significantly more expensive than ACE inhibitors, and have not been able to replace it. The improved tolerability is that they are not on the bradykinin system interacting.

Vasopeptidaseinhibitoren as Omapatrilat by the classical ACE inhibitors are derived and are currently nearing approval by the health authorities. In addition to inhibition of angiotensin converting enzyme inhibit Vasopeptidaseinhibitoren the neutral Endopeptidase, an enzyme responsible for the inactivation of the blutgefässrelaxierenden atrial natriuretischen peptide (ANP) is responsible.

Another novel point of attack is the inhibition of formed in the kidney enzyme renin, which for the synthesis of angiotensin I is responsible. With A-72517 is a selective inhibitor of this enzyme in clinical trials.

Intensive Medical Aspect

It has been in intensive care showed that patients who before the ICU stay with ACE inhibitors have been treated, often with a higher consumption of catecholamines which, by the middle arterial pressure to stabilize. The reason for this may be a Vasopressinmangel be based on the previous therapy with ACE inhibitors would be attributed. By the substitution of vasopressin, particularly in-patients who are in a Katecholamindilemma can often Katecholaminbedarf (if no other reasons for low blood pressure are available) and rapidly reduced after the vasopressin within 12 – 24 hours ausgeschlichen be.