ACE inhibitor

ACE inhibitors are drugs that especially in the treatment of high blood pressure ( hypertension) and chronic heart failure apply. They are inhibitors (inhibitors) of the angiotensin- converting enzyme ( angiotensin converting enzyme ), which is part of a cascade regulating blood pressure ( renin-angiotensin -aldosterone system ). ACE -inhibiting ingredients were first found in snake venoms.

The main agents used in the treatment of this category are captopril, enalapril, lisinopril and ramipril. These include its therapeutic significance to the top-selling drugs.

Chemistry

ACE inhibitors such as captopril, enalapril and their successors substances are structurally related to the from the snake venom of the Brazilian jararaca - lance (Bothrops jararaca ) isolated pentapeptide BPP5a (of " bradykinin potentiating peptide"; DKWAP sequence, see figure). The occurring in BPP5a tripeptide sequence tryptophan -alanine -proline has been recognized as an effective component (shown in Figure red).

As BPP5a and the tripeptide are degraded in the body very quickly, numerous modifications have been made on the molecule in order to prolong the duration of action. For this, the WAP sequence was replaced by a similar but more stable FAP sequence. The introduction of a succinic acid or glutarsäureanalogen structure ( shown in Figure green ) gave more stability and an enhancement of the inhibitory effect on angiotensin converting enzyme.

In addition, up to, captopril and lisinopril, all therapeutically used ACE inhibitor prodrugs which are activated in the body. In the case of enalapril and ramipril, this is accomplished by cleavage of the ethyl group by esterases, thereby the active form, enalaprilat or ramiprilat, to a free carboxyl group is formed that is capable of complexing the zinc of the ACE.

Pharmacology

Areas of application

ACE inhibitors are used mainly for the treatment of high blood pressure. For this, they are individually (monotherapy ) and in combination with other blood pressure lowering drugs ( combination therapy, especially with diuretics or calcium antagonists) as a drug of first choice. In hypertensive forms, associated with a decreased renin levels in the blood plasma (eg Conn's syndrome ) show ACE inhibitors, however, insufficient efficacy.

In addition, some ACE inhibitors have been shown in numerous large clinical trials in chronic heart failure and extend life. This is probably due to the reduction of afterload, and reduction of the wall voltage of the cardiac muscle by the reduction of angiotensin II

Even after myocardial infarction and myocarditis ACE inhibitors are used.

Another indication of ACE inhibitors is diabetic nephropathy. Furthermore, it was a great study that the ACE inhibitor ramipril can also relieve the symptoms of intermittent claudication in PAD and extend the distance walked.

Mechanism of Action

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

Has Inhibition of angiotensin converting enzyme, a decrease in angiotensin II concentration of the angiotensin receptors (AT1 and AT2) result. Primary thereby decreases the blood vessel tone and blood pressure decreases. So it's hemodynamically to a reduction of preload and afterload. Secondary leads the decrease in angiotensin II levels, a reduction of aldosterone release from the adrenal cortex and thus to influence the water budget (see also the renin -angiotensin -aldosterone system, RAAS). At the cellular level, a decrease in the mitogenic effects mediated by angiotensin II in fibroblasts and cardiac myocytes, leading in particular after a heart attack to adverse changes (remodeling ) are observed. The extent to which blood pressure reduction occurs depends on how high is the activity of the RAA system. In heart failure, the activity of the RAAS is very high, so you should dispense only einschleichend definitely to avoid excessive blood pressure reduction.

In renal diseases such as diabetic nephropathy, ACE inhibitors lead to decreased protein excretion and prevent progression of the disease ( renal protection ).

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

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 end of angiotensin I. As a result, are ACE inhibitors of angiotensin converting enzyme mistaken for the physiological substrate angiotensin I. In contrast to the physiological substrate but they are not enforced by the enzyme, but block it. Important for the binding of the ligand are three interactions:

• Complexation of the zinc ion of ACE. This is usually a carboxyl group or a thiol group in the captopril
• An electrostatic interaction between K511 of the ACE and the carboxylate function of the proline of the ligand
• A hydrogen bond between H353 of the ACE and the carbonyl of alanine or lysine of the ligand

Pharmacokinetics

According to their chemical differences, the ACE inhibitors differ in their pharmacokinetics. The majority of currently available ACE inhibitors are prodrugs. This means that they must be activated by enzymes in the body of a 20% ( ramipril ) to almost 100 % uptake ( absorption ) (see Chemistry). Only captopril and lisinopril not require this activation step. Maximum plasma levels of the active forms are reached after 1-8 hours. The plasma half -lives vary between 2 ( captopril ) and 40 hours ( spirapril ). Accordingly, the duration of action is varied ( from 8 to 48 hours). All ACE inhibitors are excreted predominantly by the kidney. Fosinopril, moexipril and spirapril also show a relevant biliary excretion ( excretion via bile).

Side effects

The main side effects are dry cough, hypotension, acute renal failure, hyperkalemia, and problems during pregnancy ( explained separately below ). These side effects are common to all ACE inhibitors.

Most side effects of ACE inhibitors are associated with a slower degradation and accumulation of bradykinin by ACE inhibitors. These include skin reactions such as rash ( 0.1-1 %) and urticaria ( 0.01-0.1 %). Severe allergic skin reactions are, however, only very rarely (< 0.01 %). The characteristic as applicable to ACE inhibitor side effect, the occurrence angioneurotischer edema, can also be observed rarely ( 0.01-0.1 %).

The majority of the relevant airways side effects may be associated with an accumulation of bradykinin. These include primarily a dry cough that occurs in the first three months in 5-35 % of patients. This side effect is not dose-dependent. In dry cough of ACE inhibitors should be discontinued or replaced by a different drug according to the indication.

Also, hoarseness and sore throat ( 0.1-1 %) to occur. Asthma attacks and shortness of breath may also, though rarely, occur ( 0.01-0.1 %).

Under therapy with ACE inhibitors may lead to a bradykininunabhängig hypotension, that is, to excessive blood pressure reduction. As a result, occasional dizziness, headache and dizziness are observed ( 0.1-1 %). From serious cardiovascular events such as angina pectoris, myocardial infarction, and syncope have been reported only in individual cases. This side effect (which occurs preferentially in patients with heart failure) can be prevented with safety precautions: low fluid first ( if the patient takes this ) then begin fluid resuscitation and discontinuation of diuretics, with the use of ACE inhibitors; start in heart failure patients with a lower dosage than targeted then increase the dose.

By intervening in the water and electrolyte balance may occasionally functional renal impairment was observed ( 0.1-1 %). Proteinuria ( increased excretion of proteins in urine ) to acute renal failure, however, was only rarely observed ( 0.01-0.1 %). Acute renal failure is observed almost exclusively in patients at risk, that is, with bilateral renal artery stenosis, hypertensive nephrosclerosis, heart failure, polycystic kidney disease or pre-existing chronic renal failure. Renal failure is often reversible.

A clinically significant hyperkalaemia occurs in <10%, in almost all patients, a small, clinically insignificant increase in potassium levels can be observed. The clinically significant hyperkalaemia occurs very often in patients with pre- existing renal failure, concomitant use of potassium-sparing diuretics (eg, triamterene), NSAIDs ( nonsteroidal anti-inflammatory drugs ), severe heart failure and in the elderly. Low doses of ACE inhibitors does not cause this side effect.

Due to the effects on the renin -angiotensin -aldosterone system with decrease in aldosterone secretion can this additional adverse effect of ACE inhibitors explain: Aldosterone enhances sodium and water resorption in the kidney, while it promotes potassium excretion. At reduced concentration of aldosterone it comes to the opposite effect: increased sodium and water excretion of the kidney, while increased potassium remains in the body. Thus, it can lead to dangerous, especially for the heart hyperkalemia. Rarely, also hyponatremia.

Contraindicated in pregnancy: Since ACE inhibitors can cause in pregnancy, inter alia, growth and bone formation disorders in children, associated with increased mortality, ACE inhibitors should not be taken at this time and should be replaced by other therapeutic measures.

Interactions

ACE inhibitors increase the blood -changing side effects acting immunosuppressive drugs ( immunosuppressants, cytostatics and glucocorticoid ). Also reinforce ACE inhibitor blood sugar lowering action of oral antidiabetic drugs and insulin.

By intervening in the water and electrolyte excretion of lithium can be slowed down. Likewise, a strengthening of the increase of potassium levels are observed with the combined use with potassium-sparing diuretics.

In combination with other antihypertensive drugs increased blood pressure reduction should be considered. Synergistic effects that are also used therapeutically, occur in particular with diuretics and calcium channel inhibitors. Decreased antihypertensive effect of ACE inhibitors could be observed occasionally after taking salt- rich diet.

Drugs

Currently, the following ACE inhibitors are approved as a drug in Germany:

• Benazepril
• Captopril
• Cilazapril
• Enalapril
• Fosinopril
• Imidapril
• Lisinopril
• Moexipril
• Perindopril
• Quinapril
• Ramipril
• Spirapril
• Trandolapril
• Zofenopril

History

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

14 years after the discovery of the angiotensin converting enzyme Sérgio Henrique Ferreira pharmacologist in 1970 found that the venom of the jararaca Pitviper in vitro leads to inhibition of this enzyme. With the included in this snake venom pentapeptide BPP5a once one of the active components was isolated.

Since BPP5a is very unstable in the body, launched almost simultaneously a search for more potent and stable inhibitors of the enzyme. A first success came in 1971 with the discovery of the ACE - inhibitory activity of the nonapeptide Teprotid. The manufacturer presented the clinical development of Teprotid two years later due to lack of commercial interest in.

Also at the beginning of the 1970s was the effective part structure of the ACE - inhibitory peptides BPP5a and Teprotid be elucidated. Because of these discoveries, new non-peptidic ACE inhibitors have been developed. 1974 for the first time the ACE inhibitor captopril has been described as the product of large-scale drug discovery (screening) the pharmaceutical company Squibb. In 1981 he was the first to introduce ACE inhibitors in the therapy. Two years later, with the launch of a second Enalapril ACE inhibitor.

Due to the great therapeutic and commercial success of the drugs captopril and enalapril, a second generation of ACE inhibitors has been developed, which are available since the early 1990s (eg, lisinopril, and ramipril ).

Economic Importance

In Germany occupy about 20 % of the population and every second over 55 drugs for the treatment of high blood pressure. ACE inhibitors are the most commonly prescribed antihypertensive drugs with a share of over 50%. Approximately 80% of patients treated with an ACE inhibitor hypertension patients use a single agent, the rest uses a combination preparation. The number of prescriptions, the daily doses of approximately 5 billion defined in Germany in 2009 ( DDD) reached, participated in the last ten years using the straight by about 200%. On the German market dominated by generic drug ramipril dominated (68%) well ahead of enalapril (18%) and lisinopril (10 %).

Alternatives

Newer agents from the group of AT1 antagonists ( sartans ) no longer inhibit the angiotensin-converting enzyme, but antagonize the angiotensin II receptor subtype 1, so that side effects are less common. Your better compatibility based on the fact that they do not act on the bradykinin system. AT1 antagonists for several years as well as generics in the market (eg 2008 eprosartan, losartan 2010 ), but still more expensive than ACE inhibitors.

Another point of the inhibition of the enzyme produced in the kidney, renin, which is responsible for the synthesis of angiotensin I. With Aliskiren in 2007, a selective inhibitor of this enzyme has been approved, more renin inhibitors such as Remikiren and Zankiren are in clinical testing.

Vasopeptidaseinhibitoren as omapatrilat are derived from the classical ACE inhibitors and stood 2010 before the approval by the health authorities, because there was severe angioedema in studies. In addition to the inhibition of angiotensin converting enzyme inhibiting Vasopeptidaseinhibitoren neutral endopeptidase, an enzyme which is responsible for the inactivation of the blutgefäßrelaxierenden atrial natriuretic peptide ( ANP ) is responsible.

Intensive medical aspect

In the intensive care unit has been shown that patients who were treated before the ICU stay with ACE inhibitors, often have a higher consumption of catecholamines to stabilize mean arterial pressure. Reason for this may be a vasopressin deficiency, which would be due to the previous treatment with an ACE inhibitor. By substitution of vasopressin (ADH ), especially in patients who are in a Katecholamindilemma, (no other reasons for low blood pressure as far as available) can frequently the catecholamines are rapidly reduced and then the vasopressin be tapered within 12-24 hours.