Angiotensin converting enzyme inhibitor

Captopril chemical structure, the first ACE inhibitor

The angiotensin-converting enzyme inhibitors ('ACEI:) are a class of drugs used mainly in the treatment of high blood pressure, of chronic heart failure and also of chronic kidney disease and are part of the inhibition of a series of reactions that regulate blood pressure: the renin-angiotensin-aldosterone system. ACE inhibitory substances were first discovered in snake venoms. The most important ACE inhibitors used for treatment are captopril (Capoten), enalapril, lisinopril and ramipril. Due to their great therapeutic significance, they are among the best-selling drugs.

History

From the snake Bothropoids jararaca the first angiotensin converter enzyme inhibitor was removed.

In 1956 the foundations for the development of ACE inhibitors were laid when Leonard T. Skeggs managed to explain the operation of and isolate the angiotensin-converting enzyme (ACE), without underestimating the importance of this enzyme for the regulation of blood pressure.

Some 14 years after the discovery of the angiotensin-converting enzyme (1970), the pharmacologist Sergio H. Ferreira discovered that the venom of the jararaca or lanceolate viper (Bothropoides jararaca), in vitro, is capable of inhibiting this enzyme. Likewise, with the BPP_5a pentapeptide contained in this snake venom, one of the effective components of this inhibitory action was isolated.

Since BPP_5a is highly unstable in the body, the search for more potent and stable inhibitors of the enzyme began almost simultaneously. In 1971, a first success was achieved with the discovery of the ACE-inhibiting effect of nonapeptide teprotide, which has hypotensive effects very similar to that of jararaca venom. However, two years later the further clinical development of teprotide was abandoned due to lack of of commercial interest on the part of the manufacturer.

Similarly, in the early 1970s, the effective partial structure of the peptide BPP_5a and teprotide, both ACE inhibitors, were discovered. From these discoveries new non-peptide ACE inhibitors were developed. The ACE inhibitor captopril was first described in 1974, the product of a large-scale drug search (screening) by the pharmaceutical company Squibb. In 1981 this was the first substance to be used as an ACE inhibitor. in a treatment. Two years later, the commercialization of a second ACE inhibitor with enalapril followed.

In order to minimize adverse effects and take advantage of the therapeutic and economic success of the drugs captopril and enalapril, a second generation of ACE inhibitors was developed, which had been on the market since the early 1990s, such as lisinopril and ramipril.

Chemical composition

Three-dimensional structure of the captopril, an ACE analogous to snake venom Bothrops jararaca.

ACE inhibitors such as captopril, enalapril and their derivative substances have a structure similar to that of the BPP_5a peptide or bradykinin-enhancing peptide, (BPP, "bradykinin-potentiating peptide); isolated from the venom of the jararaca snake or Brazilian lanceolate viper (Bothrops jararaca). The tripeptide sequence of tryptophan-alanine-proline consisting of three amino acids and appearing in BPP_5a has been found to be one of the active components in the properties of these molecules.^{[citation required]}

Since BPP_5a and the tripeptide are very quickly cleared by the body, numerous modifications have been made to the molecule to prolong the duration of effect, including changing the sequence of tryptophan-alanine-proline by a similar but more stable phenylalanine-alanine-proline sequence. The contribution of a structure analogous to succinic acid or glutaric acid provided more stability and reinforced the inhibitory properties of the angiotensin converting enzyme.^{[citation needed]}

In addition, all ACE inhibitors used except captopril and lisinopril are prodrugs that are activated once inside the body. In the case of enalapril, this is produced by separation of the ethyl group through esterases, thanks to which the effective form is obtained, enalaprilat, with a free carboxylic group.^{[citation required]}

Clinical indications

ACE inhibitors are used mainly for the treatment of hypertension, for which they are considered in many cases, both alone (single treatment or monotherapy) and in combination with other hypotensives (combined treatment, especially with diuretics or channel blockers). calcium), the preferred remedy. For this reason, there is a combination of products on the market that combine an ACE inhibitor with a thiazide diuretic, such as hydrochlorothiazide in a tablet for direct administration to patients who require it. On the contrary, in certain forms of hypertension accompanied by a reduced level of renin in the blood plasma (for example, Crohn's disease), ACE inhibitors show insufficient effectiveness.

In addition, numerous clinical trials have shown that angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and prolong life in patients with chronic heart failure. This is probably due to decreased afterload and reduced myocardial wall tension by reducing angiotensin II.

Even after myocardial infarctions, ACE inhibitors are used, which have reduced morbidity and mortality in patients thus treated. Enalapril has been shown to significantly improve quality of life in patients with left ventricular dysfunction by decreasing the rate of onset of ventricular enlargement.

Another indication for ACE inhibitors is diabetic nephropathy, both in the prevention of the disease and in its initial stages. ACE inhibitors preserve renal function independent of blood pressure control and decrease proteinuria in both normotensive and hypertensive diabetic patients. Although not always successful in preventing the progression of diabetic nephropathy, ACE inhibitors tend to reverse the microalbuminuric phase of renal disease. disease.

Mechanism of action

Structure of angiotensin II. ECA inhibitors act by inhibiting the angiotensin (ECA) conversion enzyme, generating two main effects independent of each other. On the one hand, they carry a reduced production of angiotensin II from angiotensin I, on the other, inhibiting the elimination of bradiquinin causing its accumulation.

The mechanism of action of ACEI inhibitors consists of inhibiting the enzyme that acts in the conversion of angiotensin I into angiotensin II. This enzyme has two main functions in the body. On the one hand, it is responsible for synthesizing angiotensin II, an effective vasoconstrictor octapeptide (peptide made up of 8 amino acids), from its inactive prestage, the decapeptide (10 amino acids) angiotensin I, separating two amino acids from the C-terminal end of the molecule.. On the other, it catalyzes the elimination of the bradykinin mediator in inactive products.

Vasoconstriction mediated by angiotensin II is rapid and intense at the level of the arterioles and not so much at the level of the veins. Arteriolar constriction increases peripheral vascular resistance relative to the heart, thus increasing arterial pressure. Venous constriction increases venous return. Angiotensin II also increases blood pressure due to its renal effect, decreasing the excretion of sodium cation and water, causing the extracellular volume to increase.

Inhibition of the enzyme that converts angiotensin into an active vasoconstrictor causes the concentration of angiotensin II at the level of the angiotensin receptors (AT₁ and AT₂) decrease. Thus, vascular tone is reduced, which attenuates systemic vascular resistance and lowers blood pressure, both systolic and diastolic. Subsequently, the reduction in the level of angiotensin II leads to a reduction in the secretion of the hormone aldosterone from the adrenal gland and thereby determines the blood water content. It is thought that angiotensin may be produced in other tissues including the heart. At the cellular level, a reversal of the effects of angiotensin II-induced mitogens can be observed in fibroblasts and myocytes of the heart, leading to adverse alterations especially after a myocardial infarction (remodeling).

Bradykinin is a potent vasodilator through the release of nitric oxide and prostacyclin. Some of the ACE inhibitors are capable of maintaining the action of bradykinin, producing a decrease in peripheral vascular resistance and, therefore, blood pressure.

In the case of kidney diseases such as diabetic nephropathy, ACE inhibitors cause a reduction in the elimination of proteins (proteinuria) and prevent the progression of the disease (nephroprotection).

Inhibition of the elimination of bradykinin supposes contrary to its accumulation and the secondary effects related to it.

Mechanism of molecular effect

It has also been possible to explain the mechanism of molecular effect of ACE inhibitors. It is based on the similarity of ACE inhibitors to one end of the angiotensin I peptide chain. Thus, the angiotensin-converting enzyme mistakes ACE inhibitors for the physiological (biochemical) substrate of angiotensin I. Without However, unlike what happens with the physiological Substrate (biochemistry), the enzyme, instead of transforming them, is blocked by them.^{[citation needed]}

Pharmacology

ACE inhibitors are distinguished from one another in pharmacokinetics based on their chemical differences. Most of the currently available ACE inhibitors are prodrugs. This implies that after 20% (ramipril) to almost 100% (resorption) absorption they must be activated by the action of enzymes present in the body (see chemical composition). The only ones that do not need this step are captopril and lisinopril. After 1 to 8 hours the maximum plasma level of the effective forms is reached. The elimination half-life ranges from 2 (captopril) to 40 hours (spirapril). The duration of effect varies accordingly (8 to 48 hours). ACE inhibitors are mainly eliminated by the kidneys. In addition, fosinopril, moexipril, and spirapril show relevant biliary excretion (elimination in the bile).

Side Effects

Most side effects of ACE inhibitors are related to slow elimination and accumulation of bradykinin. These include skin reactions such as rashes (0.1 - 1%) and urticaria in up to 10% of patients. In contrast, severe allergic skin reactions (<0.01%) are rarely observed. The secondary effect considered characteristic of ACE inhibitors, the appearance of angioneurotic edema, has been observed in a very isolated way (0.01 -0.1%).^{[citation required]}

Most side effects that affect the airways can also be related to bradykinin buildup. Among them are dry cough, dysphonia and sore throat (0.1 - 1%). Similarly, asthma attacks and respiratory failure may appear, although they are also unusual (0.01 - 0.1%).^{[citation required]}

During treatment with ACE inhibitors, the patient may suffer severe hypotension regardless of the action of bradykinin. Consequently, dizziness, headache and drowsiness may be observed (0.1 - 1%). Serious cardiovascular episodes, such as angina pectoris, myocardial infarction, and syncope, have only been reported in isolated cases. Due to their effect on the water content and electrolytes in the body, the use of ACE inhibitors can cause functional renal disorders in certain patients (0.1 - 1%). In contrast, proteinuria (elimination of protein in the urine) (0.01 - 0.1%) has been observed very rarely.^{[citation needed]}

The effects of the renin-angiotensin-aldosterone system with reduced aldosterone secretion are responsible for another unwanted effect of ACE inhibitors: aldosterone potentiates, on the one hand, the reabsorption of sodium and water in the kidneys and, on the other hand, on the other, it facilitates the elimination of potassium. A reduced concentration of aldosterone causes the opposite effect: increased elimination of sodium and water by the kidneys and increased retention of potassium in the body. In this way, hyperkalemia can occur, especially dangerous for the heart, frequent in diabetic patients and with renal failure. Hyponatremia rarely occurs. This is important in surgical interventions of patients who use ACE inhibitors chronically, increasing the risk of disturbances in the fluid balance during the operation due to the administration of anesthesia, which in turn decreases the fluid volume that reaches the cardiac ventricle, causing greater hypotension of the heart. the desired.

Since ACE inhibitors during pregnancy can cause, among others, fetal hypotension, renal failure, impaired growth and bone formation in the infant, as well as being associated with a high mortality rate, they should not be administered during pregnancy. this period and should be replaced by other indicated therapeutic measures.

Drug Interactions

Angiotensin-converting enzyme inhibitors reinforce the hemogram-transforming side effects of drugs with an immunosuppressive effect (immunosuppressants, cytostatics, and glucocorticoids). Similarly, ACE inhibitors potentiate the blood sugar-lowering effect of oral antidiabetics and insulin.

In case of interventions in the water and electrolyte content, the speed of lithium elimination can be reduced. Similarly, a potentiation of the increase in potassium level or hyperkalemia may be observed with combined use with potassium-sparing diuretics or potassium supplements.

Non-steroidal anti-inflammatory drugs tend to minimize the hypotensive effects of ACE inhibitors through bradykinin.

Combined with other drugs that lower blood pressure should be monitored if a drop in blood pressure occurs. The synergistic effects that can also be used in treatments appear especially with diuretics and calcium channel blockers. A reduction in the blood pressure-lowering effect of ACE inhibitors has been observed after the ingestion of salty foods (salt).^{[citation needed]}

Taking aspirin along with an ACE inhibitor may improve survival in patients with heart failure or ischemic heart disease.

Drugs

Currently, the following ACE inhibitors are authorized as drugs in many countries:

• Benazepril (Cibacen®)
• Enalapril (Xanef®, Pres®, many generic medicines)
• Captopril (Lopirin®, Tensobon®, (Capotén®en España) many generic drugs
• Cilazapril (Dynorm®)
• Fosinopril (Fosinorm®, Dynacil®)
• Imidapril (Tanatril®)
• Lisinopril (Acerbon®, Coric®, generic medicines)
• Moexipril (Fempress®)
• Perindopril (Coversum®, Preterax®)
• Quinapril (Accupro®, generic medicines)
• Ramipril (Delix®, Vesdil®, generic medicines)
• Espirapril (Quadropril®)
• Trandolapril (Gopten®, Udrik®)
• Zofenopril (Presiam®, Zofenil®)

Some natural compounds such as casokinins and lactokinins, which are bioactive breakdown products of casein and whey, especially present in fermented milk products, may have a role in blood pressure control, similar to to ACE inhibitors. The tri-peptide compounds Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus are similarly have been associated with antihypertensive functions through ACE inhibition.

Economic importance

In Germany, 20% of the population and one in two people over the age of 55 take drugs to treat hypertension. Approximately 35% of hypertensive patients receive treatment with an ACE inhibitor as a single treatment and approximately 55% in combination with another medication intended to reduce hypertension.^{[citation needed]}

In the United States in 2001, 114 million boxes of ACE inhibitors were prescribed. This equates to a total turnover of about 4.3 million US dollars. The main share is provided by the ACE inhibitor lisinopril (47%), followed by enalapril (17%), captopril and ramipril (each 9%). However, in the German market, where generic drugs are widespread, the drug enalapril dominates.^{[citation needed]}

Alternatives

The new substances from the group of angiotensin II receptor antagonists no longer inhibit the angiotensin-converting enzyme, but have an antagonistic effect on the angiotensin II receptor 1 subtype, possibly reducing the occurrence of side effects. However, AT₁ antagonists are still much more expensive than ACE inhibitors, which is why they have not succeeded in replacing the latter. The best tolerance is due to the fact that they do not affect the bradykinin system.

Vasopeptidase inhibitors such as omapatrilate are derived from the classic ACE inhibitors and are about to receive authorization from the health authorities. In addition to inhibiting the angiotensin-converting enzyme, vasopeptidase inhibitors block neutral endopeptidase, an enzyme responsible for inactivating atriopeptins (ANPs), whose function is to relax blood vessels.

Another novel point of intervention lies in the inhibitor of the renin enzyme secreted by the kidneys and which is responsible for synthesizing angiotensin I. With A-72517, a selective inhibitor of said enzyme is undergoing a clinical trial.

Intensive medicine aspect

In intensive medicine it has been found that patients who have received treatment with ACE inhibitors before their stay in the intensive care unit often have a higher consumption of catecholamines in order to stabilize blood pressure. The reason could be a deficiency of antidiuretic hormone, which could be attributed to previous ACE inhibitor therapy. By substituting antidiuretic hormone, especially in patients who are in a catecholamine dilemma, the need for catecholamine can be rapidly reduced (as long as there are no other reasons responsible for hypotension) and within 12 to 24 hours can be compensated for. antidiuretic hormone.^{[citation needed]}

In patients with heart failure, it is noted that they do not take the ACE inhibitors prescribed at the time of hospital discharge or stop taking them before a month after leaving the hospital. One study showed that about 33% of these patients stop taking their prescribed ACE inhibitors after one year, indicating the need for follow-up in those prescribed ACE inhibitors.