Arterial hypertonia treatment: inhibitors of angiotensin-converting enzyme

Purposeful building of inhibitors of angiotensin-converting enzyme (ACE) is huge achievement in treatment of an arterial hypertonia (AH) and others is warm - vascular diseases. They combine advantages in respect of efficacyy, low frequency of by-effects, maintenance of high quality of life with proved kardio - vaskulo - and rhinoprotect action, and also, that is especially important, frequency depressions warmly - vascular complications and augmentation of lifetime of patients at long application.

The action mechanism

ACE inhibitors is a name of a class of the preparations, applied to notation of bunch of the medical products, having an effect through competitive inhibition ACE. ACE inhibitors react, binding an active catalytic fragment of enzyme and quenching thereby transition of angiotensin I in biologically active peptide angiotensin II (A-II). Though ACE inhibitors have been pristinely framed for inhibition ACE and thus for depression of level A-II in a blood plasma, they have hypotensive an effect, possibly, and through other mechanisms.

It is proved, that in various organs all components for education A-II locally - so-called histic or local a renin - angiolensin systems are had. ACE the brain and adrenals is produced by endothelial cells of pots, and also cells of such organs, as heart, nephroses.

Discovering histic means a renin-angiotenzivnyh of systems, that locally formed inside or about vascular side А-II vasoconstrictive an effect and atherogenous effects has. Therefore the chronic hypotensive effect of ACE inhibitors is bound to inhibition not ACE blood plasmas, and locally produced or histic ACE. At the same time functional mutual relations between locally formed А-II and system regulation a renin angiotensin aldosterone system (RAAS) are not established till now.

Besides the control over production А-II from angiotensin I, ACE also is one of the enzymes responsible for degradation of the powerful vasodilate agent - a bradykinin. The bradykinin is not only a direct vasodilator, but also promotes remission from endothelial cells of two other powerful dilators - an endothelium-produced relax the factor (oxide nitrogen - NO) and Prostaglandinums. Until recently there is obscure a question on that, how much antihypertensive effect of ACE inhibitors is bound to a bradykinin. At the same time the saved up experimental data specify, and results of clinical research HOPE (acknowledgement see more low) to that, that antiatherosclerotic action of ACE inhibitors can be bound both to depressing of synthesis А-II, and with activization of system NO and Prostaglandinums.

ACE inhibitors also reduce sympathetic activity that allows to survey them as indirect antiadrenergic materials, and prevent a delay of salt and water owing to depression of level of Aldosteronum.

Under the influence of ACE inhibitors there are following changes of levels of hormones:

• augmentation of secretion of a renin
• augmentation of angiotensin I
• depression of angiotensin II
• depression of secretion of Aldosteronum
• bradykinin augmentation

Preparations and doses

ACE inhibitors (now them is about three tens), representing a uniform class, at the same time fastnesses of linkage differ from each other as linkage with enzyme, to presence or absence of a promedicine, duration of action, pathes elimination or egestions (see the table). Captopril - the first representative of this class - is the active medicine, having an effect without transformation to a liver, and is deduced by nephroses.

Other ACE inhibitors represent promedicines which as a result of an esterification in a liver are transformed to an active metabolite. Owing to steadier communications with ACE they have longer hypotensive an effect. It is necessary to notice, that now there are no establishments to assume, that mechanisms of antihypertensive action at different ACE inhibitors differ.

As all ACE inhibitors are deduced mainly by nephroses, their doses should be reduced at elderly and at patients with disturbance of function of nephroses and the raised level of a serumal creatinine. For example, at renal insufficiency the enalapril dose should be reduced half if the creatinine clearance drops below 30 ml/minutes In case of appointment Perindopril, the standard dose of 4 mg should be reduced to 2 mg and even less.

ACE inhibitors are prescribed perorally, unitary reception of the majority of them provides the control of a BP within 24 hours (see the table). Captopril should be prescribed 2-3 times a day, and enalapril in some cases - 2 times a day.

Results of clinical application

According to relative clinical researches, ACE inhibitors as monotherapy normalise or considerably reduce a BP at 60-70 % of patients AH that is quite comparable with other antihypertensive preparations. BP depression is observed during the first hours after preparation reception, however the maximum antihypertensive effect educes in some weeks of regular reception. Features of action of captopril allow to use it for cupping of a hypertensive crisis or an asymptomatic high BP, including at reception under tongue.

Expression of antihypertensive effect depends on specific features of development AH (smaller effect at representatives of black strain), conditions RAAS (hyperactivity against long application of diuretics), keepings of restriction of salt (effect intensifying), concomitant therapy (nonsteroid antiinflammatory preparations reduce effect) and other factors. ACE inhibitors can be used at patients soft, moderated and serious AH (rising of a BP I, II, III degrees on the CART, 1999), especially at treatment malignant AH.

At insufficient antihypertensive effect the combination of ACE inhibitors with diuretics (there are many fixed combined forms) and antagonists of calcium is recommended, the combination with a-blokatorami, b-blokatorami and preparations of the central action is possible. The combination of ACE inhibitors to blockers angiotensin receptors of 1 type is perspective, the further researches however are necessary.

Despite BP depression, frequency of warm reductions, a stroke output and minute volume of heart remain without changes at application of ACE inhibitors with patients with AH and the kept systolic function of a left ventricle.

Clinical advantages of ACE inhibitors

As have shown numerous researches, ACE inhibitors or do not render negative influence on constituent vital systems, or possess variety of additional favorable effects, some of which are not bound to BP depression.

Preparations of this class do not render negative influence on a condition of the central and independent excitatory systems, that allows to keep high quality of life (normal sex activity, reaction to an exercise stress), including at application at persons of advanced age. Enriching of cognitive functions against ACE inhibitors at persons of advanced age allows to use more widely them at this category of patients.

ACE inhibitors are metabolicly neutral preparations: against their application there are no changes of a lipide profile, urinary acid, glucose level in blood and insulinresistance (last indicators, according to some information, can even be enriched). Beneficial effect of ACE inhibitors on some parametres of a hemostasis (depression of level of an inhibitor of a histic plasminogen activator, augmentation of a histic plasminogen activator) is supposed. Thus, ACE inhibitors render either neutral, or beneficial effect on major factors of risk of cardiovascular diseases.

Are well proved for today organ-protective effects of ACE inhibitors: antiproteinuric action and retardation/prevention of development of terminal renal insufficiency; reduction of the hypertrophied myocardium of a left ventricle and retardation/prevention of development of systolic dysfunction of a left ventricle, including after a myocardial infarction; enriching of elastic characteristics of large arteries and overcoming of a vascular remodelling of fine and resistive arteries (restoration of a normal interrelation - a thickness of a vascular vascular wall/lumen). It is necessary to note the first clinical proofs for a long time prospective antiatherosclerotic action (not bound to influence on a lipide profile) ACE inhibitors, according to research HOPE.

The listed characteristics allow to apply successfully ACE inhibitors to treatment AH at persons of any age, sex, with concomitant disturbances of lipide, carbohydrate and purine exchanges, at any implications of ischemic illness hearts (ischemic heart disease), a bronchial asthma and chronic obstructive diseases of lungs, lesions of peripheric pots, including phenomenon Reynaud, depressions, etc.

Specific indications to application

According to last references the CART / МОAH ACE inhibitors can be prescribed by patient AH as monotherapy as the first medicine. However taking into account the circumstances set forth above preparations of this class should be preferred at combination AH to clinical implications of a circulatory unefficiency and left ventricle dysfunction, after the tolerated myocardial infarction (IT), in the presence of a diabetic nephropathy. Use of ACE inhibitors at sick of a diabetes and AH can be dilated, as in one of recently come to the end researches advantage of enalapril over antagonists of calcium (nisoldipine) in frequency of development of cardiovascular complications is shown. Value of this research should not be exaggerated, as in it did not put the primary goal an assessment of influence on disease outcomes. In other large research, lasting average 8,4 years, at sick of a diabetes of II type maintenance to the same extent BP depressions (an average index of 144/82 mm hg) captopril and atenolol has appeared in a peer measure congenial in reduction of cardiovascular complications of disease.

Noted earlier congenial kardio - and nephroprotect effects of ACE inhibitors allow to make a choice in favour of this class at presence at patients of a hypertrophy of a left ventricle and a proteinuria.

Despite high antihypertensive efficacyy and excellent organoprotect properties, until recently there was obscure an influence of ACE inhibitors on frequency of development of cardiovascular complications at patients AH without circulatory unefficiency signs. This important question has been addressed the several large researches, two of which have come to the end recently. In research CAPP captopril also was effective, as “traditional therapy” b-blokatorami and diuretics, in BP depression, however with the big number of strokes. It is necessary to notice, that the scheme of application of captopril of 1 times a day, did not provide the 24-sentry of the control over a BP. Nevertheless in captopril bunch was less cases of development of a diabetes.

In research HOPE it has been shown, that appointment of inhibitor ACE of a ramipril as the patient with high risk of development of cardiovascular complications (an ischemic heart disease, AH, the diabetes, a lesion of peripheric arteries, cerebral circulation disturbance) is authentic on 20-31 % reduces frequency of lethal outcomes, to IT and a cerebral stroke in comparison with a placebo. Thereby for the first time have found clinical acknowledgement for a long time prospective antiatherosclerotic effects of ACE inhibitors.

Thus, findings of investigation CAPP and HOPE allows to assume, that indications to application of ACE inhibitors can be dilated in the near future and they can become preparations of a choice for treatment of the patients, suffering raised a BP.

Contraindication and guard at use of ACE inhibitors

Preparations are absolutely contraindicative for treatment AH at pregnant women. Thereupon it is necessary to show the big guard at appointment of ACE inhibitors to women of the genital age, not using contraceptives. It to the full concerns and the patients having in the anamnesis a Quincke's disease and similar allergic implications, especially if they have been bound to application of ACE inhibitors.

For the prevention of a hypotension of the first dose at patients with high activity RAAS (long diuretic therapy, a hyponatremia, a renal artery stenosis) it is necessary to cancel preliminary for 1-2 days diuretics to make good the loss fluid and to use small doses.

At patients with the fixed warm outlier (the expressed mitral or aortal stenosis) at application of ACE inhibitors there can come the expressed uncontrollable falling of a BP as peripheric resistance depression cannot be compensated because of impossibility of augmentation of outlier of heart.

It is necessary to pay attention to a hyperpotassemia, especially in cases of renal insufficiency which can be enlarged at appointment or for the first time appear after appointment of ACE inhibitors. In last situation not distinguished earlier bilateral stenosis of renal arteries can be the cause.

By-effects

As the class of preparations, and it confirms experience of almost 25-year-old clinical application, ACE inhibitors are characterised by low general frequency of by-effects which, according to clinical researches, compounds less than 10 %.

Tussis is most often reported by-effect of ACE inhibitors which meets in 3-6 % of cases. To prognosticate tussis appearance at appointment of ACE inhibitors it is impossible. More often this complication arises within the first weeks of treatment, gradually strengthens and can demand full cancellation of a preparation. In other cases its expression can gradually decrease before the full termination. At changing by other inhibitor ACE tussis, as a rule, arises again, therefore in this situation it is more expedient to translate the patient on treatment by blockers angiotensin receptors.

The Quincke's disease concerns dangerous complications of therapy by ACE inhibitors, demanding immediate cancellation of a preparation. In the future (this rare enough complication - about 0,04 %) appointment of ACE inhibitors is absolutely contraindicative to such patients, and application possibility in these cases of blockers of receptors A-II while is obscure.

As already it became perceptible earlier, it is possible to avoid successfully excessive depression of a BP after the first reception of ACE inhibitors, observing a number of simple rules.

Appointment of ACE inhibitors can be accompanied by deterioration of function of nephroses in the form of augmentation of a serumal creatinine and a hyperpotassemia (at use before the big doses of captopril of 300-450 mg are described even proteinuria cases). At the same time ACE inhibitors are especially effective at a renovascular hypertonia and other hardly proceeding arterial hypertonias with a lesion of nephroses, and are recommended for the prevention/retardation of development of terminal renal insufficiency. The glomerular filtration rate and intraglomerular pressure depend on formation A-II and at depression of its production in reply to appointment of ACE inhibitors can sharply fall. It leads to appearance or increase of renal insufficiency, especially in cases of bilateral stenoses of renal arteries. Transitional rising of level of a serumal creatinine after appointment of ACE inhibitors can be observed at separate patients that demands more careful analysis of the causes of development AH and the subsequent control.

Such undesirable phenomena as a dermal eruption, taste loss, a neutropenia and other uses of captopril described in the first years, has been bound to appointment of the big doses and practically do not meet now.

Application prospects

Results of recently come to the end large clinical researches CAPP and HOPE testify that ACE inhibitors just as diuretics and B-BLOCKERS, reduce frequency of cardiovascular complications and a mortality at patients AH and render clinically significant vasoprotective the action expressed in authentic reduction of the main complications of an atherosclerosis (a myocardial infarction, a cerebral stroke, subitaneous mors), including at ischemic heart disease patients and AH without a circulatory unefficiency. Therefore it is possible to assume, that ACE inhibitors will take of a position in the future of "a choice preparation” for treatment of patients AH irrespective of presence or absence at them specified before specific indications to it. Also appearance of the new indication to appointment of ACE inhibitors - the prevention and atherosclerosis treatment is prognosticated.