THE USE OF ACE INHIBITORS IN THE CLINIC OF INTERNAL MEDICINE

Angiotensin-converting enzyme (ACE) is widely used nowadays for the treatment of various diseases. In particular, in the last century ACE inhibitors are the "gold standard in the treatment of cardiovascular diseases" (materials of XIII World Congress of Cardiology, 1998). At the same time efficiency in the specific disease and in relation to a particular patient, as well as the safety profile of the course taking these drugs depends on the treatment of some of their features. They stipulate, on the one hand, finding new ACE inhibitor, which would claim to universality of use in the clinic, and, on the other hand, the emergence of various summarizing recommendations for practical use. In the latter case leveled individualization of treatment, this may be important in specific clinical situations. And more specifically, in situations of mass usage on an outpatient basis. This is even more important that some of the mechanisms of influence of ACE inhibitors are not yet fully clarified and the ongoing experience of using them to increase the amount of knowledge as in the normal physiology of various organs and systems, and in the pathogenesis of some diseases [1-3]

Mechanism of action of ACE inhibitors

Current views on the role of the renin-angiotensin-aldosterone system in the regulation of homeostasis of water and sodium, which is considered the leader in the pathogenesis of arterial hypertension (AH) is formed in the late 50-th of last century. Later they refined the data conversion mechanism with the participation of the respective angiotensin enzyme (ACE). For the first time a substance with the activity of ACE inhibitors were derived from snake venom, and then they began to receive chemical means. A major achievement was the creation in 1975 by "Squibb" first oral ACE inhibitor – captopril.

In many ways a common mechanism of action of drugs of this group is convenient to consider the example of Enalapril (Vasotec, Berlipril, Ednit, Enap, Renitec, Enapril, Envas), perhaps the most studied of prolonged ACE inhibitors in the clinic. On the Ukrainian market, he presented more than thirty names. Enalapril, after entering the body and the hydrolysis of enalaprilate, inhibits ACE-peptidyl dipeptidase, which catalyzes the conversion of angiotensin Ι (inactive form) in the form of vasoconstrictor – angiotensin II. The enzyme also stimulates of aldosterone production in adrenal glands. Inhibition of these two processes leads to a decrease in the total pressor activity and determines the effect of enalapril in AH and heart failure (Fig. 1).

Fig. 1. Main elements of the pharmacological action of ACE inhibitors

ACE is identical in nature to kininase – an enzyme that degrades bradykinin and which is present in the cell membranes of many organs, providing both intracellular and extracellular action. In particular showed its presence in the brain, kidneys, adrenal glands, salivary glands, pituitary gland, gonads, intestine, etc., which formed the so-called "local renin-angiotensin system" (LRAS). They maintain homeostasis of blood and water-salt balance. For example the presence of LRAS to the right atrium determines the effect of ACE inhibition on central venous pressure to be used in the treatment of some congenital heart defects [4, 5].

The bioavailability of enalapril is approximately 40%. After oral administration of the drug found in blood after 1 h with a maximum concentration after 6 h (ramipril – 1-2.5 hours, captopril – 1 hour). T1/2 is 4 hours. In the blood of enalapril on 50% protein bound (captopril – by 25-30%, ramipril metabolites – 56-73%) and excreted in the urine. Excretion is slowed down with a decrease in glomerular filtration rate. In patients with hypertension and heart failure pharmacokinetics of enalapril does not change that positively distinguishes it from, for example, captopril, in which the T1/2 be increased to 21-32 hours. At the same time, the active metabolite of enalapril – lisinopril – in these circumstances may be more long term. Enalapril is prescribed for AH and heart failure in a dose of 5-10 mg 2 times per day (lisinopril – 10 mg once daily, perindopril – 8 mg once daily, ramipril – 5 mg twice daily). In order to avoid development of excessive hypotension when taking the first dose of treatment begins with the admission of 2.5 mg of the drug. Similarly, a half dose is used and referred to other ACE inhibitors [1, 4].

Classification of ACE inhibitors

There are several classifications of ACE inhibitors. Their knowledge is essential for the rational use of drugs of this group in practice, as well as to account for intermedicinal interactions. Differences between the pharmacodynamic of ACE inhibitors appear duration and effectiveness of, the presence and severity of side effects, etc.

Currently, the most widely used chemical classification of ACE inhibitors on:

1. Preparations containing sulfhydryl group;

2. Preparations containing carboxylic group;

3. Preparations containing phosphonyl group and others (Table 1).

Table 1. Classification of ACE inhibitors in its chemical structure

In this regard it is also useful for accounting ACE inhibitors on physical and chemical properties under L. Opie (1994):

Table 2. Classification of ACE inhibitors on physical and chemical properties [under L.Opie, 1994]

First class – lipophilic ACE inhibitors which have pharmacological activity, but are subject to further transformations in liver. Derive the renal excretion. The second class – prodrugs that become active after hydrolysis in the liver and other organs and tissues. Their active forms, diacidic metabolites, are excreted in different ways according to division into subclasses. The third class – the hydrophilic drugs not metabolized in the body. Circulate in the blood outside the context of plasma proteins and excreted of kidneys in unchanged state [6].

For the duration of the antihypertensive effect of ACE inhibitors are divided into three groups:

Short-acting – they should be administered 2-3 times a day (captopril).

With an average duration of action – to reception at least 2 times per day (enalapril, ramipril).

Long-acting – in most cases provide round the clock monitoring the level of blood pressure when taking single per day (lisinopril, perindopril).

The clinical use of ACE inhibitors

The most popular and most frequently used indication for ACE inhibitors – hypertension of various origins. In this role, drugs are used since its inception (captopril). The essential virtues that distinguish ACE from other antihypertensive agents, is their effectiveness in high-renin AH caused by atherosclerotic renal artery stenosis. Researchers estimate that this cause may underlie persistent increase in blood pressure in 5-22% of patients of different age groups. At the same time retain the hypotensive effect of ACE inhibitors and for low-renin AH. In general blood pressure reduction under the influence of ACE inhibition alone is, according to various estimates, 40-80% in patients with hypertension. In addition, clinical and confirmed experimentally by their pronounced effect of left ventricular hypertrophy. It manifested itself in patients regardless of the severity of the hypotensive action. In addition, improving compliance and reducing the extent of myocardial hypertrophy occurred of any origin [3, 4, 7].

Another unique feature of the treatment of AH is proven by numerous controlled trials preventive effect of ACE inhibitors. It manifests itself in reducing the number and severity of its complications. In particular, the marked decrease in the number of strokes by about 30% and myocardial infarction – 20%. In this regard, in addition to those mentioned, another aspect is the prevention of coronary events. Positive effects of ACE inhibitors on the target organs in various diseases account for their influence on the exchange of bradykinin, NO-regulation of the activator system. At the same time some patients with acute exacerbation of chronic ischemic heart disease cannot achieve improvement which leads to limited use of ACE inhibitors in angina pectoris. However chronic ischemic heart disease on the background of AH and heart failure after myocardial infarction is an indication for long-term treatment ACE inhibitor. The positive effect of the treatment are on changes in properties of the myocardium, and (to a lesser extent) to improve coronary blood flow [2, 7]. According to the literature the optimal treatments for coronary artery disease are the approaches to dosing ACE inhibitors shown in Table 3.

Table 3. Optimal doses of ACE inhibitors for the treatment of coronary artery disease (IHD, CAD)

           In the last decade confirmed the positive effect of ACE inhibitors in patients with chronic heart failure. With long-term medication, significantly increased time to first negative side effect (death + hospitalization + chronic heart failure exacerbation + myocardial infarction) and decreased the need for diuretics. Significantly reduced morbidity, improved quality of life and prognosis for these patients. It should be noted that ACE inhibitors can be used in conjunction with cardiac glycosides which is also an important it’s advantage [8].

In the experiment ACE inhibitors retarded the development of atherosclerosis and its clinical manifestations (abnormalities of cerebral, coronary and peripheral circulation), as shown in patients with homozygous dyslipoproteinemia, in which there was a threefold increase in risk of myocardial infarction. In contrast to β-blockers ACE inhibitors do not have adverse effects on lipid and carbohydrate metabolism, caused an increase in excretion of uric acid [3, 9].

Specific kidney disease in diabetes (diabetic nephropathy) has increasingly been associated with disorders of organ hemodynamic, especially constriction of the efferent vessels, which leads to increased pressure in the capillaries of the glomerular loops and hyperfiltration. The process is progressing and the development of glomerulosclerosis. ACE eliminates the efferent vasoconstriction, reduces hyperfiltration and microalbuminuria. Effect also occurs in patients with specific secondary hypertension. In recent years shows the positive effect of ACE inhibitors and glomerulosclerosis in other species. In addition demonstrated a similar positive effect of liver disease on background of diabetes [3, 6].

There are reasons for the effective use of ACE inhibitors in pulmonary hypertension in patients with congenital heart disease, especially after cardiac surgery with correction of intracardiac hemodynamic, as well as Reynaud’s syndrome, nephritis, scleroderma, migraine. Relatively new indications of ACE inhibitors include stenosis of the basilar artery, which - as shown by preliminary estimates - determines 27% of fatal strokes. Shown positive effects in more than 70% of cases, which ended in the 58% reduction of the lumen of the vessel [2, 10].

The important positive qualities of ACE inhibitors in their clinical application should include the fact that unlike other anti-hypertensive drugs are not contraindicated in asthma, chronic nonspecific lung disease, various depression, diabetes, atherosclerosis, etc. In most cases they combine well with most commonly used drugs and can be used with other antihypertensive agents – diuretics, β-blockers and calcium channel antagonists.

Side effects and cautions

All drugs of this group are the prescription and the appearance of any side effects should consult a physician. Although in general it should be noted that the use of ACE inhibitors are relatively rare. At the same time due to the fact that all drugs of this group can cause antenatal defects they are strictly contraindicated in pregnancy and breastfeeding. Should be aware of this warning when using ACE inhibitors in women of childbearing age.

In Table 4 presents the evidence, the possible side effects and the estimated cost of treating some with ACE inhibitors

The most common and well known among the side effects is a dry cough, which occurs in 8-15% of patients often with prolonged use of drugs. This effect is due to excessive degradation of bradykinin in the bronchial mucosa and increases its sensitivity to catecholamines and is different for different ACE inhibitors. Thus, for the most significant of captopril it, and, for example, enalapril and fosinopril minimal. The vast majority of patients cough is not a cause for discontinuation of the drug and disappeared after dose reduction [4, 9].

Natural elimination of negative feedback inhibited level of angiotensin II on renin secretion leads to increased plasma renin activity. That, in turn, causes the majority of ACE inhibitors for the development of "withdrawal syndrome", which consists in the aggravation of the clinical course of hypertension. In this connection stop taking the drug used should always be done gradually, and in some cases this precaution is necessary if we replace one other ACE inhibitor.

Another side effect of ACE inhibitors may be a skin rash, urticaria. In some rare cases the reaction of intolerance becomes life-threatening in the form of a localized angioedema (localized in the neck). In the literature noted that it develops more often in smokers and negroids. In all these cases recommend removal of the drug with further consultation with a doctor [1, 6, 9].

Characteristic features of ACE inhibitors, which also can enroll in the side effects, are transient hypotension after application of the first dose. In this regard, as noted above, the drugs begin to take a minimal dose, increasing it to a therapeutic every 1-2 weeks (depending on the subjective tolerability). Patients should be warned that there may be dizziness, which limit its ability to control the vehicle and perform work that requires concentration. In the remaining episodes of hypotension shown to decrease the dose ACE inhibitor (if applicable) or cancellation of another jointly received antihypertensive drugs [8].

Hyperkaliemia is a potential complication and side effect of ACE inhibitor therapy, directly related to their long anti-aldosterone effect. It is especially dangerous in patients with diabetes, various forms of ischemic heart disease, nephritic syndrome and chronic renal failure, which against the background of hyperkaliemia can develop serious complications. Required control potassium levels in plasma are necessary for patients with baseline indicators to 5.5 mmol/L or more. Monitoring is carried out after each increase in dose ACE inhibitor (after at least a week) for administration of these drugs, as well as - in this "risk groups" on a monthly basis and more often. For other categories of patients the frequency may be once a year. Increased levels of potassium to 6.0 mmol/L or more is grounds for cancellation of ACE inhibitors usage [5, 9, 11].

Given the fact that blood pressure lowering effect of ACE inhibitor monotherapy have observed no more than 40-80% of patients (and according to some data in smaller number), their use often supplemented with other antihypertensive agents. In hyperkaliemia well established combination of drugs that contain additional thiazide diuretic. On the Ukrainian market are Enap-H, Enalozid, Enafril and some other distinguished mainly economic indicators. A strengthening of the excretion of potassium this form of drug usually relieves the availability of hyperkaliemia. In addition the combination of drugs allows a single dose per day due to potentiation of antihypertensive effects.

Despite the beneficial effect of ACE inhibitors in heart failure, many patients with this pathology, they often worsen the glomerular filtration. Moreover the frequency of these adverse effects increases with prolonged therapy. In this regard these patients should be monitored baseline creatinine and further monitoring in similar terms specified for hyperkaliemia. Creatinine increase of 50% from baseline or up to 200 mcm/L more often than is acceptable. However with growth of 100% from baseline or up to 350 mcm/L or higher is an indication for the abolition of ACE inhibitors [3, 8].

Most controlled studies in unnecessary situations the use of ACE inhibitors also include heart failure on the background of hypotension, aortic stenosis as well as the presence of left bundle branch block, high pressure in the left atrium (more than 22 mm Hg), hypernatremia.

Little account of practical feature in Europe is the low efficiency of ACE inhibitors in hypertension in negroids. In different age groups it does not exceed, even with combination therapy, 8-19% and is the basis of generally accepted the recommendations of the use of calcium channel blockers [1, 3].

Other side effects of prolonged use of ACE inhibitors are also sporadic cases of photophobia, taste perversion, anorexia and headaches. As a rule they are not permanent and are solved by making the appropriate adjustments to be expanded into a course of treatment.

Thus winning the trust of physicians and patients ACE inhibitors have become part of modern clinical practice. This group of drugs reduces cardiovascular morbidity and mortality in patients with AH, significantly improves the quality of life of patients with other diseases. Important additional characteristics of ACE inhibition – tolerability, organoprotective properties and anti-atherosclerotic effects. At the same time the maximum positive effect of drug therapy cannot be separated from warning them of possible side effects that must be considered in the daily work of a pharmacist.

Table 4. Indications and possible side effects and the estimated cost of treating some with ACE inhibitors

Note: AMI - acute myocardial infarction, CCF – chronic circulatory failure, CHF – chronic heart failure, CRF – chronic renal failure, DM – diabetes, IHD – ischemic heart disease, PE – pulmonary embolism;. * – in many countries price higher because of the cost of health insurance; ** – testimony not entirely clear.

Reference

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