ACE inhibitors classification by generation. Third generation ACE inhibitor fosinopril in the treatment of patients with cardiovascular diseases
Classification of ACE inhibitors
The classification of ACE inhibitors is based on the pharmacokinetic principle: a group of active drugs (captoprit and lisino-pril) and proleksrev (the remaining ACE inhibitors) are distinguished, from which active metabolites are formed in the liver, giving a therapeutic effect (Table 16.5) .
Clinical pharmacology and pharmacotherapy
Chapter 16
Table 16.5. Classification of ACE inhibitors according to Opie (1999)
|
Lipophilic drugs: captopril, alacepril, fentiapril |
|
|
Lipophilic prodrugs |
|
|
PA class |
Drugs whose active metabolites are excreted primarily through the kidneys: enalapril, benazepril, perindopril, celazapril |
|
Class IV |
Drugs whose active metabolites have two main elimination routes: moexipril, ramipril. trandolapril, fosine opril |
|
Hydrophilic drugs: lisinopril |
Pharmacokinetics of ACE inhibitors
The pharmacokinetic features of the most commonly used ACE inhibitors are presented in table. 16.6.
Clinical use of ACE inhibitors
Main indications for the use of ACE inhibitors:
arterial hypertension of any etiology (as monotherapy and in combination with diuretics and antihypertensive drugs of other groups);
relief of hypertensive crises;
chronic heart failure;
systolic and diastolic dysfunction of the left ventricle;
IHD (to reduce the infarction area, to dilate coronary vessels and reduce dysfunction during reperfusion, to reduce the risk of recurrent myocardial infarction);
diabetic angiopathy (in particular, to slow the progression of diabetic nephropathy);
diagnosis of renovascular hypertension and primary aldosteronism (single dose of captopril).
Monitoring the effectiveness and safety of the use of ACE inhibitors.
The effectiveness of treatment with ACE inhibitors for arterial hypertension is determined by the dynamics of blood pressure.
To monitor the safety of therapy, it is also necessary to measure blood pressure to exclude possible hypotension. Hypotension develops more often in patients with chronic heart failure, renal failure, renal artery stenosis, and therefore the first dose of the drug must be taken while sitting or lying down. The development of hypotension requires a reduction in the dose of the drug, followed by titration under the control of blood pressure levels.
To exclude the growth of urate stones in patients with urolithiasis, it is necessary to determine the urate content in the urine, and to exclude hypoglycemia in patients with diabetes, monitor blood glucose levels.
ACE inhibitors remain one of the safest antihypertensive drugs. Men tolerate long-term drug therapy better than women.
Arterial hypertension< 213
Table 16.6. Pharmacokinetic features of ACE inhibitors
|
Peak them |
Prodrugsgva |
|||||||
|
enala-pri.1 |
fwna tell ril |
faux-adj |
tsila ia-nril | |||||
|
Time to achieve the "effect" | ||||||||
|
Duration >ffek1a. h | ||||||||
|
G>iolost\nn“hch. | ||||||||
|
Effect of food on absorption | ||||||||
|
Protein binding. % | ||||||||
|
Biotransformations |
11.00. gastrointestinal | |||||||
|
)kskrsnia |
T%, |
1 № |
11 points 50*. gastrointestinal tract 504 |
but-gut- |
||||
|
The influence of non-functional liver |
Decline biodos-tunno- |
Increasing the time to achieve the effect |
Increase in child life |
Increasing the time of men achieved the effect |
||||
|
In the treatment of chronic renal failure (creatinine ktirens. ml min) | ||||||||
|
Active metabolites | ||||||||
The most common ADR (from 1 to 48% during treatment with various ACE inhibitors) is a dry cough, which in some cases requires discontinuation of the drug. The mechanism of its occurrence is associated with an increase in the concentration of bradykinin in bronchial tissue. As a rule, cough is not dependent on the dose of the medicine.
The second most common (from less than 1% to 10-15% in heart failure) ADR of ACE inhibitors is the development of orthostatic hypotension. the so-called first vine effect, which occurs in patients with high RAAS activity. The development of a hypotensive reaction can also be caused by the simultaneous use of diuretics and other antihypertensive drugs.
214 # Clinical pharmacology and pharmaceuticals Granin * Chapter 16
In patients with cardiac failure (less commonly with AS), LIF inhibitors can worsen glomerular filtration and kidney function, and the incidence of severe ADRs increases with prolonged therapy. More often this happens with hidden kidney pathology and/or in patients. receiving diuretics and NSAIDs.
Clinically significant hyperkalemia (more than 5.5 µmol/l) is observed mainly in patients with kidney pathology. In renal failure, its frequency ranges from 5 to 50%,
In 0.1 0.5% of cases per<роне лечения ингибиторами АПФ развивается аши-онсвротический отек (агск Квинке), причем у женщин в 2 раза чаше, чем у мужчин.
In some cases, ACE inhibitors can cause pyEopenia (usually leukopenia, less often thrombo- and panitopenia). NK“..the schism of this NLR is connected with that. that the main substrate for ACE is the peptide N-appetyl-seryl-aspargyl-lysyl-iroline circulating in the blood - a negative regulator of temopo:) for. When the enzyme is blocked, the amount of peptide in the blood may increase. During therapy with ACE inhibitors moivi There are also such non-specific side effects. such as dizziness, headache, fatigue, weakness. dyspepsia (nausea, diarrhea), taste disturbances, skin rashes, etc.
The use of ACE inhibitors in the 11th and 3rd trimesters of pregnancy leads to the development of hypogenia. cranial typoplasia, anuria, reversible and irreversible renal failure and fetal death. In addition, a decrease in amniotic fluid, the development of joint contractures, cranial lip deformities and hypoplasia of the lungs are possible.
Contraindications to the use of LPF inhibitors
Absolute: drug intolerance: allergic reactions; pregnancy and lacgapia; bilateral sgenosis of the renal arteries (the possibility of sudden hypogenzia increases). severe chronic renal failure (serum creatine and n above 300 µmol/l), severe (above 5.5 µmol/l) hyperkalemia; hypertrophic cardomyopathy with obstruction of the outflow tract of the left ventricle: 1emodynamically significant stenosis of the aortic or mitral valve; constrictive pericarditis; transplantation of internal organs.
Otshyu/tetmye: hypotension; moderate chronic renal failure; moderate (5.0-5.5 µmol/l) hyperkatemia, gouty kidney (having a uricosuric effect, ACE inhibitors can accelerate the growth of urticaria): cirrhosis of the liver; chronic active hepatitis; obliterating agerosk-lero! arteries of the lower extremities; severe obstructive pulmonary diseases.
Reaction of LPF inhibitors with othersJIC(tide 16.7)
The pharmacokinetic interaction of ACE inhibitors is most significant with antacids. containing aluminum and/or magnesium hydroxide. "These antapids interfere with the absorption of captonril and (rosinopride) from the gastrointestinal tract.
Arterial hypertension ♦ 215
For clinical practice, the pharmacodynamic interaction of ACE inhibitors with other groups of drugs that differ from them in their mechanism of action is more important.
Table 16.7. Pharmacodynamic interaction of ACE inhibitors with drugs of other groups
|
Interaction |
Note" |
|
|
Antidiabetes drugs IHHCY.THH.ProTP- aqueous ulpho-nylureas) |
Strengthening the sugar-lowering effect | |
|
Diuretics (except imvvyharf-tatoshnkh) |
Increased risk of g and gene shn |
It is advisable to cancel the drugs 2-3 days before na shacheshtya ish iontors LPF. If the effectiveness of LPF inhibitors is insufficient, diuretics are given additionally. but not less than 2 hours before prescribing LPF inhibitors, [.if preliminary withdrawal of diuretics is impossible. then I prescribe LPF inhibitors! first in minimal jo-te |
|
Potassium-storing diuretics |
Increase rijeka rašngnya gnperka-lnemia. especially > patients with chronic renal disease |
Undesirable combination, requires repeated monitoring of potassium levels in the blood |
|
Potassium preparations |
Increased risk of rltnitka gshterka-shemin. especially in patients with chronic renal failure |
Undesirable combination |
|
Lithium preparations |
A decrease in renal tissue volume and, as a result, an increase in its capacity |
Undesirable combination |
|
|3 - L. tre nob.tokat o-ry |
Strengthening of the protective and hypotensive effect |
A useful combination in the treatment of chronic heart failure |
|
Locators SCH?ajpeiiepi11CH1CH1M1 renepures |
Strengthening the potential of action |
An advisable antihypertensive combination; blood pressure control is necessary when selecting a dot drug" |
|
Jurassic block of chalk-.tennych calcium channels |
Strengthening the spogenic effect |
An appropriate genetic combination; better tolerated. than each component separately |
|
Locators prescription ORT for angiotensin |
Increasing tittoten-zshshho. har.sho- and retshrotektivshch about tffektov |
A suitable combination for high RALS activity |
|
Peyrodeschics and grshshk.shskie actilsprsssants |
Strengthening ihjioich-tivet tffekg, the possibility of pos-gu-ratnoy typotension |
Undesirable combination. Copgrol blood pressure if it is possible to cancel LPF inhibitors |
216 -о* Clinical pharmacology And pharmacotherapy ♦ Chapter 16
Table 16.7. End
Characteristics of basic drugsCaptopril. Captopril weakly binds to ACE , which determines the prescription of large doses. The action of captopril has the shortest duration in the group of ACE inhibitors (6-8 hours compared to 24 hours for other drugs), but the earliest onset of effect, which allows its use sublingually for emergency treatment of hypertensive conditions. When taking captopril sublingually, the antihypertensive effect develops within 5-15 minutes. What distinguishes captopril from other ACE inhibitors is SH-rpynna, which determines its main side effects - nephrotoxicity and associated proteinuria (at a dose of more than 150 mg per day), cholestasis, neutropenia (usually in patients with diffuse connective tissue diseases and impaired renal function with long-term use). At the same time, the SH group promotes the antioxidant effect of captopril, increases coronary blood flow and increases tissue sensitivity to insulin.
The use of captopril in patients with acute myocardial infarction leads to a significant reduction in mortality. Long-term use of the drug (more than 3 years) reduces the risk of recurrent myocardial infarction by 25%, and the risk of death from it by 32%.
The captopril test is used in radionuclide diagnosis of renovascular hypertension and biochemical diagnosis of primary hyperaldosteronism (Conn's disease).
Enalapril in the liver it is converted into enaprilat (40-60% of the dose taken orally), which binds well to ACE.
When prescribing enalapril for the treatment of hypertension, it is necessary to discontinue diuretics for 2-3 days; if this is not possible, reduce the initial dose by 2 times.
Arterial hypertension ♦ 217
dose of the drug (5 mi). The first doses of enalapril should be minimal in patients With initially high activity of the RAAS. The effectiveness of the prescribed dose is determined every 2 weeks. The drug is prescribed 1-2 times V day.
Lyunnoprnl is an active metabolite of eialapril. LD decreases 1 hour after taking the drug. When lisinopril is prescribed once a day, its stable concentration in the blood is achieved after 3 days. The drug is excreted unchanged by the kidneys; in case of point failure, it exhibits pronounced cumulation (the half-life increases to 50 hours). In elderly patients, its concentration in the blood is 2 times higher than in young patients. When administered intravenously, the antihypertensive effect of lisinopril begins within 15-30 minutes, which allows it to be used to relieve hypertensive crises,
Perindopril is a prodrug and is converted in the liver into the active metabolite perindoprilat (20% of the administered dose of perindoprid). which binds well to ACE. The drug weakens hypertrophy of the vascular wall and myocardium. When taken, the amount of subendocardial collagen in the heart decreases.
Rnmnnril in the liver it is converted to ramiprilat. which binds well to ACE. Two pharmacokinetic features of ramipril are of great clinical importance - slow elimination from the body and double elimination pathway (up to 40% of the drug is excreted in the bile). However, in case of severe renal failure (glomerular filtration rate 5-55 ml/min), it is recommended to reduce its dose by half.
The main indication for the use of ramipril is arterial hypertension.
Trandoloprnl its effect on tissue ACE is 6-10 times greater than that of ena-dapril. Although trandoloprnl is considered a prodrug, it has pharmacological activity in its own right, but trandodoprilat is 7 times more active than grandolopril. The hypotensive effect of the drug with a single use lasts up to 48 hours.
Moexipril becomes active after biotrapsformapia in the liver in mo-zheinridate. Unlike most ACE inhibitors, up to 50% of mozsipril is excreted in bile, which makes it safer in patients with renal failure.
Moexipril is used primarily for the treatment of arterial hypertension; its antihypertensive effect lasts up to 24 hours.
Phosniopride refers to prodrugs. turning into the active substance fosinoprilat in the liver. The drug has a dual route of elimination - equally through the kidneys and the liver. In case of renal failure, the excretion of fosinopride through the liver increases, and in case of hepatic failure, through the kidneys, which makes it possible not to adjust the dose of the drug for these diseases in patients.
The drug is prescribed 1 time per day.
Fosinopril rarely causes a dry cough; therefore, if such a complication occurs during therapy with any ACE inhibitors, it is recommended to switch to fosinopril.
218 -fr Clinical pharmacology and pharmacotherapy ♦ Chapter 16
The most common among the world's population are cardiovascular diseases, so a fairly large percentage of people take “heart” medications, and this is, as a rule, not one medicine, but several. In this case, the question arises about their safe combination. In this article we will talk about dangerous combinations of “heart” drugs.
The term “heart medications” is quite general and non-specific. Medicines for the treatment of arterial hypertension, angina pectoris, myocardial infarction, cardiomyopathies, cardiac arrhythmias and conduction disorders, and many others fit this description. To bring some clarity, it is necessary to stipulate that in the article We will talk about the most widely used medications that affect the functioning of the heart, and their possible combinations with each other.
The following groups of drugs will be considered:
Note: all drugs are written by international nonproprietary name (INN).
I. Beta blockers:
1. non-selective: propranolol, carvedilol, oxprenolol, pindolol, nadolol.
2. selective: atenolol, metoprolol, bisoprolol, nebivolol, talinolol.
II. Calcium channel blockers (calcium antagonists):
1. non-dihydropyridine: verapamil, diltiazem;
2. dihydropyridine: nifedipine, amlodipine, S-amlodipine, lercanidipine.
III. ACE inhibitors: captopril, perindopril, enalapril, ramipril, zofenapril, fosinopril, lisinopril.
IV. Angiotensin II receptor blockers: losartan, valsartan, candesartan, ibresartan, telmisartan.
V. Diuretics:
1. thiazide: hydrochlorothiazide, chlorthalidone.
2. thiazide-like: indapamide.
3. loop diuretics: furosemide, torsemide.
4. potassium-sparing diuretics: spironolactone, eplerenone.
Note: the classification shows the most famous representatives of drugs. If you do not find your drug here, then you can find out which group it belongs to by looking at the instructions for it (find the line “pharmacotherapeutic group”), or in reference books on drugs (Vidal, RLS, reference book by M.D. Mashkovsky) .
Recommendations for the treatment of arterial hypertension from 2013, developed by the European Society of Hypertension and the European Society of Cardiology, established the following irrational (i.e. dangerous) combinations"heart" drugs:
1. beta-blockers + non-dihydropyridine calcium channel blockers (verapamil, diltiazem). This combination is a GROSS ERROR on the part of the doctor, since drugs of both groups cause a decrease in heart rate. When prescribed together, their total effect on heart rate is so pronounced that life-threatening conditions can occur (even heart rhythm disturbances). If, by coincidence, the patient can only be prescribed a combination of beta-blockers with calcium channel blockers, then from the group of the latter, preference is given to dihydropyridine drugs (nifedipine, amlodipine, lercanidipine).
Note: A combination of beta blockers and non-dihydropyridine calcium antagonists is sometimes used to control ventricular rate in persistent atrial fibrillation. BUT! Only in this case!
2. ACE inhibitor + potassium-sparing diuretic. Potassium-sparing diuretics include spironolactone and eplerenone. Like all diuretics, a group of potassium-sparing drugs removes excess fluid from the body while maintaining potassium in the blood. ACE inhibitors also contribute to the accumulation of potassium in the body. When combining drugs from both groups, a dangerous condition for the heart can occur - hyperkalemia - which can cause cardiac arrest in diastole. If your doctor has prescribed you a drug from any of these groups, you need to periodically check your potassium levels (during dose selection, once a week, when the optimal dose of the drug is selected - once a month). The normal level of potassium in blood plasma for adults is 3.5-5.1 mmol/l.
3. Beta-blocker and centrally acting drugs. The last group includes methyldopa, clonidine, moxonidine, rilmenidine. These groups have similar mechanisms of action, clinical effects, and - most importantly - side effects. Due to mutual enhancement of undesirable effects, these two groups are not used together.
4. ACE inhibitor and angiotensin-II receptor blocker. Previously, this combination of drugs was possible, but since 2013 it has been established that the combination of these two groups has a negative effect on the kidneys, causing renal failure in a relatively short time.
The same Recommendations talk about possible but less studied drug combinations . It is possible that someday these combinations will move into the group of rational or dangerous. Such combinations include the following:
1. ACE inhibitor + beta blocker;
2. Angiotensin-II receptor blocker + beta-blocker;
3. Dihydropyridine calcium antagonists + beta-blockers.
Rational and as safe as possible The following drug combinations are available:
1. Diuretic (thiazide) + angiotensin-II receptor blocker;
2. Diuretic (thiazide) + calcium antagonist;
3. Diuretic (thiazide) + ACE inhibitor;
4. Angiotensin-II receptor blocker + calcium antagonist;
5. ACE inhibitor + calcium antagonist.
These are, perhaps, all the features of the most common combinations of “heart” drugs. Of course, in each individual case, in relation to a particular drug, there are characteristics unique to it. But the basic rules in prescribing several “heart” medications are the above.
Published in: Rational Pharmacotherapy in Cardiology 2005; No. 1; P.49-68 Working group on ACE inhibitors of the European Society of CardiologyMembers of the working group: Jose Lopez-Sendon, Chairman* (Spain), Karl Swedberg (Sweden), John McMurray (UK), Juan Tamargo (Spain), Aldo P. Maggioni (Italy), Henry Dargie (UK), Michal Tendera ( Poland), Finn Waagstein (Sweden), Jan Kjekshus (Norway), Philippe Lechat (France), Christian Torp-Pedersen (Denmark)
European Society of Cardiology Practice Guidelines Committee: Silvia G. Priori (Chair) (Italy), Maria Angeles Alonso Garcia (Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica Dean ( France), Jaap Deckers (Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindahl (Sweden), Gianfranco Mazzotta (Italy), Keith McGregor (France), Joao Morais (Portugal), Ali Oto (Turkey) ), Otto A. Smiseth (Norway)
Reviewers: Maria Angeles Alonso Garcia (coordinator) (Spain), Diego Ardissino (Italy), Cristina Aven-dano (Spain), Carina Blomstrem-Lundqvist (Sweden), Denis Clement (Belgium), Helmut Drexler (Germany), Roberto Ferrari ( Italy), Keith A. Fox (Great Britain), Desmond Julian (Great Britain), Peter Kearney (Ireland), Werner Klein (Austria), Lars Kober (Denmark), Giuseppe Mancia (Italy), Markku Nieminen (Finland), Witold Ruzyllo ( Poland), Maarten Simoons (Netherlands), Kristian Thygesen (Denmark), Gianni Tognoni (Italy), Isabella Tritto (Italy), Lars Wallentin (Sweden)
* Contact: Jose Lopez-Sendon, Cardiology, Area 1 200, Hospital Universitario Gregorio Maranon, Doctor Esquerdo 46, 28007 Madrid, Spain. Tel.: +34-91-586-8295; Fax: +34-91-586-6672. Email address: [email protected](J. Lopez-Sendon).
The original text of the Conclusion, prepared by experts of the European Society of Cardiology on the use of ACE inhibitors in cardiovascular diseases, was published in the European Heart Jornal,
2004;25:1454-1470.
© 2004 European Society of Cardiology. Adapted translation from English and replication were made with the consent of the European Society of Cardiology.
Preamble
Recommendations and expert opinions consider all available data on a particular issue, which helps the doctor weigh the benefits and risks of a particular diagnostic or therapeutic intervention. Accordingly, such documents can be useful for a doctor in his daily practice.
In recent years, a large number of recommendations and expert opinions have been issued by the European Society of Cardiology and other organizations. This could affect the quality of published documents, which can only be guaranteed if the process of their development cannot be questioned. For this reason, these organizations have created guidelines for the preparation of recommendations and expert opinions. Although there are clear standards for preparing quality guidelines, a review of guidelines published in peer-reviewed journals from 1985 to 1988 showed that methodological standards were overwhelmingly not met. It is important that the recommendations are formatted in a way that makes them easy to interpret. Once recommendations are issued, their implementation must be monitored. The Practice Guidelines Committee of the European Society of Cardiology oversees and coordinates the preparation of new guidelines and expert opinions by working groups, expert groups and advisory boards. Experts participating in this process are encouraged to disclose potential conflicts of interest. Special forms are kept at the headquarters of the European Society of Cardiology. The Committee is also responsible for approving recommendations and expert opinions. The working group proposed a classification of recommendations and identified levels of evidence.
Levels of Evidence
Introduction
The reninangiotensin system plays an important role in the development of cardiovascular diseases. Over the past decade, numerous studies have been conducted that have examined the clinical effectiveness of angiotensin-converting enzyme (ACE) inhibitors in various clinical conditions. Based on the data obtained, it was recommended to use drugs of this group in patients with heart failure, arterial hypertension, acute and post-myocardial infarction. This document discusses the appropriateness of prescribing ACE inhibitors to patients with cardiovascular disease and provides clinical evidence supporting their benefit.
Members of the working group on ACE inhibitors in cardiovascular disease were appointed by the practice guidelines committee of the European Society of Cardiology. Peer-reviewed journals included in the Medline database were searched for original articles. In addition, the recommendations of the European Society of Cardiology, as well as the American Heart Association/American College of Cardiology were analyzed.
Highlighting gradations of recommendations makes them easier to perceive. The class of recommendations is determined based on the results of clinical studies. They are carried out on selected patients, who may not be representative of the general sample. For example, patients who have contraindications to treatment are excluded from studies. However, the “strength” of evidence may reflect different clinical effects (reduction in morbidity and mortality, reduction in symptoms and composite endpoints, small but statistically significant effect, rapid effect, or effect only seen several years after initiation of treatment). Finally, in specific cases, the recommended drug may be only one treatment option, and other remedies may be equally or even more appropriate.
The document prepared by the working group was distributed to members of the editorial board appointed by the European Society of Cardiology and approved by the society's practice guidelines committee. The final document was submitted for review to the European Heart Journal.
This opinion reflects the opinion of the European Society of Cardiology and has been prepared based on a careful analysis of the available data. Physicians should consider these data when making decisions. However, this document does not replace the responsibility of the doctor, who must make a decision in a specific situation after discussing all issues with the patient, and, if necessary, with his relatives or guardians.
Pharmacology
Definition
ACE inhibitors competitively inhibit the angiotensin-converting enzyme. ACE is a nonspecific enzyme that is involved in the metabolism of many small peptides, in particular, it converts the inactive octapeptide angiotensin I into angiotensin II. In addition, ACE inhibitors competitively inhibit kininase, an enzyme that catalyzes the destruction of bradykinin and other peptides that have powerful vasodilatory properties. The main effects of angiotensin II are listed in table. 1.
Classification of ACE inhibitors
ACE inhibitors are divided into three categories depending on the nature of the group that binds to the zinc atom in the ACE molecule - sulfhydryl, carboxyl or phosphonyl (Table 2).
Pharmacokinetics
Absorption of various ACE inhibitors is variable (25-75%). Eating does not affect the rate of absorption or reduces it, but does not change the degree of absorption. Some ACE inhibitors are prodrugs and are converted to active metabolites by hydrolysis in the liver or gastrointestinal tract. Concentrations of drugs in plasma reach a peak 1-4 hours after administration. Prodrugs are more lipophilic and penetrate better into target tissues after conversion to active metabolites.
Most ACE inhibitors and their metabolites are eliminated primarily by the kidneys, while fosinopril, zofenopril, trandolapril and spirapril have two routes of elimination (liver and kidney). Captopril is quickly eliminated from the body, which determines the short duration of its action (less than 6 hours). At the same time, ramiprilat (the active metabolite of ramipril) and especially trandolaprilat are eliminated more slowly than other ACE inhibitors (Table 2).
In patients with congestive heart failure, reduced absorption and biotransformation may delay the onset of action of ACE inhibitors. Due to deterioration of renal perfusion, renal clearance may decrease, which leads to an increase in the maximum concentrations of drugs in plasma and the duration of their action. In this regard, if renal function is impaired (creatinine clearance less than ≤30 ml/min), a dose reduction is indicated. Fosinopril, spirapril, trandolapril and zofenopril are excreted in both urine and bile, so their clearance does not change significantly with deterioration of renal function (Table 2).
Mechanism of action
ACE inhibitors competitively block the conversion of angiotensin I to angiotensin II and reduce its levels in the blood and tissues. In addition, they reduce the secretion of aldosterone and vasopressin and the activity of the sympathetic nervous system, and also suppress the trophic effects of angiotensin II. However, drugs in this group do not inhibit the action of angiotensin II, which is mediated by AT1 and AT2 receptors, and do not directly interact with other components of the reninangiotensin system. ACE inhibitors also inhibit kininase II and increase levels of bradykinin, which stimulates B2 receptors and causes the release of nitric oxide (NO) and vasoactive prostaglandins (prostacyclin and prostaglandin E2).
With long-term treatment, the decrease in plasma ACE levels appears to be less important. In this situation, the pharmacological effects of ACE inhibitors are largely associated with the suppression of ACE in various tissues (vessels, kidneys, heart).
Table 1. Effects of angiotensin II
| Vessels | Vasoconstriction Stimulates the release of norepinephrine, aldosterone, vasopressin and endothelin-1 |
| Heart | Inotropic and chronotropic effects Narrowing of the coronary arteries |
| Adrenal glands | Secretion of aldosterone and adrenaline |
| Brain | Vasopressin secretion Secretion of substance P, LHRH and ACTH Stimulation of the thirst center Activation of the sympathetic nervous system |
| Kidneys | Vasoconstriction (mainly of the efferent arteriole) Reduction of mesangial cells Increased sodium reabsorption in the proximal renal tubules Increased calcium excretion in distal nephrons Decreased renin secretion |
| Platelets | Stimulation of platelet adhesion and aggregation |
| Endothelial cells | NO inactivation (suppression of endothelial NO synthase) Expression of endothelial receptors for oxidized LDL (LOX-1) |
| Sympathetic activity | Increased impulse transmission in peripheral noradrenergic endings Release of catecholamines by the adrenal medulla |
| Fibrinolysis | Increased expression of PAI-1 and 2 |
| Inflammation | Activation and migration of macrophages Increased expression of adhesion molecules (VCAM-1, ICAM-1, P-selectin), chemotactic proteins (MCP-1) and cytokines (IL-6) |
| Trophic effects | Hypertrophy of cardiac myocytes Stimulation of migration, proliferation and hypertrophy of vascular smooth muscle cells Stimulation of proto-oncogenes (fos, myc, jun) and MAPKs (ERKs, JNK) Increased production of growth factors (PDGF, bFGF, IGF-1, TGFb1) Increased synthesis of extracellular matrix proteins (fibronectin, collagen types I and III, laminin-b1 and b2) and metalloproteinases |
| Atherosclerosis | Stimulation of NAD/NADP oxidase activity and production of superoxide anions, lipid peroxidation |
ACE inhibitors have the same mechanism of action, so their effects are common to the entire class of these drugs. However, ACE inhibitors differ significantly in their tissue ACE affinity and pharmacokinetic properties, which may result in significant differences in their tissue concentrations and clinical effects. However, the clinical significance of such differences has not been established. In fact, we can assume that all modern ACE inhibitors have the same antihypertensive effect. Therefore, the choice of drug and dose should be based on the results of clinical studies in which the benefit of a particular ACE inhibitor has been demonstrated.
Table 2. Pharmacological properties of various ACE inhibitors
| Preparation | Period half-life (h) |
Excretion by the kidneys (%) |
Standard daily dose (mg) |
Dose (mg) at renal failure (creatinine clearance 10-30 ml/min) |
| Containing a sulfhydryl group | ||||
| Benazepril* | 11 | 85 | 2.5-10 twice | 2.5-10 twice |
| Captopril | 2 | 95 | 25-100 three times | 6.25-1 2.5 three times |
| Zofenopril* | 4,5 | 60** | 7.5-30 twice | 7.5-30 twice |
| Containing a carboxyl group | ||||
| Cilazapril | 10 | 80 | 1.5-2.5 once | 0.5-2.5 one time |
| Enalapril* | 11 | 88 | 2.5-20 twice | 2.5-20 twice |
| Lisinopril* | 12 | 70 | 2.5-10 once | 2.5-5 once |
| Perindopril* | >24 | 75 | 4-8 once | 2 once |
| Quinapril* | 2-4 | 75 | 10-40 one time | 2.5-5 once |
| Ramipril* Spirapril | 8-14 1,6 | 85 50** | 2.5-10 once 3-6 once | 1.25-5 once 3-6 once |
| Trandolapril | 16-24 | 15** | 1 -1 once | 0.5-1 once |
| Containing a phosphinyl group | ||||
| Fosinopril* | 12 | 50** | 10-40 one time | 10-40 one time |
** Largely excreted by the liver
Effects of ACE inhibitors
Hemodynamic effects
ACE inhibitors reduce total peripheral vascular resistance, increase natriuresis, but cause small changes in heart rate. These effects are due in part to inhibition of tissue ACE and blockade of angiotensin II formation in certain target tissues.
In patients with normal and elevated blood pressure who do not suffer from congestive heart failure, ACE inhibitors have little effect on cardiac output or pulmonary capillary wedge pressure. When used, unlike other vasodilators, reflex tachycardia does not develop, which may be a consequence of changes in the sensitivity of baroreceptors, stimulation of the vagus nerve and/or a decrease in the activity of the sympathetic nervous system. After physical activity or changes in body position, the heart rate is not affected. ACE inhibitors cause regression of cardiac hypertrophy in patients with arterial hypertension and reduce endothelial dysfunction in patients with coronary heart disease and normal blood pressure, arterial hypertension, type 2 diabetes mellitus and heart failure. Improved endothelial function has been associated with decreased vasoconstriction and increased NO production with increased bradykinin levels.
In patients with congestive heart failure, ACE inhibitors dilate veins and arteries. With venodilation, the capacity of the peripheral vascular bed increases, the pressure in the right atrium and pulmonary artery, the wedge pressure in the pulmonary capillaries, the volume and filling pressure of the left ventricle decreases, which leads to a rapid decrease in blood stagnation in the lungs. As a result of arterial dilatation, peripheral vascular resistance decreases and cardiac output increases. ACE inhibitors improve relaxation and compliance of the heart, and their long-term use leads to a decrease in left ventricular hypertrophy and blood pressure in patients with arterial hypertension.
Neurohumoral effects
Short-term ACE inhibitor therapy is accompanied by a decrease in angiotensin II and aldosterone levels and an increase in renin production and angiotensin I concentrations. Angiotensin II increases sympathetic tone in the central nervous system and periphery and stimulates the secretion of catecholamines in the adrenal medulla, so ACE inhibitors reduce plasma levels of epinephrine, norepinephrine and vasopressin.
In addition, increased levels of angiotensin I can lead to increased production of bradykinin, which has vasodilatory properties, and increased synthesis of angiotensin II by alternative enzymes, such as chymase. With long-term treatment, angiotensin II and aldosterone levels may return to baseline values due to activation of alternative pathways (aldosterone escape phenomenon). Aldosterone secretion is maintained by steroidogenic factors such as hyperkalemia, hypermagnesemia and adrenocorticotropic hormone. On the other hand, ACE inhibitors increase the levels of kinins, prostacyclin and NO, which may partly explain their vasodilatory, antithrombotic and antiproliferative effects.
Antiproliferative effects
ACE inhibitors also have an antiproliferative effect (reduce hypertrophy of the vascular wall and myocardium and proliferation of the extracellular matrix) and suppress left ventricular remodeling after myocardial infarction. The latter effect is associated with a decrease in ventricular preload/afterload, blockade of the proliferative effects of angiotensin II, a decrease in the activity of the sympathetic nervous system, and inhibition of the action of aldosterone, which causes cardiac hypertrophy and interstitial and perivascular fibrosis. With myocardial hypertrophy, ACE inhibitors cause a decrease in heart weight and improve its diastolic function. Drugs in this group prevent apoptosis of cardiac myocytes when the heart is overloaded with pressure.
Effects on the kidneys
ACE inhibitors reduce renal vascular resistance, increase renal blood flow and increase the excretion of sodium and water ions. At the same time, the glomerular filtration rate (GFR) does not change or decreases slightly, so the filtration fraction decreases. This effect is associated with a preferential dilation of postglomerular efferent arterioles, which leads to a decrease in hydrostatic pressure in the glomerular capillaries and GFR. The increase in natriuresis is due to improved renal hemodynamics, decreased secretion of aldosterone and bradykinin, which have a direct effect on the tubules, and suppression of the direct renal effects of angiotensin II. ACE inhibitors prevent the increase in microalbuminuria and the appearance of overt proteinuria, slow down the progression of renal failure in patients with various non-diabetic nephropathies and prevent or slow down the progression of nephropathy in patients with type 1 diabetes mellitus.
Other effects
The reninangiotensin system plays an important role in the development and progression of atherosclerosis. In animal experiments, ACE inhibitors slowed down atherogenesis. The antiatherogenic properties of drugs in this group may be associated with blockade of angiotensin II formation, increased levels of bradykinin and NO, which lead to suppression of migration and proliferation of vascular smooth muscle cells, taxis and activation of inflammatory cells, reduction of oxidative stress and improvement of endothelial function. In the SAVE (The Survival And Ventricular Enlargement) and SOLVD (Studies Of Left Ventricular Dysfunction) studies, as well as in a meta-analysis of clinical trials, it was shown that ACE inhibitors reduce by 20-25% the risk of developing unstable angina and recurrent myocardial infarction in patients with left ventricular dysfunction and congestive heart failure. In the HOPE (Heart Outcomes Prevention Evaluation) study, ramipril therapy led to a reduction in morbidity and mortality in patients at risk of atherothrombotic cardiovascular complications. The SECURE study, which was conducted as part of HOPE, examined the effects of ramipril and vitamin E on the condition of the carotid arteries using ultrasound. Long-term ACE inhibitor therapy has been shown to delay the progression of carotid atherosclerosis in patients with vascular disease or diabetes mellitus who do not have heart failure or left ventricular dysfunction.
Effect on the fibrinolytic system
ACE inhibitors modulate the balance of the fibrinolytic system by reducing the formation of angiotensin II, which stimulates the synthesis of plasminogen activator inhibitor type 1 (PAM), and increasing levels of bradykinin, which stimulates tissue plasminogen activator. Thus, ACE inhibitors reduce the concentration of PAI-1 and the molar ratio of its level to the content of tissue plasminogen activator.
In addition, ACE inhibitors block platelet aggregation caused by angiotensin II, as they increase the production of NO and prostacyclin.
Side effects
ACE inhibitors are well tolerated in most patients, although they can cause various adverse reactions.
Arterial hypotension. Clinically obvious arterial hypotension may develop due to the elimination of the vasoconstrictor effect of angiotensin II, especially after taking the first dose of an ACE inhibitor, particularly in patients with high plasma renin activity (for example, during therapy with high doses of diuretics or congestive heart failure).
Dry cough develops in 5-10% of patients. It is not always easy to differentiate from cough associated with stagnation of blood in the lungs or concomitant diseases, for example, the respiratory system. The cause of cough during treatment with ACE inhibitors has not been established, but it may be a consequence of increased levels of bradykinin and/or substance P in the lung tissue. Cough does not depend on the dose, is more common in women and representatives of the Mongoloid race, develops from 1 week to several months after the start of treatment and sometimes forces you to stop therapy. Some patients tolerate treatment with ACE inhibitors, resumed after a certain break. After stopping therapy, the cough usually goes away within 3-5 days. ACE inhibitors do not differ in their ability to cause cough.
Hyperkalemia, associated with decreased aldosterone secretion, rarely occurs in patients with normal renal function, but occurs quite often in patients with congestive heart failure and the elderly. The incidence of hyperkalemia increases in patients with renal failure and diabetes mellitus, patients receiving potassium supplements or potassium-sparing diuretics, heparin or nonsteroidal anti-inflammatory drugs (NSAIDs).
Acute renal failure. ACE inhibitors may cause increases in blood urea nitrogen and creatinine levels. In most patients, creatinine concentration remains stable or decreases to baseline values as therapy is continued. Acute renal failure often develops during treatment with diuretics in high doses, in the presence of hyponatremia, bilateral renal artery stenosis, stenosis of the predominant renal artery, one kidney, and after kidney transplantation. In these conditions, renin secretion and angiotensin II levels increase, which causes selective constriction of the glomerular efferent arteriole and maintains GFR. ACE inhibitors reduce the level of angiotensin II, dilate efferent arterioles and reduce glomerular filtration, which leads to an increase in creatinine levels. The risk of acute renal failure during treatment with ACE inhibitors is especially high in elderly patients with congestive heart failure. After discontinuation of ACE inhibitors, kidney function is restored in virtually all patients.
Proteinuria. ACE inhibitors may cause proteinuria. However, its presence is not a contraindication to the use of drugs in this group, since they had a nephroprotective effect in kidney diseases accompanied by proteinuria (for example, diabetic nephropathy).
Angioedema is a rare side effect, but can be life-threatening. Symptoms range from mild gastrointestinal disturbances (nausea, vomiting, diarrhea, colic) to severe shortness of breath associated with laryngeal edema and death. Angioedema occurs more frequently during the first month of therapy and in African Americans. Manifestations disappear within a few hours after discontinuation of the ACE inhibitor. The cause of angioedema is considered to be the accumulation of bradykinin and its metabolite, desarginine bradykinin, and inhibition of complement esterase inactivator-1.
Teratogenic effect. The use of ACE inhibitors in the second and third trimesters of pregnancy can cause the development of defects in the fetus (oligohydroamnion, pulmonary hypoplasia, intrauterine growth retardation, kidney defects, anuria and neonatal death).
Other side effects not related to ACE blockade include loss of taste and other disturbances of taste (especially in older adults), neutropenia, and maculopapular rash. Neutropenia is rare. It is more often observed in patients with kidney diseases and vasculitis.
Contraindications
A history of angioedema, allergies and bilateral renal artery stenosis are absolute contraindications to the use of ACE inhibitors. Although drugs in this group can be used in women of reproductive age, they should be immediately discontinued in the event of pregnancy, including suspected pregnancy. Low blood pressure (systolic less than 90 mm Hg) during treatment with ACE inhibitors is acceptable if there are no symptoms of hypotension. ACE inhibitor therapy should be discontinued if the potassium level increases more than 6.0 mmol/L or the creatinine level increases by more than 50%, or more than 3 mg/dL (256 mmol/L). Moderate renal failure (serum creatinine not more than 3 mg/dl, or 265 mmol/l), mild hyperkalemia (<6.0 ммоль/л) и пониженное АД (снижение систолического АДдо 90 мм рт. ст.) не являются противопоказаниями к лечению ингибиторами АПФ, однако в таких случаях проводить его следует под контролем функции почек. Риск развития гипотонии и дисфункции почек повышается при увеличении дозы у пожилых больных и пациентов с тяжелой застойной сердечной недостаточностью, при лечении диуретиками в высоких дозах, дисфункции почек или гипонатриемии. Ингибиторы АПФ, как и другие вазодилататоры, не следует назначать больным с динамической обструкцией выносящего тракта левого желудочка .
Interaction with other drugs
Antacids reduce the bioavailability of ACE inhibitors. NSAIDs may reduce the vasodilatory effects of drugs in this group. Potassium-sparing diuretics, potassium supplements and salt substitutes rich in potassium may contribute to the development of hyperkalemia during treatment with ACE inhibitors, so such combinations should be avoided. However, the combination of an ACE inhibitor with spironolactone may be useful, although its use should be carefully monitored. If there is a significant increase in urea or creatinine levels, it is advisable to discontinue nephrotoxic drugs (eg, NSAIDs, cyclosporine). ACE inhibitors may cause increases in plasma digoxin and lithium levels. Patients receiving diuretics are especially sensitive to the vasodilating effects of ACE inhibitors. In some studies, concomitant therapy with salicylates reduced the effectiveness of ACE inhibitors in patients with congestive heart failure. However, a meta-analysis of treatment results in more than 20,000 patients found no evidence of a weakening of the beneficial effect of ACE inhibitors with simultaneous use of aspirin.
Dosing
The dose of the ACE inhibitor is selected taking into account the clinical situation and individual response to treatment. In table Table 2 shows the average daily doses of various drugs, and table. 4 indicates the starting and target doses in patients with chronic heart failure.
Indications for the use of ACE inhibitors
- All patients with heart failure and asymptomatic left ventricular dysfunction.
- No contraindications (history of angioedema, pregnancy, bilateral renal artery stenosis) WITH
- exercise caution
- Severe renal impairment (creatinine >2.5 mg/dL or >221 µmol/L)
- Hyperkalemia (K > 5.0 mmol/l)
- Arterial hypotension (decrease in systolic blood pressure less than 90 mm Hg), accompanied by symptoms
- Interaction with other drugs: potassium supplements, potassium-sparing diuretics (including spironolactone), high-potassium salt substitutes, NSAIDs, angiotensin II receptor blockers
What to promise to the sick?
- The primary goal of therapy is to prevent death and hospitalization. Functional class and exercise capacity may not improve
When to start treatment?
- Immediately after diagnosis and exclusion of contraindications
Doses of ACE inhibitors
- Start treatment with a low dose
- Double the dose every 2 weeks (accelerated dose titration is possible in patients with asymptomatic left ventricular dysfunction, mild heart failure, arterial hypertension and hospitalized patients)
- The dose should be increased to the target or maximum tolerated
Monitoring
- Clinical condition, blood pressure regularly during titration
- Kidney function: creatinine and serum potassium levels
- Inform the patient about the benefits of treatment
- Encourage him to report adverse events (dizziness, symptoms of hypotension, cough)
Problem Solving
Arterial hypotension- Assess the advisability of continuing the use of other drugs that lower blood pressure (nitrates, calcium antagonists, other vasodilators)
- If there is no fluid retention, discuss the possibility of reducing doses or discontinuing diuretics
- Reduce dose
- Rule out other causes of cough (lung and bronchial diseases, pulmonary edema)
- If the cough is very bothersome and reappears after temporary discontinuation and resumption of an ACE inhibitor, consider prescribing an angiotensin II receptor blocker
- At the beginning of treatment, there may be a slight increase in creatinine levels (within<3 мг/дл, или 266 мкмоль/л) и калия (<6 ммоль/л). Если эти изменения небольшие и не сопровождаются симптомами, то какиелибо действия не требуются. Продолжить наблюдение
- Discuss the possibility of discontinuing nephrotoxic drugs (NSAIDs), potassium supplements, and potassium-sparing diuretics. If there are no signs of blood stasis, reduce the dose of diuretics
- If creatinine/potassium levels remain high, reduce the dose of the ACE inhibitor by half. Repeat creatinine and potassium levels. Refer the patient for consultation with a specialist
Clinical effectiveness and practical application
ACE inhibitors are effective in many cardiovascular diseases, including chronic heart failure, asymptomatic left ventricular dysfunction, acute myocardial infarction, arterial hypertension, and in patients at high cardiovascular risk. The therapy is of particular benefit to these patients with diabetes mellitus. Therapy with ACE inhibitors should be monitored by blood pressure, renal function and serum potassium levels and should begin with a low dose and then gradually increase it, especially in patients with arterial hypotension or heart failure.
Heart failure
In the absence of contraindications, ACE inhibitors are used as first-line agents in patients with low left ventricular systolic function (ejection fraction less than 40-45%), with or without clinical signs of heart failure (Class I, Level of Evidence A) (Table 3 ) . The beneficial effects of ACE inhibitors include reductions in mortality, rehospitalization rates, and progression of heart failure observed in men and women, blacks and whites, and patients with and without diabetes, although treatment benefits were less in women. Doses of ACE inhibitors should not be titrated based on symptomatic effect, but should be increased to target doses, the effectiveness of which has been confirmed in large controlled trials in patients with heart failure and left ventricular dysfunction (Class I, Level of Evidence A) (Table 4). Although the entire class of ACE inhibitors is effective in heart failure, not all of them have been studied in this condition, and adequate doses are not known in all cases.
The CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) and SOLVD studies showed that ACE inhibitors increase survival in patients with chronic heart failure of any severity (NYHA functional classes I-IV). In patients with clinical signs of heart failure, both the incidence of sudden death and mortality from progressive heart failure are reduced. In the CONSENSUS study, patients with functional class IV were followed for an average of 188 days. When treated with an ACE inhibitor (enalapril), mortality at 6 months was significantly reduced (26 vs. 44%). In the SOLVD study, patients with functional classes II-III were observed for an average of 3.45 years. Overall mortality was 39.7% in the placebo group and 35.2% in the study group. The reduction in mortality was 45 per 1000 patients treated, and the number needed to treat for 1 year to prevent one death at 3.5 years (NNT) was 22. In large studies, ACE inhibitors reduced the incidence of hospitalization (for any reasons and especially regarding the progression of heart failure). For example, in the SOLVD study, the number of patients needed to be treated to prevent one hospitalization for heart failure and all causes at 3.5 years was 4.5 and 3.0, respectively.
The V-HeFT II (Vasodilator Heart Failure Trial) study compared the effectiveness of enalapril and the combination of hydralazine with isosorbide dinitrate in men with heart failure. After 2 years, mortality in the enalapril group was significantly lower than in the hydralazine/isosorbide dinitrate group (18 and 25%, respectively). The reduction in mortality in the enalapril group was associated with a reduction in the incidence of sudden death. This beneficial effect was greater in patients with less severe symptoms (functional classes I or II). At the same time, oxygen consumption at maximum exercise increased only during treatment with hydralazine and isosorbide dinitrate.
The AIRE (Acute Infarction Ramipril Efficacy) study examined the effectiveness of ramipril in patients with heart failure after a recent myocardial infarction (MI). A significant reduction in mortality was observed soon after the start of treatment.
Overall, there is strong evidence that ACE inhibitors improve survival, prevent progression of heart failure, and improve quality of life, although functional class reduction has not been demonstrated in all studies. In most placebo-controlled studies, ACE inhibitor therapy was associated with an increase in exercise capacity and a decrease in heart failure symptoms, but this effect was not always observed. This suggests that the beneficial effect of long-term ACE inhibitor therapy in heart failure may not be related to mechanisms that provide symptom control and increased exercise capacity.
Target dose
In the studies listed, ACE inhibitors were used in high doses (Table 4), although they varied significantly between patients. It should be emphasized that the regimen for using ACE inhibitors in clinical practice should correspond to that in large clinical trials. The large ATLAS (Assessment of Treatment with Lisinopril And Survival) study compared the results of treatment with an ACE inhibitor at low and high doses in patients with NYHA functional classes II-IV. Overall mortality did not differ between groups, but the incidence of the composite endpoint (death from any cause and hospitalization from any cause) was significantly lower in patients receiving the high dose drug, as was the total number of hospitalizations (24% reduction). For this reason, the high target doses of ACE inhibitors used in pivotal clinical trials are also recommended for routine clinical practice, although increasing the dose from moderate to high doses is likely to provide little benefit.
In the randomized NETWORK study, patients with functional class II-IV heart failure received enalapril in doses of 2.5 mg twice daily, 5 mg twice daily, or 10 mg twice daily. After 24 weeks, there was no relationship between the dose of the drug and the clinical results of treatment. Mortality in the 3 groups was 4.2, 3.3 and 2.9%, respectively (the difference is not significant). The incidence of the composite endpoint (death, heart failure-related hospitalization or progression) was also similar (1 2.3%, 1 2.9% and 14.7%, respectively).
In the ATLAS and NETWORK studies, there were no differences in the incidence of end points between treatment with ACE inhibitors at medium and high doses. Therefore, clinicians should try to increase doses of ACE inhibitors to target levels that have been demonstrated to be effective in appropriate clinical studies (if well tolerated). Practical recommendations for the use of ACE inhibitors in heart failure are given in Table. 4.
Comparison of ACE inhibitors with angiotensin II receptor blockers
Several studies have compared the clinical effectiveness of ACE inhibitors and angiotensin II receptor blockers. In most of them, receptor blockers had no advantage over ACE inhibitors. The ELITE-2 study included 3152 patients with chronic heart failure. Over an average of 555 days, mortality was comparable in the losartan and captopril groups (11.7 and 10.4%, respectively). The OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) study randomized 5447 patients with heart failure after myocardial infarction to receive losartan or captopril. Mortality after 2.7 years of follow-up was similar in the two groups (18 and 16%, respectively). The VALIANT (Valsartan in Acute Myocardial Infarction) trial randomized 15,703 patients with myocardial infarction complicated by left ventricular systolic dysfunction and/or heart failure to receive captopril, valsartan, or a combination of the two drugs. At 24.7 months, there were no differences in mortality or other outcomes between the three groups. In contrast, in the CHARM-added (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) trial, the addition of candesartan to an ACE inhibitor resulted in a clinically significant reduction in the incidence of cardiovascular events, although mortality did not change.
Given the lack of differences between ACE inhibitors and angiotensin II receptor blockers in the studies completed to date, ACE inhibitors should remain first-line drugs in patients with heart failure. Ongoing clinical trials in various subgroups of patients, as well as in patients with heart failure and preserved systolic function, will clarify the comparative role of the two groups of drugs in the treatment of heart failure.
A large study, OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events), compared the effectiveness of an ACE inhibitor and omapatrilat (an ACE inhibitor and neutral endopeptidase) in 5570 patients with chronic heart failure. At 14.5 months, there was no difference in the incidence of the composite primary endpoint (death or hospitalization for heart failure) between the two groups.
Asymptomatic left ventricular systolic dysfunction
Table 3. Use of ACE inhibitors in heart failure
Patients with asymptomatic left ventricular systolic dysfunction (ejection fraction less than 40-45%) should receive ACE inhibitors unless contraindicated (Class I, Level of Evidence A) (Table 3). One large trial (the prevention arm of SOLVD) randomized patients with low left ventricular ejection fraction (≤0.35) and no clinical signs of heart failure. They were prescribed placebo or enalapril. Most patients suffered from coronary heart disease and suffered an MI. After an average of 3.12 years, ACE inhibitor therapy reduced the risk of death or hospitalization for new or worsening heart failure from 24.5% to 20.6%. The reduction in the number of hospitalizations due to progression of heart failure was approximately 70 cases per 1000 patients treated (NNT for 3 years was 14). The risk of developing heart failure decreased from 38.6 to 29.8%, and the median time to the onset of symptoms of heart failure increased from 8.3 months in the placebo group to 22.3 months in the study group. There was no reduction in overall mortality or hospitalization for any cause with treatment with an ACE inhibitor. However, recently Jong et al. who continued the SOLVD-P study reported a significant reduction in mortality (50.9 vs. 56.4%) over 11.3 years in patients in the study group. Of interest is the fact that enalapril significantly reduced the incidence of diabetes mellitus in patients with left ventricular dysfunction, especially in the presence of impaired fasting glycemia.
The effectiveness of ACE inhibitors in patients with left ventricular dysfunction after myocardial infarction was studied in two large studies - SAVE (Survival And Ventricular Enlargement) and TRACE (Trandolapril Cardiac Evaluation). Treatment with captopril and trandolapril resulted in a reduction in mortality and readmission rates.
Diastolic heart failure
The treatment of diastolic heart failure remains controversial, mainly due to a lack of research. ACE inhibitors can improve cardiac relaxation and compliance, and also suppress neurohumoral activation and cause regression of left ventricular hypertrophy with long-term treatment. Accordingly, ACE inhibitors are recommended for the treatment of heart failure in patients with preserved left ventricular systolic function (class Pa, level of evidence C) (Table 3).
An alternative is likely to be angiotensin II receptor blockers, as evidenced by the effectiveness of candesartan in this sample demonstrated in the CHARM-preserved trial. In any case, the role of various treatments for diastolic heart failure requires further study.
Acute myocardial infarction
Oral use of ACE inhibitors within 36 hours of acute myocardial infarction is beneficial (Class Ha, Level of Evidence A), especially in the presence of left ventricular anterior wall infarction, reduced ejection fraction, and mild to moderate heart failure (Class I, Level of Evidence A) (Table 5) . After acute myocardial infarction, patients with clinical signs of heart failure or asymptomatic left ventricular dysfunction should receive long-term therapy with ACE inhibitors (Class I, Level of Evidence A). Therapy is also indicated for high-risk patients and patients with diabetes mellitus (Class I, Level of Evidence A) (Table 5). The benefit of ACE inhibitors after acute MI appears to be greatest in patients with diabetes.
Table 5. Use of ACE inhibitors in myocardial infarction
Depending on the timing of ACE inhibitor administration after acute MI, large studies can be divided into 2 groups (early and late intervention). Several short-term studies that suggested early initiation of ACE inhibitors included any patient with acute MI: CONSENSUS-2 (2nd Cooperative New Scandinavian Enalapril Survival Study), ISIS 4 (4th International Study of Infarct Survival), GISSI-3 (the 3rd Study of the Gruppo Italiano per lo Studio della Sopravivenza), CCS-1 (The 1st Chinese Cardiac Study). Other randomized trials, on the contrary, included high-risk patients, and treatment was started later and continued for a longer period: SAVE (Survival and Ventricular Enlargement), AIRE (Acute Infarction Ramipril Efficacy) and TRACE (Trandolapril Cardiac Evaluation). These studies included patients with clinical signs of heart failure (AIRE) or left ventricular systolic dysfunction (SAVE, TRACE). In both types of studies, ACE inhibitors have been shown to reduce mortality after acute myocardial infarction.
Prescription of ACE inhibitors in the early stages after myocardial infarction (<24-36 ч) оказывало небольшое влияние на смертность, что, вероятно, отражало более низкий сердечно-сосудистый риску пациентов, включенных в эти исследования, и короткую продолжительность лечения. Клиническая значимость достигнутого эффекта была спорной, что позволяет подвергнуть сомнению целесообразность применения ингибиторов АПФ у пациентов группы низкого риска.
In the ISIS 4 study, captopril or placebo was administered to 58,050 patients an average of 8 hours after the onset of symptoms of acute myocardial infarction. At 5 weeks, mortality was slightly but significantly lower in the captopril group (7.2 and 7.7%, respectively). The absolute difference was 4.9 deaths per 1000 patients over 1 month. The beneficial effect of the drug was maintained for at least 1 year (difference of 5.4 deaths per 1000 patients). After 1 month the difference was small and statistically insignificant. The absolute benefit of treatment was greater in certain high-risk subgroups, such as patients with a history of myocardial infarction (difference of 18 deaths per 1000 patients), patients with clinical evidence of heart failure (difference of 14 deaths per 1000 patients) and anterior wall infarction left ventricle. In contrast, in patients with other infarct locations, no benefit from captopril therapy was found. The rates of recurrent myocardial infarction, post-infarction angina, cardiogenic shock, and stroke were similar in the two groups. Captopril therapy was accompanied by an increase in the incidence of arterial hypotension, which required discontinuation of treatment (10.3 and 4.8%, respectively).
The GISSI-3 study included 19,394 patients who were assigned to receive lisinopril or placebo. After 6 weeks, mortality was lower in the lisinopril group (6.3 and 7.1%, respectively). This difference persisted after 6 months. The incidence of recurrent myocardial infarction, post-infarction angina, cardiogenic shock and stroke did not differ between the lisinopril and placebo groups.
The CCS-1 study randomized 13,634 patients with acute myocardial infarction to receive captopril or placebo. In the main group, a trend towards a decrease in mortality after 35 days was revealed (9.1 and 9.6%, respectively; the difference is not significant).
In the CONSENSUS-2 study, 6090 randomized patients received enalapril or placebo within 24 hours of acute MI. Therapy began with an intravenous infusion of enalapril, after which the patients continued taking the drug orally. After 1 and 6 months, mortality in the two groups did not differ significantly (6.3 and 10.2% in the placebo group and 7.2 and 11.0% in the enalapril group, respectively). Arterial hypotension in the early stages was observed in 12% of patients in the enalapril group and 3% of patients in the placebo group. It was concluded that enalapril therapy initiated within 24 hours of acute MI does not improve survival over the next 180 days.
Finally, the SMILE (Survival of Myocardial Infarction Long Term Evaluation) study enrolled 1,556 patients within 24 hours of the onset of symptoms of acute myocardial infarction (they did not receive thrombolysis). Patients were prescribed zofenopril or placebo. The incidence of death or severe heart failure at 6 weeks was significantly lower in the zofenopril group (7.1% and 10.6%, respectively). An insignificant reduction in mortality was also noted, but after 1 year it was significantly lower in the zofenopril group (10.0 and 14.1%).
A meta-analysis of the results of treatment with ACE inhibitors in more than 100,000 patients with myocardial infarction revealed a decrease in mortality within 30 days from 7.6% in the placebo group to 7.1%. The difference between the groups was 5 cases per 1000 patients receiving an ACE inhibitor for 4-6 weeks (NNT=200). The beneficial effect was more pronounced (up to 10 per 1000) in high-risk groups, such as patients with heart failure or myocardial infarction of the anterior wall of the left ventricle. In contrast, the effect was absent in low-risk patients, including patients with inferior wall MI who did not suffer from heart failure. In patients with diabetes mellitus, only a trend towards a decrease in mortality was revealed. ACE inhibitors also reduced the incidence of nonfatal heart failure (14.6 and 15.2%, respectively), but did not affect the risk of recurrent myocardial infarction or stroke. Therapy with drugs of this group was accompanied by an increase in the incidence of persistent hypotension (17.6 and 9.3%) and renal dysfunction (1.3 and 0.6%).
The results of the analysis showed that the beneficial effect manifested itself mainly during the first week: early administration of ACE inhibitors saved the lives of 239 patients, including 200 patients during the first week after MI. These data suggest that ACE inhibitors can be used in the acute phase of myocardial infarction, but only in high-risk patients. When using them, intravenous administration of enalapril should be avoided and treatment should begin with a low dose, which is gradually increased over 48 hours under the monitoring of blood pressure and renal function.
Late intervention. These studies demonstrated greater benefit from ACE inhibitor therapy when administered to selected high-risk patients later (more than 48 hours) after MI and continued for a long time.
The SAVE study included 2230 patients with left ventricular ejection fraction less than 40%. They were randomized to receive captopril or placebo for 3–16 days after MI. At 42 months, mortality was lower in the captopril group (20 and 25%, respectively). In addition, treatment with captopril resulted in a reduction in the incidence of fatal and nonfatal cardiovascular events, including heart failure, hospitalization, and recurrent myocardial infarction. The beneficial effect was independent of thrombolytic therapy and treatment with aspirin or β-blockers.
The TRACE study enrolled 1,749 patients with left ventricular systolic dysfunction (ejection fraction <35%) with or without overt heart failure who were assigned to trandolapril or placebo 3 to 7 days after myocardial infarction. Over 24–50 months, mortality was lower in the trandolapril group (34.7% and 42.3%, respectively; p<0,001). Терапия трандолаприлом привела также к снижению риска развития внезапной смерти и тяжелой сердечной недостаточности, но не влияла на риск повторного ИМ. Проанализированы отдаленные результаты лечения спустя 6 лет после его начала . Ожидаемая продолжительность жизни составила 4,6 года в группе плацебо и 6,2 года в группе трандолаприла. Таким образом, медиана продолжительности жизни у больных, получавших трандолаприл во время исследования, увеличилась на 15,3 мес (27%) Следовательно, лечение ингибитором АПФ в критический период ассоциируется с улучшением отдаленного прогноза.
In the AIRE study, 1986 patients with clinical signs of heart failure after acute MI were randomized to receive ramipril or placebo, given 3 to 10 days after MI. Patients were followed for at least 6 months (mean 15). Mortality was significantly reduced in the ramipril group (17 and 23%, respectively). The reduction in the incidence of the composite endpoint (death, severe/refractory heart failure, MI, or stroke) was also statistically significant. The beneficial effect appeared already in the first 30 days and was comparable in different samples of patients.
A meta-analysis of studies that suggested later initiation of ACE inhibitors found a reduction in mortality from 29.1 to 23.4% over an average of 2.6 years. The difference between the groups was 57 deaths per 1000 patients treated (NNT 18). Studies have also shown that ACE inhibitors reduce the risk of heart failure and the incidence of hospitalization for heart failure. When treated with ACE inhibitors, the risk of recurrent myocardial infarction decreased from 13.2 to 10.8%, and the risk of hospitalization for heart failure from 15.5 to 11.9%.
The study results have raised controversy over how ACE inhibitors should be used in patients with MI. Some authors suggested prescribing treatment to all patients and continuing it only if there are clinical signs of heart failure or left ventricular systolic dysfunction. According to other experts, the small benefit of early treatment was actually only seen in high-risk patients; Accordingly, they should be prescribed ACE inhibitors. In this case, therapy should be continued indefinitely. The HOPE (Heart Outcomes Protection Evaluation) and EUROPA (EURO-pean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease) studies put an end to these disputes, which demonstrated the benefits of using ACE inhibitors in patients with coronary atherosclerosis (or high-risk patients) ) (see secondary prevention).
Arterial hypertension
ACE inhibitors are indicated for the treatment of hypertension (Class I, Level of Evidence A) (Table 6). Current guidelines recommend lowering blood pressure to different levels depending on the risk profile (the higher the risk, the lower the target blood pressure). In patients with hypertension, the primary goal of treatment is blood pressure control, which can be achieved with a variety of medications that reduce the risk of cardiovascular complications with long-term therapy, including diuretics, beta-blockers, ACE inhibitors, calcium antagonists, and angiotensin II receptor blockers. . An adequate reduction in blood pressure can only be achieved using a combination of antihypertensive drugs. A number of large, long-term comparative studies have found no benefit to any particular treatment regimen. The results of these studies should be interpreted with caution as some of them lacked sufficient statistical power. In addition, small differences in blood pressure at the time of randomization could have a significant impact on long-term results, and the antihypertensive treatment regimen changes over the long term. Taking into account the results of these studies, as well as information obtained from other sources (for example, in patients with heart failure, MI, etc.), a specific drug should be selected individually. Thus, ACE inhibitors can be considered as first-line agents in patients with heart failure, left ventricular systolic dysfunction or diabetes mellitus, previous MI or stroke, as well as in patients at high risk of coronary heart disease, since the effectiveness of drugs in this group in these samples was confirmed in special studies (Table 6).
Table 6. Use of ACE inhibitors for arterial hypertension
In the STOP-2 study (Swedish Trial in Old Patients with hypertension), 6614 patients aged 70-84 years with arterial hypertension were randomized into two groups and received treatment with standard antihypertensive drugs (atenolol, metoprolol, pindolol or hydrochlorothiazide) or new drugs (enalapril , lisinopril, felodipine or isradipine). The reduction in blood pressure was similar in all groups. The incidence of the primary composite endpoint (fatal stroke and MI and other cardiovascular events) was comparable in the comparison groups. There were also no differences in the incidence of another combined endpoint (fatal and non-fatal stroke, fatal and non-fatal myocardial infarction, death from other cardiovascular complications).
One of the secondary objectives of the ABCD (Appropriate Blood Pressure Control Diabetes) study was to compare the effectiveness of nisoldipine and enalapril in preventing the development and progression of diabetic complications over 5 years in 470 patients. Using multiple regression analysis, nisoldipine therapy was shown to be associated with a higher incidence of fatal and nonfatal MI than enalapril treatment, but the number of such outcomes was too small to draw any conclusions. Mortality was similar in the two groups.
The CAPPP (The Captopril Prevention Project) study compared the effects of ACE inhibitors and standard therapy (diuretics, β-blockers) on cardiovascular morbidity and mortality in 10,985 patients with arterial hypertension. The two regimens did not differ in their effect on the risk of cardiovascular complications (a combination of myocardial infarction, stroke, and cardiovascular death), but the incidence of stroke was higher in the captopril group. At the same time, the incidence of diabetes decreased with captopril treatment. In a subgroup of patients with diabetes mellitus, an ACE inhibitor had advantages in the prevention of cardiovascular complications.
The randomized controlled trial UKPDS (The UK Prospective Diabetes Study) compared the effectiveness of an ACE inhibitor (captopril) and a β-blocker (atenolol) in patients with type 2 diabetes. Captopril and atenolol were equally effective in reducing blood pressure and the risk of macrovascular complications, including mortality, but the study was likely underpowered. Progression of retinopathy over the course of
9 years and the development of albuminuria was noted in the same percentage of patients in the two groups. The incidence of hypoglycemic reactions did not differ between groups. It was concluded that antihypertensive therapy with captopril and atenolol was equally effective in preventing diabetic complications. This study did not confirm any advantages or disadvantages of either of the two drugs. It can be assumed that lowering blood pressure itself is more important than the choice of a specific antihypertensive drug.
In the PROGRESS (Perindopril Protection against Recurrent Stroke Study) study, 6105 patients with and without hypertension who had suffered a stroke or transient ischemic attack were randomized into two groups and received active therapy (perindopril, to which indapamide was added if necessary) or placebo. The primary endpoint was any stroke. Over 4 years, active therapy resulted in a reduction in the incidence of stroke (10% and 14%, respectively) and the risk of any vascular complications. The reduction in stroke risk was comparable in patients with high and normal blood pressure. Combination therapy with perindopril and indapamide caused a more pronounced reduction in blood pressure and cardiovascular risk (43%) than perindopril monotherapy. However, the latter was also associated with a clinically significant reduction in the risk of stroke.
A meta-analysis of 4 placebo-controlled studies of ACE inhibitors (12,124 patients, mostly with coronary heart disease) found a reduction in the risk of stroke by 30%, coronary heart disease by 20%, and major cardiovascular outcomes by 21%. The results of antihypertensive therapy of varying intensity and the use of antihypertensive drugs of different classes are less convincing. When comparing treatment regimens with ACE inhibitors or diuretics/β-blockers, there was no difference in the incidence of endpoints. Only 2 studies directly compared regimens based on ACE inhibitors and calcium antagonists (STOP-2 and ABCD). When combining the results of the studies, a reduction in the risk of coronary heart disease was noted in patients receiving ACE inhibitors, but the incidence of stroke, cardiovascular and overall mortality did not differ significantly between the comparison groups. When analyzing the incidence of heart failure, a tendency was found to reduce the risk of its development with the use of ACE inhibitors.
Another meta-analysis included 9 randomized trials that compared “older” drugs (diuretics and β-blockers), calcium antagonists and ACE inhibitors in 62,605 patients with arterial hypertension. Outcome rates did not differ between groups.
The ANBP-2 (Australian national blood pressure study) study examined the results of treatment in 6083 patients with arterial hypertension who received an ACE inhibitor (enalapril) or a diuretic (hydrochlorothiazide). β-blockers, calcium antagonists, and α-blockers were added to treatment as needed in both groups. The reduction in blood pressure was comparable in the two groups, but after 4.1 years, the cumulative incidence of death and cardiovascular events was lower in the group of patients prescribed ACE inhibitors (56.1 and 59.8 per 1000 person-years), mainly for by reducing the incidence of myocardial infarction, while the incidence of stroke was comparable in the two groups.
Different results were obtained in the ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) study, which included 33,357 patients with arterial hypertension who had at least one other cardiovascular risk factor. Patients were divided into 3 groups and prescribed chlorthalidone, amlodipine or lisinopril. The primary endpoint was death from cardiovascular causes and nonfatal MI. Secondary endpoints included death from any cause, stroke, and various combinations of cardiovascular outcomes, including coronary revascularization, hospitalization for angina, heart failure, and peripheral arterial disease. The follow-up period was 4.9 years. There were no differences in the incidence of the primary endpoint between groups. Overall mortality was also similar in the lisinopril and chlorthalidone groups. The lisinopril group had a higher incidence of cardiovascular outcomes (33.3 and 30.9%, respectively), stroke (6.3 and 5.6%) and heart failure (8.7 and 7.7%), which makes it necessary to doubt the advisability of using ACE inhibitors as first-line agents in patients with arterial hypertension who are not at high risk and do not suffer from heart failure.
In general, it appears that the target BP or the degree of BP reduction is more important than the choice of a specific drug, although studies in patients with other cardiovascular diseases have demonstrated the benefits of ACE inhibitors in patients with heart failure, diabetes mellitus and patients at high cardiovascular risk .
Secondary prevention in high cardiovascular risk groups
Long-term therapy with ACE inhibitors in patients without heart failure is effective in the presence of cardiovascular disease or diabetes mellitus and certain other risk factors (Class I, Level of Evidence A) (Table 7). Several studies have examined the effectiveness of ACE inhibitors in patients with coronary heart disease who do not have congestive heart failure. In the PART-2 study in 600 patients with coronary, cerebral or peripheral artery disease, ramipril, compared with placebo, slightly reduced blood pressure (6 mm Hg) and left ventricular mass over 2 years, but did not affect the wall thickness of the common carotid artery and the incidence of major cardiovascular outcomes. These data suggest that the hypotensive effect of ACE inhibitors is more important than their other effects. The Quinapril Ischemic Event Trial (QUIET) assessed the incidence of cardiac endpoints during treatment with quinapril or placebo in patients with normal left ventricular function who underwent coronary angiography. Angiography did not reveal any differences in the progression of coronary atherosclerosis. The study, which included 1,750 patients without heart failure, was not statistically powered to detect a difference in clinical outcomes. The SCAT (Simvastatin/enalapril Coronary Atherosclerosis Trial) study examined the effects of a cholesterol-lowering drug (simvastatin) and an ACE inhibitor (enalapril) on coronary atherosclerosis in 460 patients with normal cholesterol levels. Enalapril did not differ from placebo in its effect on the severity of coronary lesions.
Table 7. Use of ACE inhibitors for secondary prevention
Several large multicenter studies tested the hypothesis that ACE inhibitors can reduce the risk of major cardiovascular outcomes in patients with coronary heart disease and damage to other vessels: HOPE (Heart Outcomes Prevention Evaluation Study), EUROPA (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease), PEACE (Prevention of Events with Angiotensin-Converting Enzyme Inhibition) and ONTARGET (telmisartan alone and in combination with ramipril global endpoint trial).
The HOPE study included 9297 men and women with documented atherosclerosis (coronary heart disease, peripheral artery disease, stroke) or diabetes and at least one other risk factor (hypertension, cigarette smoking, microalbuminuria, or dyslipidemia). 80% of patients had coronary heart disease, 55% had angina pectoris, 52% had a history of myocardial infarction, 43% had atherosclerosis of peripheral arteries, 25% had a history of unstable angina, 26% had a history of coronary artery bypass grafting, in 18% - percutaneous revascularization of the coronary arteries, in 11% - stroke or transient ischemic attack. Almost half of the patients suffered from arterial hypertension and about 40% from diabetes mellitus. Patients were prescribed placebo or an ACE inhibitor (ramipril) and were followed for an average of 5 years. The primary endpoint (cardiovascular death, MI, or stroke) was reported in 1.7.8% of patients in the placebo group and 14.0% of patients in the ramipril group (difference of 38 primary outcomes per 1000 patients treated; NNT at 5 years = 26.3). Ramipril treatment resulted in a reduction in all components of this endpoint, as well as various secondary endpoints, including all-cause mortality (from 12.2% to 10.4% over 5 years), need for revascularization, diabetic complications, development of diabetes mellitus, cardiac arrest, progression of angina or heart failure. It is of interest that the decrease in blood pressure in the ramipril group was relatively small (systolic blood pressure - 3.3 mm Hg), so the treatment results cannot be explained only by the antihypertensive effect of the drug.
Additional evidence of the effectiveness of long-term therapy with ACE inhibitors in secondary prevention comes from the results of the EUROPA study. It included 13,655 low-risk patients without heart failure who had stable coronary artery disease. They were treated with perindopril or placebo for an average of 4.2 years. Patients in the perindopril group showed a reduction in the incidence of cardiovascular outcomes (cardiovascular death, MI and sudden death) from 10 to 8% (this meant that to prevent one cardiovascular outcome it would be necessary to treat for 4.2 years in 50 sick). The benefit of the ACE inhibitor was comparable in all patient subgroups.
Combined with the results of studies in patients with heart failure and myocardial infarction, the HOPE and EUROPA studies convincingly demonstrated the overall protective effect of ACE inhibitors on blood vessels in patients with coronary heart disease and other forms of atherosclerosis. The PEACE trial is examining the effectiveness of an ACE inhibitor (trandolapril) in preventing cardiovascular outcomes in patients with established coronary artery disease and normal left ventricular systolic function. The ONTARGET trial compares inhibitor monotherapy
ACE (ramipril) and angiotensin II receptor blocker (telmisartan) and their combination. The results of these large ongoing studies will expand our understanding of treatment approaches for patients at high risk of atherosclerotic complications.
Prevention of sudden cardiac death
The use of ACE inhibitors for the prevention of sudden cardiac death in patients with left ventricular dysfunction or heart failure after myocardial infarction is considered a class I indication (level of evidence A) (Table 8). In patients with asymptomatic left ventricular dysfunction and moderate to severe heart failure, treatment with ACE inhibitors led to a reduction in the incidence of sudden death by 20-54%. In some studies in heart failure patients, this effect achieved statistical significance, although sudden cardiac death was not the primary endpoint.
Table 8. Use of ACE inhibitors for the prevention of sudden death
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In the treatment of arterial hypertension, ACE drugs occupy one of the leading positions. For more than 30 years, they have been actively used as an excellent alternative to diuretics, especially for people with diabetes, since they are much more effective in preventing complications. European studies have shown that such drugs, especially when combined with calcium antagonists, significantly reduce the risk of hospitalization and death due to any cardiovascular complications or heart failure.
What is the reason for the therapeutic effect?
Medicines can inhibit the synthesis in the kidneys of a hormone that causes a decrease in the lumen in blood vessels by blocking the angiotensin-converting enzyme. The latter, in turn, is responsible for the conversion of angiotensin I into the active angiotensin II, which causes vasoconstriction, increased peripheral resistance and impaired sodium metabolism in vascular smooth muscle cells, which generally increases blood pressure.
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Due to their effect, ACE inhibitors are able to reduce blood flow to the heart, which reduces the load on it, so they are used both for blood pressure and for many heart diseases, including myocardial infarction and heart failure. A course of treatment leads to a structural change in the wall of the arteries: their lumen increases and the hypertrophy of the muscular lining of the vessels undergoes reverse development.
Classification
ACE inhibitors are divided into natural and synthetic. Natural ones can appear as a result of the breakdown of whey and casein contained in dairy products and are formed naturally after their consumption. This type also includes hibiscus (hibiscus) tea. Synthetic ones, in turn, are divided into 3 groups, including:
- sulfhydryl groups;
- dicarboxylate;
- phosphonate
However, none of them has any significant advantages; they are absolutely identical in properties, have similar indications and contraindications. They are distinguished only by how they are distributed throughout the tissues and the methods of elimination from the body. Spirapril and fosinopril are excreted equally by the liver and kidneys, the remaining blockers are excreted in the urine. It follows that in case of kidney problems, the dose of such drugs should be reduced to the minimum.
Indications
The wide range of uses of ACE inhibitors allows them to be used for recovery after a heart attack. Most often, ACE inhibitors are prescribed for hypertension. Even using only these drugs in therapy, in most cases they easily lower blood pressure for any manifestations of hypertension. They are also able to slow down the development of vascular lesions in the kidneys and other complications of diabetes mellitus, if increased blood pressure is associated with this disease. In addition, ACE blockers are used for renal pathologies and normalize heart function. Medicines are used to restore the ability of the heart's left ventricle to pump out blood. This property is often used in heart failure and recovery after a heart attack.
If the patient is not found to be intolerant to beta-blockers, then ACE inhibitors are prescribed with them in complex therapy, which makes the treatment even more effective.
Contraindications
ACE inhibitors are strictly contraindicated for use during pregnancy and breastfeeding, since renal dysfunction is possible, excess potassium concentration in the blood serum is possible, there is a possibility of negative effects on the fetus, including miscarriage and intrauterine death, and the drug is excreted in breast milk. The use of inhibitors by children is not contraindicated, however, it should be noted that children are more sensitive to their effects, therefore, the risk of developing side effects increases. In addition, the use of such blockers is not recommended if:
- there is intolerance to ACE inhibitors;
- renal arteries are narrowed;
- increased potassium concentration in blood serum.
Side effects
The drug has a number of side effects that you need to pay attention to before use. In people with a lack of sodium or in those who have already been treated for arterial hypertension by other means, it is not uncommon to experience a significant and sustained decrease in blood pressure to a level below normal. In this case, taking the drugs begins with small doses. In addition, the following side effects are possible:
- rash and itching;
- cough;
- general weakness and dizziness (possible when combined with diuretics);
- taste disorders;
- excess potassium in the body:
- numbness of individual parts of the body;
- difficulty breathing;
- heaviness in the limbs;
- abnormal heartbeat rhythm;
- increased excitability of the nervous system;
- kidney dysfunction;
- swelling;
- decrease in the content of neutrophils in the blood;
- liver damage;
- stomach upsets.
Compatibility with other drugs
| Substance | Result of interaction |
| Antacids | Inhibitors are less easily absorbed by the body |
| Capsaicin | Increased cough as a side effect |
| Nonsteroidal anti-inflammatory drugs, estrogens | The hypotensive effect is reduced |
| Potassium preparations | Hyperkalemia develops |
| Diuretics | The effect of ACE inhibitors is potentiated |
| Hypothiazide, analgesics, antidepressants, anxiolytics, hypnotics | Antihypertensive effect is enhanced |
| Cytostatics, interferon, lithium preparations | Side effects increase |
| Theophylline | Reduced effect of theophylline |
| Alopurinol, immunosuppressants | The process of hematopoiesis in the body worsens |
| Insulin | Increases insulin sensitivity |
| Probenecid | The removal of captopril from the body is slowed down |
An integrated approach is practiced in the treatment of hypertension. Monotherapy is justified only in the initial stages of disease development. One of the first-line drugs is ACE inhibitors - drugs that act directly on adrenal hormones, which provoke an increase in blood pressure due to fluid retention in the body.
ACE inhibitors are medications that affect the angiotensin-converting enzyme. Under the influence of angiotensin, an increase in the production of aldesterone occurs, which entails an increase in vascular tone and fluid retention in the body, as a result of which blood pressure increases.
Angiotensin-converting enzyme inhibitors suppress the synthesis of specific hormones that cause the development of hypertension. Today, drugs in this group are prescribed to almost all patients in the absence of contraindications as a means of controlling blood pressure.
The mechanism of action of drugs in this group occurs in two stages. On the one side,
Drugs in this group are almost always included in the treatment regimen.
ACE inhibitors affect the synthesis of angiotensin, which increases vascular tone. Angiotensin, in turn, provokes increased production of aldesterone. This hormone is synthesized by the adrenal glands and causes fluid retention in the body in response to salt intake. Slowing down the production of aldesterone reduces swelling and reduces the pressure of blood on the walls of blood vessels, while a decrease in angiotensin leads to normalization of the frequency of contractions of the heart muscle and a decrease in vascular tone.
In addition, ACE inhibitors significantly increase the effectiveness of diuretics by reducing the synthesis of the hormone that causes edema. Thus, they are indicated as part of complex therapy for hypertension of degrees 2 and 3, but not as an independent remedy.
The mechanism of action of the latest generation of ACE inhibitors affects the normalization of the cardiovascular system, including the heart itself, and the urinary system. In addition, drugs in this group can reduce the risk of target organ damage when blood pressure rises above 180 mmHg.
Classification of drugs
ACE inhibitors are divided into synthetic and natural. The drugs used in the treatment of hypertension are specifically synthetic drugs. Natural inhibitors are released as a result of a specific reaction between whey and casein.
ACE inhibitors are divided into three groups, depending on the active substance. There are:
- drugs of the sulfhydryl group;
- drugs of the carboxyl group;
- phosphonate ACE inhibitors.
The mechanism of action of the drugs, regardless of the group, is absolutely the same. These drugs are complete analogues of each other, as they have the same effect on the cardiovascular system. The only difference between ACE inhibitors of different groups is the mechanism of elimination of the active substance after taking the tablet. This must be taken into account when prescribing medication to patients with renal failure.
Some ACE inhibitors are excreted by the kidneys, others are processed in the liver - this must be taken into account in case of pathologies of these organs
List of sulfhydryl group drugs
The list of ACE inhibitor drugs of the sulfhydryl group is quite wide, but the most commonly used are:
- captopril;
- benazepril;
- zofenopril.
One of the most popular and used drugs for the treatment of hypertension is captopril. The active substance has the following trade names - Captopril, Capoten, Bocordil.
The peculiarity of drugs in this group is the lack of prolonged action. The taken tablet is active for no more than six hours, so the medicine is taken 2-3 times a day. Drugs in this group are prescribed for arterial hypertension against the background of coronary heart disease, and are often combined with diuretics.
The advantage of drugs of the sulfhydryl group is that they are well tolerated by the body. They can be taken for diabetes and heart failure.
The recommended dosage of Captopril is up to 100 mg per day. It is taken an hour before meals, 1 or 2 tablets, depending on the amount of active ingredient in one tablet. When prescribing a medicine, it is taken into account that it is excreted by the kidneys, therefore, in case of renal failure, the drug is not prescribed.
Benazepril is taken a maximum of twice a day, since the active substance is released slowly. The recommended dosage regimen is one tablet in the morning and evening at regular intervals.
Zofenopril is also taken two tablets per day. Unlike other drugs of the sulfhydryl group, this medicine puts less strain on the kidneys, but in case of renal failure it can only be used under the supervision of a physician.
Captopril is among the most popular drugs
Medicines of the carboxyl group
ACE inhibitors of the carboxyl group are drugs with the following active ingredients:
- Quinapril;
- Renitek;
- Ramipril;
- Lisinopril.
The list of drugs in this group is very wide and includes more than 15 active ingredients. They all have a similar mechanism of action, contraindications and indications for use.
Features of drugs of the carboxyl group:
- prolonged action;
- pronounced vasodilating effect;
Metabolism of the active substance occurs mainly in the liver, which can significantly reduce the load on the kidneys. The drugs have a pronounced vasodilating effect, resulting in a rapid decrease in blood pressure. These properties of drugs of the carboxyl group should be taken into account when taken by patients with stage 3 hypertension. In this case, rapid normalization of blood pressure can negatively affect the functioning of the heart muscle.
Due to their prolonged action, such drugs are taken once a day. The release of the active substance occurs slowly, which allows for a long-lasting and sustainable therapeutic effect.
It is enough to take this medication once a day.
Preparations of the phosphinyl group
The third group of ACE inhibitor drugs includes two active ingredients - fosinopril and ceronapril. These drugs are intended to control morning surges in blood pressure due to hypertension, rather than for complex treatment. As an independent remedy, drugs of the phosphinyl group are not effective enough.
The peculiarity of the drugs is their prolonged action, which allows for control of blood pressure levels even during night rest. Metabolism of these drugs is carried out simultaneously in the kidneys and liver, which makes it possible to prescribe the drug for impaired renal function in older patients.
Another feature is a convenient dosage regimen. It is enough to take the drug only once a day in the morning to ensure a lasting therapeutic effect.
New generation combination drugs
Drugs of the third group belong to a new generation of drugs for hypertension, along with combination drugs.
Their advantages:
- prolonged action;
- ease of use;
- good tolerance;
- complex action.
Due to the peculiarities of the metabolism of the active substance, new generation drugs can be used to treat patients with renal failure and diabetes mellitus. This is very important, since hypertension is diagnosed mainly at older ages against the background of concomitant chronic diseases.
Combination drugs can be taken by hypertensive patients with diabetes mellitus
Combination medications include drugs containing calcium channel blockers and ACE inhibitors, or diuretics and ACE inhibitors. These medications are very convenient because you can take just one medication to control your blood pressure.
Combination of ACEI and diuretic:
- Capozide;
- Ramazid N;
- Phosicard N.
Such drugs have a more pronounced hypotensive effect and can be used as monotherapy for grade 1 and 2 hypertension. In addition, they are convenient to take - only 1 tablet per day to ensure a lasting therapeutic effect throughout the day.
In older age, there is a violation of the elasticity of large arteries. This is due to physiological changes against the background of constantly elevated blood pressure. When blood vessels lose flexibility and their permeability is impaired, treatment is carried out with combination medications that contain an ACE inhibitor and a calcium antagonist. List of such funds:
- Triapin;
- Tarka;
- Egipres;
- Coryprene.
In most cases, Coripren is prescribed. It is advisable to use such drugs for the treatment of hypertension in cases where other drugs, including ACE inhibitors as a stand-alone treatment, are ineffective. They are usually prescribed to patients over 65 years of age with an increased risk of blood clots and myocardial infarction.
Features of use for hypertension
ACE inhibitors are prescribed mainly for hypertension. However, this is not the only area of application of drugs - these are groups.
The peculiarity of drugs from the ACE inhibitor group is their positive effect on target organs. Taking such medications can minimize the risk of developing dangerous consequences such as stroke or myocardial infarction.
With grade 1 hypertension, there is a steady but slight increase in blood pressure, not higher than 140 mmHg. If the disease develops against the background of any chronic diseases and the cardiologist has reason to believe that the disease will progress rapidly, ACE inhibitors are prescribed as monotherapy. The combination of drugs in this group with diet, giving up bad habits and normalizing the daily routine allows for a sustainable reduction in blood pressure in half of the patients taking the medicine.
Stage 2 hypertension is characterized by a sustained increase in blood pressure up to 160 mmHg. and higher. This increases the risk of damage to any organ. Usually, vision is the first to suffer (angiopathy develops) or the kidneys. With such pressure, diet therapy and load reduction are no longer enough; it is necessary to take medications. In this case, drugs of the ACEI group pursue two goals - to achieve a sustainable reduction in blood pressure and to avoid the development of complications. Complex therapy is usually used, including a diuretic, calcium antagonists and ACE inhibitors. Timely treatment allows you to achieve a stable hypotensive effect in 70% of cases and prevent the development of dangerous complications.
With stage 3 hypertension, blood pressure rises above 160 mmHg. Taking diuretics and calcium antagonists as monotherapy shows poor results, so new generation combination drugs are used for treatment. The danger of grade 3 hypertension is the development of hypertensive crises, disruption of the functioning of two or more target organs (heart, kidneys, brain, organs of vision). Typically, severe hypertension occurs against the background of diabetes mellitus, vascular atherosclerosis or other chronic diseases. In this case, you must take the drugs for life.
In the initial stages of hypertension, ACE inhibitors are taken as the main drug, in later stages - as part of complex therapy
Use in heart failure
Indications for the use of ACE inhibitors include any form of heart failure. Drugs in this group help:
- Avoid progression of the disease;
- Reduce the load on blood vessels and the heart;
- Prevent the development of myocardial infarction.
The use of ACE inhibitors by patients with heart failure reduced the risk of sudden death as a result of cardiac arrest by 2.5 times. In addition, according to the patients themselves, drugs in this group significantly improve the quality of life with this diagnosis.
In case of heart failure, medications should be taken with caution. At the beginning of treatment, reduced dosages are indicated, no more than ¼ of the recommended amount given in the instructions. This precaution is due to the risk of a sudden decrease in blood pressure to critical values. As the body gets used to the drug, the dosage gradually increases, eventually reaching the recommended one.
In addition, drugs in this group can be used during the recovery period after a myocardial infarction.
ACEI for renal failure
In renal failure, ACEI drugs help reduce the rate of disease progression. They are prescribed, among other things, for impaired renal function due to diabetes mellitus. It is important to select a drug taking into account its metabolism and excretion from the body. To treat and control kidney function, drugs that are metabolized in the liver should be selected. This is an important condition for achieving a sustainable therapeutic effect.
In case of kidney damage, drugs are selected that are excreted by the liver
Contraindications
Only a doctor should prescribe drugs from the ACE inhibitor group, after collecting an anamnesis and a detailed examination of the patient. Before starting treatment, the patient is recommended to read the instructions for the drug again. The following diseases and conditions are contraindications:
- Rheumatoid arthritis;
- Lupus erythematosus;
- Pregnancy;
- Lactation period.
ACEI drugs should not be taken if you are hypersensitive. Special instructions may vary depending on the specific drug, so it is important to read the instructions carefully.
Taking medications from this group during pregnancy can cause fetal malformations that are incompatible with life.
Taking ACE inhibitors for hypotension is strictly contraindicated, otherwise there is a risk of developing coma due to a decrease in blood pressure to critical values.
Side effects
If the medicine is chosen correctly, the patient follows the doctor’s recommendations and does not exceed the dosage, the development of side effects is unlikely, since the drugs of the ACEI group are quite well tolerated by the body.
However, with hypersensitivity and violation of the dosage regimen, the development of undesirable effects may occur:
- hypotension;
- dry cough, difficult to treat;
- potassium retention in the body (hyperkalemia);
- formation of protein compounds in urine;
- renal dysfunction;
- release of glucose into urine;
- allergic rash and angioedema.
The most common side effect is a persistent cough.
The most common occurrence is a dry cough when taking medications of this group. This side effect occurs in approximately 1/5 of patients taking ACE inhibitors to control blood pressure. It is difficult to get rid of cough with the help of special medications, but it goes away on its own within a few days after stopping ACE inhibitors.
If you are hypersensitive to the drug, you may develop a severe allergic reaction and Quincke's edema. Such complications are very rare, but pose a serious danger not only to the health, but also to the life of the patient.
If blood pressure drops to dangerous levels and hypotension develops, you should consult your doctor about changing the drug regimen or reducing the dosage. Typically, this phenomenon occurs when taking too large doses of medication against the background of heart failure.
As a rule, all complications when taking ACE inhibitors are reversible or go away on their own after discontinuation of the drug. However, it is recommended that you tell your doctor about any changes in how you feel after starting a new medicine.
Drug interactions
Drugs used to treat gastritis and heartburn that have an enveloping effect (Maalox, Gaviscon) significantly reduce the absorption of inhibitors by the stomach, which reduces their bioavailability and therapeutic effect. When taking ACEIs concomitantly with such drugs, adjustments to the antihypertensive drug regimen may be necessary.
The hypertensive effect of ACE inhibitors is reduced when taken simultaneously with non-steroidal anti-inflammatory drugs (Ibuprofen, Nimesulide, Diclofenac). Simultaneous use of acetylsalicylic acid and ACE inhibitors reduces the effectiveness of the latter.
A complete list of drug interactions and important instructions is given in the instructions for use of the drug, which should be carefully studied before starting treatment.
If you need to increase or decrease the dosage of the medication you are taking, you should contact a cardiologist, but do not try to change the treatment regimen yourself. It is important to remember that any medications for the treatment of hypertension, if taken incorrectly, can lead to irreversible consequences, so you should trust your doctor, but do not try to treat the disease yourself.
