How should lisinopril be taken for optimal effectiveness. What is the recommended dosage for different conditions. When is the best time to take lisinopril. How can patients adjust their lisinopril dose safely.

Understanding Lisinopril: An Overview of the Medication

Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor widely prescribed for treating various cardiovascular conditions. It works by relaxing blood vessels, lowering blood pressure, and improving blood flow. Proper dosing and administration are crucial for maximizing its benefits while minimizing potential side effects.

Recommended Lisinopril Dosages for Different Conditions

The appropriate lisinopril dosage varies depending on the specific condition being treated. Here are the general guidelines for adult patients:

• Hypertension: Initial dose of 10 mg once daily, with a maintenance dose of 20-40 mg once daily
• Congestive Heart Failure: Initial dose of 2.5-5 mg once daily, with a target dose of 20-40 mg once daily
• Post-Myocardial Infarction: Initial dose of 5 mg within 24 hours of the heart attack, followed by 5 mg after 24 hours, then 10 mg once daily
• Diabetic Nephropathy: 10-20 mg once daily

It’s important to note that these are general guidelines, and your doctor will tailor the dosage to your specific needs based on factors such as blood pressure response, kidney function, and potential side effects.

Dosage Adjustments for Special Populations

Certain patient groups may require dosage adjustments:

• Elderly patients: Lower initial doses may be recommended due to potentially decreased kidney function
• Patients with kidney impairment: Dosage should be reduced based on creatinine clearance levels
• Pediatric patients: Dosing is based on body weight, typically starting at 0.07 mg/kg once daily (up to 5 mg total) and adjusted as needed

Timing and Administration: When and How to Take Lisinopril

Proper timing and administration of lisinopril can help maximize its effectiveness and minimize side effects. Here are some key points to remember:

• Take lisinopril once daily, at approximately the same time each day
• It can be taken with or without food
• Swallow the tablet whole with a glass of water
• For the initial dose, your doctor may recommend taking it before bedtime to minimize the risk of dizziness
• If using the liquid form, shake well before measuring the dose with the provided syringe or spoon

Consistency in timing and administration can help maintain steady blood levels of the medication and optimize its effects on blood pressure control.

Potential Side Effects and Precautions

While lisinopril is generally well-tolerated, it’s essential to be aware of potential side effects and take necessary precautions:

• Common side effects may include dizziness, headache, cough, and fatigue
• More serious side effects, though rare, can include allergic reactions, kidney problems, or high potassium levels
• Avoid taking potassium supplements or salt substitutes containing potassium without consulting your doctor
• Inform your healthcare provider of all medications you’re taking, as some may interact with lisinopril
• If you become pregnant while taking lisinopril, contact your doctor immediately, as it can harm the developing fetus

Regular monitoring of blood pressure, kidney function, and potassium levels is important for patients taking lisinopril.

Managing Missed Doses and Overdose Situations

Adhering to the prescribed dosing schedule is crucial, but mistakes can happen. Here’s what to do in case of missed doses or potential overdose:

Missed Doses

If you forget to take a dose of lisinopril:

• Take it as soon as you remember, unless it’s almost time for your next scheduled dose
• If it’s close to your next dose, skip the missed dose and continue with your regular schedule
• Never take a double dose to make up for a missed one

Overdose Concerns

Taking more than the prescribed dose of lisinopril can lead to symptoms such as severe dizziness, fainting, or unusually slow or fast heartbeat. If you suspect an overdose:

• Seek immediate medical attention or contact a poison control center
• Provide information about the amount taken and when
• Bring the medication container or packaging with you to the healthcare facility

Long-Term Use and Monitoring

For many conditions, lisinopril is prescribed as a long-term medication. To ensure continued effectiveness and safety:

• Attend regular check-ups with your healthcare provider
• Monitor your blood pressure at home if recommended by your doctor
• Undergo periodic blood tests to check kidney function and potassium levels
• Report any new or worsening side effects promptly
• Discuss any concerns or questions about your medication regimen with your healthcare team

Long-term adherence to your prescribed lisinopril regimen, combined with lifestyle modifications, can help effectively manage your condition and reduce cardiovascular risks.

Lisinopril and Lifestyle Considerations

While taking lisinopril, certain lifestyle factors can impact its effectiveness and your overall health:

Diet and Nutrition

Pay attention to your diet while on lisinopril:

• Maintain a low-sodium diet to support blood pressure control
• Avoid excessive consumption of high-potassium foods unless directed by your doctor
• Stay well-hydrated, but consult your healthcare provider about appropriate fluid intake if you have heart failure

Exercise and Physical Activity

Regular physical activity can complement the effects of lisinopril:

• Engage in moderate aerobic exercise for at least 150 minutes per week, as tolerated
• Start slowly and gradually increase intensity if you’re new to exercise
• Be aware that lisinopril may cause dizziness, especially when starting or increasing doses, so exercise caution during physical activities

Alcohol and Smoking

Consider the following regarding alcohol and tobacco use:

• Limit alcohol consumption, as it can enhance the blood pressure-lowering effect of lisinopril and increase the risk of dizziness
• If you smoke, consider quitting or reducing tobacco use, as smoking can counteract some of the cardiovascular benefits of lisinopril

Adopting a heart-healthy lifestyle in conjunction with lisinopril therapy can significantly improve your overall cardiovascular health and quality of life.

Interactions with Other Medications and Supplements

Lisinopril can interact with various medications and supplements, potentially affecting its efficacy or increasing the risk of side effects. Be aware of the following:

Medications to Use with Caution

• Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or naproxen
• Potassium-sparing diuretics
• Lithium
• Other blood pressure medications

Supplements and Over-the-Counter Products

Exercise caution with:

• Potassium supplements
• Salt substitutes containing potassium
• Herbal products that may affect blood pressure

Always inform your healthcare provider about all medications, supplements, and over-the-counter products you’re taking to avoid potential interactions.

Special Considerations for Specific Patient Groups

Certain patient populations may require special attention when taking lisinopril:

Elderly Patients

• May be more sensitive to the effects of lisinopril
• May require lower initial doses and more gradual dose increases
• Should be monitored closely for side effects and efficacy

Patients with Kidney Disease

• May need dosage adjustments based on kidney function
• Require regular monitoring of kidney function and potassium levels
• Should be aware of the increased risk of hyperkalemia (high potassium levels)

Diabetic Patients

• May benefit from lisinopril’s protective effects on kidney function
• Should monitor blood sugar levels closely, as lisinopril can potentially affect glucose control
• Need to be aware of the risk of hyperkalemia, especially if also taking diabetes medications

Pregnant and Breastfeeding Women

• Should not take lisinopril during pregnancy due to the risk of fetal harm
• Should discuss alternative blood pressure management strategies with their healthcare provider if planning to become pregnant
• Should avoid lisinopril while breastfeeding, as it can pass into breast milk

These special considerations highlight the importance of individualized treatment plans and close monitoring for patients with specific health conditions or in certain life stages.

How and when to take lisinopril

Always follow your doctor’s advice, and the instructions that come with your medicine.

Dosage

The dose of lisinopril you take depends on why you need the medicine. Take it how your doctor tells you to.

To decide your dose, your doctor will check your blood pressure and ask you if you’re getting any side effects from your medicine.

You may also have blood tests to check how well your kidneys are working and the amount of potassium in your blood.

Depending on why you’re taking lisinopril, the usual starting dose for adults is between 2.5mg and 10mg, once a day.

This will be increased gradually over a few weeks to the usual dose for your condition:

• high blood pressure – 20mg once a day (the maximum dose is 80mg once a day)
• after a recent heart attack – 10mg once a day
• heart failure – 5mg to 35mg once a day
• diabetic kidney disease – 10mg to 20mg once a day

Doses are usually lower for children. The doctor will work out the right dose based on your child’s age, weight and why they need this medicine.

Your child will usually start on a low dose of lisinopril. This dose may gradually increase depending on your child’s blood pressure and other symptoms.

How to take it

You’ll usually take lisinopril once a day.

Your doctor may suggest that you take your first dose before bedtime because it can make you dizzy.

After the very first dose, you can take lisinopril at any time of day. Try to take it at the same time every day.

You can take lisinopril with or without food. Swallow lisinopril tablets whole with a drink of water.

If you’re taking lisinopril as a liquid, it will come with a plastic syringe or spoon to help you measure out the right dose. If you do not have one, ask your pharmacist for one. Do not use a kitchen teaspoon as it will not measure the right amount of medicine.

Changes to your dose

You’ll probably be prescribed a low dose of lisinopril at first so it does not make you feel dizzy.

This will usually be increased gradually until you reach the right dose for you.

Speak to your pharmacist or doctor about your dose if you’re worried about side effects of lisinopril.

How long to take it for

After a heart attack, you usually take lisinopril for 6 weeks. Your doctor will then decide if you need to keep taking it for longer.

For high blood pressure, heart failure and diabetic kidney disease, treatment with lisinopril is usually long term, even for the rest of your life.

Important

Take lisinopril even if you feel well, as you’ll still be getting the benefits of the medicine.

If you get ill while taking it

Contact your doctor if you get ill, such as a high temperature, sweats and shaking or severe diarrhoea or vomiting. Your doctor may advise you to stop taking lisinopril until you recover and are eating and drinking normally.

If you forget to take it

If you miss a dose of lisinopril, take it as soon as you remember. If you do not remember until the following day, skip the missed dose and take your next dose at the usual time.

Do not take a double dose to make up for a forgotten one.

If you forget doses often, it may help to set an alarm to remind you. You could also ask your pharmacist for advice on other ways to help you remember to take your medicine.

If you take too much

Taking more than your prescribed dose of lisinopril can make you feel dizzy, sleepy and give you a pounding heartbeat (heart palpitations).

The amount of lisinopril that can lead to an overdose varies from person to person.

Urgent advice: Contact 111 for advice now if:

• you take more than your prescribed dose of lisinopril

Go to 111.nhs.uk or call 111

If you need to go to A&E, do not drive yourself. Get someone else to drive you or call for an ambulance.

Take the lisinopril packet or leaflet inside it, plus any remaining medicine, with you.

Page last reviewed: 17 December 2021

Next review due: 17 December 2024

Lisinopril Dosage Guide + Max Dose, Adjustments

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Medically reviewed by Drugs.com. Last updated on Apr 24, 2023.

Applies to the following strengths: 2. 5 mg; 5 mg; 10 mg; 20 mg; 40 mg; 30 mg; 1 mg/mL

Usual Adult Dose for:

• Hypertension
• Congestive Heart Failure
• Myocardial Infarction
• Diabetic Nephropathy

Usual Geriatric Dose for:

• Hypertension

Usual Pediatric Dose for:

• Hypertension

Additional dosage information:

• Renal Dose Adjustments
• Liver Dose Adjustments
• Dose Adjustments
• Precautions
• Dialysis
• Other Comments

Usual Adult Dose for Hypertension

Initial dose: 10 mg orally once a day; 5 mg orally once a day
Maintenance dose: 20 to 40 mg orally once a day
Maximum dose: 80 mg orally once a day

Comments:

• The initial dose is 5 mg orally once a day in patients receiving a diuretic.
• The 80 mg dose is used but does not appear to give greater effect.
• If blood pressure is not controlled with lisinopril alone, a low dose of a diuretic may be added (e. g., hydrochlorothiazide, 12.5 mg). After the addition of a diuretic, it may be possible to reduce the dose of lisinopril.

Usual Adult Dose for Congestive Heart Failure

Initial dose: 2.5 to 5 mg orally once a day
Maintenance dose: Dosage should be increased as tolerated
Maximum dose: 40 mg orally once a day

Comments:

• The diuretic dose may need to be adjusted to help minimize hypovolemia, which may contribute to hypotension. The appearance of hypotension after the initial dose of lisinopril does not preclude subsequent careful dose titration with the drug.

Usual Adult Dose for Myocardial Infarction

Initial dose: 5 mg orally (within 24 hours of the onset of acute myocardial infarction)
Subsequent doses: 5 mg orally after 24 hours, then 10 mg orally after 48 hours.
Maintenance dose: 10 mg orally once a day. Dosing should continue for at least 6 weeks.

Comments:

• Therapy should be initiated at 2. 5 mg in patients with a low systolic blood pressure (less than or equal to 120 mm Hg and greater than 100 mmHg) during the first 3 days after the infarct. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour) therapy should be withdrawn.

Uses: Reduction of mortality in acute myocardial infarction

Usual Adult Dose for Diabetic Nephropathy

Initial dose: 10 to 20 mg orally once a day
Maintenance dose: 20 to 40 mg orally once a day
Dosage may be titrated upward every 3 days

Comments:

• Not an approved indication.

Usual Geriatric Dose for Hypertension

Initial dose: 2.5 to 5 mg orally once a day
Maintenance dose: Dosages should be increased at 2.5 mg to 5 mg per day at 1 to 2 week intervals.
Maximum dose: 40 mg orally once a day

Usual Pediatric Dose for Hypertension

Pediatric patients greater than or equal to 6 years of age:
Initial dose: 0. 07 mg/kg orally once a day (Maximum initial dose is 5 mg once a day)
Maintenance dose: Dosage should be adjusted according to blood pressure response at 1 to 2 week intervals.
Maximum dose: Doses above 0.61 mg/kg or greater than 40 mg have not been studied in pediatric patients

Comments:

• This drug is not recommended in pediatric patients less than 6 years old or in pediatric patients with glomerular filtration rate less than 30 mL/min.

Renal Dose Adjustments

CrCl greater than 30 mL/min: No adjustment recommended
CrCl 10 mL/min to less than or equal to 30 mL/min: Recommended initial dose is half of the usual recommended dose (i.e., hypertension, 5 mg; systolic heart failure, 2.5 mg, and acute MI, 2.5 mg. Up titrate as tolerated to a maximum of 40 mg daily)
CrCl less than 10 mL/min or on hemodialysis: Recommended initial dose is 2.5 mg orally once a day

Liver Dose Adjustments

Patients who develop jaundice or marked elevations of hepatic enzymes should discontinue therapy and receive appropriate medical treatment.

Dose Adjustments

• The antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered dose, but most commonly with a dose of 10 mg or less daily. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, an increase in dose should be considered. If blood pressure is not adequately controlled with lisinopril alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of lisinopril.
• In all high risk patients, such as patients with ischemic heart or cerebrovascular disease, in whom excessive falls in blood pressure may lead to myocardial infarction or cerebrovascular accident the manufacturer advises treatment initiation at lower dosages.
• Dosage adjustments in the elderly should be made with particular caution.
• In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy. Then, if blood pressure is not controlled with lisinopril alone, diuretic therapy should be resumed. If diuretic therapy cannot be discontinued, an initial dose of 5 mg should be used with careful medical supervision for several hours and until blood pressure has stabilized.

Precautions

US BOXED WARNINGS:

• FETAL TOXICITY: Angiotensin converting enzyme (ACE) inhibitor use during pregnancy can cause morbidity and death to the developing fetus. When used during the second and third trimesters, ACE inhibitors have been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Exposure to ACE inhibitors during the first trimester of pregnancy has been associated with prematurity, intrauterine growth retardation, patent ductus arteriosus, other structural cardiac malformations, and neurological malformations. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. If no alternative to ACE inhibitor therapy is available, patients should be made aware of the risks to their fetuses and the intra-amniotic environment should be evaluated by serial ultrasound examinations. If oligohydramnios develops, this drug should be discontinued unless it is considered lifesaving for the mother. Depending on the week of pregnancy, contraction stress testing, a nonstress test, or biophysical profiling may be appropriate. Oligohydramnios may not show until after the fetus has suffered irreversible injury.

Safety and efficacy have not been established in patients younger than 6 years.

Consult WARNINGS section for additional precautions.

Dialysis

This drug can be removed by hemodialysis.

Other Comments

Administration advice:

• Should be given as a single daily dose.
• May be given with or without food.
• In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with this drug. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of may be necessary.

General:

• This drug is indicated as adjunctive therapy with diuretics and digitalis for treating heart failure.
• Following first time MI, all ACE inhibitors, at comparable appropriate dosages, appear to be equally effective for reducing mortality and recurrent MI rates.
• Prior to therapy, patients at high risk of symptomatic hypotension such as patients with salt depletion with or without hyponatremia, hypovolemia or those receiving vigorous diuretic therapy should have these conditions corrected. Renal function and serum potassium should be monitored.
• If it is not feasible to discontinue diuretic therapy prior to starting lisinopril, the patient should be closely monitored for several hours following the initial dose of this drug, and until the blood pressure has stabilized. The antihypertensive effects of lisinopril and diuretics used in combination are approximately additive.
• Achievement of optimal blood pressure reduction may require 2 to 4 weeks of therapy.
• Acute myocardial infarction: in addition to this drug, patients should receive, if appropriate, standard treatments, such as thrombolytics, aspirin, and a beta-blocker.
• Antihypertensive effects of this drug are maintained during long-term therapy. Abrupt withdrawal has not been associated with a rapid increase in blood pressure, or a significant increase in blood pressure compared to pretreatment levels.

Patient advice:

• This drug may be taken with or without food, but should be taken at the same time each day.
• This drug may impair your ability to drive or operate machinery.

Frequently asked questions

• How long after taking 5 mg lisinopril will my blood pressure drop down?
• Does lisinopril cause weight gain?
• Do ACE inhibitors make COVID-19 worse?
• Can I just stop taking lisinopril?
• What is the strength of Qbrelis (lisinopril) oral solution?

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Related treatment guides

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Medical Disclaimer

Clinical efficacy of lisinopril in diabetic nephropathy | Shestakova M.V., Vikulova O.K.

The renin-angiotensin system (RAS) has traditionally been considered the main regulatory mechanism that maintains blood pressure and circulating blood volume. The classical position that the RAS activity is reduced in diabetes mellitus contributed to the formation of an erroneous opinion about the insignificant role of this system in the pathogenesis of diabetic nephropathy. However, recent research has radically changed our understanding. Rethinking the significance of this system in the formation of diabetic microangiopathies is associated with the detection of local tissue RAS – in the tissue of the kidneys, heart, brain, adrenal glands and vascular endothelium.

The endothelium is an insulin-independent tissue of the body [1], and therefore, under conditions of hyperglycemia, glucose can easily penetrate into endothelial cells, triggering pathological biochemical reactions (processes of non-enzymatic glycosylation of proteins, hyperproduction of free radicals), resulting in endothelial dysfunction [2–4]. Chronic hyperactivation of the RAS is the most important factor in endothelial dysfunction. This is due to the fact that the main part of the key enzyme of this system, angiotensin-converting enzyme (ACE), is located directly on the membrane of endothelial cells [5]. An increase in the activity of local RAS organs and tissues, which include the kidneys and vascular endothelium, leads to hyperproduction of angiotensin II, a powerful mediator of the progression of kidney pathology [5].
The mechanism of the pathogenic effect of angiotensin II is due not only to active vasoconstrictor action leading to the formation of intraglomerular and systemic hypertension, but also to proliferative, prooxidant and proaggregant activity. It has been established that angiotensin II promotes the activation of growth factors, such as transforming growth factor b (TGF-b), platelet growth factor (PDGF) [6], and also increases the expression of their receptors [7]. It has been shown that under conditions of hyperglycemia TGF-b is involved in excessive synthesis of the substance of the mesangial matrix, causes hypertrophy of mesangial cells and tubular cells, and accelerates apoptosis of renal cells [8]. It is these processes that underlie the development of glomerulosclerosis [7,8].
Another mechanism is associated with the kininase activity of ACE. This enzyme catalyzes the breakdown of bradykinin with the development of its relative deficiency [9]. In turn, the lack of adequate stimulation of bradykinin B2 receptors leads to a decrease in the synthesis of nitric oxide (NO) and an increase in the tone of vascular smooth muscle cells [10].
In addition, angiotensin II is a stimulator of the formation of free radicals, in particular, superoxide anions, which inactivate nitric oxide [11]. NO has a vasodilating and antiproliferative effect, inhibits the production of adhesion molecules and the adhesion of macrophages and platelets, blocks the synthesis of endothelin, that is, it is a “biological vasoprotector” that is opposite in its action to angiotensin II [10,12–13].
Thus, the polyfunctional factor – angiotensin II – is at the center of a complex of interrelated relationships of several groups of tissue regulators: kinins, growth factors, nitric oxide, the interaction of which leads to the activation of tissue remodeling and the acceleration of the development of glomerulosclerosis. The RAS plays a key role in closing the vicious circle: hyperglycemia – endothelial dysfunction – activation of tissue RAS – NO / A-II imbalance – development of microangiopathy.
The leading pathogenetic significance of RAS in the formation of diabetic microangiopathies, in particular, nephropathy (DN), has become the basis for the widespread use of drugs that block this system for the treatment of diabetic kidney pathology. Over the past years, ACE inhibitors have proven to be the drugs of choice for the treatment of DN and arterial hypertension in patients with diabetes mellitus due to their specific nephroprotective properties independent of hemodynamic action.
Under nephroprotection is meant therapeutic effects aimed at preventing the development and / or slowing down the rate of progression of an already developed kidney pathology. Thus, the end points of nephroprotective therapy are a decrease in the level of albuminuria (AU) and the maintenance of a stable glomerular filtration rate (GFR).
Lisinopril is one of the drugs in the ACE inhibitor group that has shown its effectiveness in diabetic kidney disease from the standpoint of evidence-based medicine. In Russia, lisinopril is registered and used under the trade name Diroton® (“Gedeon Richter” A.O., Hungary) in tablets of 2.5, 5, 10 and 20 mg.
Pharmacokinetics of lisinopril
The drug is not subject to first pass metabolism. Peak plasma concentration (Cmax) occurs after 6 hours. Bioavailability varies from 25 to 50%. Eating does not affect the bioavailability of the drug. Does not bind to plasma proteins. Lisinopril is not metabolized in the liver, it is excreted unchanged by the kidneys due to tubular secretion, followed by partial reabsorption. In the fast elimination phase, the elimination half-life is 12.6 hours. The second phase of elimination is about 30 hours (due to the time of binding to ACE). The state of stable equilibrium concentration occurs on the second or third day of constant intake. The average renal clearance when used at a dose of 2. 5-5 mg is 3.11-3.76 l / h. Lisinopril clearance correlates with creatinine clearance, therefore, as creatinine clearance decreases, so does the excretion of lisinopril. In patients with renal insufficiency, the excretion of the drug is slowed down, and therefore dose adjustment is required.
The effect of lisinopril
on the renin-angiotensin-aldosterone system
The main effect of lisinopril is achieved by blockade of plasma and tissue ACE. The effect of 10 mg lisinopril on the plasma concentration of angiotensin II (p
The severity of the inhibitory effect of lisinopril was studied in vitro on rabbit lungs. The affinity constant of ACE for lisinopril was comparable to that of enalaprilat and captopril, however, the dissociation half-life of the drugs was 105, 27 and 9, respectively.minutes. These data indicate a greater affinity of lisinopril for ACE [15].
Unlike most other ACE inhibitors, lisinopril does not require biotransformation to form active metabolites, and does not contain a sulfhydryl group, which is the cause of a number of side effects (neutropenia and proteinuria) [16].
The nephroprotective effect of lisinopril has been demonstrated at various stages of diabetic nephropathy, regardless of the presence of arterial hypertension.
Thus, in a placebo-controlled study of lisinopril in normotensive patients with type 1 and type 2 diabetes with microalbuminuria (MAU), by the end of 1 year of therapy in the lisinopril group, AU decreased by 2 times compared with the baseline, with more than half of the patients (7 of 12) – AC level is completely normalized. While there was no decrease in AC in the placebo group, the majority of patients (9 of 15) remained at the stage of MAU, and 3 had progression of DN to the stage of proteinuria (PU) [17].
In another study in patients with type 1 diabetes with MAU without hypertension, lisinopril therapy for 1.5 years led not only to a significant decrease in the level of AC, but also to a significant decrease in the size of hypertrophied kidneys, a morphological marker of the initial stage of DN; in the placebo group, the size of the kidneys did not change, and the level of AC increased significantly compared with the baseline [18].
In one of the largest studies using lisinopril in patients with type 2 diabetes, which included 3463 patients with initial and severe DN and arterial hypertension, the appointment of lisinopril even for a short period (3 months) showed not only a high antihypertensive efficacy of the drug, but also improvement in the nitrogen excretion function of the kidneys – in almost 50% of patients with an initially elevated creatinine level, this indicator stabilized. The studies also noted the positive effect of lisinopril on metabolic control indicators (glycated hemoglobin and blood lipids) and good tolerability of therapy – side effects developed in only 2.2% of patients [19].
EUCLID study (The EURODIAB controlled trial of lisinopril in insulin diabetes dependent) is the most well-known international study that proved the nephroprotective effect of ACE inhibitors at the initial stage of diabetic nephropathy [20]. The purpose of this double-blind, placebo-controlled study, conducted in 18 European medical centers, was to investigate the effect of early administration of ACE inhibitors on the progression of kidney disease. The study included 530 patients with type 1 diabetes aged 20–59years with normoalbuminuria (85% of patients) and microalbuminuria (15%) without arterial hypertension, 265 patients were randomized to the lisinopril group and 265 to the placebo group. At the end of the 2-year follow-up period, AC levels were 18.8% (2.2 µg/min.) lower in the lisinopril group than in the placebo group. Stratification of patients by AC level showed that the initial AC level before the start of treatment is a strong predictor of the effectiveness of therapy. Thus, in patients with baseline normoalbuminuria, the decrease in urinary albumin excretion compared with placebo was 12.7% (1.0 μg / min.), while in patients with baseline MAU – 49.7% (34.2 µg/min.). Thus, the EUCLID study proved the ability of ACE inhibitors to slow both the development and progression of the initial stage of diabetic nephropathy. At the same time, the greatest nephroprotective properties were manifested precisely at the MAU stage.
In the EUCLID study, it was shown that the severity of the antiproteinuric effect of the drug depended on the polymorphism of the ACE gene of the insertion/absence type (I / D – insertion / deletion) by the presence or absence of a fragment consisting of 287 base pairs. The level of AC on lisinopril therapy compared with placebo decreased significantly more in carriers of genotype II (by 51.3%) than in patients with ID and DD genotypes (14.8 and 7.7%, respectively) [21]. There were no significant differences in clinical and laboratory parameters, including blood pressure and HbA1c, depending on the genotype. It has been established that the ACE gene polymorphism determines the level of ACE in the blood and tissues: the ACE gene genotype II is characterized by a low level of the enzyme, the DD genotype is approximately 2 times higher, and heterozygotes have an intermediate level of the enzyme [22]. Since the therapeutic effect of ACE inhibitors is based on the blockade of ACE and, accordingly, the production of angiotensin II, it can be assumed that patients with genotype II with the lowest ACE level were more susceptible to the blocking effect of ACE inhibitors on the RAS of the kidneys, which was expressed in the maximum nephroprotective effect.
The EUCLID study also evaluated the effect of ACE inhibitor therapy on the development and progression of diabetic retinopathy (DR) [23]. In the lisinopril group, a 50% reduction in the risk of progression of DR by 50% (OR=0.5) compared with placebo was found, while the maximum protective effect of ACE inhibitors on the development and progression of DR (OR=0.34) was observed in patients with carbohydrate compensation. exchange – at the level of HbA1c less than 7%. It was also noted that the positive effect of ACE inhibitor therapy on the condition of the fundus did not depend on the presence of DN, i.e. persisted even in the absence of microalbuminuria.
Significant antiproteinuric effect of ACE inhibitors has been demonstrated in a number of studies with lisinopril compared with traditional antihypertensive therapy with b-blockers [24,25]. Patients with type 2 diabetes with PU and hypertension were randomized to lisinopril 10–20 mg/day. or atenolol 50–100 mg/day. Mean BP values ​​significantly decreased in both groups. However, with the same antihypertensive efficacy of these drugs, lisinopril was significantly superior to atenolol in terms of the strength of the antiproteinuric effect – 55% and 15%, respectively [24,25]. At the same time, in one of the studies [25], along with a decrease in the level of PU during lisinopril therapy, indicators of endothelial function significantly improved, namely the level of transcapillary excretion of albumin (TERalb), while this indicator significantly increased in the atenolol group.
The results of comparative studies of the effectiveness of lisinopril and various drugs of dihydropyridine calcium antagonists confirm the priority of ACE inhibitors in the treatment of hypertension in diabetic nephropathy [26–32]. More pronounced antiproteinuric effect of lisinopril 10-20 mg / day. demonstrated compared with nisoldipine 20–40 mg/day. in patients with type 1 diabetes with MAU [26], proteinuria and initial CRF [27]; nifedipine retard 20-40 mg/day. at the MAU stage in type 1 diabetes [28] and type 2 diabetes [29], as well as in patients with type 1 diabetes with proteinuria [30,31] and the initial stage of CRF [30]; lacidipine 8 mg/day. in patients with type 2 DM with various stages of DN [32]. The nephroprotective effect of lisinopril did not depend on the antihypertensive effect of the drug. A decrease in blood pressure was achieved in all groups of patients, regardless of the type of therapy. At the same time, the level of albuminuria significantly decreased only in patients treated with an ACE inhibitor – by about 30-50% compared with baseline in all studies, while on therapy with calcium channel blockers, the level of AC either did not change significantly or even increased [30 ,31].
One of the largest studies examining the effect of ACE inhibitors on renal function was the ALLHAT (Antihypertensive and Lipid–lowering Treatment to prevent Heart Attack Trial) study [33]. The aim of the study was to evaluate the effect of long-term antihypertensive therapy with various groups of drugs (ACE inhibitor lisinopril, calcium antagonist amlodipine compared with the diuretic chlorthalidone) on the risk of developing cardiovascular and renal complications in patients with arterial hypertension and high cardiovascular risk with initially reduced renal function. . The study involved more than 33 thousand patients over the age of 55 with arterial hypertension and other risk factors for cardiovascular disease (including diabetes). At the end of the 6-year follow-up period, the following endpoints were assessed: the development of end-stage renal disease, defined as death due to kidney disease, the need for chronic dialysis and kidney transplantation; a decrease in GFR of more than 50% and the level of glomerular filtration rate (GFR) at the end of the study. ALLHAT showed no benefit of ACE inhibitors over other drugs in either the general patient population or the diabetes subgroup. When interpreting the ALLHAT data, it must be taken into account that in this study, conducted only in US medical centers, 35% of randomized patients were blacks. It is known that the pathophysiological features of the development of hypertension in these individuals determine the high efficacy of diuretic therapy (due to the hypersensitivity to salt) and the low efficacy of ACE inhibitor therapy. Therefore, the results of the ALLHAT study cannot be unequivocally transferred to the European population.
Reducing the rate of progression of diabetic kidney disease during long-term therapy with lisinopril was demonstrated in a 4-year study in patients with type 1 diabetes with PU and initial chronic renal failure and arterial hypertension [27]. Baseline creatinine before therapy was 107 (72–223) µmol/l, GFR was 85±5 ml/min/1.73 m2. The initial decrease in GFR in the first 6 months of therapy was 1.3 ml/min./month/1.73 m2, then the rate of decrease in GFR slowed down by more than 2 times and remained stable during the subsequent study period at the level of 0.5± 0.1 ml/min/month/1.73 m2. When conducting a multivariate regression analysis, diastolic blood pressure, the level of glycated hemoglobin and albuminuria were independent predictors of a decrease in the filtration function of the kidneys.
In another study, during 1 year of lisinopril therapy in patients with type 2 DM with various stages of DN (11 – MAU, 5 – PU, 6 – CRF), along with a significant decrease in the level of albuminuria, there was an increase in GFR (from 61±26 to 77±41 ml/min/month/1. 73 m2), blood creatinine levels remained stable throughout the treatment period [34]. The only parameter that in this study significantly correlated with the parameters of the functional state of the kidneys (namely, the level of AC) was the level of excretion of MCP-1 (monocyte chemoattractant protein-1). This protein is activated by angiotensin II and promotes the migration of monocytes and macrophages into the mesangial and interstitial tissue of the kidneys, the production of cytokines and growth factors, which ultimately leads to the development of aseptic inflammation and sclerotic changes. The level of excretion of MCP-1 during therapy with lisinopril significantly decreased, indicating a non-hemodynamic mechanism of nephroprotection of ACE inhibitors.
Summing up the results of the studies, it should be noted that lisinopril has shown itself to be an effective antihypertensive drug with high nephroprotective properties that meets the established indications for the use of ACE inhibitors in diabetic kidney disease and arterial hypertension. The nephroprotective effect of this drug has been proven both in the early stages of DN in normotensive patients, and after the onset of microalbuminuria and proteinuria, and is associated with slowing down the decline in GFR and maintaining a stable level of creatinine.

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Principles for choosing an angiotensin-converting enzyme inhibitor. Peculiarities of perindopril

Cardiovascular diseases (CVD) continue to be the most pressing health problem in most countries of the world, including Russia, despite significant progress in the diagnosis and treatment of CVD in the last decade. World Health Organization experts predict a further increase in cardiovascular morbidity and mortality in both developed and economically developing countries, due to population aging and lifestyle characteristics [1, 2].

A variety of risk factors (RF) contribute to an increase in the total risk of developing CVD and their complications, the most common of which is arterial hypertension (AH). The prevalence of hypertension in Russia for a long time remains at the level of 40% [3]. It is this disease that practitioners most often encounter and it is it that is a serious predictive risk factor for the development of myocardial infarction (MI), cerebral stroke, chronic heart failure (CHF), death from all diseases and CVD, as well as the development of vascular dementia and, possibly, Alzheimer’s disease [4, 5].

Among the numerous classes of antihypertensive drugs, angiotensin-converting enzyme (ACE) inhibitors occupy a special place, which are widely used in the treatment of patients with hypertension with CHF, MI, diabetic and non-diabetic nephropathy. Such a multidisciplinary use is associated with a specific effect on the renin-angiotensin-aldosterone system (RAAS), the increased activity of which plays an important role in various pathological conditions. In addition, their ability to increase the concentration of bradykinin and nitric oxide in blood plasma and inhibit the sympathetic part of the autonomic nervous system is of great importance.

The results of a large meta-analysis pooling data from 26 randomized clinical trials involving 108,212 hypertensive patients without CHF showed that ACE inhibitors are superior to angiotensin II receptor blockers (ARBs) for most of the main evaluated clinical outcomes (“hard endpoints”): death from all causes and from CVD, MI and stroke, as well as new cases of CHF.

In particular, this analysis showed that ACE inhibitors, compared with placebo, statistically significantly reduced the incidence of all-cause death by 8.3%, CVD by 10%, MI by 17.7%, stroke by 19.6%, the number of new cases of CHF – by 20.5%, diabetes mellitus (DM) – by 13.7%. ARBs were effective on the combined outcome of study (“combined endpoint”) by reducing the risk of stroke by 7% and new cases of DM by 10.6%, but ARBs did not significantly affect the risk of death from all causes, MI and new cases of CHF [6]. This once again emphasizes that the high frequency of use of ACE inhibitors in real clinical practice in patients of different categories is a justified and reasonable approach.

The advantages of ACE inhibitors are explained by the peculiarities of their action and the ability (unlike ARBs) to influence not only the pressor, but also the depressor mechanisms of BP regulation. Taken together, data from experimental and clinical studies suggest that the ability of ACE inhibitors to prevent severe cardiovascular complications (CVS) is at least partially related to their tissue effects leading to the restoration of the structure and function of the arterial wall endothelium. In this regard, suppression of local ACE activity, inhibition of the development of endothelial dysfunction (DE) and the atherosclerotic process with the help of drugs that block the activity of the RAAS, reduce the production of angiotensin II (ATII) and the destruction of bradykinin, is a pathogenetically justified approach.

ACE inhibitors. However, ACE inhibitors are a large and heterogeneous group of drugs, the representatives of which have significant differences from each other.

Although the clinical significance of differences in the physicochemical properties of ACE inhibitors has been discussed for many years, there is still no clear answer to the question of what their clinical significance is. It is obvious that differences are of real clinical significance not so much in the chemical structure of individual representatives of this class of drugs, but in pharmacokinetic parameters, such as the duration of inhibition of ACE activity and, accordingly, action, absorption in the gastrointestinal tract, bioavailability, binding to plasma proteins, and, of course, , affinity for tissue components of the RAAS. It is the latter property that is an important distinguishing characteristic of inhibitors. The comparative severity of the vasodilating effect of ACE inhibitors, in which captopril activity is taken as a unit, can be represented as follows: captopril (1) < enalapril (3.4) < fosinopril (3.7) < perindopril (6.9). An important characteristic is also the lipophilicity index, which is very high for perindopril and is 0.872 (for comparison, for enalapril it is 0.108) [7].

What is DE and why is it dangerous? DE can be defined as inadequate (increased or reduced) formation of various biologically active substances in the endothelium. Damage to the vascular endothelium triggers reactions of aggregation, coagulation, causes vasospasm, and contributes to the progression of atherogenesis. No less important factors contributing to the damage of atherosclerotic plaques than the degree of narrowing of the blood vessel are the level of inflammatory activity and the degree of macrophage activation.

One of the methods for assessing the severity of DE is the determination in the blood of factors that damage the endothelium, the level of which correlates with DE. Such factors (mediators of endothelial damage) include hypercholesterolemia, hyperhomocysteinemia, cytokines (interleukins, tumor necrosis factor), etc. [8].

Among the drugs that improve the impaired function of the endothelium, ACE inhibitors undoubtedly occupy a leading position due to the fact that the most important factor leading to the formation of DE is chronic activation of the RAAS. It is ATII that directly affects the function of the endothelium by stimulating the formation of superoxide anion, which causes the degradation of nitric oxide (II) – NO. With insulin resistance (IR), when the formation of NO synthase is reduced, this can lead to severe endothelial dysfunction, increased vascular tone, and the development of proliferative processes in the vascular wall. ACE inhibitors increase insulin sensitivity by decreasing ATII levels and increasing kinin levels.

The clinical efficacy of ACE inhibitors throughout almost the entire cardiovascular continuum is due to their ability to modulate the activity of the RAAS, the chronic activation of which is the most important factor leading to the formation of DE. One of the main components of RAAS is ACE, most of which is localized directly on the membranes of endothelial cells of large, small arteries and arterioles, as well as in the adventitia of vessels [9, 10].

It is necessary to take into account intra-class differences of ACE inhibitors and their individual properties. There are important differences between drugs in affinity for tissue ACE and individual pharmacokinetic properties, which can determine significant differences in tissue concentration and various clinical effects [11].

ACE inhibitors differ in chemical structure and pharmacokinetic parameters (half-life, excretion routes, bioavailability and tissue penetration) [12]. This difference in pharmacokinetic and pharmacodynamic characteristics may lead to differences in the effectiveness of drugs within the class. In this regard, the question arose about the likelihood of achieving a comparable effect when using ACE inhibitors with a lower ability to penetrate tissues [13]. The results of laboratory studies suggested that with a higher degree of penetration into vascular tissues, more favorable indicators of the state of fibrinolysis markers are observed [14].

An important characteristic of ACE inhibitors is their tissue specificity, i. affinity for tissue components of the RAAS, as well as the effect on the ratio of bradykinin/ATII. The greatest effect should be expected from ACE inhibitors with high tissue specificity, since it is known that almost 90% of ACE is localized in organs and tissues, in particular, in the membranes of endocardial cells and endothelial cells, and only 10% in blood plasma [9].

Pharmacological features of perindopril. Perindopril (prestarium A) is a leader in terms of the level of evidence of its positive effect on endothelial function, and it is with this effect that special indications for the use of the drug are associated. It has proven itself as a drug for the treatment of hypertension, as it has demonstrated the ability to lower blood pressure (BP), slow target organ damage and improve prognosis, which has been convincingly proven in such large international clinical studies as PROGRESS (Perindopril pROtection a Gainst Recurrent Stroke Study). ) [15, 16], EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery) [17], etc. The antihypertensive efficacy of Prestarium A has also been proven in international and Russian randomized clinical trials involving hundreds of thousands of patients [18, 19].

In this article, we pay special attention to those effects of perindopril that distinguish it from other ACE inhibitors, going beyond the class effects of this group of drugs. Currently, experts indicate that preference should be given to those representatives of the class of ACE inhibitors that have tissue and, in particular, vascular effects. There are already a number of studies that show that perindopril, in addition to antihypertensive and organoprotective properties, exhibits pleiotropic effects – it improves the functions of the vascular endothelium and reduces the concentration of systemic inflammation markers, which may partially explain the protection against CVD.

A feature of perindopril is that it has the highest affinity for tissue RAAS and meets exactly the requirements mentioned above. This ACE inhibitor, according to international randomized clinical trials, is highly effective in secondary drug prevention of CV events (myocardial infarction, stroke, CHF, DM) and in reducing the risk of death from CVD, combined with high safety in long-term use [20].

Perindopril has a high affinity for tissue ACE and, unlike lipid-insoluble ACE inhibitors (such as lisinopril), perindopril significantly increases local tissue production of bradykinin. Perindopril is characterized by the highest selectivity of binding to bradykinin among ACE inhibitors and significantly reduces apoptosis of endothelial cells. Bradykinin increases the expression of NO-synthesis, improves endothelial function, has an antioxidant effect, enhances fibrinolysis (due to the release of tissue plasminogen activator) and reduces remodeling of the heart and blood vessels, thus counteracting the effects of ATII realized through AT1 receptors. The effect of Prestarium A on apoptosis indices exceeds that of other ACE inhibitors [21, 22].

In this regard, the use of ACE inhibitors in general and perindopril in particular to correct DE seems to be a pathogenetically justified and appropriate approach. Perindopril has a direct positive effect on the vascular endothelium and reduces apoptosis not only in patients with hypertension, but also in other CVDs (stable forms of coronary artery disease, acute coronary syndrome).

Our own experience in studying the pharmacodynamic effects of perindopril in hypertensive patients with various concomitant diseases also indicates a high efficacy of the drug in patients of different categories, and also explains the high antihypertensive efficacy of perindopril in those categories of patients in whom it is difficult to achieve good treatment results in everyday clinical practice . We are talking primarily about patients in whom the presence of concomitant diseases reduces the potential positive effects of any antihypertensive therapy. In particular, prestarium A improves the functional state of the endothelium and makes it possible to influence the coronary and myocardial reserves of the heart in patients with AH in combination with coronary artery disease [23-26].

Perindopril in patients with disorders of lipid and carbohydrate metabolism. One of the many categories of patients – patients with obesity and metabolic syndrome (MS). It is well known that the combination of certain risk factors ultimately leads to a significant increase in the total risk of developing CVD and CVC, and the activity of various biochemical markers, indicating a high activity of adipocytes, undoubtedly contributes to this. An important advantage of prestarium is its beneficial effects in patients with impaired carbohydrate and lipid metabolism.

The positive effect of Prestarium A on blood lipid composition and glucose levels has quite a lot of evidence [27, 28].

The favorable effect of Prestarium A on lipid metabolism contributes to a significant reduction in the individual risk of developing CVS in patients.

The effect of perindopril-based therapy on the risk of macro- and microvascular complications in diabetic patients has been well studied in the large randomized ADVANCE trial (Action in Diabetes and VAscular disease – preterax and Diamicron MR Controlled Evaluation), the results of which served as a convincing argument in favor of prescribing ACE inhibitors in patients with diabetes.

Mechanisms of influence of perindopril on carbohydrate metabolism are diverse. First, the antihypertensive effect of perindopril is based on the blockade of the RAAS. It is known that ATII plays a central role in the development of the inflammatory process in the vascular wall due to its interaction with NO. Secondly, and most importantly, perindopril has a positive effect on the metabolism of carbohydrates and the sensitivity of peripheral tissues to insulin, which is probably associated with the direct action of ACE inhibitors – a decrease in the concentration of ATII and an increase in the level of kinins in the blood. ATII is a competitive antagonist of insulin, and kinins increase insulin-stimulated peripheral glucose uptake by cells, accelerate its oxidation, and reduce endogenous glucose production. ACE inhibitors can also restore the early peak of insulin secretion.

The improvement in blood lipid composition during therapy with Prestarium A is one of the key mechanisms that explain the improvement in the elasticity of large vessels, and cannot be considered an accidental artifact. The ability of prestarium A to reduce hypertriglyceridemia explains the beneficial effect of the drug on the amount of body fat, uric acid levels and reduced risk of fibrosis in non-alcoholic fatty liver disease. It is important to note that in terms of the effect on leptin, adiponectin, C-reactive protein (CRP), tumor necrosis factor α, interleukin-1β, and other markers of adipokine activity, perindopril is superior to another ACE inhibitor, enalapril, which has a lower affinity for tissue components of the RAAS [ 29, thirty].

The work carried out at our department also confirmed the favorable effect of perindopril on IR. The study included 24 AH patients with MS according to the AHA/NHLBI (2005) criteria, aged 37 to 76 years. In patients, the levels of intercellular adhesion molecules (iCAM), CRP, glucose, and insulin were assessed at baseline and after 12 weeks of treatment with perindopril at a dose of 2.5 to 10 mg/day. IR was determined by the HOMA-IR index, calculated according to the formula: IR index = fasting blood glucose level (in mmol/l) · basal insulin level (in mcd/ml)/22.5. After 12 weeks of therapy with perindopril, the antihypertensive effect was the same in men and women with an average decrease in the average daily systolic blood pressure by 11.0 mm Hg, diastolic blood pressure – by 6.0 mm Hg. Along with the antihypertensive effect, a significant decrease in the HOMA-IR index, a decrease in the levels of iCAM and CRP were noted.

Perindopril in patients with cognitive impairment. Another extremely important aspect of hypertension is the effect of elevated blood pressure and various antihypertensive drugs on cerebral circulation and brain function. Damage to the brain as a target organ in hypertension is manifested not only by strokes, but also by impaired cognitive functions (memory, thinking, attention, etc.), and long-term uncorrected hypertension, even without a history of cerebrovascular complications, may be accompanied by impaired cognitive functions. No one doubts the need for long-term active therapy, which can reduce the risk of stroke. The results of the PROGRESS study allowed for the widespread use of perindopril for these purposes. In fact, this is the first randomized trial to study the possibility of therapy based on the ACE inhibitor perindopril to reduce the risk of recurrent stroke in patients with a history of cerebrovascular disease. The addition of perindopril to traditional therapy reduced the risk of recurrent stroke by 28% in patients with cerebrovascular diseases both with and without hypertension, the total number of CV events by 26%, including MI by 38%. It is also extremely important that the use of perindopril not only prevents the development of a recurrent stroke, but also reduces the risk of developing cognitive impairment and post-stroke dementia in patients who have had a stroke or transient ischemic attack [15, 16].

Although most ACE inhibitors are approximately equally effective in lowering blood pressure, those that cross the blood-brain barrier and suppress tissue RAAS activity have theoretical advantages in reducing cognitive impairment.

Experience in the treatment of patients with hypertension of I-II degrees without cerebrovascular diseases ( n =41) in history with perindopril at a daily dose of 5-10 mg showed that against the background of such therapy, according to neuropsychological testing, cognitive function indicators significantly improved: the total number of complaints decreased to deterioration of memory and attention from 2.27±0.9to 1.27±0.5 points ( p <0.001), scores on the MMSE scale increased from 28. 56 to 29.45 points ( p <0.05), according to the Veksler-7 subtest - from 36, 9±13.12 to 48.31±10.41 points ( p <0.05). In addition, there was a significant improvement in indicators on the visual analogue scale of memory from 73.95±16.83 to 85.84±13.11 mm ( p <0.05) and attention from 70.75±15.0 to 81 .60±11.75 mm ( p <0.05).

This dynamics was accompanied by a significant decrease in the initially elevated level of endothelin-1 (ET-1) – a biochemical marker of endothelial dysfunction – and the level of ATII ( p <0.005). In terms of the effect on the level of ET-1, perindopril was superior to enalapril by almost 3 times (&Dgr; = -0.1 and -0.03 fmol / ml, respectively; p <0.05). These data are of great practical importance and indicate that perindopril has the greatest effect on DE compared with enalapril. This is due to the pharmacological features and differences that are indicated earlier.

Conclusion

The rational use of ACE inhibitors is based on taking into account the results of clinical studies, indications and contraindications for the appointment.