Hydrochlorothiazide, lisinopril

Pharmacological properties

co-dirotone is a fixed-dose combination drug of lisinopril, an angiotensin-converting enzyme inhibitor (APF) and hydrochlorothiazide, a thiazide diuretic. both components exhibit a complementary and additive antihypertensive effect.

Lisinopril is a peptidyldipeptidase inhibitor. It inhibits ACE, which catalyzes the conversion of angiotensin I to the angiotensin II vasoconstrictor peptide. Angiotensin II also stimulates the secretion of aldosterone in the adrenal cortex. Inhibition of ACE leads to a decrease in the concentration of angiotensin II, which leads to a decrease in vasopressor activity and a decrease in the secretion of aldosterone. A further decrease can lead to an increase in potassium in the blood plasma.

Although the mechanism by which lisinopril lowers blood pressure is considered to be primary suppression of the renin-angiotensin-aldosterone system, lisinopril lowers blood pressure even in patients with low-rhenin hypertension. ACE is identical to kininase II, an enzyme that breaks down bradykinin. It remains to be seen whether elevated levels of bradykinin, a potent vasodilator peptide, play any role in the therapeutic effect of lisinopril.

Hydrochlorothiazide is a diuretic and antihypertensive agent. It acts on the mechanism of reabsorption of electrolytes in the distal tubular part of the kidneys, increases the excretion of sodium and chloride approximately the same. Natriuresis may be accompanied by some loss of potassium and bicarbonates. The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides usually do not affect normal blood pressure.

Pharmacokinetics The simultaneous administration of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of both components. No clinically significant pharmacokinetic interactions between the two components were noted when they were taken in 1 tablet.

Lisinopril

Absorption. Following oral administration of lisinopril C_max in the blood plasma is observed for approximately 7 hours. Based on data on excretion in the urine, the average absorption of lisinopril in the studied dose range (5–80 mg) is approximately 25% with an interindividual variability of 6–60%. Absolute bioavailability is reduced by about 16% in patients with heart failure. The absorption of lisinopril is independent of food intake.

Distribution. Lysinopril probably does not bind to plasma proteins, except for circulating ACE. It is known that lisinopril penetrates poorly through the BBB.

Elimination. Lisinopril is not metabolized and excreted by the kidneys completely unchanged. With repeated administration, lisinopril has an effective T_½ 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 ml / min. A decrease in plasma concentration indicates a prolonged terminal phase, which is not a consequence of the cumulation of the drug. This terminal phase probably indicates saturable binding to ACE and is not proportional to the dose.

Heart failure. Patients with heart failure are more susceptible to lisinopril than healthy volunteers (an increase in the area under the concentration / time curve (AUC) by an average of 125%), but based on data on urinary lysinopril excretion, it was found that approximately 16% absorption compared with healthy volunteers.

Elderly patients have higher plasma AUC values ​​(increased by about 60%) compared to younger volunteers.

Renal failure. Impaired renal function reduces the elimination of lisinopril, which is excreted by the kidneys, but this becomes clinically significant only if the glomerular filtration rate is lower than 30 ml / min.In mild and moderate renal failure (creatinine clearance ≥30–80 ml / min), the average AUC was increased by only 13%, while in severe renal failure (creatinine clearance ≥5–30 ml / min), the average AUC was increased 4.5 times.

Lisinopril can be eliminated by dialysis. During 4 hours of hemodialysis, the concentration of lisinopril in blood plasma decreased on average by 60%, clearance on dialysis was between 40 and 55 ml / min.

Impaired liver function. Impaired liver function in patients with cirrhosis led to a decrease in the absorption of lisinopril (about 30% when determined by excretion in the urine), as well as an increase in its effect (about 50%) compared with healthy volunteers due to a decrease in clearance.

Hydrochlorothiazide. Hydrochlorothiazide is rapidly absorbed in the digestive tract. In humans, about 70% of an oral therapeutic dose is absorbed mainly in the duodenum and upper small intestine. Eating does not affect absorption, and C_max achieved within 2–4 hours after administration. It is reported that the volume of distribution is from 0.8 to 3 l / kg. Hydrochlorothiazide is not metabolized, but is rapidly excreted by the kidneys. At least 61% of the dose is excreted unchanged within 24 hours. T_½ is 8-12 hours, and 95% of the absorbed hydrochlorothiazide is excreted by the kidneys. After oral administration of hydrochlorothiazide, diuresis begins after 2 hours, the peak occurs after about 4 hours and lasts 6-12 hours. Hydrochlorothiazide crosses the placenta, but does not cross the BBB.

Indications

Treatment of patients with mild to moderate ag, having a stable course during therapy with individual drugs in the same dosages.

Application

Ag

Adults The use of a combined drug with a fixed dose is not suitable for starting therapy. A fixed-dose combination drug can replace a combination of 10 mg or 20 mg of lisinopril and 12.5 mg of hydrochlorothiazide in patients whose condition has been stabilized during therapy with individual active substances in the same dosages prescribed as separate drugs. The usual dose is 1 tablet 1 time per day. Like any other medication that is taken once a day, Co-Diroton should be taken at approximately the same time every day.

If it is not possible to achieve the desired therapeutic effect within 2-4 weeks of treatment, the dose can be increased to 2 tablets 1 time per day.

Previous diuretic therapy. After taking the first dose of Co-Diroton, symptomatic hypotension may develop; the development of this condition is more likely in patients with depletion of fluid and / or salt as a result of previous diuretic therapy. Diuretic therapy should be discontinued 2-3 days before the start of therapy with Co-Diroton. If this is not possible, treatment with individual components in a low dose should be started (lisinopril at a dose of 5 mg).

Patients with renal failure. The drug Co-Diroton can not be used as initial therapy in patients with renal failure.

In patients with mild or moderate renal failure (creatinine clearance of 30 and 80 ml / min), the drug Co-Diroton can be used only after titration of a dose of individual components. In this case, the recommended dose of lisinopril, administered as a separate drug, is 5–10 mg.

Elderly patients. It is known that the efficacy and tolerability of lisinopril and hydrochlorothiazide when administered concurrently were the same both in elderly patients and in younger patients with hypertension. In the dosage range from 20 mg to 80 mg, the effectiveness of lisinopril was the same in the elderly (65 years and older) and younger patients with hypertension. In elderly patients with hypertension, lisinopril monotherapy was as effective in reducing diastolic blood pressure as monotherapy with hydrochlorothiazide or atenolol. If an elderly patient has a decrease in renal function, the initial dose of lisinopril should be adjusted. (see Patients with renal failure).

Contraindications

• Hypersensitivity to lisinopril and other apf inhibitors, hydrochlorothiazide and sulfonamide derivatives or other components of the drug; a history of angioedema associated with the use of APF inhibitors; hereditary or idiopathic angioedema; hemodynamically significant stenosis of the aortic or mitral valve, or hypertrophic cardiomyopathy; severe renal failure or terminal stage of the disease; severe liver disease; ii and iii trimester of pregnancy (see special instructions); lactation period (see special instructions); exacerbation of gout; anuria hyperuricemia hyperaldosteronism; renal artery stenosis (bilateral or unilateral). cardiogenic shock; a condition with unstable hemodynamics after acute myocardial infarction; use in patients on hemodialysis using high-flow membranes (e.g. an69); plasma creatinine level 220 μmol / l.

Side effects

On the background of the intake of individual components, adverse reactions were reported that could potentially develop on the background of taking the drug co-diroton.

Side effects due to lisinopril and other ACE inhibitors

On the part of the blood and lymphatic system: lymphadenopathy, anemia, agranulocytosis, inhibition of bone marrow function, hemolytic anemia, leukopenia, thrombocytopenia, neutropenia, autoimmune diseases.

From the side of the cardiovascular system: palpitations, tachycardia, arterial hypotension (including orthostatic hypotension), cerebrovascular accident, Raynauds phenomenon, imbalance, myocardial infarction or stroke, possibly due to severe arterial hypotension in high-risk patients.

Mental disorders: mood changes, sleep disturbances, confusion, disorientation.

From the nervous system: dizziness, imbalance, paresthesia, headache, impaired taste, impaired sense of smell.

From the side of the organ of hearing and balance: vertigo.

From the respiratory system, chest and mediastinal organs: cough *, bronchospasm, dyspnea, rhinitis, sinusitis, allergic alveolitis, eosinophilic pneumonia, upper respiratory tract infection.

From the gastrointestinal tract: diarrhea, vomiting, nausea, dry mouth, glossitis, pancreatitis, angioedema of the intestine, abdominal pain, indigestion, loss of appetite, constipation.

From the hepatobiliary system: hepatitis, hepatocellular or cholestatic jaundice, liver failure **.

On the part of the skin and subcutaneous tissue: rash, hypersensitivity, angioedema ***, symptom complex ****, alopecia, urticaria, pruritus, psoriasis, increased sweating, sensation of heat, flushing of the skin, skin disorders (pemphigus, toxic epidermal necrolysis, syndrome Stevens-Johnson, erythema multiforme, pseudolymphoma of the skin).

Disorders of metabolism and nutrition: hypoglycemia.

From the musculoskeletal system and connective tissue: muscle spasm, muscle weakness.

From the endocrine system: impaired secretion of antidiuretic hormone.

From the kidneys and urinary tract: oliguria / anuria, renal dysfunction, acute renal failure, proteinuria.

Complications of a general nature: increased fatigue, asthenia, chest discomfort.

From the reproductive system and mammary glands: impotence, gynecomastia.

Laboratory indicators *****: increased activity of liver enzymes, increased plasma creatinine concentration, increased blood urea, decreased hemoglobin, decreased hematocrit, and bilirubin in blood plasma.

* Cough caused by therapy with ACE inhibitors is characterized as persistent, unproductive, disappears when the drug is canceled.This should be considered when conducting differential diagnosis of cough.

** Very rarely, there have been reports of patients whose unwanted development of hepatitis led to liver failure. Patients who develop jaundice during therapy or have a significant increase in the activity of liver enzymes should stop taking Co-Diroton and undergo a proper medical examination.

*** Isolated cases of angioedema of the face, limbs, lips, tongue, glottis and / or larynx have been reported (see SPECIAL INSTRUCTIONS).

**** The development of a symptom complex has been reported, which may include one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia / arthritis, positive antinuclear antibodies (ANA), increased ESR, eosinophilia and leukocytosis, rash, photosensitivity or other dermatological manifestations .

***** A slight increase in the concentration of creatinine and urea in blood plasma was noted. These phenomena are usually reversible when you stop taking the drug. A slight decrease in hemoglobin and hematocrit was reported. Bone marrow depression has been reported, which is manifested by anemia and / or thrombocytopenia. Hyper- or hypokalemia and hyponatremia were detected. Isolated cases of increased activity of liver enzymes and / or bilirubin content of blood plasma have been reported, but no connection with the administration of a drug containing lisinopril and hydrochlorothiazide has been established.

Isolated cases of syncope and chest pain have been reported, but no association has been established with a drug containing lisinopril and hydrochlorothiazide.

There are reports of the development of neuropathy while taking ACE inhibitors.

Side effects due to hydrochlorothiazide

Infections and infestations: sialadenitis.

From the immune system: hypersensitivity reactions, including anaphylactic reactions, shock.

On the part of the blood and lymphatic system: leukopenia, neutropenia / agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, inhibition of bone marrow function.

Metabolic and nutritional disorders: anorexia; hyperglycemia; glucosuria; hyperuricemia, which can provoke gouty attacks in patients with asymptomatic disease; imbalance in electrolytes, including hyponatremia and hypokalemia; hypomagnesemia; hypercalcemia; increased blood lipids; gout; a decrease in glucose tolerance, which may cause a manifestation of latent diabetes mellitus; hypochloremic alkalosis, which can induce hepatic encephalopathy or hepatic coma.

Mental disorders: anxiety, depression, mood changes, sleep disturbances, confusion, disorientation, drowsiness, nervousness.

From the nervous system: dizziness, headache, cramps, paresthesia.

From the side of the organ of vision: xanthopsia, temporary visual impairment.

From the side of the organ of hearing and balance: vertigo.

From the cardiovascular system: arrhythmia, orthostatic arterial hypotension.

From the respiratory system, chest and mediastinal organs: respiratory distress syndrome, including pneumonitis and pulmonary edema.

From the digestive system: irritation of the gastric mucosa, constipation, dry mouth, thirst, nausea, vomiting.

From the hepatobiliary system: jaundice (jaundice due to intrahepatic cholestasis), pancreatitis, cholecystitis.

On the part of the skin and subcutaneous tissue: vasculitis, necrotizing angiitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, photosensitivity reactions, rash, eczema, skin lupus-like reactions, reactivation of skin manifestations of systemic lupus erythematosus, urticaria, purple.

From the musculoskeletal system and connective tissue: muscle spasm and pain.

From the kidneys and urinary tract: renal failure, renal dysfunction and interstitial nephritis.

On the part of the genitals: genital disorders.

Complications of a general nature: exhaustion.

special instructions

Arterial hypotension and disturbances in the water-electrolyte balance

As with any other antihypertensive therapy, some patients may develop arterial hypotension. In patients with hypertension, a hypotensive state is more likely to develop if there is a lack of fluid, for example, during diuretic therapy, diets with a restriction of salt, dialysis, diarrhea or vomiting, or if the patient has severe renin-dependent hypertension (see INTERACTIONS AND ADVERSE EFFECTS).

Symptomatic hypotension is also observed in patients with heart failure with / without renal failure. This condition is more likely to develop in patients with severe heart failure as a result of the use of high doses of loop diuretics, hyponatremia, or functional renal failure. Patients at risk of developing symptomatic hypotension should be closely monitored at the beginning of therapy and during dose adjustment. In such patients, at certain intervals, the determination of blood plasma electrolytes should be carried out. Particular attention should be paid to the treatment of patients with coronary artery disease or cerebrovascular disease, since an excessive decrease in blood pressure can lead to myocardial infarction or stroke.

With the development of arterial hypotension, the patient should be laid on his back and, if necessary, start IV infusion of a physiological solution. A transient hypotensive response is not a contraindication to continued therapy. After the restoration of blood volume and blood pressure, it is possible to resume therapy in a reduced dose or use one of the components of the drug separately.

Patients should be monitored appropriately to identify the clinical signs of water-salt imbalance (e.g. hypovolemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia) that may develop in the event of diarrhea or vomiting. In the warm season, patients with edema may experience hyponatremia due to blood thinning.If possible, hypovolemia and / or a decrease in the volume of intercellular fluid should be eliminated before treatment with lisinopril and the effect of the initial dose on blood pressure should be carefully monitored. In the case of acute myocardial infarction, it is forbidden to use lisinopril if treatment with vasodilator drugs can worsen the hemodynamic status of the patient (for example, if systolic blood pressure is 100 mm Hg or lower) or in case of cardiogenic shock.

Aortic or mitral valve stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors, lisinopril should be used with caution in patients with left ventricular outflow tract obstruction. If the obstruction is hemodynamically significant, then taking Co-Diroton is contraindicated (see CONTRAINDICATIONS).

Impaired renal function

Thiazides are not suitable for use in patients with renal failure, they are ineffective with creatinine clearance of 30 ml / min or lower (i.e., severe renal failure). The drug Co-Diroton should not be prescribed to patients with mild or moderate renal failure (creatinine clearance from 30 to 80 ml / min), until it is established by titration of the individual components that the patient needs precisely such doses as in a combination tablet.

In case of impaired renal function (creatinine clearance of 80 ml / min), the initial dose of lisinopril should be selected depending on the creatinine clearance indicators (see APPLICATION) and the clinical response to treatment. For such patients, continuous monitoring of the concentration of potassium and creatinine in the blood is recommended. In patients with heart failure, arterial hypotension that occurs after starting treatment with ACE inhibitors can lead to impaired renal function. ARF has been reported, which in such cases is usually reversible.

In some patients with unilateral or bilateral renal artery stenosis or artery stenosis of a single kidney treated with ACE inhibitors, there was an increase in the concentration of blood urea and plasma creatinine, usually reversible after discontinuation of therapy. The likelihood of developing this condition is higher in patients with renal failure. If renovascular hypertension also occurs, there is an increased risk of developing severe arterial hypotension and renal failure. In such patients, treatment should be started with low doses under close medical supervision, careful dose titration is required. Since treatment with diuretics can lead to the development of the above situations, during the first few weeks of therapy with Co-Diroton, kidney function should be monitored.

In some patients with AH who do not have a history of kidney disease, with the simultaneous use of lisinopril and a diuretic, a weak transient increase in the concentration of blood urea and plasma creatinine developed, as a rule. If this occurs during therapy with Co-Diroton, you should stop taking the combined drug.The resumption of therapy is possible in a reduced dosage or one of the components of the drug can be used separately.

Condition after a kidney transplant. Since there is no data on the use of lisinopril in patients after a kidney transplant, the use of Co-Diroton in this group of patients is not recommended.

Patients on hemodialysis. The use of the drug Co-Diroton is not indicated for patients undergoing hemodialysis due to renal failure.

Anaphylactic reactions in patients on hemodialysis. High risk of anaphylactic reactions in patients undergoing hemodialysis using a membrane with high hydraulic permeability (e.g. AN69) with simultaneous treatment with ACE inhibitors has been reported. In such patients, the use of a different type of dialysis membrane or the administration of a different group of antihypertensive drugs should be considered.

Liver disease, liver failure. Very rarely, ACE inhibitors are associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is unclear. Patients who have developed jaundice or have a marked increase in liver enzymes while taking Co-Diroton should stop taking Co-Diroton and under appropriate medical supervision.

Thiazides, including hydrochlorothiazide, should be used with caution in patients with impaired liver function or progressive liver disease, since the drug can cause intrahepatic cholestasis, and minimal changes in the water-salt balance can provoke the development of hepatic coma (see CONTRAINDICATIONS).

Surgery / Anesthesia In patients during extensive surgery or during anesthesia with drugs that cause arterial hypotension, lisinopril can additionally block the formation of angiotensin II during compensatory release of renin. If the development of arterial hypotension is considered a consequence of this mechanism, it can be eliminated by introducing a large amount of fluid.

Metabolic and endocrine effects. It is known that the simultaneous administration of ACE inhibitors and antidiabetic drugs (insulin, oral hypoglycemic drugs) can cause an increase in blood glucose concentration, which reduces the risk of hypoglycemia. This phenomenon is more likely to develop during the first weeks of combination therapy and in patients with renal failure (see INTERACTIONS).

Thiazide therapy may decrease glucose tolerance. Dosage adjustment of antidiabetic drugs, including insulin, may be required. Thiazides can reduce the excretion of calcium in the urine, cause a spasmodic and insignificant increase in calcium in the blood plasma. Severe hyperkalemia may be a sign of latent hyperparathyroidism.You should stop taking thiazide diuretics before conducting tests to evaluate the function of the parathyroid glands. An increase in the concentration of XE and TG may be associated with thiazide diuretic therapy.

Thiazide therapy may precipitate hyperuricemia and / or gout in some patients. However, lisinopril can increase uric acid levels in the urine and thereby weaken the hyperuricemic effect of hydrochlorothiazide.

Hypersensitivity / angioedema. Rare cases of the development of angioedema of the face, limbs, lips, tongue, vocal cords and / or larynx have been reported in patients treated with ACE inhibitors, including lisinopril. These phenomena can develop at any stage of treatment. In this case, lisinopril should be immediately withdrawn and appropriate monitoring should be established to ensure that the symptoms disappear completely before the patient is discharged. Even in cases where there is only swelling of the tongue without the development of respiratory failure, prolonged monitoring of the patient may be required, since therapy with antihistamines and corticosteroids may not be enough. Death has been reported very rarely due to angioedema (swelling of the larynx or tongue). In cases where swelling of the tongue, glottis or larynx develops, which is likely to cause obstruction of the airways, appropriate emergency therapy should be started immediately. It may include prescribing epinephrine and / or maintaining the patients airway. The patient should be under close medical supervision until the symptoms disappear completely and persistently. Angioneurotic edema can also affect the intestines and cause acute abdominal pain, nausea, vomiting, and diarrhea.

Patients who have a history of angioedema that is not associated with ACE inhibitors may be at increased risk of developing it during treatment with ACE inhibitors (see CONTRAINDICATIONS).

In patients receiving thiazide diuretic therapy, a hypersensitivity reaction may develop regardless of the presence or absence of a history of allergies or AD. An exacerbation or activation of systemic lupus erythematosus with thiazide has been reported.

Race. The frequency of development of angioedema due to the use of ACE inhibitors is higher in representatives of the ethnic group of African Americans in comparison with patients of other races. As with other ACE inhibitors, lisinopril can lower blood pressure less effectively among members of the African American ethnic group than patients of other races, which may be a consequence of the higher incidence of low-root hypertension in these patients.

Anaphylactic reactions due to apheresis of LDL. In rare cases, patients receiving therapy with ACE inhibitors have developed life-threatening anaphylactic reactions during LDL apheresis with dextran sulfate. These symptoms can be avoided by temporarily discontinuing therapy with ACE inhibitors before each apheresis.

Desensitization. Patients receiving ACE inhibitors during desensitizing therapy (such as hymenoptera venom) can develop an anaphylactic reaction. In these same patients, such a reaction was avoided by temporarily refusing to take ACE inhibitors, but it appeared again when the drug was accidentally re-prescribed.

Hyperkalemia Some patients treated with ACE inhibitors, including lisinopril, showed an increase in potassium in the blood plasma. The risk group for the development of hyperkalemia included patients with renal failure, diabetes mellitus, and those taking potassium-sparing diuretics at the same time, consuming potassium supplements or salt substitutes containing potassium, and those taking other drugs that could cause an increase in plasma potassium blood (e.g. heparin). If the simultaneous use of the above funds is considered necessary, regular monitoring of potassium in the blood plasma is recommended.

Neutropenia / agranulocytosis / thrombocytopenia / anemia. The development of neutropenia, agranulocytosis, thrombocytopenia, and anemia has been reported in patients receiving therapy with ACE inhibitors. In patients with normal renal function without other complicating factors, neutropenia rarely develops. Neutropenia and agranulocytosis disappear when you stop taking ACE inhibitors.

In patients with vascular collagenosis receiving immunosuppressive therapy, treatment with allopurinol or procainamide or having a combination of these complicating factors, especially against the background of an existing renal dysfunction, lisinopril should be used with extreme caution. Some of these patients developed serious infections, which in several cases did not respond to intensive antibiotic therapy. When prescribing lisinopril to such patients, the white blood cell count should be regularly monitored, and the patient should be advised to report all signs of infections.

Cough. Cough development has been reported in patients taking ACE inhibitors. The cough is unproductive, persistent, and stops after discontinuation of therapy. The fact that ACE inhibitors cause a cough should be considered when conducting a differential diagnosis of cough.

Lithium preparations. A combination of ACE inhibitors and lithium preparations should be avoided (see INTERACTIONS).

Photosensitization reactions. During treatment with thiazide diuretics, cases of photosensitization reactions have been reported. If photosensitization reactions occur during treatment, it is recommended to cancel the drug. If the doctor believes that you need to re-prescribe the drug, it is recommended to protect parts of the body that are exposed to sunlight or artificial UV radiation.

Laboratory indicators. The drug can affect the results of the following laboratory tests: plasma hydrochlorothiazide can reduce protein-bound iodine (treatment with hydrochlorothiazide should be discontinued before a laboratory examination to evaluate parathyroid function) and increase the concentration of free bilirubin in blood plasma.

Use during pregnancy and lactation. The use of ACE inhibitors is not recommended in the first trimester of pregnancy (see SPECIAL INDICATIONS and CONTRAINDICATIONS).The use of ACE inhibitors is contraindicated in the II and III trimester of pregnancy (see CONTRAINDICATIONS and SPECIAL INDICATIONS).

The available data on the risk of developing a teratogenic effect when exposed to ACE inhibitors in the first trimester of pregnancy were not final; however, a slight increase in this risk cannot be ruled out. While continued therapy with ACE inhibitors is considered necessary, patients planning a pregnancy should be transferred to alternative antihypertensive therapy, including drugs with an established safety profile for use during pregnancy. If pregnancy has occurred, treatment with ACE inhibitors should be stopped immediately and, if possible, alternative therapy should be started (see CONTRAINDICATIONS).

The use of ACE inhibitors in the II and III trimester of pregnancy, as is known, causes fetotoxic effects in humans (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If ACE inhibitors were used in the third trimester of pregnancy, ultrasound monitoring of the skull bones and renal function is recommended. Newborns whose mothers have taken ACE inhibitors should be closely monitored in connection with the possible development of arterial hypotension (see CONTRAINDICATIONS and USAGE sections).

The use of diuretics in healthy pregnant women is not recommended, since the woman and the fetus are exposed to unnecessary danger, including the possible development of jaundice of the fetus and newborn, thrombocytopenia and other adverse reactions similar to those observed in adult patients.

Hydrochlorothiazide cannot be used to treat edema, hypertension, or preeclampsia in pregnant women, because instead of having a beneficial effect on the course of the disease, it increases the risk of a decrease in plasma volume and worsens the uteroplacental blood supply.

Lysinopril penetrating the placenta was excreted from the bloodstream of newborns by