Hydrochlorothiazide, ramipril

Pharmacological properties

mechanism of action

Ramipril. Ramiprilat, an active metabolite of the ramipril prodrug, inhibits the enzyme dipeptidyl carboxypeptidase I (ACE or kininase II).

In plasma and tissues, this enzyme catalyzes the conversion of angiotensin I into the active vasoconstrictor substance angiotensin II, and also causes the destruction of the active vasodilator bradykinin. A decrease in the formation of angiotensin II and inhibition of the destruction of bradykinin leads to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat leads to a decrease in aldosterone secretion. In patients of a Negroid race (Afro-Caribbean origin) with hypertension (usually a low level of renin activity is characteristic of the population), the response to ACE inhibitor monotherapy was on average less pronounced than in representatives of other races.

Hydrochlorothiazide. Hydrochlorothiazide is a thiazide-type diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not yet fully understood. They slow down the reabsorption of sodium and chlorine ions in the distal tubules. The increased excretion of these ions through the kidneys is accompanied by an increase in urination (due to osmotic binding of water). Excretion of potassium and magnesium increases, uric acid excretion decreases. Possible mechanisms of the antihypertensive effect of hydrochlorothiazide may be a change in sodium balance, a decrease in extracellular volume of water and blood plasma, a change in the resistance of renal vessels, and also a decrease in sensitivity to angiotensin II.

Pharmacodynamics

Ramipril. The use of ramipril causes a marked decrease in peripheral resistance of the arteries. As a rule, there are no significant changes in the blood plasma flow in the kidneys and the glomerular filtration rate. In patients with hypertension, the use of ramipril leads to a decrease in blood pressure in a standing and lying position without a compensatory increase in heart rate. In most patients, the onset of the hypotensive effect after taking a single dose appears 1–2 hours after ingestion. The peak effect of a single dose is usually achieved within 3-6 hours after ingestion. The antihypertensive effect of a single dose usually lasts for 24 hours. With prolonged treatment with ramipril, the maximum hypotensive effect is usually achieved after 3-4 weeks of treatment. It is proved that with prolonged therapy, the hypotensive effect persists for 2 years. The sudden cessation of ramipril does not cause a rapid and excessive increase in blood pressure.

Hydrochlorothiazide. When taking hydrochlorothiazide, the onset of the diuretic effect takes place after 2 hours, and its peak after about 4 hours, the effect lasts for 6-12 hours.

The antihypertensive effect occurs on the 3-4th day from the start of therapy and can continue for 1 week after cessation of treatment.

The effect of lowering blood pressure is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance and plasma renin activity.

The simultaneous use of ramipril and hydrochlorothiazide.In clinical studies, it was found that the use of the combination leads to a more significant decrease in blood pressure than the use of individual components. Perhaps due to the blockade of the renin-angiotensin-aldosterone system (RAAS), the simultaneous use of ramipril with hydrochlorothiazide reduces the potassium loss accompanying the diuretic effect. The combination of an ACE inhibitor with a thiazide diuretic causes a synergistic effect, and also reduces the risk of hypokalemia caused by the use of the diuretic itself.

Pharmacokinetics

Ramipril. After taking ramipril, it is rapidly absorbed in the digestive tract. Absorption is 50-60% and does not depend on food intake. C_max in plasma achieved within 1 h. T_½ ramipril is 1 hour. Ramipril is metabolized in the liver. The main metabolite is ramiprilat, whose power as an ACE inhibitor is 6 times higher compared to ramipril. C_max ramiprilat in blood plasma is reached after 2–4 hours after administration, a constant concentration in plasma is reached after 4 days.

Approximately 73% of ramipril and 56% of ramiprilat binds to plasma proteins.

Ramipril and ramiprilat are mainly excreted in the urine (approximately 60%), mainly in the form of metabolites, and less than 2% of the administered dose is excreted unchanged in ramipril.

Ramiprilat is excreted through several stages. After ramipril is administered at a therapeutic dose, the final T_½ is from 13 to 17 hours

In patients with renal insufficiency, the excretion of ramipril, ramiprilat, and their metabolites slows down, so the dose must be adjusted depending on the function of the kidneys (see APPLICATION).

In patients with hepatic insufficiency, the metabolic conversion of ramipril to ramiprilat may slow down due to a decrease in the activity of hepatic esterases, which causes an increase in the concentration of ramipril in the blood plasma (see APPLICATION).

Hydrochlorothiazide. After oral administration, 70% of hydrochlorothiazide is absorbed in the digestive tract. C_max in blood plasma is reached after 1.5-5 hours. It binds to blood plasma proteins by approximately 40%. Hydrochlorothiazide is metabolized in the liver in very small amounts. 95% of hydrochlorothiazide is excreted by the kidneys unchanged. Excretion is the result of tubular excretion. After oral administration of a single dose, 50–70% is excreted within 24 hours. T_½ 5-6 hours

Patients with impaired renal function (see APPLICATION). The excretion of hydrochlorothiazide by the kidney is reduced in patients with impaired renal function, the clearance of hydrochlorothiazide is proportional to the creatinine clearance. This leads to an increase in the concentration of hydrochlorothiazide in blood plasma, which decreases more slowly than in patients with normal renal function.

Patients with impaired liver function (see APPLICATION). In patients with cirrhosis, the pharmacokinetics of hydrochlorothiazide are unchanged in a significant way. The pharmacokinetics of hydrochlorothiazide has not been studied in patients with heart failure.

Ramipril and hydrochlorothiazide.The simultaneous use of ramipril and hydrochlorothiazide does not affect their bioavailability. A combined preparation can be considered a bioequivalent preparation containing individual active substances.

Preclinical safety data. In rats and mice, the use of a combination of ramipril and hydrochlorothiazide at a dose of up to 10,000 mg / kg body weight did not lead to acute toxic effects. Studies with repeated doses of rats and monkeys showed only the occurrence of electrolyte imbalance. Studies on the mutagenicity and carcinogenicity of this combination have not been conducted, since no risks have been identified in studies of the individual components. Studies on reproductive toxicity have shown that the combination is slightly more toxic than any of the active substances taken separately, however, none of the studies showed teratogenic effects of this combination.

Indications

Hypertension treatment.

The use of this fixed combination is indicated for patients in whom blood pressure is not adequately controlled with ramipril or hydrochlorothiazide monotherapy.

Application

The combination of ramipril with hydrochlorothiazide in a fixed dose is recommended to be used only after preliminary individual titration of doses. start treatment with the lowest possible dose. if necessary, the daily dose can be gradually increased over 2-3 weeks until the target hell is reached. the usual maintenance dose is 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide per day, the maximum dose is 5 mg of ramipril and 25 mg of hydrochlorothiazide per day.

The drug is recommended to be taken 1 time per day at the same time, preferably in the morning. The drug can be taken before, during and after a meal, since eating does not affect the bioavailability of the drug. The tablet should not be chewed or broken, but should be swallowed whole, washed down with liquid (at least half a glass).

Missed dose. If the dose is missed, it should be taken as soon as possible. However, if the fact of skipping the dose was detected at a time close to the time of the next dose, then you should not take the missed dose, but follow the regular dosing schedule. Do not double the dose.

Patients with impaired renal function. Due to the presence of the hydrochlorothiazide component, the drug is contraindicated in patients with severe renal failure (creatinine clearance of 30 ml / min) (see CONTRAINDICATIONS).

Patients with impaired renal function may require a reduction in the dose of Ampril HL / Ampril HD. Patients with creatinine clearance levels in the range of 30 to 60 ml / min should only be treated with a combination of low fixed doses of ramipril and hydrochlorothiazide after ramipril monotherapy. The maximum permitted doses are 5 mg of ramipril and 25 mg of hydrochlorothiazide per day.

Patients using diuretics. It is recommended to pay attention to patients who use diuretics in combination, since after the start of treatment arterial hypotension may develop.Before starting therapy with the drug, you should reduce the dose of the diuretic or stop its use.

Patients with impaired liver function. In patients with mild to moderate hepatic impairment, treatment should be started under close medical supervision. The maximum daily doses are 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide.

Ampril HL / Ampril HD is contraindicated in cases of severe impairment of liver function (see CONTRAINDICATIONS).

Elderly patients. The initial dose should be lower, the next dose titration should be more gradual, given the high likelihood of adverse reactions, especially in the elderly over 70 years.

Contraindications

• Hypersensitivity to ramipril or any other substance that is part of the drug, as well as to other APF inhibitors; hypersensitivity to hydrochlorothiazide or other sulfonamides; hypersensitivity to other thiazide diuretics; hepatic encephalopathy, severe dysfunction of the liver; arterial hypotension or hemodynamically unstable condition; anuria a history of angioedema (hereditary, idiopathic, or previously transferred with the use of apf inhibitors or angiotensin II receptor antagonists ii); primary hyperaldosteronism; extracorporeal treatment, which leads to contact of blood with negatively charged surfaces; significant bilateral renal artery stenosis or renal artery stenosis of a single functioning kidney; severe renal failure (creatinine clearance 30 ml / min) in patients who do not undergo hemodialysis; clinically significant electrolyte imbalance, which may worsen after treatment with the drug ampril hl / ampril hd; pregnant women or women planning a pregnancy (see use during pregnancy and lactation).

Side effects

The safety profile of the combination of ramipril and hydrochlorothiazide includes adverse reactions that occur in case of arterial hypotension and / or hypovolemia due to increased diuresis. the active substance ramipril can cause a persistent dry cough, and the active substance hydrochlorothiazide can disrupt the metabolism of glucose, lipids and uric acid. two active substances have opposite effects on the level of potassium in blood plasma. serious adverse reactions include angioedema or anaphylactic reactions, impaired renal or hepatic function, pancreatitis, severe skin reactions and neutropenia / agrunolocytosis.

The frequency of adverse reactions was determined using the following classification: very often (≥1 / 10); often (≥1 / 100–1 / 10); infrequently (≥1 / 1000–1 / 100); rarely (≥1 / 10,000–1 / 1000); very rarely (1/10 000), unknown (impossible to calculate according to available data).

Within each group, adverse reactions are listed in decreasing order of severity.

special instructions

Patients at particular risk of arterial hypotension. patients with increased activity raas. patients with very activated raas have a risk of a significant decrease in hell and impaired renal function due to inhibition of apf. this is especially true in cases where an apf inhibitor or concomitant diuretic is used for the first time or the dose is increased for the first time.

Significant activation of RAAS is to be expected, therefore medical observation is required, including monitoring of blood pressure, for example, for patients with:

• severe hypertension;
• decompensated heart failure with congestion;
• hemodynamically significant obstruction of the pathways of the inflow or outflow of blood from the left ventricle (for example, stenosis of the aortic or mitral valve);
• unilateral renal artery stenosis in the presence of a second functioning kidney;
• who have or may develop a water-salt imbalance (including patients taking diuretics);
• cirrhosis of the liver and / or ascites;
• who undergo extensive surgery or during anesthesia with drugs that can cause arterial hypotension.

As a rule, before starting treatment, it is recommended to correct dehydration, hypovolemia or lack of electrolytes (however, in patients with heart failure, such corrective measures should be carefully weighed taking into account the risk of volume overload).

Surgical intervention. If possible, it is recommended that ACE inhibitors, such as ramipril, be discontinued 1 day before surgery.

Patients at risk of cardiac or cerebral ischemia in case of acute arterial hypotension. The initial phase of leche