Hydrochlorothiazide, quinapril

Pharmacological properties

Accuzide is a combined preparation consisting of an apf inhibitor quinapril hydrochloride and a hydrochlorothiazide diuretic.

Quinapril and hydrochlorothiazide are used in monotherapy or as part of combination therapy for hypertension. The antihypertensive effect of these two components is approximatively additive. Quinapril may reduce the potassium loss associated with hydrochlorothiazide.

Mechanism of action

Quinapril

Quinapril is hydrolyzed in the liver to quinaprilat (quinapril diacid, the main metabolite), which is an ACE inhibitor.

ACE is a peptidyldipeptidase, which affects the conversion of angiotensin I into a vasoconstrictor substance angiotensin II. ACE inhibition leads to a decrease in the formation of angiotensin II, which has a vasoconstrictor effect in tissues and blood plasma, and this leads to a decrease in the secretion of aldosterone and, as a result, to an increase in the concentration of potassium in blood plasma. Increased plasma renin activity is the result of the cessation of negative feedback between angiotensin II and renin secretion.

Since ACE also metabolizes bradykinin (a vasodilator peptide), inhibition of ACE leads to increased activity of circulating and local kallikrein-kinin systems (and, consequently, to the activation of the prostaglandin system). Perhaps this mechanism plays a role in the reduction of blood pressure by ACE inhibitors and the development of certain adverse reactions.

Hydrochlorothiazide

Hydrochlorothiazide is a benzothiadiazine. Thiazides act directly on the kidneys, enhancing the excretion of sodium chloride and the associated excretion of water. The clinically significant primary site where the action is directed is the distal tubule. Thiazides inhibit the electrically neutral NaCl cotransport in the luminal membrane of the cells lining the tubule. Excretion of potassium and magnesium increases, and excretion of calcium decreases. Hydrochlorothiazide leads to low excretion of bicarbonate, and the excretion of chloride exceeds the excretion of sodium. In the case of the use of hydrochlorothiazide, metabolic alkalosis may develop. Hydrochlorothiazide is actively secreted in the proximal tubules. The diuretic effect is maintained with metabolic acidosis or metabolic alkalosis.

The mechanisms of the antihypertensive effect of hydrochlorothiazide are changes in sodium balance, a decrease in the volume of extracellular fluid and blood plasma, a change in renal vascular resistance and a decrease in sensitivity to norepinephrine and angiotensin II.

Pharmacodynamics

Quinapril

In patients with hypertension, quinapril reduces blood pressure while lying and standing without a compensatory increase in heart rate.

During hemodynamic studies, quinapril caused a significant decrease in peripheral arterial resistance. Typically, clinically significant changes in renal plasma flow and glomerular filtration rate are absent.

In most patients, the onset of antihypertensive action was observed approximately 1 hour after ingestion of Accuside, and the maximum effect was achieved after approximately 2–4 hours. The maximum hypotensive effect of a certain dose of quinapril was mainly observed after 3-4 weeks.

In the case of a daily dose, the antihypertensive effect persists even with prolonged therapy. The sudden cessation of the use of the drug Accuzide does not lead to a rapid excessive increase in blood pressure (recoil phenomenon).

The concomitant use of an ACE inhibitor and angiotensin II receptor blocker was evaluated in two large randomized controlled trials (ONTARGET study [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D study [The Veterans Affairs Nephropathy in Diabetes / Veterans Study with Nephropathy and Diabetes]).

The ONTARGET study was performed in patients with a history of cardiovascular or cerebrovascular disease or type II diabetes mellitus with signs of target organ damage. The VA NEPHRON-D study was conducted in patients with type II diabetes mellitus and diabetic nephropathy.

These studies found a slight beneficial effect in the treatment of renal and / or cardiovascular diseases and a decrease in mortality, while compared with monotherapy, there was an increased risk of hyperkalemia, acute kidney damage, and / or arterial hypotension. The results also apply to other ACE inhibitors and angiotensin II receptor blockers, given similar pharmacodynamic properties.

Therefore, patients with diabetic nephropathy should not simultaneously use ACE inhibitors and angiotensin II receptor blockers.

The ALTITUDE study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was conducted to evaluate the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blockers in patients with type II diabetes mellitus and chronic kidney disease, cardiovascular disease, or two diseases simultaneously. The study was terminated prematurely due to an increased risk of unwanted effects. Quantitatively, cases of both fatal outcome from cardiovascular diseases and stroke were noted more often in the aliskiren group compared with the placebo group; adverse events and some serious adverse reactions (hyperkalemia, arterial hypotension and impaired renal function) also more often occurred in the aliskiren group compared with the placebo group.

Hydrochlorothiazide

Excretion of electrolytes and water begins 2 hours after taking hydrochlorothiazide; the maximum effect is achieved after 3–6 hours and lasts for 6–12 hours.

Antihypertensive effect occurs in 3-4 days and can last up to 1 week after the end of therapy.

Pharmacokinetics

Quinapril. Following oral administration of C_max quinapril in plasma is reached within 1 hour. Eating does not affect the absorption of quinapril. After absorption, quinapril is rapidly and almost completely metabolized to its main metabolite, quinaprilat. Several other quantitatively unimportant and pharmacologically inactive metabolites are also formed. C_max quinaprilat in plasma is observed approximately 2-3 hours after oral administration of quinapril. The binding of quinapril and quinaprilat to proteins is approximately 97%. About 60% of the administered dose of quinapril is excreted by the kidneys, and 40% is excreted in the feces. Quinaprilat is secreted mainly by the kidneys with an effective cumulation half-life of 3 hours, the ACE dissociation half-life is about 26 hours. Normal dynamics of plasma levels of quinapril and quinaprilat were observed in patients with impaired renal function with creatinine clearance up to 60 ml / min. In patients with creatinine clearance of 60 ml / min, the levels of quinaprilat increase, the time to reach C increases_max, T_½ also increasing.

Pharmacokinetic studies in patients with end-stage kidney disease who underwent continuous hemodialysis or ambulatory peritoneal dialysis showed that dialysis only slightly affects the excretion of quinapril and quinaprilat.

The excretion of quinaprilat is also slower in elderly patients (65 years old) and in people with severe heart failure and correlates with impaired renal function, often noted in elderly people. You may need to reduce the dose of quinapril for patients with moderate renal impairment (creatinine clearance of 30-60 ml / min) and elderly patients. Decreased plasma quinaprilate levels were observed in patients with cirrhosis. It is caused by a decrease in the metabolism of quinapril when passing through the liver.

Hydrochlorothiazide.60–80% of hydrochlorothiazide is absorbed after oral administration. The peak concentration of hydrochlorothiazide in blood plasma, which is 70 ng / ml, is reached 1.5-4 hours after ingestion of 12.5 mg of hydrochlorothiazide; 142 ng / ml - 2–5 hours after ingestion of 25 mg of hydrochlorothiazide; 260 ng / ml - 2-4 hours after ingestion of 50 mg of hydrochlorothiazide.

65% of hydrochlorothiazide binds to plasma proteins; the relative volume of distribution is 0.5–1.1 l / kg body weight.

Hydrochlorothiazide is secreted by almost completely unchanged kidneys (95%). After oral administration of a single dose, 50–70% of the dose is excreted within 24 hours, and the minimum amount of the drug is determined in the urine after 60 minutes.

T_½ is 6–8 hours

Decreased excretion and elongation T_½ observed in renal failure. This process has a close correlation of renal clearance of hydrochlorothiazide with creatinine clearance.

In the presence of cirrhosis, there are no corresponding changes in the pharmacokinetics of hydrochlorothiazide. Studies of the kinetics of hydrochlorothiazide in patients with heart failure have not been conducted.

Bioavailability

Quinapril. According to the results of determining the drug in the urine, the absorption rate of quinapril after oral administration is about 60%.

After a single oral administration of quinapril at a dose of 20 mg by six women breast-feeding, the ratio between the levels of quinapril in milk / blood plasma was 0.12. 4 hours after the use of quinapril in breast milk was not detected. In all cases, the concentration of quinapril in breast milk was below the limit of determination (5 μg / L). It is estimated that a breastfed infant will receive approximately 1.6% of the quinapril dose used by the mother.

Hydrochlorothiazide. The bioavailability of hydrochlorothiazide is about 70% after oral administration.

The combined use of quinapril and hydrochlorothiazide

Film-coated Accuzide tablets are bioequivalent to the simultaneous administration of the corresponding individual substances.

Indications

Essential ag, when it is impossible to provide adequate control of hypertension using only quinapril.

Application

For oral use.

Accuzide can be used regardless of food intake. All the indicated daily amount of the drug must be taken in the morning (once), washed down with a large amount of liquid.

The strip on the tablet serves only for breaking it in order to facilitate swallowing, and not for distribution into equal parts.

The duration of use is determined by the doctor.

In general, treatment of hypertension should begin with low doses of one active substance, and then gradually increase the dose.

Combined therapy with Accuzide is recommended to start only after titration of doses of the individual components (quinapril and hydrochlorothiazide). In the presence of clinical indications, the possibility of an immediate transition from monotherapy to combination therapy should be considered.

Note

Since an excessive decrease in blood pressure is possible when the treatment regimen is changed from quinapril monotherapy to Accuzid combination therapy, in particular in patients with salt and / or liquid deficiency (for example, in case of vomiting, diarrhea, treatment with diuretics), severe hypertension - such patients require observation at least within 6 hours

The usual dose for patients who are shown combination therapy is 1 tablet of Accuzide 10 (corresponding to 10 mg of quinapril and 12.5 mg of hydrochlorothiazide) or Accuside 20 (corresponding to 20 mg of quinapril and 12.5 mg of hydrochlorothiazide) in the morning. The maximum daily dose should not exceed 1 tablet Accuzidea 20.

Special patient groups

Patients with impaired renal function (creatinine clearance - 30-60 ml / min) and elderly patients (65 years).

A careful selection of the dose (titration of the individual components) should be carried out.

Treatment of patients with mild renal failure (creatinine clearance of 30-60 ml / min) should begin with 5 mg of quinapril as monotherapy. The maintenance dose, as a rule, is from 5 to 10 mg of quinapril per day. The maximum dose should not exceed 20 mg of quinapril per day.

A dose titration of hydrochlorothiazide is performed for patients who additionally require a diuretic. In the future, blood pressure control can be performed with Accuzide.

Patients with severe renal insufficiency (creatinine clearance 30 ml / min) should not use Accuzide.

Contraindications

Hypersensitivity to the active substance or other components of the drug, thiazides or sulfonamides (possible cross-reactions should be taken into account).

The presence of a history of congenital / idiopathic angioedema, including that associated with prior therapy with ACE inhibitors.

Impaired renal function (serum creatinine 1.8 mg / dl or creatinine clearance 30 ml / min).

Dialysis procedures.

Bilateral renal artery stenosis or artery stenosis of a single kidney.

After kidney transplantation.

Anuria

Hemodynamically significant stenosis of the aortic or mitral valve or hypertrophic cardiomyopathy.

Decompensated heart failure.

Primary hyperaldosteronism.

Severe hepatic impairment (precoma / coma) or primary liver disease.

Severely impaired liver function.

Clinically significant electrolyte imbalance (hypercalcemia, hypokalemia, hyponatremia).

Childrens age (due to insufficient experience of use).

Pregnancy or women planning to become pregnant (see Use during pregnancy or lactation).

Breastfeeding (see Use during Pregnancy or Breastfeeding). Breastfeeding should be discontinued.

Life-threatening hypersensitivity reactions were observed in patients who underwent LDL apheresis with dextrin-sulfate absorption. This method should not be used in individuals taking ACE inhibitors.

Patients treated with ACE inhibitors during desensitizing insect venom therapy (such as bee or wasp sting) have identified life-threatening hypersensitivity reactions (e.g., decreased blood pressure, shortness of breath, vomiting, allergic skin reactions). These reactions were avoided by the use of alternative therapy before desensitization.

Dialysis or hemofiltration using polyacrylonitrile membranes with high flow rate (AN69) is contraindicated during therapy, since there is a risk of hypersensitivity reactions, including shock. If hemodialysis is necessary, the drug should be replaced with a drug that is not an ACE inhibitor, or alternative membranes for dialysis should be used.

The simultaneous use of the drug Accuzide and medicines containing aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (glomerular filtration rate of 60 ml / min / 1.73 m²) (see Pharmacodynamics and INTERACTIONS).

Side effects

During treatment with quinapril / hydrochlorothiazide, the following adverse reactions were noted with the following frequency: very often (≥1 / 10); often (from ≥1 / 100 to 1/10); infrequently (from ≥1 / 1000 to 1/100); rarely (from ≥1 / 10,000 to 1/1000); very rarely (1/10 000); the frequency is unknown (impossible to estimate from the available data).

^√More often, such increases occurred in patients who used diuretics concomitantly during treatment than those undergoing quinapril monotherapy. Observed increases were often reversible if therapy was continued.

* Adverse reactions associated with quinapril; frequency - with quinapril / hydrochlorothiazide.

** Adverse reactions associated with quinapril; frequency - with the use of quinapril. Reactions not associated with quinapril / hydrochlorothiazide components.

^∞In patients with congenital deficiency of glucose-6-phosphate dehydrogenase, isolated cases of hemolytic anemia * were noted.

Results of clinical laboratory tests

Plasma electrolytes: see SPECIAL INSTRUCTIONS.

Analysis of the level of uric acid, glucose, magnesium in blood plasma, the function of the parathyroid glands and calcium: see SPECIAL INSTRUCTIONS.

Hematological analysis: see SPECIAL INSTRUCTIONS.

Notes

Monitoring of the above laboratory parameters should be carried out before treatment and regularly during the use of the drug Accuzide.It is necessary to carefully monitor the level of electrolytes and creatinine in blood plasma, blood glucose and blood counts, especially at the beginning of therapy and in people at risk (patients with impaired renal function, collagenosis; patients receiving treatment with immunosuppressive drugs, cytostatics, allopurinol, procainamide, glycosides digitalis, corticosteroids, laxatives; in the elderly).

In case of symptoms such as fever, swollen lymph nodes, and / or sore throat, you should immediately check your white blood cell count.

special instructions

Accuid should not be used when performing LDL apheresis with dextran sulfate absorption using high-intensity polyacrylonitrile membranes (an69) or during desensitizing therapy against insect venoms (see Contraindications).

Hypersensitivity reactions. Hypersensitivity reactions are possible (e.g. purpura, photosensitivity, urticaria, necrotizing angiitis, respiratory distress, including pneumonia and