Pharmacy No. 84. Delivery of medicines to your home and office.

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Amlodipine + Perindopril (Amlodipinum + Perindoprilum)

When taking ACE inhibitors, incl. and perindopril, in rare cases, the development of angioedema of the face, extremities, lips, mucous membranes, tongue, vocal folds and/or larynx may occur. If symptoms appear, the drug should be stopped immediately and the patient should be observed until signs of edema completely disappear. If the swelling affects only the face and lips, it usually resolves on its own, although antihistamines may be used to treat symptoms.

Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal cords, or larynx can lead to airway obstruction. If such symptoms occur, epinephrine (adrenaline) should be immediately administered subcutaneously and/or the airway should be secured. The patient should be under medical supervision until symptoms disappear completely and permanently.

Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group.

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases, without previous angioedema of the face and with normal levels of C1-esterase. The diagnosis is made using computed tomography of the abdominal region, ultrasound, or at the time of surgery. Symptoms disappear after stopping ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

Anaphylactoid reactions during desensitization

There are isolated reports of the development of anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy (for example, hymenoptera venom). In these same patients, an anaphylactoid reaction was avoided by temporarily discontinuing ACE inhibitors, and if the drug was accidentally taken, the anaphylactoid reaction occurred again.

Neutropenia, agranulocytosis, thrombocytopenia, anemia

While taking ACE inhibitors, neutropenia/agranulocytosis, thrombocytopenia and anemia may occur. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Perindopril should be used with extreme caution in patients with systemic connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function.

Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should report any signs of infectious diseases (eg, sore throat, fever) to their doctor.

Arterial hypotension

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic arterial hypotension rarely develops in patients without concomitant diseases. The risk of an excessive decrease in blood pressure is increased in patients with reduced blood volume, which can be observed during diuretic therapy, following a strict salt-free diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe arterial hypertension with high renin activity. In patients at increased risk of developing symptomatic hypotension, blood pressure, renal function, and serum potassium levels should be carefully monitored during drug therapy.

A similar approach is also used in patients with angina pectoris and cerebrovascular diseases, in whom severe arterial hypotension can lead to myocardial infarction or cerebrovascular accident.

If arterial hypotension develops, the patient should be placed in a supine position with legs elevated. If necessary, the bcc should be replenished with the intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle to further taking the drug. After restoration of blood volume and blood pressure, treatment can be continued.

Mitral stenosis, aortic stenosis, hypertrophic obstructive cardiomyopathy

Like other ACE inhibitors, the drug should be administered with caution to patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as to patients with mitral stenosis.

Renal dysfunction

In patients with renal failure (creatinine clearance less than 60 ml/min), individual selection of doses of perindopril and amlodipine is recommended. Such patients require regular monitoring of potassium and creatinine levels in the blood serum.

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney during therapy with ACE inhibitors, an increase in serum urea and creatinine levels is possible, which usually resolves when therapy is discontinued. This effect is most often observed in patients with renal failure. The additional presence of renovascular hypertension causes an increased risk of severe hypotension and renal failure in such patients.

In some patients with arterial hypertension without signs of renal vascular damage, an increase in the concentration of urea and creatinine in the blood serum is possible, especially when perindopril is co-administered with a diuretic, usually slight and transient. This effect is more often observed in patients with pre-existing renal impairment.

Liver failure

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in the activity of liver enzymes occurs while taking ACE inhibitors, you should stop taking the drug.

Ethnic differences

In patients of the Negroid race, angioedema develops more often than in representatives of other races while taking ACE inhibitors.

Perindopril, like other ACE inhibitors, may have a less pronounced antihypertensive effect in patients of the Black race compared to representatives of other races. This difference may be due to the fact that black patients with arterial hypertension are more likely to have low renin activity.

Cough

During therapy with an ACE inhibitor, a dry cough may occur. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should be aware of the possible iatrogenic nature of this symptom.

Surgery/general anesthesia

The use of ACE inhibitors in patients undergoing major surgery and/or general anesthesia can lead to a significant decrease in blood pressure if general anesthesia agents with a hypotensive effect are used. This is due to blocking the formation of angiotensin II against the background of a compensatory increase in renin activity. If the development of arterial hypotension is associated with the described mechanism, the volume of circulating plasma should be increased. It is recommended to warn the surgeon/anesthesiologist that the patient is taking ACE inhibitors and stop taking the drug 24 hours before surgery.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, incl. and perindopril. Risk factors for hyperkalemia are renal failure, age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), and also potassium preparations or potassium-containing substitutes for table salt, as well as the use of other drugs that increase the content of potassium in the blood plasma (for example, heparin). The use of potassium supplements, potassium-sparing diuretics, and potassium-containing table salt substitutes can lead to a significant increase in potassium levels in the blood, especially in patients with reduced renal function.

Hyperkalemia can cause serious, sometimes fatal, abnormal heart rhythms. If simultaneous use of perindopril and the above drugs is necessary, treatment should be carried out with caution against the background of regular monitoring of potassium levels in the blood serum.

Patients with diabetes mellitus

When prescribing the drug to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentrations should be carefully monitored during the first month of therapy.

Amlodipine

The effectiveness and safety of amlodipine in hypertensive crisis has not been established.

Heart failure

Patients with heart failure should be treated with caution. When using amlodipine in patients with chronic heart failure of functional class III and IV according to the NYHA classification, pulmonary edema may develop. Slow calcium channel blockers, including amlodipine, should be used with caution in patients with chronic heart failure due to a possible increased risk of cardiovascular adverse events and mortality.

Liver failure

In patients with impaired liver function, T1/2 and AUC of amlodipine are increased. Taking amlodipine should be started with the lowest doses and precautions should be taken both at the beginning of treatment and when increasing the dose. In patients with severe hepatic impairment, the dose should be increased gradually, ensuring careful monitoring of the clinical condition.

Elderly patients

In elderly patients, T1/2 may increase and amlodipine clearance may decrease. No dose changes are required, but more careful monitoring of patients in this category is necessary.

In patients with impaired renal function, monitoring of the condition is necessary.

Kidney failure

Patients with renal failure can take amlodipine in standard doses. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal failure. Amlodipine is not excreted from the body by dialysis.

Excipients

Due to the presence of lactose in the drug, it should not be prescribed to patients with hereditary lactose intolerance, lactase deficiency and glucose/galactose malabsorption syndrome.

Impact on the ability to drive vehicles and operate machinery

Although no negative effects on the ability to drive vehicles or other complex mechanisms were observed while taking the drug, due to a possible excessive decrease in blood pressure, the development of dizziness, drowsiness and other adverse reactions, caution should be exercised in these situations, especially at the beginning of treatment and when increasing the dose.

Discussion

It is generally accepted that home BP measurement is an essential adjunct to IPV [2, 3]. It is emphasized that for optimizing dynamic monitoring, AMS is more effective than 24-hour blood pressure monitoring (ABPM) [2]. Thus, compared to ABPM, ABPM provides data over a long period of time, allows one to assess blood pressure variability on different days, is cheaper, more accessible and easier to repeat [2]. The prognostic significance of home blood pressure measurements is very high [2]. Thus, home BP correlates more strongly with hypertension-induced target organ damage, in particular with LVMH, than IPV [16]. A number of meta-analyses of prospective studies conducted in the general population, in primary care and in patients with hypertension indicate that home BP helps predict cardiovascular morbidity and mortality much more accurately than IPV [17, 18].

Therefore, the data obtained in this subanalysis are extremely important: during treatment with Prestance, the morning and evening values of SBP and DBP, according to SBP data, significantly and statistically significantly decrease at each subsequent visit compared to the previous one, and the target level of blood pressure according to DMBP at the end of the period observations were noted in almost 80% of cases.

We should also not forget that standard blood pressure measurement (RBP) remains the “gold standard” for the diagnosis and treatment of hypertension [2, 3]. Therefore, it deserves special attention that target blood pressure levels for IPV were achieved by 93% of patients in the sample considered in this subanalysis. Transferring patients to a fixed combination of perindopril arginine/amlodipine, starting from the 2nd visit, led to a significant decrease in SBP and DBP during IPV, and subsequently this effect increased from visit to visit. Therefore, it can be concluded that Prestance demonstrates a very good antihypertensive effect in clinical practice, and this is confirmed by data from both IPV and DMAD.

In recent years, interest in increased blood pressure variability as a risk factor for the development of CVD, cerebral and renal complications, as well as death from CVD has grown significantly [4–7]. There are different types of blood pressure variability and, although there is no generally accepted classification, variability is usually divided into short-term and long-term [19], although some authors also distinguish medium-term blood pressure variability [20]. According to various classifications, blood pressure variability on different days is classified as either long-term [19] or medium-term [20]. Variability of A.D. on different days is determined based on the results of SCAD, including separately for morning and evening measurements [21, 22]. Increased BP variability (SBP and DBP) on different days is an independent prognostic factor for death from CVD, and increased SBP variability is a predictor of stroke [23]. According to the results of a Finnish study [22], variability in SBP and/or DBP on different days, morning SBP and DBP, and differences between morning and evening SBP and DBP values were independent predictors of death from any disease and the risk of developing fatal and nonfatal CV events. The prognostic significance of evening DBP variability in relation to overall mortality has also been revealed [22]. In light of the above, it seems extremely important that Prestance therapy in clinical practice led to a significant decrease in all parameters characterizing blood pressure variability according to SBP.

The prognostic significance of BP variability between visits is beyond doubt [4, 5, 19, 20]. The results of the NHANES III study (The National Health and Nutrition Examination Survey) [5] involving 956 subjects demonstrated that SBP variability between visits was >4.80 mmHg. is associated with a 57% increase in overall mortality. The present subanalysis documented that treatment with Prestance significantly reduced inter-visit SBP variability to less than 4.8 mmHg. (at the end of the observation period it averaged 3.8 mm Hg). A decrease in SBP variability between visits during treatment with Prestance was previously found in other Russian studies performed in clinical practice [24, 25].