pharmachologic effect
Perindopril is an angiotensin-converting enzyme (ACE) inhibitor, or kininase II, an exopeptidase. Converts angiotensin I into the vasoconstrictor angiotensin II and destroys the vasodilator bradykinin to an inactive heptapeptide. Suppression of ACE activity leads to a decrease in the concentration of angiotensin II and an increase in renin activity in the blood plasma (suppressing the negative feedback of renin release) and a decrease in aldosterone secretion. Since ACE also destroys bradykinin, suppression of ACE also leads to an increase in the activity of the circulating and tissue kallikrein-kinin system, while the prostaglandin system is activated.
Perindopril has a therapeutic effect due to its active metabolite, perindoprilat.
Perindopril reduces both systolic and diastolic blood pressure (BP) in the supine and standing positions. Perindopril reduces total peripheral vascular resistance (TPVR), which leads to a decrease in blood pressure. At the same time, peripheral blood flow accelerates. However, the heart rate (HR) does not increase.
Renal blood flow usually increases, while the glomerular filtration rate does not change. The maximum antihypertensive effect is achieved 4-6 hours after a single oral dose of perindopril; the antihypertensive effect lasts for 24 hours.
The decrease in blood pressure develops quickly.
Stabilization of the antihypertensive effect is observed after 1 month of therapy and persists for a long time.
Termination of therapy is not accompanied by the development of withdrawal syndrome.
Perindopril reduces left ventricular myocardial hypertrophy.
With long-term use, it reduces the severity of interstitial fibrosis and normalizes the myosin isoenzyme profile.
Increases the concentration of high-density lipoproteins (HDL); in patients with hyperuricemia, reduces the concentration of uric acid.
Perindopril improves the elasticity of large arteries and eliminates structural changes in small arteries.
Perindopril normalizes heart function, reducing pre- and afterload.
In patients with chronic heart failure (CHF) during therapy with perindopril, the following was noted:
- decrease in filling pressure in the left and right ventricles,
- decrease in OPSS,
- increase in cardiac output and cardiac index.
Taking an initial dose of perindopril 2 mg in patients with CHF functional class I-II according to the NYHA classification is not accompanied by a statistically significant decrease in blood pressure compared to placebo.
Parnavel Amlo
Special instructions regarding perindopril and amlodipine apply to Parnavel Amlo.
Perindopril
Hypersensitivity/angioedema
When taking ACE inhibitors, including 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 folds, 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 a normal level 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 low-density lipoprotein (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 desensitization 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 diffuse 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 hypotension rarely develops in patients without concomitant diseases. The risk of excessive reduction in blood pressure is increased in patients with reduced circulating blood volume, which can be observed during diuretic therapy, while 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 transferred to the “lying” position on his back with his legs elevated. If necessary, the volume of circulating blood should be replenished with intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle to further taking the drug. After restoration of circulating blood volume and blood pressure, treatment can be continued.
Mitral stenosis/aortic stenosis/hypertrophic cardiomyopathy
The drug, like other ACE inhibitors, 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.), it is recommended that the doses of perindopril and amlodipine be adjusted individually. 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 the concentration of urea and creatinine in the blood serum 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 and consult a doctor.
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 hypotensive effect in patients of the Black race compared to representatives of other races. Perhaps this difference is due to the fact that patients with arterial hypertension of the Negroid race more often 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. When patients develop 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 anesthetic 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 blood plasma should be increased. It is recommended to stop taking 24 hours before surgery.
Hyperkalemia
Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, old 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 ), as well as potassium preparations or potassium-containing substitutes for table salt, as well as the use of other drugs that help increase the content of potassium in the blood plasma (for example, heparin). The use of potassium supplements, potassium-sparing diuretics, and potassium-containing 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 prescribed 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, the metabolism of amlodipine slows down. 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, the half-life of amlodipine may increase and the 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.
Parnavel Amlo
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.
Impact on the ability to drive vehicles and operate machinery
Due to the possible development of weakness, dizziness, and drowsiness, caution should be exercised when driving vehicles and engaging in certain activities that require increased concentration and rapid motor response.
Contraindications
- Hypersensitivity to perindopril or other components of the drug, as well as to other ACE inhibitors;
- pregnancy;
- breastfeeding period;
- history of angioedema (hereditary, idiopathic or angioedema due to taking ACE inhibitors);
- age under 18 years (efficacy and safety have not been established).
- Concomitant use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 body surface area),
- simultaneous use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy.
