Instructions for Prenesa tablets 4 mg blister No. 30
Composition
active ingredient: perindopril;
1 tablet contains 4 mg of perindopril as tert-butylamine salt;
Excipients: calcium chloride hexahydrate, lactose monohydrate, crospovidone, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: white to off-white, oval, slightly biconvex, with beveled edges and a notch on one side.
Pharmacotherapeutic group
Angiotensin-converting enzyme (ACE) inhibitors, monocomponent. Perindopril. ATC code C09A A04.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (angiotensin-converting enzyme ACE). The converting enzyme, or kinase, is an exopeptidase that enables the conversion of angiotensin I to the vasoconstrictor angiotensin II and also causes the breakdown of the vasodilator bradykinin to an inactive heptapeptide. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which increases the activity of plasma renin (by a feedback mechanism) and reduces the secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also leads to an increase in the activity of the circulating and local kallikrein-kinin system (and, thus, also leads to activation of the prostaglandin system). This mechanism of action is responsible for the blood pressure lowering effect of ACE inhibitors and is partly responsible for some of their side effects (e.g. cough).
Perindopril acts through its active metabolite, perindoprilat. Other metabolites do not demonstrate activity in inhibiting ACE under experimental conditions.
Pharmacodynamic effect
Arterial hypertension.
Perindopril effectively lowers blood pressure in all stages of arterial hypertension: mild, moderate and severe; a decrease in systolic and diastolic blood pressure is observed in the patient both in the supine and standing positions.
Perindopril reduces peripheral vascular resistance, which leads to a decrease in blood pressure. As a result, peripheral blood flow increases without affecting heart rate.
Typically, renal blood flow also increases, while glomerular filtration rate (GFR) is usually unchanged.
The maximum antihypertensive effect develops 4–6 hours after a single dose and persists for at least 24 hours: the T/P ratio (minimum efficacy/maximum efficacy during the day) of perindopril is 87–100%.
Blood pressure decreases rapidly. In patients who respond to treatment, blood pressure normalization occurs within a month and is maintained without tachyphylaxis.
There is no withdrawal effect when perindopril is discontinued.
Perindopril reduces left ventricular hypertrophy.
Clinical studies have shown that perindopril has vasodilating properties. It improves the elasticity of large arteries and reduces the ratio of wall thickness to lumen for small arteries.
Combination therapy with a thiazide diuretic shows an additive synergistic effect. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of diuretic-induced hypokalemia.
Heart failure.
In experimental studies of congestive heart failure induced by coronary artery ligation, perindopril has been shown to reduce myocardial hypertrophy and excessive subendocardial collagen, restore the myosin to isoenzyme ratio, and reduce the incidence of reperfusion arrhythmia.
Perindopril tert-butylamine facilitates the work of the heart by reducing pre- and afterload on the heart.
Studies involving patients with heart failure have demonstrated:
reduction of right and left ventricular filling pressures; reduction of systemic peripheral resistance; increase in cardiac index and improvement of cardiac output; increase in regional muscle blood flow in the myocardium.
In comparative studies, the initial administration of 2 mg perindopril to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure compared with placebo.
Clinical efficacy and safety
Patients with stable coronary artery disease
The primary efficacy endpoint was the composite of cardiovascular mortality, non-fatal myocardial infarction and/or cardiac arrest with subsequent successful revascularization. Treatment with perindopril 8 mg (equivalent to perindopril arginine 10 mg) once daily resulted in a significant absolute reduction in the primary endpoint of 1.9% (20% relative risk reduction, 95% CI [9.4; 28.6] – p<0.001). In patients with a history of myocardial infarction and/or revascularization, an absolute reduction of 2.2% in the primary endpoint was observed, corresponding to a relative risk reduction of 22.4% (95% CI [12.0; 31.6] – p<0.001) compared with placebo.
Use in children
The safety and efficacy of perindopril in children and adolescents under 18 years of age have not been established.
In an open-label, non-comparative clinical study, 62 children aged 2 to 15 years with a glomerular filtration rate > 30 ml/min/1.73 m2 were given perindopril at a mean dose of 0.07 mg/kg. The dose was titrated individually, up to a maximum of 0.135 mg/kg/day, depending on the patient profile and blood pressure response to treatment. 59 patients were enrolled in the study for 3 months, 36 patients continued treatment for at least 24 months (mean study duration 44 months). Systolic and diastolic blood pressure remained stable (from baseline to last visit) in patients previously treated with other antihypertensive drugs and decreased in patients previously untreated. More than 75% of the children had systolic and diastolic blood pressure below the 95th percentile at their last study visit. The safety profile in children was consistent with the known safety profile of perindopril.
Clinical trial data with dual blockade of the renin-angiotensin-aldosterone system (RAAS)
The concomitant use of ACE inhibitors and angiotensin II receptor blockers has been investigated in two large-scale randomized controlled trials [ONTARGET (ONgoing Telmisartan Alone and Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)].
ONTARGET is a study in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with evidence of target organ damage. VA NEPHRON-D is a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
The studies did not show a significant beneficial effect for patients with renal and/or cardiovascular diseases and on mortality from them, while compared with monotherapy there was an increased risk of hyperkalemia, acute kidney injury and/or hypotension. Given the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.
Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren in Type 2 Diabetes with Cardiovascular and Renal Endpoints) is a study of the treatment benefits of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes and/or chronic kidney disease, cardiovascular disease. The study was stopped early due to an increased risk of adverse events. Cardiovascular mortality, stroke, and reports of adverse events and serious complications (hyperkalemia, hypotension, and renal dysfunction) were more frequent in the aliskiren group compared with the placebo group.
Pharmacokinetics
Absorption
After oral administration, perindopril is rapidly absorbed, with peak plasma concentrations occurring within 1 hour. The plasma half-life of perindopril is 1 hour.
Perindopril is a prodrug. 27% of the total amount of perindopril taken is determined in the blood in the form of an active metabolite - perindoprilat. In addition to the active metabolite - perindoprilat, the drug forms 5 metabolites that are inactive. The maximum concentration of perindoprilat in the blood plasma is reached 3-4 hours after administration.
Food intake reduces the conversion of perindopril to perindoprilat, thus reducing its bioavailability, so it is recommended to take the daily dose of perindopril once in the morning before meals.
There is a linear relationship between the dose of perindopril and its concentration in blood plasma.
Distribution
The volume of distribution of unbound perindoprilat is approximately 0.2 l/kg. The binding of perindoprilat to plasma proteins is 20%, mainly to ACE, but this indicator is dose-dependent.
Breeding
Perindoprilat is excreted in the urine. The terminal half-life of the unbound fraction is approximately 17 hours. Steady-state plasma concentrations are reached within 4 days of initiation of treatment.
Special patient groups
Elderly patients
The elimination of perindoprilat is slowed in elderly patients and in patients with heart or renal failure.
It is recommended to select the dose for patients with renal insufficiency, taking into account the degree of insufficiency (creatinine clearance). Dialysis clearance of perindoprilat is 70 ml/min.
Liver dysfunction
The kinetics of perindopril are altered in patients with cirrhosis: the hepatic clearance of perindopril is halved. However, the amount of perindoprilat formed is not reduced. Therefore, no dose adjustment is required in such patients.
Indication
Arterial hypertension. Heart failure. Prevention of recurrent stroke in patients with cerebrovascular disease. Prevention of cardiovascular complications in patients with documented stable ischemic heart disease.
Long-term treatment reduces the risk of myocardial infarction and heart failure (according to the results of the EUROPA study).
Contraindication
Hypersensitivity to the active substance or to any other ingredient of the drug, as well as to other ACE inhibitors.
History of angioedema associated with previous treatment with ACE inhibitors (see section "Special warnings and precautions for use").
Hereditary or idiopathic angioedema.
Concomitant administration with drugs containing the active substance aliskiren in patients with diabetes mellitus or renal insufficiency (glomerular filtration rate < 60 ml/min/1.73 m2) (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).
For women planning pregnancy and pregnant women.
Extracorporeal treatments that result in blood coming into contact with negatively charged surfaces (see section “Interaction with other medicinal products and other types of interactions”).
Significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section "Special warnings and precautions for use").
Interaction with other medicinal products and other types of interactions
Clinical trial data suggest that dual blockade of the RAAS through the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared with the use of a single RAAS-acting agent (see sections 4.3 and 4.4).
Drugs that cause hyperkalemia
Some medicinal products or therapeutic classes of medicinal products may cause hyperkalaemia, such as: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. Concomitant use of these medicinal products increases the risk of hyperkalaemia.
Concomitant use is contraindicated (see Contraindications section).
Aliskiren
In patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalemia, deterioration of renal function, and cardiovascular morbidity and mortality is increased.
Extracorporeal therapy brings blood into contact with negatively charged surfaces, such as high-flux membranes for dialysis or hemofiltration (e.g. polyacrylic membranes) and for low-density lipoprotein apheresis with dextran sulfate, which may increase the risk of severe anaphylactoid reactions (see section 4.3). If such therapy is necessary, consideration should be given to using a different type of dialysis membrane or prescribing a different class of antihypertensive drug.
Sacubitril/Valsartan
Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as concomitant inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).
Concomitant use is not recommended (see section "Special warnings and precautions for use")
Aliskiren: in all other patients, as well as in patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalemia, worsening of renal function and cardiovascular morbidity and mortality is increased.
Estramustine: increased risk of adverse reactions such as angioedema.
Co-trimoxazole (trimethoprim/sulfamethoxazole)
In patients receiving concomitant co-trimoxazole (trimethoprim/sulfamethoxazole), there may be an increased risk of developing hyperkalemia (see section "Special warnings and precautions for use").
Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium supplements, or potassium-containing salt substitutes
Although potassium is usually within normal limits, hyperkalemia may occur in some patients receiving perindopril. Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes may lead to significant increases in serum potassium. Caution should also be exercised when perindopril is administered concomitantly with other agents that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic to amiloride. Therefore, concomitant use of perindopril with the above-mentioned drugs is not recommended. However, if concomitant administration of the above-mentioned substances is necessary, they should be used with caution and with careful monitoring of plasma potassium levels.
Lithium. When using ACE inhibitors with lithium preparations, a reversible increase in the concentration of lithium in the blood plasma is possible and, accordingly, an increase in the risk of its toxic effects. It is not recommended to use perindopril with lithium preparations. In case of proven need for such an appointment, it is necessary to carefully monitor the level of lithium in the blood plasma (see section "Special instructions").
Concomitant use requiring special attention
Antidiabetic agents (insulin, oral hypoglycemic agents). Epidemiological studies suggest that the concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may lead to an increased hypoglycemic effect with a risk of hypoglycemia. This phenomenon is most likely to occur in the first weeks of combined treatment and in patients with renal insufficiency.
Baclofen: increased antihypertensive effect. If necessary, blood pressure should be monitored and the dose of antihypertensive drugs should be adapted.
Potassium-sparing diuretics
In patients taking diuretics, and especially those with impaired water and electrolyte metabolism, an excessive decrease in blood pressure is possible after starting treatment with an ACE inhibitor. The likelihood of developing a hypotensive effect is reduced by discontinuing the diuretic, increasing the circulating blood volume or salt intake before starting therapy with perindopril. Treatment should be started with low doses and gradually increased.
In hypertension, when a previously prescribed diuretic may have caused water/electrolyte depletion, it should be discontinued before starting treatment with an ACE inhibitor (in such cases, the diuretic may be resumed over time), or an ACE inhibitor should be prescribed at a low dose with a gradual increase in dose.
In congestive heart failure on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose.
In any case, it is necessary to monitor kidney function (creatinine level) during the first weeks of treatment with an ACE inhibitor.
Potassium-sparing diuretics (eplerenone, spironolactone)
In the case of simultaneous use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day with low doses of an ACE inhibitor, it is necessary:
If the recommendations for the appointment of this combination are not followed, there is a risk of hyperkalemia (possibly fatal) during the treatment of patients with NYHA class II-IV heart failure and an ejection fraction < 40%, who were previously treated with an ACE inhibitor and a loop diuretic; before prescribing such a combination, it is necessary to ensure the absence of hyperkalemia and renal failure; it is recommended to carefully monitor potassium and creatinine weekly during the first month of treatment and monthly thereafter.
Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day. A reduction in the antihypertensive effect may occur when ACE inhibitors are used concomitantly with NSAIDs such as: acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, non-selective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including the possibility of acute renal failure, and an increase in plasma potassium, especially in patients with a history of impaired renal function. This combination should be administered with caution, particularly in elderly patients. Patients should be rehydrated and renal function should be monitored closely, immediately after initiation of combination therapy and periodically thereafter.
Racecadotril
Treatment with ACE inhibitors (e.g. perindopril) is known to cause angioedema. This risk may be increased by concomitant use with racecadotril (a medicine used to treat acute diarrhoea).
Patients taking concomitant mTOR inhibitors may be at increased risk of developing angioedema (see section 4.4).
Concomitant use requiring some attention
Antihypertensives and vasodilators: Concomitant use of antihypertensives may increase the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or with other vasodilators may contribute to an additional decrease in blood pressure.
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): Patients receiving a combination of a gliptin and an ACE inhibitor may be at increased risk of angioedema due to the gliptin's inhibition of dipeptidyl peptidase-IV (DPP-IV) activity.
Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may lead to a further decrease in blood pressure (see section "Special warnings and precautions for use").
Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.
Gold preparations: a nitrate-like reaction (symptoms include facial flushing, nausea, vomiting and hypotension) has been reported rarely in patients receiving concomitant ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate).
Application features
Before starting and during use of the drug, it is necessary to monitor blood pressure, kidney function and potassium levels in the blood plasma.
Stable ischemic heart disease
If an episode of unstable angina (of any severity) occurs during the first month of treatment with perindopril, the risk/benefit ratio should be carefully weighed before deciding whether to continue therapy.
Arterial hypotension
ACE inhibitors may cause a decrease in blood pressure. Symptomatic hypotension is less common in patients with uncomplicated hypertension and is more likely in patients who are volume-depleted, taking diuretics, on a salt-restricted diet, undergoing dialysis, experiencing diarrhoea or vomiting, or in patients with severe renin-dependent hypertension (see sections 4.5 and 4.8). Symptomatic hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal insufficiency. Symptomatic hypotension is most likely to occur in patients with more severe heart failure, who are receiving high doses of loop diuretics, who have hyponatremia or functional renal failure. To reduce the risk of symptomatic hypotension, patients should be closely monitored during initiation of therapy and during dose titration (see sections 4.2 and 4.8). The same precautions apply to patients with ischemic heart disease or cerebrovascular disease, in whom an excessive decrease in blood pressure could result in myocardial infarction or stroke.
If hypotension occurs, the patient should be placed in a horizontal position with a low head and, if necessary, intravenously administered 0.9% (9 mg/ml) sodium chloride solution. Transient hypotension is not a contraindication to further use of the drug, which can usually be used without any problems after restoration of blood volume and increase in blood pressure.
In some patients with congestive heart failure with normal or low blood pressure, perindopril may cause an additional decrease in systemic blood pressure. This effect is expected and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, it may be necessary to reduce the dose or discontinue the drug.
Aortic and mitral valve stenosis/hypertrophic cardiomyopathy
As with other ACE inhibitors, perindopril should be administered with caution to patients with mitral valve stenosis or left ventricular outflow obstruction (aortic stenosis or hypertrophic cardiomyopathy).
Kidney dysfunction
In case of renal insufficiency (creatinine clearance < 60 ml/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section 4.2) and then according to the patient's response to treatment. Monitoring of potassium and creatinine is standard practice in such patients (see section 4.8).
In some patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney, increases in serum urea and creatinine levels have been observed during treatment with ACE inhibitors, which usually return to normal after discontinuation of treatment. This is especially true in patients with renal insufficiency. In the presence of concomitant renovascular hypertension, the risk of severe hypotension and renal insufficiency increases. In such patients, treatment should be initiated under close medical supervision with low doses and with careful dose titration. Given the above, diuretic treatment may contribute to the development of arterial hypotension, so they should be discontinued and renal function should be monitored during the first weeks of treatment with perindopril.
Some hypertensive patients without pre-existing renovascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, particularly when perindopril has been given concomitantly with a diuretic. However, this is more likely to occur in patients with pre-existing renal impairment. A dose reduction and/or discontinuation of the diuretic and/or perindopril may be necessary.
Patients on hemodialysis
Anaphylactic-type reactions have been reported in patients receiving high-flux polyacrylic membrane dialysis and concomitant ACE inhibitor therapy. Therefore, a decision should be made to use a different type of dialysis membrane or a different class of antihypertensive drug in these patients.
Patients after kidney transplantation
There is no experience with the administration of perindopril to patients after a recent kidney transplant.
Renovascular hypertension
When ACE inhibitors are prescribed to patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney, there is an increased risk of hypotension and renal failure (see section 4.3). Diuretic treatment may be a beneficial factor. Loss of renal function may be manifested by minimal changes in serum creatinine levels even in patients with stenosis of the artery to a single kidney.
Hypersensitivity/angioedema
Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported in patients receiving ACE inhibitors, including perindopril (see section 4.8). This may occur at any time during treatment. In such cases, the drug should be discontinued immediately and the patient should be monitored until symptoms resolve. In those rare cases where the swelling is limited to the face and lips, the patient's condition usually improves without treatment. Antihistamines may be useful in reducing symptoms.
Angioedema associated with laryngeal oedema can be fatal. In cases where the oedema involves the tongue, glottis or larynx causing airway obstruction, urgent emergency treatment is required, which may include administration of adrenaline and/or maintenance of a patent airway. Patients should be kept under close medical supervision until symptoms resolve and the condition stabilizes.
Patients with a history of angioedema unrelated to ACE inhibitor therapy are at increased risk of developing angioedema while receiving an ACE inhibitor (see section 4.3).
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section 4.3). Sacubitril/valsartan should not be started until 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril should not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5). Concomitant use of other neutral endopeptidase (NEP) inhibitors (e.g. racecadotril) and ACE inhibitors may also lead to an increased risk of angioedema (see section 4.5). Therefore, a careful benefit/risk assessment should be performed before initiating treatment with NEP inhibitors (e.g. racecadotril) in patients taking perindopril.
Patients concomitantly treated with mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) may be at increased risk of developing angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5).
Anaphylactoid reactions during low-density lipoprotein (LDL) plasmapheresis
Rarely, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during plasmapheresis of LDL using dextran sulfate. The development of anaphylactoid reactions can be avoided by temporarily stopping ACE inhibitor treatment before each plasmapheresis.
Anaphylactoid reactions during desensitization therapy
Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization treatment with bee venom-containing drugs. These reactions can be avoided by temporarily discontinuing the ACE inhibitor, but the reactions may recur if provocation tests are performed carelessly.
Liver failure
Cases of a syndrome that begins with cholestatic jaundice and progresses to transient hepatic necrosis and sometimes fatal outcome have been reported rarely in patients receiving ACE inhibitors. The mechanism of this syndrome is unknown. Patients who develop jaundice or significant elevations of liver enzymes while receiving ACE inhibitors should discontinue the drug and receive appropriate medical evaluation and treatment (see section 4.8).
Neutropenia/agranulocytosis/thrombocytopenia/anemia
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients taking ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other risk factors. Perindopril should be administered with great caution to patients with collagen vascular diseases, immunosuppressants, allopurinol or procainamide, or a combination of these factors, especially in the presence of pre-existing renal impairment. Serious infections may occasionally develop in these patients, which in rare cases may not respond to intensive antibiotic therapy. If perindopril is prescribed to such patients, periodic monitoring of white blood cell counts is recommended and patients should be advised to report any signs of infection (sore throat, fever).
Racial characteristics
ACE inhibitors cause angioedema more often in black patients than in non-black patients. As with other ACE inhibitors, perindopril is less effective in lowering blood pressure in black patients than in non-black patients, possibly because of lower renin levels in the blood of black hypertensive patients.
Cough
Cough has been reported with ACE inhibitor therapy. The cough is typically nonproductive, persistent, and resolves after discontinuation of the drug. Cough associated with ACE inhibitors should be considered in the differential diagnosis of cough.
Surgery/anesthesia
Perindopril may block the secondary formation of angiotensin II in response to compensatory renin release in patients undergoing surgery or during anesthesia with drugs that cause hypotension.
