Perindopril

Perindopril is an antihypertensive agent belonging to angiotensin-converting enzyme (ACE) inhibitors.

Perindopril is approved for the treatment of chronic hypertension, Heart Failure, and Stable coronary artery disease.

It is rapidly absorbed from the gastrointestinal tract and slightly reduced absorption with food with a bioavailability of approx 65-75%. The Volume of distribution was Approx 0.2 L/kg with plasma protein binding of approx 60% (perindopril). It is extensively metabolized in the liver via hydrolysis by hepatic esterases to perindoprilat (in active form) and inactive metabolites including glucuronides. It gets excreted via urine (75%, 4-12% as unchanged drug) with a terminal elimination half-life of about 25-30 hours or longer (perindoprilat).

The more common side effect that can occur with Perindopril includes Body aches or pain, Chills, Cough, Difficulty breathing, Ear congestion, Fever, Headache, Loss of voice, Nasal congestion, Runny nose, Sneezing, Sore throat, Unusual tiredness or weakness, etc.

Perindopril is available in the form of dosage forms as tablets

Perindopril is available in India, China, Japan, and the USA.

Perindopril, a prodrug of perindopril at, is an ACE inhibitor that prevents the conversion of angiotensin I to angiotensin II, thereby increasing plasma renin activity and decreasing vasoconstriction and aldosterone secretion.

Perindoprilat, the active metabolite of perindopril, competes with ATI for binding to ACE and inhibits enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressure effects of ATII as described in the Pharmacology section above. Perindopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.

The onset of action of Perindopril occurs within 1-2 hours.

The Duration of action of Perindopril in the body is 10 to 12 hours hours.

The Tmax was found within 1 hour following the administration of Perindopril, and Cmax was reached within 1 hour.

Perindopril is available in the form of tablets.

Perindopril tablets are to be swallowed whole with water.

Perindopril is approved for the treatment of chronic hypertension, Heart Failure, and Stable coronary artery disease

Perindopril works by blocking a substance in the body that causes the blood vessels to tighten. As a result, perindopril relaxes the blood vessels. This lowers blood pressure and increases the supply of blood and oxygen to the heart.

Perindopril is approved for use in the following clinical indication.

Chronic Hypertension: Management of hypertension.

Stable coronary artery disease: To reduce the risk of cardiovascular mortality or nonfatal myocardial infarction in patients with stable coronary artery disease.

Although not approved there has been certain label use documented for Perindopril which include:

Heart Failure with reduced ejection.

Perindopril is available in the form of tablets in potencies of 2mg, 4 mg, and 8 mg.

Oral

Hypertension

• Adult: As perindopril erbumine: Initially, 4 mg once daily, may be titrated according to clinical response. Max: 8 mg daily. As perindopril arginine: Initially, 5 mg once daily may be titrated according to clinical response. Max: 10 mg daily. Patient with renovascular hypertension, volume depletion, severe hypertension, or patient on diuretics: As perindopril erbumine: Initially, 2 mg once daily; As perindopril arginine: 2.5 mg once daily.
• Elderly: As perindopril erbumine: Initially, 2 mg once daily, may increase the dose to 4 mg if necessary. Max: 8 mg daily. As perindopril arginine: 2.5 mg once daily, may increase the dose to 5 mg if necessary. Max: 10 mg daily.

Heart failure

• Adult: As perindopril erbumine: Initially, 2 mg once daily, preferably in the morning, may adjust according to clinical response. Usual maintenance dose: 4 mg once daily. As perindopril arginine: Initially, 2.5 mg once daily, preferably in the morning, may adjust the dose according to clinical response. Usual maintenance dose: 5 mg once daily.

Stable coronary artery disease

• Adult: As perindopril erbumine: Initially, 4 mg once daily for 2 weeks, maybe titrated according to clinical response. Max dose: 8 mg daily. As perindopril arginine: Initially, 5 mg once daily for 2 weeks, maybe titrated according to clinical response. Max dose: 10 mg daily.
• Elderly: As perindopril erbumine: Initially, 2 mg once daily for 1 week, then may increase the dose to 4 mg once daily, may further titrate to 8 mg once daily according to clinical response. As perindopril arginine: Initially, 2.5 mg once daily for 1 week, then may increase the dose to 5 mg once daily, may further titrate to 10 mg once daily according to clinical response.

Perindopril can be administered orally after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Perindopril is available in various dosage strengths as 2 mg, 4 mg, and 8 mg.

Perindopril is available in the form of tablets.

Dose Adjustment in Kidney Patients:

Kidney impairment prior to treatment initiation:

Altered kidney function :

Oral:

● CrCl >80 mL/minute: No dosage adjustment necessary.

● CrCl ≥30 to ≤80 mL/minute: Initial: 2 mg/day; maximum maintenance dose: 8 mg/day.

● CrCl <30 mL/minute: Use is generally not recommended; however, an initial dose of 2 mg every 48 hours may be considered; titrate cautiously based on tolerability and response, not to exceed 4 mg/day.

Hemodialysis, intermittent (thrice weekly):

Oral: Initial: 2 mg 3 times per week after dialysis on dialysis days; titrate cautiously based on tolerability and response, not to exceed 4 mg/day.

Peritoneal dialysis:

Oral: Use is generally not recommended; however, if use is necessary, an initial dose of 2 mg every 48 hours may be considered; titrate cautiously based on tolerability and response, not to exceed 4 mg/day.

CRRT:

Oral: Use is generally not recommended; however, if use is necessary, an initial dose of 2 mg every 48 hours may be considered; titrate cautiously based on tolerability and response, not to exceed 4 mg/day Avoid use if an AN69 hemofilter is used (associated with anaphylactoid reaction).

PIRRT (eg, sustained, low-efficiency diafiltration):

Oral: Use is generally not recommended; however, if use is necessary, an initial dose of 2 mg every 48 hours may be considered; titrate cautiously based on tolerability and response, not to exceed 4 mg/day (expert opinion). Avoid use if an AN69 hemofilter is used.

Kidney impairment during therapy:

Small, transient increases in serum creatinine are expected within 4 weeks following the initiation of therapy or an increase in dose. If serum creatinine increases by >30%, review for possible etiologies (eg, acute kidney injury, volume depletion, concomitant medications, renal artery stenosis), then determine if dose reduction or discontinuation of perindopril therapy should be considered.

Perindopril is approved for the treatment of chronic hypertension, Heart Failure, and Stable coronary artery disease.

Hypertension: It has been observed that the low-salt Dietary Approach to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per patient requirements

Perindopril may be contraindicated in the following

Hypersensitivity (eg, angioedema) to perindopril, other ACE inhibitors, or any component of the formulation; hereditary/idiopathic angioedema; concomitant use with aliskiren in patients with diabetes mellitus; concomitant use or within 36 hours of switching to or from a neprilysin inhibitor (eg, sacubitril)

Concomitant use with aliskiren in patients with moderate to severe renal impairment (GFR <60 mL/minute/1.73 m²); while pregnant, planning to become pregnant, or patients of childbearing potential not using adequate contraception; breastfeeding; hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the congenital lactase deficiency; concomitant use with sacubitril/valsartan; extracorporeal treatments leading to contact of blood with negatively charged surfaces; unilateral or bilateral renal artery stenosis

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• Angioedema: At any time during treatment (especially following the first dose), angioedema may occur rarely with ACE inhibitors; it may involve the head and neck (potentially compromising the airway) or the intestine (presenting with abdominal pain). Black patients and patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE inhibitor therapy may be at an increased risk. The risk may also be increased with concomitant use of mTOR inhibitor (eg, everolimus) or neprilysin inhibitor (eg, sacubitril) therapy. Prolonged frequent monitoring may be required especially if the tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Use in patients with previous angioedema associated with ACE inhibitor therapy is contraindicated.

• Cholestatic jaundice: A rare toxicity associated with ACE inhibitors includes cholestatic jaundice, which may progress to fulminant hepatic necrosis (some fatal); discontinue if the marked elevation of hepatic transaminases or jaundice occurs.

• Cough: An ACE inhibitor cough is a dry, hacking, nonproductive one that usually occurs within the first few months of treatment and should generally resolve within 1 to 4 weeks after discontinuation of the ACE inhibitor. Other causes of cough should be considered (eg, pulmonary congestion in patients with heart failure) and excluded prior to discontinuation.

• Hematologic effects: Another ACE inhibitor, Perindopril, has been associated with neutropenia with myeloid hypoplasia and agranulocytosis; anemia and thrombocytopenia have also occurred. Patients with renal impairment are at high risk of developing neutropenia. Patients with both renal impairment and collagen vascular disease (eg, systemic lupus erythematosus) are at an even higher risk of developing neutropenia. Periodically monitor CBC with a differential in these patients.

• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions can occur with ACE inhibitors. Severe anaphylactoid reactions may be seen during hemodialysis (eg, CVVHD) with high-flux dialysis membranes (eg, AN69), and rarely, during low-density lipoprotein apheresis with dextran sulfate cellulose. Rare cases of anaphylactoid reactions have been reported in patients undergoing sensitization treatment with Hymenoptera (bee, wasp) venom while receiving ACE inhibitors.

• Hypotension/syncope: Symptomatic hypotension with or without syncope can occur (usually with the first several doses); effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation; close monitoring of the patient is required especially with initial dosing and dosing increases; BP must be lowered at a rate appropriate for the patient's clinical condition. Although dose reduction may be necessary, hypotension is not a reason for discontinuation of future ACE inhibitor use, especially in patients with heart failure where a reduction in systolic BP is a desirable observation.

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in BUN and serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose GFR is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function (Bakris 2000).

Disease-related concerns:

• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.

• Ascites: Generally, avoid use in patients with ascites due to cirrhosis or refractory ascites; if use cannot be avoided in patients with ascites due to cirrhosis, monitor BP and renal function carefully to avoid rapid development of renal failure.

• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling BP (eg, MI, stroke). Fluid replacement, if needed, may restore BP; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.

• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant renal impairment; may be at increased risk for hematologic toxicity.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction: Use with caution in patients with hypertrophic cardiomyopathy and left ventricular outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition (AHA/ACC [Ommen 2020]).

• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented unilateral or bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh the risks.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.

Drinking alcohol while taking Perindopril can increase drowsiness and dizziness, which in turn increases the risk of accidental injury.

Perindopril use in breastfeeding patients is not recommended.

Pregnancy Category D

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Perindopril as soon as possible.

Potassium-Rich Foods: Bananas, sweet potatoes, nuts, and other foods rich in potassium when taken along with Perindopril, can be led to an increase in blood potassium levels.

Pleurisy Root: Pleurisy roots are not recommended with most heart medications due to the cardiac glycoside content of the root.

The adverse reactions related to the molecule Perindopril can be categorized as

• Common Adverse effects:

Body aches or pain, Chills, Cough, Difficulty breathing, Ear congestion, Fever, Headache, Loss of voice, Nasal congestion, Runny nose, Sneezing, Sore throat, Unusual tiredness or weakness, etc,

• Less Common adverse effects:

Bladder pain, bloody or cloudy urine, change in hearing, chest pain, cold, congestion, diarrhea, difficulty, burning, or painful urination, dryness of the throat, earache or pain in the ear, ear drainage, etc.

• Rare adverse effects:

Vasculitis, flushing, impaired peripheral circulation, epistaxis, Raynaud’s phenomenon, etc.

The clinically relevant drug interactions of Perindopril is briefly summarized here

● Increased hypotensive effect with antihypertensive agents, diuretics, nitrates, and baclofen. Increased risk of hyperkalemia with K-sparing diuretics (e.g., spironolactone, eplerenone), K supplements, or other agents affecting serum K concentrations (e.g., trimethoprim, ciclosporin, heparin).

● May increase hypoglycaemic effect with insulin and oral hypoglycaemic agents. Increased risk of angioedema with mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus), neutral endopeptidase (NEP) inhibitors (e.g. racecadotril), and dipeptidyl peptidase-IV (DPP-IV) inhibitors (e.g. sitagliptin, linagliptin).

● Concomitant use with NSAIDs, including selective COX-2 inhibitors may result in renal function deterioration and reduced antihypertensive effect. May increase serum levels and toxicity of lithium.

● Coadministration with parenteral gold (e.g. Na aurothiomalate) may cause a nutrition reaction characterized by facial flushing, nausea, vomiting, and hypotension.

● Potentially Fatal: Increased risk of hypotension, hyperkalemia, and changes in renal function with aliskiren. Increased risk of angioedema with sacubitril/valsartan. May cause anaphylactoid reactions with dextran sulfate in LDL apheresis.

The common side of Perindopril includes the following

Body aches or pain, Chills, Cough, Difficulty breathing, Ear congestion, Fever, Headache, Loss of voice, Nasal congestion, Runny nose, Sneezing, Sore throat, Unusual tiredness or weakness, etc.

The use of Perindopril should be prudent in the following group of special populations:

Pregnancy

Pregnancy Category D

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Perindopril as soon as possible.

Nursing Mothers

Since Perindopril is secreted in human milk, nursing should not be undertaken by mothers receiving this drug.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

There is no FDA guidance on the use of Perindopril in geriatric settings.

Symptoms:

Hypotension, bradycardia, circulatory shock, renal failure, hyperventilation, electrolyte disturbances, tachycardia, palpitations, dizziness, anxiety, and cough.

Management:

Administer IV infusion of NaCl 0.9%. If hypotension occurs, place the patient in a shock position. May also consider the administration of angiotensin II infusion and/or IV catecholamines. Haemodialysis may be beneficial.

Pharmacodynamics:

Perindopril is a nonsulfhydryl prodrug that is metabolized via first pass effect (62%) and systemic hydrolysis (38%) to perindoprilat, its active metabolite, following oral administration. Perindoprilat lowers blood pressure by antagonizing the effect of RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, and water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the bloodstream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collects a tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland.

Pharmacokinetics:

• Absorption: Rapidly absorbed from the gastrointestinal tract. Slightly reduced absorption with food. Bioavailability: Approx 65-75% (perindopril); approx 25% (perindoprilat). Time to peak plasma concentration: Approx 1 hour (perindopril); 3-4 hours (perindoprilat).

• Distribution: Volume of distribution: Approx 0.2 L/kg (perindoprilat). Plasma protein binding: Approx 60% (perindopril); 10-20% (perindoprilat).

• Metabolism: Extensively metabolized in the liver via hydrolysis by hepatic esterases to perindoprilat (in active form) and inactive metabolites including glucuronides.

• Excretion: Via urine (75%, 4-12% as unchanged drug). Terminal elimination half-life: 25-30 hours or longer (perindoprilat).

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