Candesartan - Drug Monograph

Introduction

Candesartan is an angiotensin II receptor blocker (ARB) used primarily in the management of hypertension and heart failure. As a selective AT1 receptor antagonist, it blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Candesartan cilexetil, the prodrug form, is hydrolyzed to the active compound candesartan during gastrointestinal absorption.

Mechanism of Action

Candesartan selectively blocks the binding of angiotensin II to the AT1 receptor found in vascular smooth muscle and adrenal cortex. By inhibiting angiotensin II-mediated vasoconstriction and aldosterone release, candesartan produces:

• Peripheral vasodilation
• Reduced systemic vascular resistance
• Decreased blood pressure
• Reduced afterload in heart failure
• Attenuation of cardiac remodeling

The drug does not inhibit angiotensin-converting enzyme (ACE) nor does it affect bradykinin metabolism, resulting in a lower incidence of cough compared to ACE inhibitors.

Indications

FDA-approved indications:

• Hypertension (monotherapy or combination therapy)
• Heart failure with reduced ejection fraction (NYHA Class II-IV)
• Reduction of cardiovascular mortality in clinically stable patients with left ventricular systolic dysfunction following myocardial infarction

Off-label uses may include:

• Diabetic nephropathy
• Proteinuric chronic kidney disease

Dosage and Administration

• Initial dose: 16 mg once daily
• Maintenance dose: 8-32 mg once daily (maximum 32 mg daily)
• May be administered with or without food

• Initial dose: 4 mg once daily
• Titrate to target dose of 32 mg once daily as tolerated
• Double dose at approximately 2-week intervals

• Initial dose: 4 mg once daily
• Titrate to target dose of 32 mg once daily

• Renal impairment: No initial dosage adjustment necessary for mild-moderate impairment; use caution in severe impairment
• Hepatic impairment: Initial dose 8 mg daily in mild-moderate impairment; contraindicated in severe impairment
• Elderly: No dosage adjustment necessary
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

• Candesartan cilexetil is rapidly hydrolyzed to active candesartan during absorption
• Absolute bioavailability approximately 15%
• Peak plasma concentrations reached within 3-4 hours
• Food does not significantly affect bioavailability

• Volume of distribution: 0.13 L/kg
• Plasma protein binding: >99% (primarily albumin)

• Minimally metabolized by hepatic CYP2C9
• No active metabolites

• Primarily excreted unchanged in urine (33%) and feces (67%)
• Terminal elimination half-life: 9-10 hours
• Not removed by hemodialysis

Contraindications

• Hypersensitivity to candesartan or any component of the formulation
• Concomitant use with aliskiren in patients with diabetes
• Pregnancy (second and third trimesters)
• Severe hepatic impairment

Warnings and Precautions

• Category D in second and third trimesters
• Can cause fetal injury and death
• Discontinue immediately if pregnancy detected

• May cause acute renal failure in susceptible patients
• Monitor renal function in patients with renal artery stenosis

• Risk increased in patients with renal impairment, diabetes, or those taking potassium-sparing diuretics

• May occur in volume-depleted patients or those with heart failure
• Correct volume depletion prior to initiation

• Rare but serious adverse effect
• Requires immediate discontinuation and appropriate management

Drug Interactions

• Lithium: Increased lithium concentrations and toxicity
• NSAIDs: May reduce antihypertensive effect and increase risk of renal impairment
• Potassium-sparing diuretics/potassium supplements: Increased risk of hyperkalemia
• ACE inhibitors: Increased risk of hyperkalemia, hypotension, and renal impairment
• Aliskiren: Contraindicated in diabetic patients due to increased risk of renal impairment, hyperkalemia, and hypotension

Adverse Effects

• Dizziness (4%)
• Upper respiratory infection (3%)
• Pharyngitis (2%)
• Back pain (2%)
• Headache (2%)

• Angioedema
• Acute renal failure
• Severe hypotension
• Hyperkalemia
• Hepatotoxicity
• Rhabdomyolysis

Monitoring Parameters

• Blood pressure
• Renal function (BUN, creatinine)
• Serum electrolytes (especially potassium)
• Liver function tests
• Pregnancy test in women of childbearing potential

• Blood pressure at regular intervals
• Renal function and electrolytes within 2 weeks of initiation and after dosage changes
• Serum potassium, especially in patients with renal impairment or diabetes
• Signs and symptoms of hypotension
• Monitor for edema (face, lips, tongue, larynx)

Patient Education

• Take medication at the same time each day, with or without food
• Do not stop taking abruptly without consulting healthcare provider
• Rise slowly from sitting or lying position to prevent dizziness
• Report any signs of pregnancy immediately
• Notify healthcare provider of any swelling of face, lips, tongue, or difficulty breathing
• Maintain regular follow-up appointments for blood pressure monitoring
• Avoid potassium supplements unless specifically prescribed
• Inform all healthcare providers about candesartan use, especially before surgery
• Use effective contraception while taking candesartan

References

1. FDA Prescribing Information: Atacand (candesartan cilexetil) 2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. J Am Coll Cardiol. 2018;71(19):e127-e248. 3. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 4. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349(20):1893-1906. 5. Burnier M. Angiotensin II type 1 receptor blockers. Circulation. 2001;103(6):904-912. 6. Micromedex Solutions. Candesartan Drug Information. Truven Health Analytics.