Candesartan + Hydrochlorothiazide

Usage

Candesartan + Hydrochlorothiazide is prescribed for the treatment of essential hypertension (high blood pressure) in patients whose blood pressure is not adequately controlled by monotherapy with either drug alone. It can also be used as a replacement therapy for patients already titrated on candesartan and hydrochlorothiazide. It is not indicated as initial therapy. It can be used to treat patients with hypertension who are not volume depleted.

It is also used in some cases to manage heart failure with reduced ejection fraction (HFrEF) when other treatments are not tolerated or not adequate, though candesartan monotherapy is preferred.

• Pharmacological Classification: Antihypertensive, Angiotensin II Receptor Blocker (ARB) combined with a Thiazide diuretic.

• Mechanism of Action: This combination therapy addresses hypertension through two distinct mechanisms:

  • Candesartan: Blocks the angiotensin II receptor, preventing vasoconstriction and aldosterone secretion, thus lowering blood pressure.
  • Hydrochlorothiazide: Increases the excretion of sodium and water by the kidneys, reducing blood volume and further lowering blood pressure.

Alternate Names

• International and Regional Variations: Candesartan cilexetil/hydrochlorothiazide is a common alternative name.

• Brand Names: Atacand HCT, PrAPO-CANDESARTAN/HCTZ, and various generic formulations are available.

How It Works

• Pharmacodynamics:
  • Candesartan acts as an angiotensin II receptor antagonist, blocking the vasoconstricting and aldosterone-secreting effects of angiotensin II. This leads to vasodilation, reduced sodium and water retention, and a decrease in blood pressure. Hydrochlorothiazide inhibits sodium reabsorption in the distal convoluted tubule of the kidney, increasing the excretion of sodium, chloride, and water. This diuresis contributes to the overall reduction in blood pressure.
• Pharmacokinetics:
  • Absorption: Candesartan cilexetil, the prodrug of candesartan, is well absorbed orally and rapidly converted to candesartan in the gastrointestinal tract. Hydrochlorothiazide is also readily absorbed from the gastrointestinal tract. The presence of food does not significantly affect the absorption of either medication.
  • Metabolism: Candesartan is minimally metabolized by the liver. Hydrochlorothiazide is not metabolized.
  • Elimination: Candesartan is primarily eliminated unchanged in both the urine and feces. Hydrochlorothiazide is eliminated primarily unchanged through renal excretion.
• Mode of Action: Candesartan competitively binds to the AT1 subtype of the angiotensin II receptor, preventing the binding of angiotensin II. Hydrochlorothiazide inhibits the sodium-chloride symporter in the distal convoluted tubule of the kidney, leading to increased excretion of sodium, chloride, and water in the urine. This increases urinary output and further reduces blood volume and pressure.
• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Candesartan specifically blocks the angiotensin II type 1 receptor (AT1 receptor). Hydrochlorothiazide affects sodium reabsorption in the kidneys. Neither drug significantly interferes with neurotransmitter function or inhibits enzymes involved in drug metabolism (such as CYP450).
• Elimination Pathways: Candesartan is eliminated through biliary (feces) and renal (urine) excretion. Hydrochlorothiazide is excreted primarily unchanged through renal excretion.

Dosage

Standard Dosage

Adults:

• Initial dose: Candesartan 16 mg/Hydrochlorothiazide 12.5 mg once daily.
• The dosage may be increased by titrating either component of Candesartan/HCTZ depending on patient response and needs. Maximal dose 32 mg/25mg once daily.
• The maximum antihypertensive effect is generally achieved within 4 weeks.

Children:

Use in children is not recommended as safety and efficacy have not been established.

Special Cases:

• Elderly Patients: No initial dose adjustment is necessary; however, initiate therapy with caution, and careful monitoring for hypotension is warranted.
• Patients with Renal Impairment: For mild to moderate renal impairment (CrCl 30-80 mL/min), dose titration of candesartan is recommended. Start with candesartan 4 mg and adjust as needed. Candesartan/HCTZ is contraindicated in severe renal impairment (CrCl < 30 mL/min).
• Patients with Hepatic Dysfunction: For mild hepatic impairment (Child-Pugh A), no initial dose adjustment is necessary. For moderate impairment (Child-Pugh B), initiate candesartan at a lower dose (e.g., 8 mg) and titrate as needed. The fixed-dose combination is not recommended in this group initially, as appropriate lower candesartan starting doses are unavailable in this form. Candesartan/HCTZ is contraindicated in severe hepatic impairment.
• Patients with Comorbid Conditions: Close monitoring is needed for patients with diabetes, heart failure, or other cardiovascular diseases due to increased risk of adverse effects like hypotension, hyperkalemia, or worsening renal function.

Clinical Use Cases

Candesartan/HCTZ is not indicated for the specific acute scenarios listed below (intubation, surgical procedures, mechanical ventilation, ICU use, emergency situations). Other short-acting antihypertensive drugs that allow easier titration and more rapid response are generally preferred in these settings.

Dosage Adjustments

Dosage adjustments may be necessary based on individual patient responses and tolerance. Renal and hepatic function should be assessed before and during therapy. Concurrent medications can also influence dosage adjustments.

Side Effects

Common Side Effects

• Dizziness
• Headache
• Upper respiratory tract infections
• Back pain
• Fatigue
• Hypotension (especially with volume depletion)

Rare but Serious Side Effects

• Angioedema
• Renal impairment (including acute renal failure)
• Hyperkalemia
• Hyponatremia
• Hypotension (severe)
• Syncope
• Rhabdomyolysis

Long-Term Effects

• Electrolyte imbalances
• Worsening renal function (in susceptible individuals)
• Increased risk of gout

Adverse Drug Reactions (ADR)

• Angioedema
• Severe hypotension
• Acute renal failure
• Hyperkalemia
• Hyponatremia

Contraindications

• Hypersensitivity to candesartan, hydrochlorothiazide, or sulfonamides
• Pregnancy (second and third trimesters)
• Anuria
• Severe renal impairment (CrCl < 30 mL/min)
• Severe hepatic impairment and/or cholestasis
• Refractory hypokalemia or hypercalcemia
• Concomitant use with aliskiren in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73m²)
• Gout

Drug Interactions

• Other Antihypertensives: Additive hypotensive effects.
• NSAIDs: Decreased antihypertensive effect of candesartan, increased risk of renal impairment.
• Potassium Supplements or Potassium-Sparing Diuretics: Increased risk of hyperkalemia.
• Lithium: Increased serum lithium levels.
• Digoxin: Increased risk of digoxin toxicity.
• Alcohol: Increased risk of hypotension.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D (Australia and US). Contraindicated in the second and third trimesters. Not recommended during the first trimester.
• Fetal Risks: Fetal or neonatal injury and/or death, especially during the second and third trimesters.
• Breastfeeding: Candesartan/HCTZ is not recommended as it is excreted in breast milk and the effects on the infant are unknown. Discontinue the drug or do not breastfeed, taking into consideration the importance of the drug to the mother.

Drug Profile Summary

• Mechanism of Action: Angiotensin II receptor blocker (ARB) and thiazide diuretic; reduces blood pressure by blocking angiotensin II effects and increasing sodium and water excretion.
• Side Effects: Dizziness, headache, hypotension, upper respiratory infections, back pain, hyperkalemia, hyponatremia, renal impairment.
• Contraindications: Pregnancy (second and third trimesters), anuria, severe renal or hepatic impairment, hypersensitivity to sulfonamides, concomitant use with aliskiren (in some cases).
• Drug Interactions: Other antihypertensives, NSAIDs, potassium supplements, lithium, digoxin.
• Pregnancy & Breastfeeding: Contraindicated in second and third trimesters of pregnancy; not recommended in first trimester or during breastfeeding.
• Dosage: Adults: Initial 16 mg/12.5 mg once daily, titratable up to 32 mg/25 mg once daily. Not for pediatric use. Renal/hepatic adjustments needed.
• Monitoring Parameters: Blood pressure, renal function (serum creatinine, BUN), electrolytes (potassium, sodium), uric acid.

Popular Combinations

Candesartan/HCTZ is itself a popular combination. Further combination with other antihypertensive medications like calcium channel blockers or beta-blockers might be employed as needed. Close monitoring is required with combined use.

Precautions

• General Precautions: Assess renal and hepatic function, monitor electrolytes, especially in patients with renal impairment or taking other medications that affect potassium levels.
• Specific Populations:
  • Pregnant Women: Contraindicated in the second and third trimesters, avoid use in the first trimester.
  • Breastfeeding Mothers: Not recommended.
  • Children & Elderly: No pediatric indication. Caution in the elderly due to potential for hypotension and renal impairment.
  • Lifestyle Considerations: Limit alcohol intake, advise caution with driving and other activities requiring alertness.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Candesartan + Hydrochlorothiazide?

A: The initial dose is usually Candesartan 16 mg/Hydrochlorothiazide 12.5 mg once daily in adults. This can be titrated up to a maximum of 32 mg/25 mg once daily depending on response and tolerance. Not recommended for pediatric use.

Q2: How should I manage a patient who develops hypotension on Candesartan/HCTZ?

A: Temporarily discontinue the medication. Assess volume status and electrolytes. Consider resuming at a lower dose once stabilized. If hypotension persists, alternative antihypertensive therapy may be necessary.

Q3: Can this combination be used in patients with diabetes?

A: Yes, but close monitoring of blood pressure, renal function, and potassium levels is crucial. Aliskiren should be avoided in patients with diabetes receiving Candesartan/HCTZ.

Q4: What are the contraindications for this combination drug?

A: Contraindications include pregnancy (second and third trimesters), hypersensitivity to sulfonamides, anuria, severe renal or hepatic impairment, refractory hypokalemia or hypercalcemia, concomitant aliskiren in patients with diabetes or moderate to severe renal impairment, and gout.

Q5: What should I do if a patient experiences angioedema while on Candesartan/HCTZ?

A: Discontinue the medication immediately and administer appropriate medical treatment (e.g., antihistamines, corticosteroids, epinephrine). Angioedema can be life-threatening.

Q6: Is there a risk of drug interactions with Candesartan/HCTZ?

A: Yes, clinically significant interactions can occur with other antihypertensives, NSAIDs, potassium supplements, lithium, and digoxin. Monitor closely for additive or synergistic effects.

Q7: Can I prescribe this drug to a pregnant woman?

A: No. Candesartan/HCTZ is contraindicated during the second and third trimesters of pregnancy due to the risk of fetal harm. It is also not recommended during the first trimester.

Q8: What monitoring parameters are essential for patients on Candesartan/HCTZ?

A: Monitor blood pressure, renal function (serum creatinine, BUN), serum electrolytes (potassium, sodium), and uric acid. Regular monitoring is particularly important for patients with existing renal impairment, diabetes, or heart failure.

Q9: My patient’s blood pressure is not controlled on hydrochlorothiazide monotherapy. Can I switch them directly to Candesartan/HCTZ?

A: Yes, although it is generally recommended to titrate candesartan to an appropriate dose for the individual patient. A lower starting dose of candesartan might be considered, especially in patients at risk for hypotension. Closely monitor blood pressure response.