Candesartan and Hydrochlorothiazide

Pronunciation

(kan de SAR tan & hye droe klor oh THYE a zide)

U.S. Brand Names

Atacand HCT™

Synonyms

Candesartan Cilexetil and Hydrochlorothiazide

Generic Available

Canadian Brand Names

Atacand® Plus

Use

Treatment of hypertension; combination product should not be used for initial therapy

Pregnancy Risk Factor

C/D (2nd and 3rd trimesters)

Pregnancy Implications

Candesartan: C/D (2nd and 3rd trimesters): Discontinue as soon as possible when pregnancy is detected. Drugs that act directly on renin-angiotensin can cause fetal and neonatal morbidity and death. Adverse effects to the fetus appear to be limited to the 2nd and 3rd trimesters.

Hydrochlorothiazide: B (per manufacturer), D (based on expert analysis): Although there are no adequate and well-controlled studies using hydrochlorothiazide in pregnancy, thiazide diuretics may cause an increased risk of congenital defects. Hypoglycemia, hypokalemia, hyponatremia, jaundice, and thrombocytopenia are also reported as possible complications to the fetus or newborn.

Lactation

Enters breast milk/contraindicated

Contraindications

Hypersensitivity to candesartan, hydrochlorothiazide, or any component of the formulation; hypersensitivity to other A-II receptor antagonists, thiazides, or sulfonamide-derived drugs; anuria; renal decompensation; bilateral renal artery stenosis; pregnancy (2nd and 3rd trimesters)

Warnings/Precautions

Correct hypokalemia and volume depletion before initiating therapy; excessive reduction in blood pressure could occur. Use with caution in patients with hepatic impairment or renal insufficiency. Safety and efficacy has not been established in children <18 years of age.

Candesartan: Deterioration in renal function can occur with initiation. Use caution in patients with CHF. Use with caution in unilateral renal artery stenosis and pre-existing renal insufficiency; significant aortic/mitral stenosis.

Hydrochlorothiazide: Hepatic coma can be caused by electrolyte disturbances in patients with severe hepatic dysfunction. Can cause SLE exacerbation or activation. Hypersensitivity reactions can occur and may be more likely in patients with bronchial asthma. Gout can be precipitated in certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure. Electrolyte disturbances (hypokalemia, hypochloremic alkalosis, hypomagnesemia, hypercalcemia, hyponatremia) can occur. Cautious use in diabetics; may see a change in glucose control. Avoid in severe renal disease (ineffective); may precipitate azotemia; discontinue or consider withholding if renal impairment occurs. Use with caution in patients with moderate or high cholesterol concentrations; increased cholesterol and triglyceride levels have been reported with thiazides. Photosensitization may occur.

Adverse Reactions

Reactions which follow have been reported with the combination product; see individual drug monographs for additional adverse reactions that may be expected from each agent.

1% to 10%:

Central nervous system: Dizziness (3%), headache (3%, placebo 5%)

Neuromuscular & skeletal: Back pain (3%)

Respiratory: Upper respiratory tract infection (4%)

Miscellaneous: Flu-like symptoms (2%)

<1%: Abdominal pain, abnormal ECG, abnormal hepatic function, agranulocytosis, angina pectoris, angioedema (<0.5%), anxiety, arthralgia, arthritis, arthrosis, asthenia, bradycardia, bronchitis, BUN increased, chest pain, conjunctivitis, cough, CPK increased, cystitis, depression, dermatitis, diaphoresis increased, diarrhea, dyspepsia, dyspnea, eczema, epistaxis, extrasystoles, fatigue, gastritis, gastroenteritis, hematuria, hepatitis, hypesthesia, hyperglycemia, hyperuricemia, hypokalemia, infection, insomnia, leg cramps, leukopenia, myalgia, MI (<0.5%), nausea, neutropenia, pain, palpitation, paresthesia, peripheral edema, pharyngitis, pruritus, rash, rhinitis, sciatica, sinusitis, tachycardia, tinnitus, transaminases increased, urinary tract infection, urticaria, vertigo, viral infection, vomiting; rhabdomyolysis has been reported (rarely) with angiotensin-receptor antagonists

Overdosage/Toxicology

Candesartan: Information is limited; expected symptoms would be dizziness, hypotension, tachycardia. Bradycardia may also occur. Treatment is supportive. Not removed by hemodialysis.

Hydrochlorothiazide: Hypochloremia, hypokalemia, hyponatremia, and dehydration may occur. Treatment is supportive.

Drug Interactions

Candesartan: Substrate of CYP2C8/9 (minor); Inhibits CYP2C8/9 (weak)

Also see individual agents.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may potentiate orthostatic hypotension).

Stability

Store at 25°C (77°F). Store in tightly closed container.

Mechanism of Action

Candesartan: Candesartan is an angiotensin receptor antagonist. Angiotensin II acts as a vasoconstrictor. In addition to causing direct vasoconstriction, angiotensin II also stimulates the release of aldosterone. Once aldosterone is released, sodium as well as water are reabsorbed. The end result is an elevation in blood pressure. Candesartan binds to the AT1 angiotensin II receptor. This binding prevents angiotensin II from binding to the receptor, thereby blocking the vasoconstriction and the aldosterone-secreting effects of angiotensin II.

Hydrochlorothiazide: Inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions

Pharmacodynamics/Kinetics

See individual agents.

Dosage

Oral: Adults: Replacement therapy: Combination product can be substituted for individual agents; maximum therapeutic effect would be expected within 4 weeks

Usual dosage range:

Candesartan: 8-32 mg/day, given once daily or twice daily in divided doses

Hydrochlorothiazide: 12.5-50 mg once daily

Dosage adjustment in renal impairment: Serum levels of candesartan are increased and the half-life of hydrochlorothiazide is prolonged in patients with renal impairment. Do not use if Clcr<30 mL/minute

Dosage adjustment in hepatic impairment: Use with caution

Elderly: No initial dosage adjustment is recommended in patients with normal renal and hepatic function; some patients may have increased sensitivity

Monitoring Parameters

Assess weight, I & O reports daily to determine fluid loss; blood pressure, symptomatic hypotension, and tachycardia; serum electrolytes, BUN, creatinine

Dietary Considerations

May be given with or without food.

Patient Education

See individual agents. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant; contraceptives may be recommended. Do not breast-feed.

Nursing Implications

Take blood pressure with patient lying down and standing.

Cardiovascular Considerations

Combination therapy for the treatment of hypertension should be individualized for each patient. Potential advantages for candesartan and hydrochlorothiazide combination therapy may include improved compliance and synergistic reductions in blood pressure with an accompanying reduction in side effects.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness

Mental Health: Effects on Psychiatric Treatment

May cause decreased renal lithium clearance; monitor serum lithium levels

Dosage Forms

Tablet:

16-12.5: Candesartan 16 mg and hydrochlorothiazide 12.5 mg

32-12.5: Candesartan 32 mg and hydrochlorothiazide 12.5 mg

References

Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report," JAMA , 2003, 289(19):2560-71.

Conlin P, Moore T, Swartz S, et al, "Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients," Hypertension , 2000, 36(3):461-5.

Kaplan NM and Sever PS, "Combination Therapy: A Key to Comprehensive Patient Care," Am J Hypertens , 1997, 10(7 Pt 2):127S.

Reif M, White WB, Fagan TC, et al, "Effects of Candesartan Cilexetil in Patients With Systemic Hypertension. Candesartan Cilexetil Study Investigators," Am J Cardiol , 1998, 82(8):961-5.

International Brand Names

Atacand® Plus (CA)

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