AMILORIDE HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE
Clinical safety rating: safe
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
Amiloride is a potassium-sparing diuretic that blocks epithelial sodium channels (ENaC) in the distal convoluted tubule and collecting duct, inhibiting sodium reabsorption and reducing potassium excretion. Hydrochlorothiazide is a thiazide diuretic that inhibits the sodium-chloride cotransporter (NCC) in the distal convoluted tubule, increasing sodium, chloride, and water excretion.
| Metabolism | Amiloride is not metabolized; excreted unchanged in urine. Hydrochlorothiazide is not extensively metabolized; small amounts are metabolized hepatically via CYP450 enzymes, but the exact pathways are not well defined. |
| Excretion | Amiloride: 50% unchanged in urine, 40% in feces (biliary); Hydrochlorothiazide: >95% unchanged in urine. |
| Half-life | Amiloride: 6-9 hours (prolonged in renal impairment); Hydrochlorothiazide: 6-15 hours (prolonged in renal impairment, heart failure). |
| Protein binding | Amiloride: ~23%; Hydrochlorothiazide: 40-68% (primarily to albumin). |
| Volume of Distribution | Amiloride: 350-440 L (5-6 L/kg in 70 kg adult), indicating extensive tissue distribution; Hydrochlorothiazide: 3-5 L/kg, distributes into extracellular space. |
| Bioavailability | Amiloride: 50-80% (oral); Hydrochlorothiazide: 60-80% (oral). |
| Onset of Action | Oral: Diuresis within 1-2 hours; maximal effect at 4-6 hours. |
| Duration of Action | Amiloride: 24 hours; Hydrochlorothiazide: 6-12 hours; combination provides sustained diuresis over 24 hours. |
| Molecular Weight | Amiloride HCl: 266.1 Da; Hydrochlorothiazide: 297.7 Da |
One tablet (amiloride 5 mg/hydrochlorothiazide 50 mg) orally once daily initially, increased if needed to twice daily. Maximum dose: amiloride 10 mg/hydrochlorothiazide 100 mg daily.
| Dosage form | TABLET |
| Renal impairment | Contraindicated if GFR <30 mL/min or serum creatinine >2.5 mg/dL. For GFR 30-50 mL/min: use with caution and monitor electrolytes; avoid if further renal impairment. |
| Liver impairment | Child-Pugh Class A: no adjustment; Class B: reduce dose or use alternative; Class C: avoid use (risk of hepatic encephalopathy). |
| Pediatric use | Not established; safety and efficacy not determined in children. |
| Geriatric use | Start at lowest dose, monitor electrolytes and renal function; increased sensitivity to hypotension and electrolyte disturbances; avoid if creatinine clearance <30 mL/min. |
| 1st trimester | Avoid. Use only if potential benefit justifies risk to fetus. Associated with fetal abnormalities in animal studies, including renal agenesis and oligohydramnios. |
| 2nd trimester | Avoid. Use only if potential benefit justifies risk to fetus. May cause fetal diuresis, electrolyte imbalance, and oligohydramnios. |
| 3rd trimester | Avoid. Use only if potential benefit justifies risk to fetus. High risk of neonatal morbidity including electrolyte disturbances, hypoglycemia, and adverse cardiovascular effects. May prolong labor. |
Clinical note
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
| FDA category | Animal |
| Placental transfer | Both amiloride and hydrochlorothiazide cross the placenta. Hydrochlorothiazide reaches fetal serum levels similar to maternal levels; amiloride transfer is limited but present. |
■ FDA Black Box Warning
None
| Common Effects | edema |
| Serious Effects |
AnuriaAcute or chronic renal insufficiency (creatinine clearance <30 mL/min)Diabetic nephropathy (if using amiloride alone or in combination with potassium-sparing diuretics)Hyperkalemia (serum potassium >5.5 mEq/L)Concomitant use with other potassium-sparing diuretics or potassium supplementsHypersensitivity to amiloride, hydrochlorothiazide, or sulfonamide-derived drugsAddison's disease
| Precautions | Hyperkalemia risk, especially with renal impairment, diabetes, or concomitant use of potassium supplements, ACE inhibitors, or aldosterone antagonists, Electrolyte imbalances (hyponatremia, hypomagnesemia, hypochloremia), Azotemia and renal impairment, Sulfonamide hypersensitivity cross-reactivity (hydrochlorothiazide is a sulfonamide derivative), Acute angle-closure glaucoma (rare with thiazides), Monitor serum electrolytes, renal function, and blood glucose |
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| Breastfeeding | Minimal excretion into breast milk. Both components are considered compatible with breastfeeding, but caution is advised due to potential for infant electrolyte disturbances. Monitor infant for signs of diuresis or electrolyte imbalance. |
| Lactation Rating | L2 (Safer) |
| Teratogenic Risk | First trimester: Limited data; thiazide use associated with possible increased risk of congenital anomalies including neural tube defects and limb reduction defects, but evidence is inconclusive. Second and third trimesters: Hydrochlorothiazide may cause fetal/neonatal electrolyte disturbances, jaundice, and thrombocytopenia. Amiloride has not been associated with major teratogenic effects in animal studies, but human data are inadequate. Overall risk is moderate; avoid in pregnancy if possible, especially for treatment of hypertension, as alternatives exist. |
| Fetal Monitoring | Serum electrolytes (potassium, sodium, magnesium), renal function (BUN, creatinine), blood pressure, and fetal growth ultrasound. Periodic monitoring for fetal heart rate abnormalities or signs of fetal distress in late pregnancy. Neonatal monitoring for hypoglycemia, jaundice, and electrolyte imbalance postpartum. |
| Fertility Effects | No well-documented effects on fertility in humans. Animal studies have not shown impaired fertility at therapeutic doses. Thiazides have been associated with transient ejaculatory dysfunction in males in rare reports. |
| Food/Dietary |
| Avoid high-potassium foods (e.g., bananas, oranges, spinach, potatoes) in large amounts. Limit salt intake. Grapefruit juice may increase hydrochlorothiazide absorption; avoid concurrent consumption. |
| Clinical Pearls | Amiloride is potassium-sparing; hydrochlorothiazide causes potassium loss. The combination offsets hypokalemia risk. Monitor serum potassium, especially in renal impairment or with NSAIDs. Avoid in anuria or severe renal disease. Onset of diuresis: 2 hours; peak effect: 6-12 hours; duration: 24 hours. |
| Patient Advice | Take this medication exactly as prescribed, usually once daily in the morning to avoid nighttime urination. · This drug increases urine output and may cause dizziness or lightheadedness; rise slowly from sitting or lying down. · Avoid potassium supplements or salt substitutes containing potassium unless directed by your doctor. · Limit alcohol intake as it can increase dizziness and orthostatic hypotension. · Notify your doctor if you experience muscle cramps, weakness, irregular heartbeat, or excessive thirst. |