Citric Acid Monohydrate

Approved Indications:

• Urinary Alkalinization: Used to alkalinize urine and prevent the formation of uric acid and cystine kidney stones.
• Metabolic Acidosis: Adjunct in the treatment of mild to moderate metabolic acidosis, especially in renal tubular acidosis.
• Hypocitraturia: Management of low urinary citrate levels to prevent calcium stone formation.
• Anticoagulant Component: Utilized as a component in anticoagulant citrate solutions (e.g., ACD solution) during blood collection and preservation.

Clinically Accepted Off-Label Uses:

• Pharmaceutical Buffering Agent: Used to adjust pH in oral and parenteral drug formulations.
• Inhalation Therapy (Cystic Fibrosis): Occasionally used in acidic nebulization solutions for mucus clearance in cystic fibrosis.
• Supportive Use in Gout: Employed as a urinary alkalinizer in patients with hyperuricemia or gout to reduce uric acid crystallization risk.

Adults:

• Oral Alkalinizer/Metabolic Acidosis:
  1 to 2 grams dissolved in water, taken 2–3 times daily.
  Adjust based on urinary pH (target: 6.5–7.5).
• As Part of Compound Formulas:
  Often combined with sodium or potassium salts. Example: 334 mg citric acid per 5 mL solution.

Pediatrics:

• Dose based on body weight and age.
  Usual initial dose: 0.5–1 g/day in divided doses.
  Adjust based on urinary pH and clinical response.

Elderly:

• Begin at lower end of dosing range.
  Monitor kidney function and urinary pH closely.

Renal Impairment:

• Use with caution.
  Avoid in severe renal dysfunction due to risk of acid-base imbalance or electrolyte disturbances.

Hepatic Impairment:

• No specific adjustment needed; use cautiously in advanced hepatic insufficiency.

Route of Administration:

• Oral (solution or powder dissolved in water)
• Intravenous use only as part of anticoagulant citrate solutions under medical supervision.

Monitoring:

• Urinary pH
• Serum bicarbonate and electrolytes
• Renal function parameters

Citric acid monohydrate, when administered orally, is rapidly absorbed and metabolized to bicarbonate, contributing to systemic alkalinization. This increase in serum and urinary pH inhibits the crystallization of uric acid and cystine, aiding in the prevention of stone formation. It also chelates calcium in the urine, reducing calcium salt precipitation. When used as part of citrate-based anticoagulants, citric acid binds calcium ions, thereby inhibiting coagulation by blocking calcium-dependent steps in the clotting cascade.

• Absorption: Rapid gastrointestinal absorption.
• Distribution: Distributes in total body water and enters the Krebs cycle intracellularly.
• Metabolism: Metabolized primarily in the liver via the citric acid cycle to produce bicarbonate and carbon dioxide.
• Excretion: Primarily renal excretion of metabolic end products.
• Onset of Action: Begins within 1–2 hours after oral ingestion.
• Half-life: Not specifically defined due to integration into natural metabolic pathways.
• Bioavailability: Approximately 90% or higher when taken orally.
• Active Metabolites: Bicarbonate (functional metabolite for alkalinization).

• Pregnancy:
  Not formally assigned an FDA pregnancy category. Generally considered safe when used at therapeutic doses. No known teratogenic effects reported in animal or human studies.
• Lactation:
  Citric acid is naturally present in breast milk. It is not expected to harm the nursing infant when used at standard therapeutic doses. No adverse events have been reported.
• Caution:
  Due to limited controlled data, use with caution in pregnant or lactating individuals, especially in high doses or for extended periods.

• Primary Therapeutic Class: Urinary Alkalinizing Agent
• Secondary Classifications:
• Acidulant
• Buffering Agent
• Component of Blood Anticoagulant Solutions

• Known hypersensitivity to citric acid or formulation components
• Severe renal impairment or acute kidney injury
• Metabolic or respiratory alkalosis
• Concomitant use with potassium-sparing diuretics in potassium citrate-containing combinations
• Sodium-restricted patients (when combined with sodium citrate)

• High-Risk Populations:
• Patients with chronic kidney disease
• Patients on sodium- or potassium-restricted diets
• Elderly patients with comorbidities
• Potential Risks:
• Metabolic alkalosis with excessive use
• Electrolyte disturbances (hypokalemia, hypernatremia)
• Calcium chelation in blood if used intravenously without control
• Monitoring Recommendations:
• Regular assessment of serum electrolytes
• Frequent urinary pH checks
• Monitor renal function during prolonged use
• Black Box Warnings:
  None reported for citric acid monohydrate.

Common Adverse Effects:

• Gastrointestinal:
• Nausea
• Diarrhea
• Abdominal bloating

Occasional Effects:

• Musculoskeletal cramps (due to electrolyte imbalance)
• Headache

Serious/Rare Effects:

• Electrolyte imbalance (especially with long-term or excessive use)
• Metabolic alkalosis
• Seizures (secondary to electrolyte derangements)
• Precipitation of calcium phosphate stones (with over-alkalinization)

Dose-Dependence and Timing:

• GI symptoms are dose-dependent and usually appear early.
• Metabolic effects are gradual and occur with chronic use or overdose.

Major Drug–Drug Interactions:

• Aluminum-based antacids: Increases aluminum absorption, especially in renal dysfunction.
• Potassium-sparing diuretics: Risk of hyperkalemia in combination with potassium citrate formulas.
• Calcium or magnesium supplements: May reduce citric acid’s chelating effects or precipitate complexes.
• Antibiotics (tetracyclines/fluoroquinolones): Reduced absorption due to chelation.

Drug–Food Interactions:

• Can be taken with food to minimize gastric irritation.
• Avoid high-sodium diets when on sodium citrate/citric acid combinations.

CYP450 Interactions:

• Citric acid is not metabolized by CYP450 enzymes. No significant interactions through this pathway.

• Nephrology Practice Guidelines:
  Citrate supplementation (including citric acid monohydrate) remains a key recommendation for managing hypocitraturia and uric acid stone prevention.
• Labeling & Formulation Updates:
  Manufacturers have refined formulations to enhance palatability and reduce GI side effects.
  Enhanced safety labeling now emphasizes urinary pH monitoring during chronic use.
• Regulatory Status:
  No major regulatory restrictions or reclassifications in recent years.

• Recommended Temperature:
  Store at 20°C to 25°C (68°F to 77°F).
  Allowable excursions: 15°C to 30°C.
• Environmental Protection:
• Keep container tightly sealed.
• Protect from moisture and excessive humidity.
• Store away from direct sunlight.
• Handling Instructions:
• Use clean, dry utensils when dispensing powder.
• For oral solutions, prepare fresh before use. Shake well if suspension.
• Reconstitution (if applicable):
• Mix powder in adequate water.
• Follow specific product instructions for reconstitution and stability.