Citrates (Monograph)

Brand names: Bicitra, Cytra-2, Cytra-3, Cytra-K, Oracit
Drug class: Alkalinizing Agents
VA class: TN400
CAS number: 77-92-9

Introduction

Alkalinizing agents.^{104 105 106 107 108 109 a}

Uses for Citrates

Preparations containing sodium citrate and citric acid are especially useful when administration of potassium salts is undesirable or contraindicated,^{105 109} while those containing potassium citrate and citric acid are used when administration of sodium salts is undesirable or contraindicated.^{107 108 111}

Alkalinization of Urine

Citrates are used for alkalinization of urine (as alternatives to sodium bicarbonate) in conditions where long-term maintenance of an alkaline urine is desirable (e.g., management of uric acid and cystine calculi of the urinary tract).^{104 106 107 108 109 111 112 a}

Chronic Metabolic Acidosis

Citrates are used for management of chronic metabolic acidosis associated with conditions such as chronic renal insufficiency or renal tubular acidosis.^{104 105 106 107 108 109 111 114 a}

Adjuvant in Gout Therapy

Citrates are used as adjuvants to uricosuric agents in gout therapy.^{108 111 112}

Prevention of Milk Curdling

Sodium citrate has been used to alter cow’s milk so that large hard curds are not formed in the stomach of feeding infants^{† [off-label]}.^a

Gastric Acid Neutralization

Some citrate salts (e.g., sodium citrate and citric acid) also used for buffering and neutralizing gastric hydrochloric acid.^{105 109}

Compounding Uses

Sodium citrate and citric acid may be used as a buffer to maintain an approximate pH in various extemporaneous formulations.^a (See Compatibility under Stability.)

Citrates Dosage and Administration

General

• Selection of a specific preparation may in part be determined by potassium and sodium content.^a

• Unlike sodium bicarbonate solution, citrate solutions generally are considered highly palatable and pleasant tasting, and may be particularly useful as alkalinizing agents in patients who do not tolerate the taste of sodium bicarbonate oral solution.^{105 106 107 108 109 111 112 a}

Administration

Oral Administration

Dilute oral citrate solutions with adequate amounts of water prior to administration to minimize the risk of GI complications, and follow with additional water after administration;^{104 105 106 108 109 111 112 a} enhance palatability by chilling the solution before administration.^{109 a}

Reconstitute contents of single-dose packets containing potassium citrate and citric acid for oral solution with cool water or juice prior to administration; give additional water or juice after administration.^{100 108}

Administer oral citrate solutions after meals to avoid the saline laxative effect of the drugs as well as upset stomach.^{105 106 107 108 109 111 112 a}

Shake oral solutions well before use, unless otherwise directed.^{105 106 107}

Reconstitution

Reconstitute contents of single-dose packets containing potassium citrate and citric acid for oral solution with at least 180 mL of cool water or juice prior to administration.^{100 108}

Dosage

Pediatric Patients

General Pediatric Dosage

Potassium Citrate and Citric Acid

Oral

Usually, 5–15 mL of solution, diluted with 1/2 glass of water, after meals and at bedtime.^{107 111}

Do not use single-dose packets of potassium citrate and citric acid for oral solution in pediatric patients, since dosage for these patients can be more easily regulated with the commercially available oral solution.¹⁰⁸ Individualize dosage according to the patient’s tolerance and response.^a

Sodium Citrate and Citric Acid

Oral

Children ≥2 years of age: Usually, 5–15 mL of solution, diluted in 30–90 mL of water, after meals and at bedtime;^{105 109} individualize dosage according to patient’s tolerance and response.^a Consult a clinician for use in children <2 years of age.^{105 109}

Tricitrates

Oral

Usually, 5–15 mL 4 times daily, after meals and at bedtime;^{106 112} individualize dosage according to patient’s tolerance and response.^a

Prevention of Milk Curdling

Sodium Citrate

Oral

Prevention of the formation of large curds in the stomach of feeding infants: Add 100 mg of sodium citrate to each 30 mL of cow’s milk.^a

Adults

General Adult Dosage

Potassium Citrate and Citric Acid

Oral

Usually, 15–30 mL of solution, diluted with 1 glass of water, after meals and at bedtime.^{107 111} The usual dosage of potassium citrate and citric acid for oral solution is one single-dose packet (containing 3300 mg of potassium citrate monohydrate and 1002 mg of citric acid monohydrate), reconstituted as directed 4 times daily, after meals and at bedtime.¹⁰⁸ Individualize dosage according to patient’s tolerance and response.^a

Sodium Citrate

Oral

Usually, 1–2 g every 2–4 hours as necessary for alkalinization effect.^a

Sodium Citrate and Citric Acid

Oral

Usually, 10–30 mL of solution,¹⁰⁴ diluted in 30–90 mL of water, after meals and at bedtime.^{104 105} Individualize dosage according to patient’s tolerance and response.^a

Tricitrates

Oral

Usually, 15–30 mL of solution diluted in water 4 times daily, after meals and at bedtime.^{106 112} Individualize dosage according to the patient’s tolerance and response.^a

Gastric Acid Neutralization

Sodium Citrate and Citric Acid

Oral

15 mL of solution, diluted in 15 mL of water, taken as a single dose.¹⁰⁵

Cautions for Citrates

Contraindications

• Potassium citrate and citric acid (oral solution and for oral solution [Cytra-K Crystals]): Manufacturer states that preparation is contraindicated in severe renal impairment with oliguria or azotemia, untreated Addison’s disease, adynamia episodica hereditaria, acute dehydration, heat cramps, anuria, severe myocardial damage, or hyperkalemia (from any cause).^{108 111}

• Sodium citrate and citric acid oral solution (Bicitra, Cytra-2): Manufacturers state that preparations are contraindicated in patients requiring sodium-restricted diet and those with severe renal impairment.^{105 109}

• Sodium citrate and citric acid (Oracit): Manufacturer states that preparation is contraindicated in severe renal impairment, oliguria or azotemia, untreated Addison’s disease, adynamia episodica hereditaria, acute dehydration, heat cramp, anuria, severe myocardial damage, and hyperkalemia.¹⁰⁴

• Tricitrates oral solution (e.g., Cytra-3): Manufacturer states that preparation is contraindicated in severe renal impairment with oliguria and azotemia, untreated Addison’s disease, and severe myocardial damage.^{112 a}

Warnings/Precautions

Warnings

Electrolyte and Acid-Base Disturbances

Potassium-containing formulations: Large doses may cause hyperkalemia and alkalosis, especially in patients with renal impairment.^{108 111} Listlessness, weakness, mental confusion, and tingling of the extremities may be associated with hyperkalemia.^{108 111 112}

Sodium-containing formulations: Excessive doses may cause metabolic alkalosis, especially in patients with hypocalcemia or renal impairment.^{105 109 a} Possible tetany or depression of the heart associated with decreased ionized calcium concentrations may occur with large doses.^a

General Precautions

Concomitant Disease

Sodium-containing formulations: Use with extreme caution in patients with low urine output (unless patient is closely supervised), CHF, hypertension, renal dysfunction, peripheral or pulmonary edema, or toxemia of pregnancy.^{105 109 112}

Potassium-containing formulations: Use with extreme caution in patients in whom excessive potassium may cause deleterious effects.^a

Adequate Patient Evaluation and Monitoring

Evaluate patient’s clinical condition and monitor serum electrolyte concentrations and acid-base balance periodically, especially in patients with renal impairment, to avoid complications.^{104 105 108 109 a}

Laxative Effects

Possible saline laxative effects; dilute citrate solution with water and administer after meals to minimize this effect.^{104 105 108 a}

Specific Populations

Pregnancy

Potassium citrate: Category A.¹¹⁰

Lactation

Not known whether potassium citrate is distributed into milk.¹¹⁰ Because potassium freely distributes into and out of milk, use of potassium citrate by nursing woman with normal plasma potassium concentrations should have no adverse effect on nursing infant; milk potassium concentrations may be increased in hyperkalemic women.¹¹⁰

Renal Impairment

Use citrates with caution in patients with renal impairment.^{105 109 112} Monitor serum electrolyte concentrations and acid-base balance to avoid complications (see Warnings/Precautions under Cautions).^{104 105 108 109 111 112 a} Manufacturers state that citrates are contraindicated in patients with severe renal impairment (see Contraindications under Cautions).^{104 105 108 109 111 112 a}

Common Adverse Effects

Generally well tolerated at recommended dosages in patients with normal renal function and urine output.^{104 105 108 109 a} (See Warnings under Cautions.)

Drug Interactions

Specific Drugs

Citrates Pharmacokinetics

Distribution

Extent

Not known whether potassium citrate is distributed into milk.¹¹⁰

Elimination

Metabolism

Metabolism of citrates appears to be associated with bicarbonate formation. ^{105 108 109 111 a}

Elimination Route

Citrates are excreted in urine, mainly as metabolites; <5% of an oral dose is excreted in the urine unchanged.^{104 105 108 109 a}

Stability

Storage

Oral

Solution

Potassium citrate and citric acid oral solutions (e.g., Cytra-K): Tight, light-resistant containers at 20–25°C; protect from excessive heat or freezing.^{107 111}

Potassium citrate and citric acid for oral solution (Cytra-K Crystals): Protect from excessive heat or freezing.¹⁰⁸

Sodium citrate and citric acid oral solution (Oracit): Well-closed containers at 15–30°C.¹⁰⁴

Sodium citrate and citric acid oral solution (Cytra-2): Tight, light-resistant containers at 20–25°C; protect from freezing.¹⁰⁵

Sodium citrate and citric acid oral solution (Bicitra): Tight containers; protect from freezing or excessive heat.¹⁰⁹

Tricitrates oral solution (e.g., Cytra-3): Tight, light-resistant containers at 20–25°C; protect from excessive heat or freezing.^{106 112}

Compatibility

Oral

Solution

May use sodium citrate and citric acid as a buffer to maintain an approximate pH in various extemporaneous formulations.^a In general, the addition of the following concentration of the drugs should produce a solution buffered to the approximate pH listed:

Adapted from Schumacher GE. Buffer formulations. Am J Hosp Pharm. 1966; 23:628-9.

Actions

• Potassium citrate is absorbed and then appears to be metabolized to potassium bicarbonate, resulting in systemic alkalinization.^{108 111}

• Sodium citrate is absorbed and then appears to be metabolized to sodium bicarbonate, resulting in systemic alkalinization.^{105 109}

• Sodium citrate has anticoagulant activity;^a prevents the clotting of blood by forming an undissociated calcium citrate complex, making calcium unavailable to the clotting mechanism. ^a Anticoagulant sodium citrate solution, when added to blood, prevents the clotting of blood and the crenation or swelling of cells.^a Sterile solution is used as an anticoagulant for banked blood for transfusion and to prepare citrated human plasma and blood for fractionation.^a

• Sodium citrate prevents the curdling of milk by rennin; has been used to alter cow’s milk so that large hard curds are not formed in the stomach of feeding infants.^a

Advice to Patients

• Importance of following instructions for dosage preparation, including reconstitution and/or dilution recommendations.^{104 105 106 107 108 109} (See Oral Administration under Dosage and Administration.)

• Importance of taking drugs only as prescribed, unless otherwise instructed by a clinician.^{105 106 107 109 111}

• Importance of taking doses after meals to avoid saline laxative effect.^{104 105 106 107 108 109 111 112}

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{104 105 106 107 108 109}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{105 106 107 108 109}

• Importance of informing patients of other important precautionary information.^{104 105 106 107 108 109} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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