Usage
Probenecid is primarily prescribed for the treatment of hyperuricemia associated with gout and gouty arthritis. It’s also used as an adjuvant to enhance plasma levels of certain beta-lactam antibiotics (like penicillin, ampicillin, cephalosporins) in treating infections like gonorrhea and pelvic inflammatory disease. It is classified as a uricosuric agent and an organic anion transport inhibitor. Probenecid works by blocking the reabsorption of uric acid in the kidneys, thus increasing its excretion and lowering blood uric acid levels. It also inhibits the renal tubular secretion of certain antibiotics, increasing their duration of action.
Alternate Names
Probenecid is the generic name. Brand names include Benemid and Probalan. There are no widely recognized international variations for Probenecid.
How It Works
Pharmacodynamics: Probenecid’s primary effect is to reduce uric acid levels in the blood by inhibiting its reabsorption in the proximal renal tubules. This action is mediated by inhibiting the urate transporter 1 (URAT1) and organic anion transporters (OATs) in the kidneys. For antibiotic enhancement, probenecid competes with the antibiotics for OAT-mediated excretion, increasing their serum half-life.
Pharmacokinetics:
- Absorption: Probenecid is well-absorbed orally.
- Metabolism: It is primarily metabolized in the liver, with minor metabolism by CYP2C9.
- Elimination: Primarily eliminated by the kidneys, both as the unchanged drug and metabolites. Minor excretion occurs in the bile.
Dosage
Standard Dosage
Adults:
- Gout: Initially 250 mg orally twice daily for one week, then increased to 500 mg orally twice daily. The dose can be further titrated upwards by 500 mg increments every 4 weeks, as needed, to a maximum of 2000 mg/day, usually taken in divided doses.
- With Antibiotics: 2000 mg daily in divided doses. This should be reduced in elderly patients or those with suspected renal impairment.
Children:
- With Antibiotics (2 years and older): Initial dose of 25 mg/kg (or 700 mg/m²) orally, followed by 40 mg/kg/day (or 1200 mg/m²/day) in four divided doses. Maximum single dose: 500 mg.
- Gout: Not typically used.
Special Cases:
- Elderly Patients: Reduced dose due to potential renal impairment.
- Patients with Renal Impairment: Avoid use if eGFR < 30 mL/min/1.73m². Dose adjustment may be needed for mild to moderate impairment.
- Patients with Hepatic Dysfunction: Use with caution, dose adjustment may be required.
- Patients with Comorbid Conditions: Individualized dosing based on specific conditions.
Clinical Use Cases
Probenecid’s use in situations like intubation, surgical procedures, mechanical ventilation, ICU use, and most emergencies is limited to its role in enhancing antibiotic levels when co-administered with specific beta-lactam antibiotics. It is not independently indicated for these clinical scenarios.
Side Effects
Common Side Effects
Headache, dizziness, nausea, vomiting, loss of appetite, rash, sore gums, flushing. Gout flares may also increase at the beginning of treatment.
Rare but Serious Side Effects
Aplastic anemia, hemolytic anemia (particularly in patients with G6PD deficiency), nephrolithiasis, hepatic necrosis, anaphylaxis.
Adverse Drug Reactions (ADR)
Severe hypersensitivity reactions, renal failure, blood dyscrasias.
Contraindications
Absolute contraindications include hypersensitivity to probenecid, blood dyscrasias, uric acid kidney stones, age under 2 years, current gout attack, and concomitant use with salicylates.
Drug Interactions
Probenecid interacts with numerous drugs. It increases levels of drugs like methotrexate, some NSAIDs, and certain antibiotics by inhibiting their renal clearance. Salicylates antagonize the uricosuric action of probenecid. It can also potentiate the effects of sulfonylureas, increasing the risk of hypoglycemia. Consult a comprehensive drug interaction resource for a full list.
Pregnancy and Breastfeeding
Pregnancy Safety Category: B (Animal studies show no risk, but adequate human studies are lacking). Use only if clearly needed. Excreted in breast milk in low levels. Monitor infant for potential gastrointestinal issues.
Drug Profile Summary
- Mechanism of Action: Inhibits renal tubular reabsorption of uric acid and secretion of some antibiotics.
- Side Effects: Headache, nausea, rash, rarely blood disorders and kidney stones.
- Contraindications: Hypersensitivity, blood dyscrasias, uric acid stones, age <2 years.
- Drug Interactions: Numerous; increased levels of methotrexate, NSAIDs, some antibiotics. Decreased efficacy with salicylates.
- Pregnancy & Breastfeeding: Category B, caution advised; excreted in breast milk.
- Dosage: Gout: Initially 250 mg BID, then 500 mg BID, titrate to max 2g/day; Antibiotic adjunct: 2g/day divided.
- Monitoring Parameters: Serum uric acid levels, renal function, CBC.
Popular Combinations
Probenecid is combined with certain antibiotics, like penicillin or ampicillin, to treat gonorrhea or other infections where prolonged antibiotic action is desired. It’s also sometimes used in combination with allopurinol for gout, although this can alter the pharmacokinetics of oxypurinol.
Precautions
Pre-existing peptic ulcers require caution. Hypersensitivity reactions warrant discontinuation. Monitor renal function and CBC. Alcohol consumption should be minimized.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Probenecid?
A: For gout: Initial dose is 250 mg twice daily for one week, then 500 mg twice daily, titratable to a maximum of 2 g/day. As an antibiotic adjunct: 2 g/day in divided doses.
Q2: How does Probenecid work in gout?
A: It increases uric acid excretion by inhibiting its reabsorption in the kidneys.
Q3: Can Probenecid be used during a gout attack?
A: No, it is contraindicated during an acute gout flare.
Q4: What are the common side effects of Probenecid?
A: Headache, dizziness, nausea, vomiting, and loss of appetite are common side effects.
Q5: Does Probenecid interact with other medications?
A: Yes, it interacts with numerous drugs. Significant interactions include increased levels of methotrexate, some NSAIDs, and certain antibiotics. Salicylates decrease its uricosuric effect.
Q6: Can Probenecid be used in patients with kidney disease?
A: It should be avoided in patients with severe renal impairment (eGFR < 30 mL/min/1.73m²). Dose adjustment is necessary in moderate renal impairment.
Q7: Is Probenecid safe during pregnancy?
A: Pregnancy Category B. Use cautiously and only if clearly needed. Discuss risks and benefits with the patient.
Q8: How should Probenecid be administered?
A: Administer orally with food to reduce gastrointestinal upset.
Q9: What monitoring is required for patients taking Probenecid?
A: Monitor serum uric acid levels, renal function (creatinine, eGFR), and complete blood count (CBC).
Q10: Can I take aspirin while on probenecid for gout?
A: No, concomitant use with salicylates, including aspirin, is contraindicated as it antagonizes the uricosuric action of probenecid.
