Antirheumatics

Allopurinol: MOA, Indication, Dose, Interaction and Side effects

  • Pharmacology
  • Antirheumatics
  • 2020-08-04 04:11:19
  • 7 minutes, 1 second

Allopurinol: MOA, Indication, Dose, Interaction and Side effects

Allopurinol (Alloprim) is a purine analog that is the preferred and standard-of-care therapy for chronic gout. It is also used in the prevention of increased uric acid levels in patients on cancer chemotherapy. These patients can have increased uric acid levels because of the release of uric acid from dying cancer cells.

It works by reducing total uric acid body burden by inhibiting xanthine oxidase.

Read more about Gout in our article here

Allopurinol is used as long-term prophylaxis for patients with recurrent gout, especially tophaceous gout, urate renal stones, gout with renal failure and acute urate nephropathy.

Chemically, Allopurinol is an isomer of hypoxanthine.

mechanism of action of allopurinol

The drug is classified in pregnancy category C

Trade names: Aloprim, Apo-Allopurinol (CAN), Purinol (CAN), Zyloprim

The plasma uric acid concentration should be kept below 0.42 mmol/L. Allopurinol may provoke acute gout during the first few weeks of treatment. It must not be commenced until several weeks after an acute attack has completely resolved.

Mechanism of action of Allopurinol

Allopurinol is a xanthine oxidase inhibitor specifically a uricostatic agent.

Allopurinol competitively inhibits the synthesis of uric acid by inhibiting xanthine oxidase, an enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Allopurinol is metabolized by xanthine oxidase to alloxanthine, which also inhibits xanthine oxidase.

This inhibition decreases the production of uric acid and reducing its concentration in extracellular fluid, thereby preventing precipitation of crystals in joints or elsewhere. In the long run, it relieves the signs and symptoms of gout.

Allopurinol also inhibits de novo purine synthesis.

Uric acid is mobilized from tophaceous deposits which slowly disappear.

Note that Allopurinol is not uricosuric, rather they inhibit xanthine oxidase, which is involved in the synthesis of uric acid.

Febuxostat is another drug that belongs to the same class as allopurinol but it may be more selective for xanthine oxidase.

Therapeutic uses.

Allopurinol is often the first urate-lowering drug used prophylactically to treat chronic, tophaceous gout because it reduces the size of the established tophi; colchicine is administered concomitantly during the first week of therapy to prevent gouty arthritis.

Apart from this agent, chronic gout is treated with the uricosuric agent probenecid or sulfinpyrazone, which increases the elimination of uric acid, or febuxostat.

Treatment of gout with allopurinol, as with uricosuric agents, is begun with the expectation that it will be continued for years if not for life.

When starting allopurinol, colchicine should also be used until steady-state serum uric acid is normalized or decreased to less than 6 mg/dL. Thereafter colchicine can be stopped, while allopurinol is continued.

Aside from gout, allopurinol is used as an antiprotozoal agent and is indicated to prevent the massive uricosuria following therapy of blood dyscrasias that could otherwise lead to renal calculi.

Used in the management of patients with malignancies that result in elevations of serum and urinary uric acid

Also management of patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day (males) or 750 mg/day (females)

Orphan drug use:

Treatment of Chagas' disease; cutaneous and visceral leishmaniasis

Unlabeled uses:

Amelioration of granulocyte suppression with fluorouracil; as a mouthwash to prevent fluorouracil-induced stomatitis

Contraindications and cautions

It is contraindicated with an allergy to allopurinol,

Allopurinol should be used with caution in patients with liver disease, renal failure, lactation, pregnancy or bone marrow depression (blood dyscrasias).

Avoid drinking alcohol. It can make your condition worse.

Safety in children and during pregnancy has not been established.

Available forms

Tablets—100, 300 mg; powder for injection—500 mg

Dosages

The drug is given orally (300–800 mg/d). Except for infrequent allergic reactions, it is well tolerated and is the drug of choice for gout prophylaxis.

At the start of therapy, gout attacks may occur, but they can be prevented by concurrent administration of colchicine (0.5–1.5 mg/d).

The initial dosage of allopurinol is 100 mg/d. It may be titrated upward until serum uric acid is below 6 mg/dL; this level is commonly achieved at 300 mg/d but is not restricted to this dose.

Colchicine or an NSAID should be given during the first weeks of allopurinol therapy to prevent gouty arthritis episodes that sometimes occur.

Adults

Gout and hyperuricemia: 100–800 mg/day PO in divided doses, depending on the severity of the disease (200–300 mg/day is the usual dose).

Maintenance: Establish a dose that maintains serum uric acid levels within normal limits.

Prevention of acute gouty attacks: 100 mg/day PO; increase the dose by 100 mg at weekly intervals until uric acid levels are within normal limits.

Prevention of uric acid nephropathy in certain malignancies: 600–800 mg/day PO for 2–3 days; maintenance dose should then be established as above.

Recurrent calcium oxalate stones: 200–300 mg/day PO; adjust the dose up or down based on 24-hr urinary urate determinations.

Parenteral: 200–400 mg/m2/day IV to maximum of 600 mg/day as continuous infusion or at 6, 8, 12 hr intervals.

Pediatric patients

Secondary hyperuricemia associated with various malignancies:

6–10 yr: 300 mg/day PO.

< 6 yr: 150 mg/day; adjust dosage after 48 hr of treatment based on serum uric acid levels.

Parenteral: 200 mg/m2/day IV as continuous infusion or at 6, 8, 12 hr intervals.

Geriatric patients or patients with renal impairment

For geriatric patient or patients with creatinine clearance 10–20 mL/min, 200 mg/day; for creatinine clearance < 10 mL/min, 100 mg/day; for creatinine clearance < 3 mL/min, extend intervals between doses based on patient's serum uric acid levels.

Pharmacokinetics

Allopurinol is approximately 80% absorbed after oral administration and has a terminal serum half-life of 1-2 hours.

Administer drug following meals to prevent stomach upsets.

Encourage patient to drink 2.5 to 3 L/day to decrease the risk of renal stone development.

On oral administration, it has a slow onset compared to parenteral administration with an onset of 10-15 minutes

Like uric acid, allopurinol is itself metabolized by xanthine oxidase, but the resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a day.

Bioavailability of 49-53%

Metabolism: Hepatic; T1/2: 1–1.5 hr, then 23–24 hr

Distribution: Crosses placenta; may enter breast milk.

Protein-bound <1%

Excretion: Urine

The drug is dialyzable by both hemodialysis and peritoneal dialysis.

 Pharmacodynamics

Dietary purines are not an important source of uric acid. Quantitatively important amounts of purine are formed from amino acids, formate, and carbon dioxide in the body.

Those purine ribonucleotides not incorporated into nucleic acids and derived from nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to uric acid.

Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the size of the urate pool. The more soluble xanthine and hypoxanthine are increased.

Preparation:

Dissolve contents of each vial with 25 ml of sterile water for injection. Further, dilute with NSS or D5W to a final concentration of < 6 mg/ml. Administer within 10 hr of reconstitution.

Infusion:

Administer as a continuous infusion or infused q 6, 8, or 12 hr with rate dependent on the volume used.

Incompatibilities:

Incompatible with many other drugs; do not mix with any other drug in the same solution.

Adverse effects

CNS: Headache, drowsiness, peripheral neuropathy, neuritis, paresthesias

Dermatologic: Maculopapularrashes, scaly or exfoliative and sometimes fatal

GI: Nausea, vomiting, diarrhea, abdominal pain, gastritis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice.

GU: Exacerbation of gout , hypoxanthine stones, and renal calculi, renal failure

Hematologic: Anemia, leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, bone marrow depression

Drug-drug Interactions

There is an increased risk of hypersensitivity reaction with ACE inhibitors.

Increased toxicity with thiazide diuretics

Increased risk of rash with ampicillin

Increased risk of bone marrow suppression with cyclophosphamide, other cytotoxic agents.

The increased half-life of oral anticoagulants. ( Metabolism of warfarin is inhibited)

Increased serum levels of theophylline.

Increased risk of toxic effects with thiopurines, 6-MP (azathioprine dose and the dose of 6-MP should be reduced to one-third to one-fourth the usual dose)

When chemotherapeutic mercaptopurines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%.

Allopurinol may also increase the effect of cyclophosphamide.

Allopurinol inhibits the metabolism of probenecid and oral anticoagulants and may increase hepatic iron concentration.


References:
author

Daniel Ogera

Medical educator, passionate about simplifying difficult medical concepts for easier understanding and mastery by nursing and medical students.

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About this article:
  • Topic:Pharmacology
  • Duration:7 minutes, 1 second
  • Subtopic:Antirheumatics

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