Urikosurika

Uricosurics - along with uricostats and uricolytics (Dellas 2017) - are among the medications used in the setting of chronic gout disease (Beubler 2011).

Uricosurics include:

• Benzbromarone (the most commonly used drug in German-speaking countries [Freissmuth 2016]).
• Probenecid (the most commonly used drug in Anglo-Saxon countries [Freissmuth 2016]).
• Lesinurad (only approved since 2016) (Herold 2021).

Mode of action

Uricosurics are a group of drugs that increase renal uric acid excretion by blocking the uric acid transporter URAT 1, thereby decreasing tubular reabsorption of uric acid from the tubular lumen (Freissmuth 2016). Lesinurad additionally inhibits the organic anion transporter OAT 4 (Aktories 2017). The target uric acid level should be < 6.0 mg /dl (Bruhn 2016).

Pharmacokinetics

Benzbromarone: Absorption from the gastrointestinal tract is only about 50% after oral administration (Hofmann 2017), but this can be significantly increased by a micronized preparation. Metabolization occurs hepatically. The half-life is 3 - 4 h. Excretion is predominantly biliary (Freissmuth 2016).

Probenicid: With probenicid, gastrointestinal absorption is almost complete. Metabolism occurs hepatically. The half-life is 5 - 8 h. Excretion is primarily renal. Because of active metabolites, the duration of action of probenicid is significantly longer than that of benzbromarone (Freissmuth 2016).

Lesinurad: Bioavailability is close to 100% after oral administration (Bruhn 2016). The metabolization occurs hepatically. The half-life is about 5 h (Jobst 2020). Excretion is primarily renal (Bruhn 2016).

Indikatonen: The indication for treatment with uricosurics is intolerance or allergy to allopurinol (Herold 2021). They are also a back-up agent for patients with normal renal function who require rapid lowering of elevated uric acid levels (Freissmuth 2016) and, with the exception of lesinurad, find prophylactic use as an alternative to allopurinol in cytostatic treatment (Dellas 2017).

Lesinurad can be used in patients in whom uricostatic agents do not show sufficient effect, but always in combination with a xanthine oxidase inhibitor (such as allopurinol) to minimize the risk of renal failure (Hofmann 2017).

Contraindications

• Gouty nephropathy
• Renal insufficiency
• Nephrolithiasis
• Overproduction of uric acid

(Herold 2021)

• acute gout attack
• hyperuricemia due to hematological diseases
• Pregnancy and lactation (Freissmuth 2016).

For lesinurad:

• Cardiovascular pre-existing conditions (Lunzer 2018).

Side effects

At the beginning of treatment, the uric acid concentration may be so high that the following complications may occur:

• crystallization of uric acid in the tubules with
  • formation of kidney stones
  • resulting anuria
• Liver damage (described for benzbromarone and probenecid, but rarely occurring).

(Freissmuth 2016)

• allergic reactions (rare)
• gastrointestinal complaints such as nausea, vomiting, diarrhoea

(Herold 2021)

With lesinurad additional possible side effects:

• increase in serum creatinine levels
• Cardiovascular symptoms in the form of myocardial infarction, apoplexy, etc. described in studies (but the causal relationship is unclear)

(Bruhn 2016)

Combination

With simultaneous administration of azathioprine or 6- mercaptopurine, no dose reduction is required (as is the case with therapy with uricostatic drugs ), but severe damage to the liver occurred in combination with benzbromarone in increased numbers (Dellas 2017).

Interactions

The following applies to benzbromarone and probenecid:

• Attenuation of the effect of allopurinol due to increased excretion of the active allopurinol metabolite oxipurinol.
• tubular secretion of various organic acids is inhibited (especially by probenicid), thereby reducing the excretion of:
  • penicillin (does not apply to benzbromarone)
  • Indometacin
  • Naproxen
  • Ketorolac
  • Ketoprofen (Freissmuth 2016)
  • Diuretics (Dellas 2017)
• following drugs attenuate the effect of uricosurics:
  • Pyrazinamide (tuberculostat)
  • Salicylates
  • Sulfinpyrazone

(Freissmuth 2016)

Benzbromarone:

• Enhances the effect of coumarin anticoagulants (Hofmann 2017).

Lesinurad:

• The effect of hormonal contraceptives is limited (additional contraceptive measures required)

(Bruhn 2016)

Pregnancy and lactation

Uricosurics are considered contraindicated in both pregnancy and lactation (Freissmuth 2016).

Dosage recommendation

Benzbromarone: 50 mg - 100 mg / d

Probenecid: 2 x 250 mg / d in the 1st week, then 2 x 500 mg / d.

(Actories 2017)

Lesinurad: 200 mg / d plus xanthine oxidase inhibitors such as allopurinol (Hofmann 2017).

• Uricosurics should be dosed gradually, as there is a risk of tubular uric acid precipitation and urinary stone formation before normal uric acid levels are reached (Herold 2021)
• Alternatively, colchicine or NSAIDs can be given prophylactically for 3 months (Delas 2017)
• the drinking quantity should be 2 l / d during therapy
• the simultaneous administration of Uralyt U is recommended to keep the urine at a pH value between 6.5 - 7

(Herold 2021)

• Benzbromarone is no longer effective above a creatinine clearance of < 20 ml / min.
• Probenecid is no longer effective above a creatinine clearance of < 50 ml / min.
• Probenecid is on the list of the anti-doping agency as a so-called prohibited substance.
• Lesinurad should no longer be used above a creatinine clearance of 45 ml / min.

(Hofmann 2017)

1. Aktories K et al (2017) General and special pharmacology and toxicology. Urban and Fischer Publishers 526
2. Beubler E (2011) Compendium of pharmacology: common drugs in practice. Springer Verlag Vienna 118
3. Boeckh M (2002) Original examination questions with commentary GK 2. general pharmacology and toxicology. Thieme Verlag 315
4. Bruhn C (2016) Lesinurad. Drug therapy: independent information on pharmacotherapy. (34) 357 - 361
5. Dellas C (2017) Short textbook pharmacology. Elsevier Urban and Fischer Publishers 192 - 193.
6. Droste U (2003) Rheumatology: diagnosis - clinic - therapy. Thieme Verlag 302
7. Freissmuth M et al (2016) Pharmacology and toxicology: from molecular basis to pharmacotherapy. Springer Verlag 680
8. Gellrich L et al (2016) New active principle in gout. Pharmazeutische Zeitung (6)
9. Herold G et al (2021) Internal medicine. Herold Publishers 708
10. Hofmann F B, Starke K, Förstermann U. (2017). General and special pharmacology and toxicology: founded by W. Forth, D. Henschler, W. Rummel. Germany: Urban & Fischer Verlag GmbH & Company KG 526 - 527.
11. Jobst E E et al (2020) Pharmacology for the Physical Therapist. McGraw- Hill Education 410
12. Lunzer R (2018) Hyperuricemia and gout: presentation of a new therapeutic option. Universimed Medicine in Focus
13. Oberdisse E et al (2002) Pharmacology and toxicology. Springer Verlag 549
14. Rieke H et al. (2016) Gout: the current state of knowledge on etiology, pathogenesis, diagnosis, clinic and therapy. De Gruyter Verlag 7.5.3