Antiuricaemic Drugs Flashcards
Causes of hyperuricaemia
- Excessive intake
- Increased production
- Defective excretion
Causes of excessive uric acid production
Leukaemia
Rhabdomyolysis
Cytotoxic therapy
Enzyme deficiency HGPRT
Causes of defective uric acid (UA) excretion
Glomerulopathy
Tubular pathology
Diuretics
Diabetic ketoacidosis
Starvation ketosis
Reduced tubular secretion
ABCG2 transporter polymorphisim
GLUT9 polymorphism
URAT 1 transporter dysfunction
Uric acid synthesis steps
A I I H X U
ATP
IMP
Inosine
Hypoxanthine
Xanthine
Uric acid
Manifestations of hyperuricaemia
- Asymptomatic
- Gout
- Nephrolithiasis (kidney stone)
- Uric acid nephropathy
- A component of metabolic syndrome
Gout pathology
It is a metabolic and inflammatory disorder. The deposition of sodium urate crystals in the synovial membrane causes an activation of the inflammatory cascade.
Gout symptoms
It usually presents as a monoarticular arthritis affecting the big toe.
It is characterized by pain and swelling of the affected joint.
Classes of drugs used in treating gout
- Anti-inflammatory drugs
- Anti-uricaemic drugs
Anti-inflammatory drugs used in gout treatment
NSAIDs
Steroids
Colchicine
Classes of urate-lowering drugs
Uric acid synthesis inhibitors
Uricosuric drugs
Selective uric acid reabsorption inhibitors
Recombinant urate oxidase
Examples of uric acid synthesis inhibitors
Allopurinol
Febuxostat
Examples of uricosuric drugs
Probenecid
Benzbromarone
Sulfinpyrazone
Examples of selective uric acid reabsorption inhibitors
Lesinuraud
Examples of recombinant urate oxidase
Pegloticase
Rasburicase
Colchicine uses
The drug is used for the management of acute attacks and to prevent gouty attacks on commencement of anti-uricaemic drugs.
Colchicine MOA
It inhibits migration of neutrophils to the affected joint by binding to tubulin. Also prevents activation and degranulation of neutrophils to generate inflammatory cytokines.
Colchicine RODA
It is given via the oral route
Colchicine adverse effects
Nausea, vomiting, abdominal pain.
Allopurinol MOA
It is a xanthine oxidase inhibitor, a hypoxanthine analog that reduces the production of uric acid by competing as substrate for the oxidase enzyme in place of hypoxanthine. It inhibits the last two steps in uric acid biosynthesis, both catalysed by this enzyme. Its metabolite, alloxanthine, has a similar MOA
Allopurinol MOA
Routes of administration – oral, intravenous
Bioavailability - 49-53%
Onset of action - 2-3 days
Peak plasma time – 0.5 -2 hours
Time to peak effect – 7-14 days
Distribution - protein bound <1%
Volume of distribution – 1.6-2.4 L/kg
Metabolized in the liver – oxypurinol (active), allopurinol riboside
Half –life – Parent drug 1-3 hours
Active metabolites 15-20 hours
Adverse effects of allopurinol
Gastrointestinal disturbances
Allergic reactions – skin rashes
Febuxostat MOA
A xanthine oxidase inhibitor, less likely to cause severe hypersensitivity reaction. Does not inhibit other enzymes involved in purine and pyrimidine synthesis.
Probenecid MOA
Competitively inhibits reabsorption of uric acid in PCT. Contraindicated in uric acid nephrolithiasis.
Probenecid side effects
GI disturbance
Hypersensitivity reactions
Selective uric acid reabsorption inhibitor example and MOA
Lesinuraud
Inhibits URAT1 and OAT4
Recombinant urate oxidase enzyme examples
Pegloticase
Rasburicase
Recombinant urate oxidase enzyme MOA
Converts urate to allantoin, a soluble form excreted in urine
What is the specific use of Pegloticase?
Indicated if xanthine oxidase inhibitors fails/contraindicated
Rasburicase specific use
For prophylaxis and treatment of hyperuricaemia associated with treatment of malignancies.
Which drugs are used for uric acid nephropathy in cytotoxic therapy
Uric acid synthesis inhibitors
