Module 1.3.1 (Pharmacological management of Gout) Flashcards
What is gout? How is it classified? What are the two general causes?
Increased uric acid in joints
- >6.4 mg/dl insoluble (average female = 4.1, male = 5.0)
Two general causes
- Overproduction of purine nucleotides, giving excessive uric acid
- Impaired uric acid excretion through kidneys (drugs/toxins can contribute here)
The main treatment used to treat gout? What is its MOA?
Treat with allopurinol, an analogue of hypoxanthine
- Strongly inhibits xanthine oxidase.
- Hypoxanthine reused through salvage pathways indirectly reducing PRPP levels
What are the biochemical causes of GOUT?
- Increased PRPP synthetase activity
- Increased PRPP amidotransferase
- Decreased HGPRT (partial activity)
- Decreased glucose 6-phosphatase activity
Deposits in joints –> arthritis
Deposits in kidney –> renal disease
For the drugs used in GOUT;
A) What decreases leukocyte migration into the joint?
B) What decreases uric acid synthesis?
C) What increases uric acid excretion?
A)
- Colchicine
B)
- Allopurinol or Febuxostat
C)
- Probenecid, Benzbromarone
- Non specific anti-inflam & analgesi
- NSAIDs – except aspirin (NO SALYCYLATES allowed)
- Corticosteroids
For colchicine (acute management of gout);
A) What is it used for?
B) What is its MOA
C) When to give
D) When is relief achieved, peak plasma conc and when is it detectable in leukocytes?
A)
- Acute gouty arthritis: Anti-inflammatory action only
- Antimitotic - tubulin inhibitor (depolymerisation)
B)
Loss of fibrillar tubules in granulocytes – Inhibits neutrophil migration, chemotaxis, adhesion & phagocytosis in inflamed areas
- decreased mast cell histamine release
- decreased production of inflammatory glycoprotein (neutrophils)
- decreased body temperature
- decreased respiratory centre
- decreased collagen formation
C)
- Give less than or equal to 1 day after attack
- 80% of patients experience a decrease in joint inflammation
D)
- Relief in <12hours
- Peak plasma conc (1-2h)
- Detectable in leukocytes in 9 days
What are some considerations for colchicine? Is it used prophylactically in chronic gout?
Considerations:
- Gastrointestinal disease
- Renal impairment
- Hepatic impairment
- Pregnancy
- Elderly
Yes, it is prophylactically used in chronic gout
What are the side effects/toxicity of colchicine? Is there less GI effects if IV injection?
nausea, vomiting, diarrhoea (80% of patients experience NVD), abdominal pain (GI tract), rash – possible myopathy, bone marrow - leukopenia
- Less GI effects if IV injection, but narrow therapeutic window – IV –> increased risk of sepsis (death)
What is the preferred medication to be used in acute gout? Why so? When may colchicine be the better drug?
- Indomethacin
- Ibuprofen
- Both preferred for acute gouty arthritis –> less side effects especially gastrointestinal
- High doses needed initially for first day (otherwise recurrent attacks possible)
for HF patients –> colchicine better (no fluid retention effects of the drug)
For allopurinol
A) MOA
B) Properties
C) CI
D) Prophylactic use?
A)
- Xanthine oxidase inhibitor
- Decrease uric acid concentration in urine to below solubility
B)
- Orally absorbed - peak <1 h
- 2-3 h plasma ½ life
- Faecal excretion
Active meatbolite 25 h 1/2 life –> renal excreted = oxypurinol
C)
- nursing mothers
- children
- hypersensitive (skin rash with drug)
D)
- leukaemia, lymphoma, (antineoplastic agent use)
For Uricosuric Agents;
A) What is its MOA
B) Properties of Probenecid/Benzbromarone
C) Dosage regimen of probenecid? Why are high doses desired?
A)
- Increases rate of uric acid excretion by kidneys
> inhibition of tubular resorption
- Normally 90% of uric acid reabsorbed
B)
- no analgesic or anti-inflammatory activity
- inhibits organic acids from crossing back from the tubule
- uric acid only endogenous one affected
- also keeps penicillins, methotrexate, clofibrate in circulation
- and many NSAIDs
- Not useful if low kidney function (Cr CL<50%)
- Plasma ½ life 5-8h (dose-dependent)
C)
- ~12h duration (use bd)
- Small doses may actually decrease uric acid excretion
- High doses needed to increase excretion
When acute attack of gout occurs, what to give and what not to give?
What to give:
- Anti-inflammatory agents first (including corticosteroids)
> Not salicylates (contraindication as they can elevate uric acid levels) and also antagonise the action of probenecid and sulfinpyrazone
- If renally impaired = corticosteroids preferred, reduce allopurinol dose, avoid colchicine, probenecid
What not to give:
- DO NOT give uricosuric acids or allopurinol (they could increase severity as urate mobilised from joints)
- Nor ethanol, thiazide diuretics, cyclosporin A
