Drug therapy of gout Download PPT

Drug therapy of gout, 2009 Dr Attia Jabr 1.Definition: Familial metabolic disease characterized by 4 characters 2.How uric acid is formed? Xanthineoxidase 3.How uric acid is secreted? Active secretion 10% 4.What is the role of diet?? 5.Etiology of gout? A.Overproduction►10% What are the drugs that ▲Production? B.Under excretion►90% What are the drugs that ▼secretion? Stages of gout 1.Asymptomatic hyperuricemia 2.Acute gouty arthritis 3.Intercritical gout 4.Chronic tophaceous gout 5.Others; e.g. Gouty nephropathy Gout

Pathogenesis of gouty arthritis
qHyperuricemia ►urate crystals in joints ►phagocytosed by phagocytic synoviocytes►inflammatory mediators (Leuko-prost-Cytok)►▲endothelial cells ►inflamatory mediators + chemokines►phagocytes ►phagocytose crystals ►inflammtory mediators►rupture of lysosomes ►death of phagocytes ► release of hydrolytic lysosymes & lactic acid►more inflammation ►more deposition of crystals ►increase vascular permeability and pain (Damage of cartilage & joint)
qLong standing cases destroy cartilages and bones

Purine nucleotides
Uric acid
Xanthine oxidase
Alimentary excretion
Urinary excretion
Tissue deposition in excess
Urate crystal
Phagocytosis with acute inflammation and arthritis
Therapeutic strategies for treatment of gout
1.Inhibit leukocyte entry into joints: By Colchicine
2.Anti-inflammatory:like NSAID or Cortisone
3.Decrease of serum uric acid by:
A.▼productionby Allopurinol& Febuxostat
B.▲Excretionby Probenecid
4.Conversion of uric acid to a soluble metabolite: Rasburicase
5.Losartan: ARB
ARB given as 50mg/dLcan be uricosuric.
6.Fenofibrate: ▼TG
combination with Allopurinolproduced additional lowering of the urate

Drugs used in acute attacks
1.Non-steroidal anti-inflammatory drugs:
qNon-selective: Endomethacin, diclofenac, naproxyn,
qbut not salicylates. Why?
qSelective Cox2 inhbitors: Etoricoxib, Celecoxib, Valdecoxicib
qSaferthan colchicines for acute attacks.
qBut not for prophylaxis. Why?
qWhat is the mechanism of action of NSAIDs?
qSide Effects? Contraindications?
qDose of indomethacin?

2. Colchicine
Mechanism of action:
q▲Phagocytes ▼tubulin formation▼migration▼ phagocytosis & ▼release of inflammatory mediators(IL-1, 8) ▼inflammtion ▼lactic acid ▼ deposition of urate crystals
q▼Synthesis & Release of inflammatory mediators & chemokines
qAntimitotic effect?
qNot analgesic except in gouty arthritis (selective, effective, diagnostic)
qNo effect on uric acid
qCould be used in prophylaxis also? When? 80% effective

qAbsorption: orally rapidly-peak level within 2h
qMetabolism: partlyby liver-Drug & metabolites to intestine. Drugs inhibiting like ketokonazole, cyclosporine, clarithromycin; (entero-hepatic circulation enhances its toxicity)).
qExcretion: Excretedby feces mainly (70-85%) and urine (15-30%). Avoided if CrCl< 50 ml/min qT1/2 is 9 h-30H. qDistribution: Wide distribution, concentrated in many tissues especially leukocytes. qAdministration: Orally, Could be given IV (When?). But dangerous and rarely used. Therapeutic uses of colchicine 1.Acute attacks of gout 1.Orally; 1mg first then 0.5mg/1h until (pain relief, diarrhea, 6mg) course not repeated with 3 days 2.IV: 2mg then 0.5mg/6h (maximum 4mg) 3.In gouty with HF, With anticoagulants # NSAIDS 2.Prophylaxis in chronic gout 1.Alone or + allopurinolor Uricosurics(0.5mg 1-3/day) 2.Prophylaxis of gout during surgery 3.Other indications 1.Primary biliarycirrhosis, FMF, Behcet’sdiseas, Psoriaic arthritis, aphthousstomatitis Side effects & Precautions A. Acute: With acute courses 1.The most common and earliest are: qN, V, Diarrhea,Abd. Pain 80% of patients (Why? 2 reasons). 2.Overdose (A dose 8 mg IV): qHemorrhagic GE, shock, nephrotoxicity, hematuria, oliguria, hepatotoxicity, and CNS depressionmay be fatal. B. Chronic:Withlong courses: 1.Hair loss, BMD , PN, azoospermia 2.Myopathy(if used in renal impairment) 1.Do you know a drug of gout which could be fatal just with increase its dose? C. Contraindications & Precautions: A.Contraindicated in pregnancy B.Used with caution in severeHepatic, renal, CVD, GIT diseases, blood dyscrasia. Fatal dose is (7-10 mg) 3. Corticosteroids 1.Mechanism of action: qThey are potent anti-inflammatory drugs. ▼cytokines 2.Safety:Safer than colchicine 3.Indications: qPostoperative, elderly people, failureof other measures. HF, RF. qWhy they are not indicated routinely in acute attacks? 4.Administration: qLocal (IA) & systemically (orally or Parenterally) 5.What are the most important side effects of cortisone in gout? Treatment Acute Gout no yes no yes Lipsky PE, Alarcon GS, Bombardier C, Cush JJ, Ellrodt AG, Gibofsky A, Heudebert G, Kavanaugh AF, et al. Am J Med 103(6A):49S-85S, 1997 >1
NSAIDs Contraindicated?§Renal insufficiency §Peptic ulcer disease §Congestive heart failure §NSAID intoleranceAre Corticosteroids Contraindicated?NSAIDs Antiinflamatory dosesCorticosteroidsOral ColchicineOral or Intraarticular Steroid# Joints Involved?Intraarticular PO Steroid
Drugs used in prophylaxis (In between attacks) 1. Allopurinol
Mechanism of action:
1.Inhibits xanthine oxidase enzyme competitively while its metabolite alloxanthineinhibits it non-competitively → inhibits uric acid synthesis → reduce serum uric acid and its urinary excretion (urates areinsoluble→ stones)
2.Increase xanthines and hypoxanthinesin plasma and urine (Soluble, no problem)→ reincorporation into the purine metabolic cycle &by a feed back mechanism they ▼De Novo synthesis of uric acid.

Pharmacokinetics of allopurinol
1.Rapid oral absorption 80%→ liver alloxanthine (oxypurinol)
2.Not bound appreciably to plasma proteins.
3.T1/2of Allopurinolis 2h
4.T1/2ofalloxanthineis 15-30 h(so given once daily)
5.Allopurinol& Oxypurinolare excreted by kidney, Bile.Importance?
6.Dose: 50-900 mg/day once daily (M 200-300 mg/day)

Therapeutic uses of allopurinol
1.Primary hyperuricemia: It is used life long in the following:
A.When serum uratelevel is grossly elevated > 10 mg/dl
B.Chronic tophaceousdeposits (better than uricosurics)
C.Gouty nephropathy &Impaired renal function. Cr Cl< 50 ml/min Why? D.Renal uratestonesor increased urateexcretion > 1000 mg/24h. Why?
2.Secondary hyperuricemia:
qblood disease, malignancies, anti-cancer drugs or radiation for leukemiasor lymphoma
qCan you use uricosuricsin secondary hyperuricemia? Why?
3.Hyperuricemiaassociated:withdiuretics or uricosuricdrugs.
4.If uricosuricsare ineffective or contraindicated.
qCan you prescribe it for a patient with an acute attack? Why?

Adverse effects& drug interactions
1.Skin: Hypersensitivity reactions(the mostcommon )3% May be fatal (exfoliativedermatitis-Steven-Johnson syndrome). Kidney-liver
2.Gout: Acute attack of gout early in the treatment Why?How can we prevent it?)
3.GIT; GIT disturbances & Hepatotoxicity.
4.Kidney: Interstitial nephritis.
5.CNS→ Headache & psychological changes, PN.
6.Bone marrow; BMD (leucopenia, aplasticanemia).
7.Eye; Very rare; Cataract?
8.Better avoided in children & during pregnancy & lactation.
Drug interactions:
1.# 6 mercaptopurineand azathioprineWhy? Solve the problem?
2.▲Probenecidand oral anticoagulants, cyclophosphamide(metabolism)
3.# Amoxycillin& ACEI→▲skin rash to 20%
4.The actions are not antagonized by co-administration of salicylates.
5.Thiazides▲toxicity & hypersensitivity of allopurinol

2. Febuxostat
Mechanism; Is a non-purineinhibitor of xanthineoxidaseenzyme
qAborption: Orally 80%-Peak 1h
qMetabolism; Liver 95%
qExcretion; Urine only 5%. Importance?
1.Like Allopurinol
2.Hypersensitivity to allopurinol
Dose: 80-120 mg/day=300 mg allopurinol
Adverse effects:
1.Acute attack of gout?Solve?
2.Liver function abnormalities (Most common)

Drugs which increase uric acid excretion (Uricosuricdrugs)
Effects of uricosuricdrugs:
1.Increase urinary excretion of uric acid
2.Decrease body uratepool
3.Block tubular secretionof organic acids likepenicillins, ketoprofen, indomethacin, naproxen (Importance?)
Mechanism of action:
1. At therapeutic doses, they compete with uric acid for its carrier mediated transport mechanisms → Block uric acid reabsorptionfrom PCT → increase its excretion
2. At low dosethey decrease secretion of uric acid from PCT → Increases serum uric acid
3. ↓ Active tubular excretion of weak acid drugs
a. Penecillin→↑ duration of action (DurapenLAP)
b. Thiazide& loop diuretics→ antagonize their diuretic action.

Indications of uricosurics
1.Gouty under excretionof uric acid < 700 mg/24h, when allopurinolor febuxostatare contraindicated.
2.Repeated severe attacks of gouty arthritis
4.Very high plasma uratelevels? Precautions?
What are the expected contraindications of uricosurics?
Precautions of using uricosuricdrugs:
1.Acute attack may occur at the beginning of therapy
2.Do not prescribe them until 1 month after acute attack
3.Render urine alkaline+ increase urine volume
4.Not used in renal failure? < 50 ml.min Why? 5.Not used in cases of kidney stones 6.Urateoverproducers > 800 mg/day
7.Do not prescribesalicylates(up to 2.6 g/d) at all for patients of gout? Why?

Pharmacokinetics of uricosurics
1.Probenecid:Oralabsorption-Bound to PP-liver metabolism-excreted by kidney (Active)-dose 1-2gm (<1gm worsens gout) •DDI with heparin 2. Sulphinpyrazone: Inhibits metabolism of oral hypoglycemic and oral anticoagusants-It has antiplatelet effect-Not used in cases of RI. Dose 200-800 mg/day 3. Benzbromarone: used in cases of allergy or refractory to previous drugs .Could be used in cases of mild to moderate RF. GFR 25-50%. Dose 40-80 mg/day 4. Azapropazone: NSAID + uricosuric. Can be used in acute attack.Dose 1200 mg/day Side effects of uricosuric drugs 1.GIT: Sulphin> probenecid
2.Allergic reactions: Probenecid> Sulphin.
3.Acute attacks of gout
4.Deterioration of kidney function. Why?
6.Hemolytic anemia in G6PD
8.Drug-drug interactions;
1.▼Excretion of acidic drugs like penicillins, cephalosporines, acyclovir, cyclosporines, NSAIDS, sulphonlureas.
2.Salicylates▼action of uricosurics. Why?

4. Conversion of uric acid to a soluble metabolite
qMechanism of action: = Recombinant Urateoxidasewhich catalyses oxidation of uric acid to allantoin(soluble)
qIndications: prophylaxis of hyperuricemiaduring treatment of malignancy and chemotherapy when IV therapy is indicated.
qGiven IV-Metabolized by peptide hydrolysis in plasma-long T1/2
qNo accumulation on repeated doses
qSide effects: Very expensive
3.Blood hemolysis
4.Kidney: ARF

Questions for revisionof gout:
1.What are the complications of hyperuricemia?
2.Enumerate drug therapy of acute gouty arthritis?
3.What is the mechanism of action of colchicines?
4.What are the therapeutic uses of colchicines?
5.What are the adverse effects of colchicines?
6.Enumerate drugs used in between acute gouty arthritis?
7.What is the mechanism of action of allopurinol?
8.What are the indications of allopurinol?
9.What are the side effects of allopurinol?
10.Give examples and explain the mechanism of action of uricosuricdrugs?
11.What are the drugs that produce hyperuricemiaand may precipitate acute gout?
12.Compare indications of allopurinolwith uricosuricdrugs?
13.What are the drugs of gout that could be fatal? How?
14.What are the drugs of gout that can cause BM suppression?
15.What are the drugs of gout that could be given in renal impairment?
16.What are the drugs of gout that are contraindicated in renal & liver failure?