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PHARMACOLOGY OF GOUT

Pr Nermine Bouchi
4ème Année S2 durée:45MIN
Objectifs
 Expliquer la pathologie de la goutte
 Classification des principaux médicaments de la
maladie de la goutte
 Expliquer le mécanisme d’action des trois classes
pharmacologiques
 Expliquer les principaux effets indésirables
 Expliquer les indications thérpeutiques
Acquis
 Connaître la pathologie de la goutte
 Connaitre les buts du traitement de la maldie
 Connaitre la classification des médicaments
 Savoir citer un représentant pour chaque classe
 Connaitre le mécanisme d’action de la colchicine, de
l’allopurinol , du probénécid
 Connaître leurs effets indésirables
 Savoir citer un médicament indiqué dans le traitement de la crise
aigue de la goutte
 Savoir citer un médicament ou plus indiqué dans le traitement de
la goutte chronique
Plan

 Pathologie de la goutte
 Classification des médicaments
 Colchicine
 Les inhibiteurs de la synthèse de l’acide urique
 Les uricosuriques
The disease …

 Gout is a rheumatic disease ( acute


inflammation) resulting from
deposition of uric acid crystals
(monosodium urate) in tissues and
fluids within the body primarily in
the large toe, instep, ankle, or
heel.

 Gout is characterized
 Biochemically as a disorder of

uric acid metabolism


 Clinically by hyperuricemia and

recurrent attacks of acute


arthritis
Maladie de la goutte :

 Une évolution qui va crescendo


 Les crises de goutte ont tendance à augmenter au fil du temps.

 Symptômes articulaires
 Les douleurs articulaires se font de plus en plus violentes et de plus en plus longues : elles

deviennent mécaniques (au mouvement).


 L'atteinte inflammatoire concerne les tissus voisins et entraîne :

 des tendinites,
 Symptômes cutanés :
 Si l'évolution n'est pas contrôlée, les cristaux d'acide urique vont finir par générer des tophus.

 Il s'agit de dépôts de cristaux sous la peau, notamment au niveau :

 de l'oreille,
 des coudes,
 des doigts ou des doigts de pieds,
 à proximité du tendon d'Achille (tendon calcanéen).
 Dans certains cas, les tophus se retrouvent au niveau des os, constituant ainsi des arthropathies

goutteuses.
 Symptômes rénaux:
 Une insuffisance rénale ou des calculs rénaux (entraînant des coliques néphrétiques) peuvent

également apparaître du fait de l'excès d'acide urique dans le sang.


 La lithiase urinaire (calculs rénaux) concerne 20 % des personnes atteintes de goutte
The disease …
 If the condition remains untreated over years,
 Sodium urate crystals may form in the subcutaneous tissue, joints, renal parenchyma, and
renal pelvis.
 Uric acid stones may form in the lumen of the urinary tract, and progressive renal failure
often occurs in the later stages of untreated gout.
 Microcrystalline deposits of sodium urate frequently result in inflammatory bulges or
bumps, termed tophi, appearing in the subcutaneous tissue of the earlobes, elbows, and
hands and at the base of the large toe.

 Hyperuricemia can result from


 Overproduction of uric acid
 Under excretion of uric acid

 Hyperuricemia can be
 Primary : metabolic disease
 Secondary : hematological malignancy, sickle cell anemia, lead nephropathy, iatrogenic
(salicylates, pyrazinamide, alcohol, ethambutol, nicotinic acid, cyclosporine, fructose,
cytotoxic agents, and certain diuretics (e.g., thiazides, furosemide, bumetanide)
Progression of gout
Pathophysiology
 Hyperuricemia, while a prerequisite, does not inevitably lead to gout
 Acute gout usually causes an exquisitely painful distal monoarthritis, but it also
can cause joint destruction, subcutaneous deposits (tophi), and renal calculi and
damage.
 Acute attacks are generally the result of granulocytic phagocytosis of the urate
crystals.
 This engulfing of the crystals is accompanied by cellular release of chemotactic
lipids, lysosomal enzymes, and acidic substances into the synovial tissues. The
lipids appear to trigger further phagocytosis, whereas the acidic compounds
decrease local pH to the point that increased urate crystal formation is favored.
 In addition to the phagocytic activity of the leukocytes, small peptide substances,
such as the kinins, which are thought to be partially responsible for the local
inflammatory response in gouty arthritis, accumulate in the joint space.
 The inflammation is associated with local vasodilation, increased vascular
permeability, and pain.
Gout : pathology

Local pH
Neutrophils decrease
secrete urate
Secretion of precipitate
cytokines and inflammatory
attraction of mediators:
Mono neutrophiles to glycoproteine
sodium urate the site of responsible of
crystals inflammation.
activate acute attack
Urate monocytes/
crystallize macrophages
as mono
sodium
urate in
acidic
conditions
Uric acid metabolism

dietary intake purine bases cell breakdown

xanthine hypoxanthine
oxidase
catalyzes
hypoxanthine to xanthine
xanthine &
xanthine to uric
acid uric acid
Classification

Aims of gout
treatment ↓symptoms of an acute
Lower serum attack
urate levels ↓ the risk of recurrents
attack
Inhibit urate Relieve Prevent
formation: Augment urate
excretion: inflammation inflammatory
ALLOPURIN PROBENICID and pain responses to
OL :NSAIDs, crystals :
BENZBROMAR COLCHICINE,
FEBUXOSTA ONE Glucocoticoids
COLCHICINE NSAIDs
T
Acute arthritis drugs
Colchicine
NSAIDs
Glucocorticoids
Colchicine
 Plant extract (Colchicum automnale)  one of the oldest medications
 second-line therapy : narrow therapeutic window and high rate of adverse
effects

 Pharmacological effects
 No activity in synthesis or excretion of uric acid
 Decreases inflammation related to gout
 Antimitotic effects 
 Arresting cell division in G1 by interfering with microtubule and spindle formation
 Effect is greatest on cells with rapid turnover (e.g., neutrophils, GI epithelium).
 Inhibits the motility of inflammatory leukocytes  blocks their ability to cause urate
crystal–induced joint inflammation.
 Prevents the release of the chemotactic factors and/or inflammatory cytokines from
the neutrophils  decreases the attraction of more neutrophils into the affected area
 Inhibits the release of histamine-containing granules from mast cells & the secretion
of insulin from -pancreatic cells  clinical significance ?
 Others , e.g., lowering of body temperature
Colchicine
 PK
 Rapid oral absorption
 Metabolized by CYP3A4
 Significant enterohepatic circulation
 T1/2 = 9 hours, but the drug can be detected in leukocytes and in the urine for at
least 9 days after a single IV dose

 Therapeutic uses
 The major use of colchicine is as an anti-inflammatory agent in the treatment
of acute gouty arthritis; it is not effective in reducing inflammation in other
disorders
 Acute gout : effective in roughly 2/3 of patients if given within 24 hours of attack
onset
 Prevention of acute gout : particularly in the early stages of antihyperuricemic
therapy.
 A minimum of 3 days, but preferably 7 or 14 days, should elapse between courses
of gout treatment with colchicine to avoid cumulative toxicity
Colchicine
 Adverse effects
 GI toxicity (80%):
 Nausea, vomiting, diarrhea, and abdominal pain
 Earliest signs of impending colchicine toxicity
 Cause : rapid turnover rate of GI mucosa (l cellules a proliferation rapide ) and
frequent exposure because of enterohepatic circulation
 latent period of several hours or more between the administration of the drug and
the onset of symptoms
 Not induced if administerd by IV route

 Systemic toxicity : Myelosuppression, leukopenia, granulocytopenia,


thrombopenia, aplastic anemia, and rhabdomyolysis

 Life-threatening toxicities are associated with administration of


concomitant therapy with P-glycoprotein or CYP3A4 inhibitors.
Urate lowering drugs
INHIBITORS OF URATE SYNTHESIS
URICOSURIC AGENTS
Uric acid metabolism and sites of drug
action.
 Purines obtained from the diet or from

catabolism of nucleic acids are


converted to hypoxanthine.
 Under normal conditions, xanthine

oxidase converts hypoxanthine to


xanthine and then to uric acid.

 Allopurinol and febuxostat act by


inhibiting xanthine oxidase.

 Pegloticase and rasburicase


administration provides a recombinant
uricase enzyme that converts uric acid to
allantoin, which is then excreted.

 Probenecid, sulfinpyrazone, and high-


dose salicylates inhibit the renal tubular
reabsorption of uric acid, whereas
diuretics and low-dose salicylates inhibit
the renal tubular secretion of uric acid
Urate-lowering drugs
 Prevents arthritis, tophi & stones by lowering total
body pool of uric acid
 Not indicated after first attack
 Initiation of therapy can worsen or bring on
acute gouty arthritis
 No role to play in managing acute gout
INHIBITORS OF URATE SYNTHESIS
Allopurinol: ZYLORIC
Febuxostat ULORIC
Rasburicase : ELITEK
Allopurinol: ZYLORIC
 MOA:
 Allopurinol is a substrat for xanthine oxydase → oxypurinol active metabolite

 Allopuriniol & oxypurinol are xanthine oxydase inhibitors:

 Low concentration→competitive inhibitor(allopurinol)


 High concentration→ non competitive inhibitor (allopurinol,oxypurinol)
 ↓plasmatic concentration of uric acid :
 prevents the development or the progression of chronic gouty

arthritis
 excretion of hypoxanthine, xanthine, uric acid
 Allopurinol facilitates the dissolution of tophi (localized deposit of
monosodium urate )
 Allopurinol mobilizes uric acid stored in tissues:

  Incidence of acute attacks of gouty arthritis during the early months of


allopurinol therapy.
 Co-administration of colchicine helps suppress such acute attacks
Allopurinol
PK
 Metabolized to oxypurinol, do not bound to PP

 Allopurinol :20% excreted in the feces in 48-72 h as unabsorbed drug, 10-

30% excreted unchanged in the urine


 t1/2 : allopurinol =1-2h , Oxypurinol =18-30h

 Oxypurinol:

Excreted slowly in the urine


Persists longtime in tissues & is responsible for much of the pharmacological
activity of allopurinol
Therapeutic uses:
 Not indicated in acute gout attack

 Chronic gout : Primary and secondary gout

 Hyperuricemia

 secondary to malignancie
secondary to cancer chemotherapy
Allopurinol
Adverse effects:
hypersensitivity after months or year of therapy

pruritic, erythematous.

Rash may precede severe hypersensitivity reactions

patients who develop a rash should discontinue allopurinol

Risk for Stevens-Johnson syndrome limited primarly to the first 2 months

fever, malaise and myalgias more frequently in patients with renal impairment

Drug interactions :
 Allopurinol increases t
1/2 of Probenicid and enhances its uricosuric effec
 Clearance of oxypurinol is increased by Probenicid

 Allopurinol inhibits metabolism of Mercaptopurine and Azathioprine

Allopurinol is an enzymatic inhibitor : I.M. THEOPHYLLINE, WARFARINE…

Ampicillin and Amoxicilline increase the risk of hypersensitivity


Rasburicase : ELITEK
Febuxostat ULORIC
MOA: MOA:
 Xanthine oxydase non competitive  Recombinant urate oxydase
inhibitor
→metabolizes uric acid into
PK:
inactive metabolite
 Absorption is delayed by Mg
allantoin→lower urate levels
(OH)2and Al(OH)3 for 1h.
more effectively than
 T1/2 =5-8H allopurinol
Side efects
 Liver function abnormalities
Therapeutic uses
 Nausea ,joint pain and rash.
 Initiation of therapy urate
 Hyperuricemia secondary to
mobilization from tissues → leukemia, lymphoma in
NSAIDs or colchicine pediatric patient
Therapeutic uses:
 Treatment of hyperuricemia with
URICOSURIC AGENTS
Probenicid
Lesunirade
Benzbromarone DESURIC
Sulfinpyrazone : ANTURANE
URAT1 is responsible for the
Uricosuric agents majority of the renal reabsorption
of uric acid.

ABCG, ATP binding cassette sub-family


G;
GLUT, glucose transporter;
Probenicid
MOA:
 Inhibits the reabsorption of uric acid by organic anion transporters, URAT1

 Effect blunted by the co-administration of salicylates

 Inhibits tubular secretion of organic acids of a number of drugs and their glucuronide metabolites

 Inhibits the transport of (5-HIAA) and other acidic metabolites of cerebral monoamines from

CSF to plasma
 Decrease biliary secretion of rifampin

Pk:
 Highly liposolubleCompletely absorbed after oral administration
 t1/2 is dose dependant .

 80-90% bound to PP
 Majority of the drug is secreted actively by the proximal tubule

 Renal reabsorption because of high lipid solubility (unless if urine is markedly alkaline)
Probenicid
Adverse effects
 Mild GI irritation increased by higher doses

 Hypersensitivity

Therapeutic uses
 Chronic gout with concomitant Colchicine or
NSAIDs association early in the course of therapy to
avoid acute gout attack
 Combination with Penicillin : used as an adjuvant to
prolong penicillin concentrations
MAO: lesinurade
 inhibits the urate transporter, URAT1
 Inhibits organic anion transporter 4(OAT4), a uric acid
transporter associeted with diuretic induced
hyperuricemia
 Does not interact with the uric acid transporter GLUT9
 Unlike probenicid does not inhibit OAT1 or OAT3
Lesinurad : ZURAMPIC
 PK:
 Bioavailability :100%
 PP >98%

 Side effects :
 Risk of acute renal failure more common when used without a xanthine
oxidase inhibitor (xoi

 Indication
 Not used as monotherapy :
 is specifically indicated in combination with a xanthine oxidase inhibitor for the
treatment of hyperuricemia associated with gout in patients who have not
achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.
 Not recommended for the treatment of asymptomatic hyperuricemia
URICOSURIC GENTS

Benzbromarone DESURIC Sulfinpyrazone : ANTURANE

 Potent uricosuric agent  Low doses ↓urinary


secretion of uric acid
 Uricosuric activity is
blunted by ASPIRIN, or  Therapeutic doses inhibits
sulfinpyrazone acid uric tubular
reabsorption
 antagonized by ASPIRIN
 Effective in patients allergic
or refractory to other drugs  potentiated by probenicid
Other NSAIDs
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 Apazone
 Nonselective COX inhibitor
 Anti inflammatory, analgesic, antipyretic and potent uricosuric
 Inhibits neutrophils migration, degranulation, and superoxide
production
 Restricted to cases where other tNSAIDs have failed
 Adverse effects : nausea, dyspepsia, migraine

 Nimesulide
 Sulfonanilide compound COX2 inhibitor
 Other effects : Inhibition neutrophils activation, decrease in cytokine
production, activation of glucocorticoid receptors
 Risk of hepatotoxicity (use <15 days)