Treatment of gout

By Irigo Christiana,
A. Rubagavaagini

Treatment
1. To treat gout
attacks
a) NSAIDs
b) Colchicine
c) Corticosteroids

2. To prevent gout
complications
a)
b)

Uricosuric agents
Xanthine oxidase
inhibitors
c) Colchicine

NSAIDs
Mechanism of action:
anti-inflammatory effects through
inhibition of prostaglandin
synthesis and inhibition of motility of
PMNs
-not specific for goutadequate
doses will relieve inflammation from
any cause

INDOMETHACIN (INDOCIN, INDOMETACIN)

first choice gout treatment for relieving
immediate gout pain. Works by blocking the Cox -1
and Cox -2 enzymes which are vital for producing
prostaglandins.
Dosage Prescription (RX). Capsules, sustained
release capsules, suppositories. (Suppositories
are forms of a drug for people who cannot take a
drug orally. They can be placed in the rectum and
vagina). 100 200mg two or three times daily. Less
as the attack subsides. Take with food to prevent
stomach irritation.
Possible side effects include Lethargy; dizziness;
mental confusion, nausea; vomiting; diarrhea;
stomach pains; ulcers; gastrointestinal bleeding.

SODIUM DICLOFENAC (VOLTAREN,VOLTARENRX,VOLTAROL,DICLOFENAC SODIUM)

an RX (prescription) medicine
Dosage Prescription(RX). A 50mg tablet taken three
times daily for a total of 150mg daily. Perhaps more if
this amount doesn't work. Tablets are also manufactured
at 25mg strength.
Possible side effects include Headache, nausea,
vomiting, diarrhoea, mild skin reactions. These are all
common side effects of NSAIDs in some people.
OTC NSAIDS - NO RX (PRESCRIPTION) REQUIRED
include aspirin (which should NOT be taken during a gout
attack - it will worsen it), ibuprofen, naproxen and others.
Note that aminacetophin, aka paracetamol, (panadol,
tylenol and others) is not an effective gout attack reliever
because it has no anti inflammatory effect.

OTHER NSAIDS
Two NSAIDs, Valdecoxib (Bextra) and Rofecoxib (Vioxx), both
Cox -2 inhibitors, were taken off the market a few years ago
because of concern about their side effects which included
cardiovascular, high blood pressure and allergic reaction
problems.
Etoricoxib
more effective than Indomethacin for pain relief and it may
have fewer side effects.
mainly a Cox-2 inhibitor only, and therefore more selective
than inhibitors such as indomethacin that inhibit both Cox-1
and -2.
concerned about its potential for heart attacks, strokes and
serious or even fatal skin reactions. But they did not request
its withdrawal, judging that the benefits still outweighed the
risks.
Celecoxib (Celebrex) is also a Cox-2 only inhibitor, used to
treat pain and inflammation.

 Adverse Effects:
Stomach ulcers and gastrointestinal bleeding
Increased blood pressure
Delayed digestion
Dizziness
Tinnitus (ringing in the ear)
Headache
Depression
Kidney damage
Erectile dysfunction

Colchicine
An alkaloid isolated from autumn locus
1. Mechanism of action
1. binds tubulin --> prevents polymerization
into tubules
2. inhibits leukocyte migration and proinflammatory agents release (like PGE)
It is a substrate for CYP3A4 and P-glycoprotein
efflux transporter.
2. Efficacy: somewhat diagnostic for gout because
-90% respond to colchicine if treatment is initiated
within a few hours after onset, response rates decline
if acute attack is >24hrs old
-colchicine is relatively specific therapy for acute gout
and preventive for gout complications too.

3. Dosing:
narrow therapeutic index
readily absorbed orally; often used IV
doses should be decreased in renal and hepatic
dysfunction, but there are no standard guidelines
decrease total dose to 2mg/24hrs in elderly patients
or patients who have been on colchicine
maintenance
give only to patients who cannot tolerate the oral
tablets
avoid extravasation because causes soft tissue
necrosis
* Extravasation: a discharge or escape, as of blood,
from a vessel into the tissues; blood or other
substance so discharged.

4. Adverse reactions
gastrointestinal: diarrhea, nausea, vomiting,
hemorrhagic
colitis, occurs in 70-80% of patients on oral
therapy, less frequent with IV therapy but may
see with high doses
bone marrow depression: cumulative toxicity
renal dysfunction: toxic side effect seen after
large doses,
hematuria, oliguria
necrosis of soft tissue after extravasation: so, do
not give IM/SQ

Corticosteroids
given to patients with gout who cannot use
NSAIDs or colchicine, but adrenocorticotropic
hormone (ACTH) would be preferred.
Dosing: can be given orally, intravenously,
intramuscularly, intra-articularly, or indirectly
via ACTH.
MOA:
1. reduce the production of inflammatory
mediators
2. inhibit COX and PLA2 --> inhibits
production of arachadonic acid (precursor
to PGE and leukotrienes)

Adverse effects:
Cushing syndrome
Adrenal insufficiency at withdrawal of the
treatment, which occurs even in neonates
when the mother was treated during
pregnancy. Discontinuation of the treatment
can induce various symptoms: fever, myalgias,
arthralgias.
Bone disorders: development of osteoporosis
Neuropsychiatric disorders: nervousness,
insomnia, depression, aggravation of epilepsy,
increase in intracranial pressure in children.
Ocular disorders after local and general
administration: glaucoma, cataract.

 Hematologic modifications: increase of

leukocytes and thrombocytes, decrease of
T lymphocytes .
Digestive disorders, ulcer with an
atypical symptomatology and cause of
bleedings, as well as pancreatic damages.
Infections
Growth retardation: administered to
children, long term administration to
children can induce growth retardation
requiring treatment with growth hormone.
Exceptionally shock during their
administration by intravenous route.

TREATMENT OF CHRONIC GOUT

Chronic Gout can be as a result of:

1. Genetic defect.
2. Renal deficiency.
3. Lesch-Nyhan syndrome( def. in
HGPRT)
4. Excessive production of uric acid
associated with cancer
chemotherapy

Long-term treatment of hyperuricemia may

be recommended for people who have:
A risk for tophaceous gout
More than two or three acute attacks of
gout in the past
Unusually severe attacks or attacks that
affect more than one joint
Joint damage from gout, shown on x-rays
Hyperuricemia caused by an identifiable
inborn metabolic deficiency

COLCHICINE
Plant alkaloid
Derivative of the autumn crocus (also
called the meadow saffron).
Used for prophylaxis of recurrent attacks
Given between 24-48hrs of onset of an
attack.

MECHANISM OF ACTION
Binds to tubulin
inhibit
microtubule formation
disrupts
cellular function.
Blocks cell division by binding to
mitotic spindles.
Arrest the migration of granulocytes
anti-inflammatory action.

PHARMACOKINETICS
Given orally, rapidly absorbed from GI tract
Low therapeutic index
Undergoes enterohepatic circulation and
excreted unchanged in feces or urine

ADVERSE EFFECTS
May cause:
Nausea, vomiting, diarrhea and abdominal
pain
CHRONIC USE: Myopathy, neutropenia, aplastic
anemia and alopecia.

CONTRAINDICATIONS
Pregnancy.
Used with caution in patients with
renal, hepatic or cardiovascular
disease.
Dosage adjustment in patients taking
CYP3A4 inhibitors like clarithromycin
and protease inhibitors.
Avoid use in patients with creatinine
clearance less than 10ml/min

XANTHINE OXIDASE
INHIBITORS

ALLOPURINOL
Purine analog
Competitively inhibits the last two steps in uric
acid biosynthesis which are catalysed by
xanthine oxidase
Used to treat primary hyperuricemia of gout and
hyperuricemia secondary to other conditions
like renal disease.
Initially allopurinol may trigger further attacks
of gout, and thus during the first months of
therapy the patient is also given a NSAID or
colchicine to reduce that possibility.

PHARMACOKINETICS
Orally.
Half life of 2hours.
Drug and metabolite is excreted in
urine and feaces.
Can be used in patient with
creatinine clearance less than
50ml/min, with dosage adjustment.

ADVERSE EFFECTS
Well tolerated
Hypersensitivity reactions are the
most common e.g. skin rashes
GI side effects may also occur
Interferes with metabolism of 6mercaptopurine, azathioprine and
theophylline

FEBUXOSTAT
Structurally unrelated to allopurinol
but has the same indications

URICOSURIC AGENTS
These drugs increase the excretion of
uric acid in the urine therefore
reducing their plasma concentration.
They are weak organic acids that act
by inhibiting the urate-anion
exchanger in the proximal tubule

PROBENECID
General inhibitor if tubular secretion of
organic acids.
Blocks tubular secretion of penicillin and is
also used to increase levels of some
antibiotics
Should be avoided if patients creatinine
clearance is less than 50ml/min.
More effective when combined with
colchicine
Few adverse effects

SULFINPYRAZONE
Derivative of phenylbutazone.
May cause gastric distress
Contraindicated in patients with bone
marrow suppression .
Periodic blood count monitoring is
recommended during treatment.
Rarely used.

 Patients should drink plenty of fluids

to reduce risk of uric acid stones.
NSAIDs, particularly aspirin, as well
as other salicylate drugs, interfere
with uricosuric drugs and reduce
effectiveness.