Gout is the most common inflammatory joint disorder caused by deposition of urate crystals in joints. It affects around 1-2% of adults and is more common in men. Risk factors include genetics, diet high in purines, alcohol, obesity, and medications. Gout progresses through acute inflammatory attacks, intercritical periods, and chronic tophaceous stages if urate levels remain elevated. Treatment involves NSAIDs to rapidly alleviate acute attacks and urate-lowering drugs like allopurinol or febuxostat long-term to prevent future attacks and reduce urate levels. Lifestyle modifications and diet control are also important for gout management.

1. GOUTY ARTHRITIS
T. SOUJANYA
16DC1T0021
PHARM. D

2. CONTENT:
• Definition
• Epidemiology
• Etiology
• Pathophysiology
• Classification of gout
• Risk factors
• Stages of gout
• Signs and symptoms
• Diagnosis
• Treatment
• Lifestyle modifications

3. DEFINITION:
Gout is the most common inflammatory and metabolic joint
disorder which is caused by the deposition of monosodium urate
crystals in joints and soft tissues following chronic hyperuricaemia.
chronic hyperuricaemia is associated with disorders of purine
metabolism due to underexcretion or overproduction of uric acid, the
final metabolite of endogenous and dietary purine metabolism.

4. EPIDEMIOLOGY:
Gout is one of the oldest recognised disease and was identified by
the Egyptians in 2460 B.C. Gout affects 1-2% of adults in developed
countries and in recent decades there has been a great significant rise
in its prevalence and incidence. The USA has seen a doubling in the
number of cases with a rate of gout increasing to 4.1% in older males.
Gout is predominantly a disease of men with a male to female ratio of
36:1. In women, it tends to develop after menopause when levels of
oestrogen, a known uricosuric fall.

5. ETIOLOGY:
Although environmental factors are clearly implicated in the
development of gout, inheritance also play an important role. In recent
years, research into genetic background of gout has identified several
renal urate transporters including URAT-1 & GLUT-9 and the genes
encoding for them. E.g. SLC22A12 & SLC2A9 respectively.
Polymorphism in these genes are associated with increased
hyperuricaemia and gout.

6. PATHOPHYSIOLOGY:
In humans, uric acid is the end product of the degradation of
purines. Uric acid has no known physiologic purpose and therefore is
regarded as a waste product. In lower animals, the enzyme uricase
breaks down uric acid to the more soluble allantoin, and thus uric acid
does not accumulate. Gout occurs exclusively in humans in whom a
miscible pool of uric acid exists.
Under normal conditions, the amount of uric acid is about 1200mg in
men & about 600mg in women. The size of the urate pool is increased
several fold in individuals with gout. This excess accumulation may
result from either overproduction or underexcretion.

7. Contd...
The purines from which uric acid is produced originate from three
sources:
1. Dietary purine
2. Conversion of tissue nucleic acid to purine nucleotides
3. de novo synthesis of purine bases
The purines derived from these three sources enter a common
metabolic pathway leading to the production of either nucleic acid or
uric acid. Under normal circumstances, uric acid may accumulate
excessively if production exceeds excretion.

8. Contd...
Several enzyme systems regulate purine metabolism. Abnormalities
in these regulatory systems can result in overproduction of uric acid.
Two enzyme abnormalities resulting in an overproduction of uric acid
are:
1. Increase in the activity of phosphoribosyl pyrophosphate (PRPP)
synthetase, which leads to increased concentration of PRPP. PRPP is
a key determinant of purine synthesis and thus uric acid
production.
2. Deficiency of hypoxanthine guanine phosphoribosyl transferase
(HGPRT), which is responsible for the conversion of guanine to
guanylic acid & hypoxanthine to inosinic acid.

9. Contd...
These two conversions require PRPP as the co-substrate and are
important reutilization reactions involved in the synthesis of nucleic
acids. A deficiency in the HGPRT enzyme leads to increased metabolism
of guanine and hypoxanthine to uric acid and more PRPP to interact
with glutamate in the first step of purine pathway.
Complete absence of HGPRT results in the childhood Lesch-nyhan
syndrome, characterised by choreoathetosis, spasticity, mental
retardation and markedly excessive production of uric acid. A partial
deficiency of the enzyme may be responsible for marked
hyperuricaemia in otherwise normal, healthy individuals.

10. Purine metabolism

11. CLASSIFICATION OF GOUT:
Gout can be classified as primary or secondary, depending upon the
presence or absence of an identified cause of hyperuricaemia.
1. Primary gout: Here the basic metabolic defect is unknown. Elevated
serum uric acid levels may be due to following:
a) Increased production of uric acid due to excessive dietary purines
or due to rare enzyme mutation defects (Lesch-Nyhan syndrome
due to deficiency of hypoxanthine guanine phosphoribosyl
tranferase (HGPRT); variants in enzyme phosphoribosyl- 1-
pyrophosphate (PRPP) have increased de novo purine production).
b) Undersecretion of uric acid results from a defect in renal excretion.

12. Contd...
2. Secondary gout: It is associated with increased nucleic acid turnover,
decreased renal function, increased purine production or drug induced
(diuretics, aspirin less than 2g/day, pyrazinamide, ethambutol, nicotinic
acid, ethanol, cyclosporine, methoxyflurane, levodopa and
epinephrine), deficiency of glucose- 6 –phosphatase, myeloid
proliferative disorders, psoriasis, exercise and uncontrolled diabetes.

13. RISK FACTORS:
Hyperuricaemia is one of the main risk factors for gout and occurs in
about 15-20% of the population. Fortunately, only a minority of individuals
with increased serum uric acid levels develop gout suggesting the
importance of other contributing factors:
1. Genetics
2. Renal disease
3. Diet
4. Alcohol consumption
5. Co-morbidities e.g. Obesity, dyslipidaemia, glucose intolerance,
hypertension
6. Medication

14. STAGES OF GOUT:

15. SIGNS AND SYMPTOMS:
• Fever
• Intense pain
• Erythema
• Warmth and swelling of involved joints.
• Excruciating pain, swelling and inflammation involving one or more
joints, most commonly starting in the great toe, but sometimes
involving other joints of the extremities.

16. DIAGNOSIS:
Tests that help to diagnose gout may include:
• Joint fluid test: A needle is inserted to draw a fluid from the affected
joint. Urate crystals may be visible when the fluid is examined under a
microscope.
• Blood test: Blood test is recommended to measure the levels of uric
acid and creatinine in blood. Blood test results can be misleading,
though. Some people have high uric acid levels, but never experience
gout and some people have signs & symptoms of gout, but don’t have
unusual levels of uric acid in their blood.

17. Contd...
• X-ray imaging: Joint X-rays cam be helpful to rule out other causes of
joint inflammation.
• Ultrasound: Musculoskeletal ultrasound can detect urate crystals in a
joint or in a tophus. This technique is more widely used in Europe
than in the United States.
• Dual energy CT scan: This type of imaging can detect the presence of
urate crystals in a joint, even when it is not acutely inflamed. This test
is not used routinely in clinical practice due to the expense and is not
widely available.

18. TREATMENT:
Treatment aims in gout:
• Rapid alleviation of the acute attack.
• Prevention of future attacks.
• Lower serum uric acid levels to below saturation point.
• Reduce risk of co-morbidities. E.g. Cardiovascular disease.
• Lifestyle modification.

19. MANAGEMENT OF ACUTE GOUT:
Drugs used in the management of an acute attack include:
1. First line: NSAIDs (use maximum dose)
2. Second line: Colchicine
3. Third line: Corticosteroids like prednisolone, methylprednisolone,
triamcinolone

20. 1. NSAIDs:
MOA: NSAIDs (Non steroidal anti-inflammatory drugs) act by direct
inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)
via blockade of the cyclooxygenase enzyme site. The subsequent
inhibition of prostaglandin production reduces inflammation, but also
results in additional activities on platelet aggregation, renal
homeostasis and mucosal injury.
ADRs: Upper GI effects, acute tubular necrosis, hepatotoxicity,
vasculitis etc.
Dose: Indomethacin-25mg TID, Diclofenac-25-50mg TID.

21. 2. COLCHICINE:
MOA: It is an alkaloid used to relieve acute attack of gouty arthritis. It is
not an analgesic and uricosuric agent, although it relieves pain in acute
attack. Colchicine inhibits migration of neutrophils to the affected area.
ADRs: Andominal cramps, nausea, vomiting, diarrhoea and rarely bone
marrow supression, neuropathy and myopathy.
Dose: Tablets-0.5, 0.6mg (0.5-1.2mg PO followed by 0.5-1.2mg every 1-
2hrs). Injection-1mg/2ml (1mg initially, followed by 500mcg every 2-
3hrs).

22. 3. CORTICOSTEROIDS:
MOA: Corticosteroids act by inhibiting cytokine release and give rapid
relief of symptoms and decrease inflammation. They can be given oral,
intravenous or intraarticular routes.
ADRs: Diabetes, increased risk of infection, hypertension, weight gain,
insomnia, menstrual irregulations, osteoporosis, psychosis etc.
Dose: Methyl prednisolone-80mg or 40mg, Triamcinolone-40mg, Oral
prednisolone-30mg.

23. Algorithm for managing acute gout

24. MANAGEMENT OF CHRONIC GOUT:
Some patients may only experience a single episode and a change in
lifestyle, diet or concurrent medication may be sufficient to prevent
further attacks. Patients who suffer one or more acute attacks within
12 months of the first attack should normally be prescribed
prophylactic urate-lowering therapy. Classification of prophylactic
agents used to lower serum urate:
1. Uricostatic agents: allopurinol, febxostat
2. Uricosuric agents: Benzbromarone, probenecid, sulphinpyrazone
3. Uricolytic agents: rasburicase, polyethylene glycol-uricase

25. Contd...
The criteria for starting prophylactic treatment for gout:
1. One or more acute attacks within 12 months of the first attack.
2. Tophi present at the first presentation of an acute attack.
3. Presence of uric acid stones.
4. Need to continue medication associated with raised uric acid levels. e.g.
Diuretics.
5. Young patients with a family history of renal or cardiac disease.

26. 1. URICOSTATIC AGENTS:
MOA: They inhibit the enzyme xanthine oxidase, which is essential for
the conversion of hypoxanthine to xanthine and then to uric acid.
Thereby they prevent the synthesis of uric acid and the plasma
concentration of uric acid is reduced.
ADRs: Rashes, itching, erythema, GI disturbances like nausea, vomiting,
diarrhoea, hepatotoxicity, fever, headache.
Dose: Allopurinol-100mg/day
Febuxostat-80mg or 120mg/day

27. 2. URICOSURIC AGENTS:
MOA: They inhibit active tubular reabsorption of uric acid in proximal
tubules and thereby increase excretion of uric acid.
ADRs: GI disturbances like nausea, vomiting, skin rashes, ulceration,
blood disorders.
Dose: Benzobromarone-50-200mg/day
Probenecid-0.5-2gm/day
Sulphinpyrazone-200-800mg/day

28. 3. URICOLYTIC AGENTS:
MOA: They convert the uric acid to more soluble allantoin and increase
its excretion through urine.
ADRs: Haemolysis, GI disturbances, hypersensitivity reactions like skin
rashes may occur.
Dose: Rasburicase-0.2mg/day for 5-7days
Poly ethylene glycol-uricase-3.5gm/day

29. Algorithm for managing chronic gout

30. LIFESTYLE MODIFICATIONS:
Medications are often most effective way to treat acute gout and
can prevent recurrent attacks of gout. However, making certain lifestyle
changes also are important, such as:
1. Limiting alcoholic beverages & drinks sweetened with fruit sugar
(fructose). Instead, drink plenty of non-alcoholic beverages,
especially water.
2. Limiting intake of foods high in purines such as red meat, organ
meats and seafood.
3. Exercising regularly and losing weight. Keeping body at a healthy
weight reduces the risk of gout.

31. REFERENCES/BIBLIOGRAPHY:
• Clinical Pharmacy and Therapeutics- Roger & Walker, Churchill
Livingstine publication-5th edition.
• Pharmacotherapy: A Pathophysiological approach by Joseph T. Dipiro.
• Elements of clinical pharmacy by Dr. Ramesh K.Goyal, Dr. Parloop A.
Bhatt, Dr. Mahesh D. Burande.