Name: SADIA SALEEM

Roll No: BP-1750138

Final year Morning
Clinical pharmacy
Gout and hyperuricemia: Gout is the most common inflammatory joint disease in men and
the most common inflammatory arthritis in older women. It is caused by deposition of
monosodium urate crystals in joints and soft tissues following chronic hyperuricemia. Chronic
hyperuricemia is associated with disorders of purine metabolism due to under excretion or
overproduction of uric acid, the final metabolite of endogenous and dietary purine metabolism.
Gout usually presents as a monoarthritis in the first metatarsophalangeal joint (big toe) of the
foot and is often referred to as podagra (from the Greek ‘seizing the foot’). Subsequent attacks
may be polyarticular. Other commonly affected joints include the midfoot, ankle, knee, wrist and
finger joints.Gout can be classified as primary or secondary, depending on the presence or
absence of an identified cause of hyperuricemia.

Primary gout: is not a consequence of an acquired disorder, but is associated with rare inborn
errors of metabolism and isolated renal tubular defects in the fractional clearance of uric acid. A
rare group of enzyme defects result in an increased de novo purine synthesis such as
hypoxanthine-guanine phos- phoribosyl transferase deficiency (Lesch-Nyhan syndrome),
phosphoribosyl pyrophosphate synthetase super activity, glucose-6 phosphatase deficiency and
myogenic hyperuricemia.

Secondary gout: is the consequence of the use of specific drugs or develops as a

consequence of other disorders. Certain diseases are associated with enhanced nucleic acid
turnover, for example, myeloproliferative and lymphopro- liferative disorders, psoriasis and
haemolytic anaemia, and can lead to hyperuricemia. Renal mechanisms are responsible for the
majority of hyperuricemia in individuals with over production representing less than 10% of
patients with gout. The URAT-1 transporter which causes reabsorption of utare is targeted by a
number of drugs including benzbromarone, probenecid, losartan and sulfinpyrazone.

Pathophysiology: Uric acid is mainly a by-product from the breakdown of cellular

nucleoproteins and purine nucleotides synthesised. Uric acid is mainly present as monosodium
urate due to the high concentration of sodium in the extracellular compartment. Human beings
and higher primates lack the enzyme uricase that degrades uric acid to the highly soluble
allantoin resulting in higher concentrations of urate close to the level of solubility. Monosodium
urate has a solubility limit of 380 μmol/L; when the concentration exceeds 380μmol/L, there is a
risk of precipitation and the formation of monosodium urate crystals. The production of urate is
dependent upon the balance between purine ingestion, de novo synthesis in the cells and the
actions of xanthine oxidase at the distal end of the purine pathway. Xanthine oxidase is the
enzyme that catalyses the oxidation of hypoxanthine, the breakdown product from the catabolism
of cellular nucleoproteins and purine nucleotides, to xanthine and xanthine to uric acid.

Presentation and diagnosis: An acute attack of gout has a rapid onset, with pain being
maximal at 6–24 h of onset and spontaneously resolving within several days or weeks. The first
attack usually affects a single joint in the lower limbs in 85–90% of cases, most commonly the
first metatarsophalangeal joint (big toe). The next most frequent joints to be affected are the mid
tarsi, ankles, knees and arms. The affected joint is hot, red and swollen with shiny overlying
skin. Even the touch of a sheet on the affected joint is too painful for the patient to bear. The
patient may also have a fever, leukocytosis, raised erythrocyte sedimentation rate (ESR), and the
attack may also be preceded by prodromal symptoms such as anorexia, nausea or change in
mood. Following resolution of the attack, there may be pruritus and desquamation of the
overlying skin on the affected joint. Monosodium urate crystals preferentially form in cartilage
and fibrous tissues, The deposition of crystals may continue for months or years without causing
symptoms; it is only when the crystals are shed into the joint space that inflammatory reaction
occurs precipitating an acute attack of gout by a number of factors including direct trauma,
dehydration, acidosis or rapid weight loss. The acute phase response associated with intercurrent
illness or surgery may also precipitate an attack; causes increased urinary urate excretion with a
lowering of serum uric acid which leads to partial dissolution of monosodium urate crystals and
subsequent shedding of crystals into the joint space. The shed crystals are phagocytosed by
monocytes and macrophages, activating the NACHT–LRR–PYD-containing protein-3 (NALP3)
inflammasome and triggering the release of interleukin-1β (IL-1β) and other cytokines, a
subsequent infiltration of neutrophils and the symptoms of an acute attack. The gold standard for
the diagnosis of gout is the demonstration of urate crystals in synovial fluid or in a tophus by
polarised light microscopy. Crystals may be found in fluid aspirated from non-inflamed joints,
even in those joints which have not previously experienced an attack. The crystals are large (10–
20μm) and needle shaped with a strong, intense, characteristic light pattern under polarised light.
In contrast, the calcium pyrophosphate dihydrate crystals associated with pseudogout are small
rhomboid crystals of low intensity. Gout and septic arthritis may co-exist and in order to exclude
septic arthritis synovial fluid is sent for Gram staining and culture.

Risk factors for gout

● Genetics
● Renal disease
● Comorbidities, for example, obesity, dyslipidemia, glucose intolerance, hypertension
● Diet
● Alcohol consumption
● Medication such as Cyclosporine, Cytotoxic chemotherapeutic, Diuretics (both loops and
thiazides) Ethambutol, Levodopa, Pyrazinamide, Ribavirin and interferon Teriparatide

Treatment :The management of gout can be split into the rapid resolution of the initial acute
attack and long-term measures to prevent future episodes. Gout is often associated with other
medical problems including obesity, hypertension, excessive alcohol and the metabolic
syndrome of insulin resistance, hyperinsulinemia, impaired glucose intolerance and
hypertriglyceridemia. This contributes to the increased cardiovascular risk and deterioration of
renal function seen in patients with gout. Management is not only directed at alleviating acute
attacks and preventing future attacks, but also identifying and treating other comorbid conditions
such as hypertension and hyperlipidaemia. Pharmacological measures should be combined with
non-pharmacological measures such as weight loss, changes in diet, increased exercise and
reduced alcohol consumption.

Management of an acute attack: Drugs used in the management of an acute attack

include NSAIDs, colchicine and corticosteroids. NSAIDs are the recommended first-line agents,
but in a number of patients their use is contraindicated and a second-line agent is indicated where
the pain is not adequately controlled by treatment, paracetamol and weak opiate analgesics, for
example, codeine or dihydrocodeine may be added to the regimen to provide additional relief.
Treatment should be continued until the attack is terminated, usually between 1 and 2 weeks.
The affected joints should also be rested for 1–2 days and initially treated with ice which has a
significant analgesic effect during an acute attack. A complete medication review should be
performed, and ideally medication which is likely to have contributed to the attack discontinued.
Where loop and thiazide diuretics are being used for the management of hypertension alone, an
alternative anti-hypertensive agent should be considered. Losartan, an angiotensin receptor
blocker effective in hypertension, has been shown to have uricosuric properties and is a suitable
agent in hypertensive patients with gout. In patients with heart failure, diuretics are often
essential and cannot be discontinued. Certain NSAIDs may be preferable in patients on diuretics
with both indomethacin and azapropazone demonstrating an increased uric acid secretion.
Allopurinol should not be commenced during an acute attack as it may prolong or precipitate
another attack. However, in patients already established on allopurinol therapy, allopurinol
should always be continued during the attack. Aspirin at analgesic doses (600–2400mg/day)
should be avoided as it blocks urate secretion. The continuation or initiation of low-dose aspirin
(75–150mg/day) is recommended in patients with cardiac disease as the benefits outweigh the
minimal effect on serum uric acid levels.

Management of chronic gout: Patients who suffer one or more acute attacks within 12
months of the first attack should normally be prescribed prophylactic urate-lowering therapy.
The aim of prophylactic gout treatment is to maintain the serum urate level below the saturation
point of monosodium urate (300μmol/L). If the serum urate is maintained below this level,
crystal deposits dissolve and gout is controlled. Prophylactic treatment should not be initiated
until an acute attack of gout has completely resolved, usually 2–3 weeks after symptom
resolution. Once started, prophylactic treatment should be continued indefinitely even if further
acute attacks develop. Drugs that lower serum uric acid can be classified into three groups
according to their pharmacological mode of action.

 Uricostatic agents
 Uricosuric agents
 Uricolytics