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Gout Pathophysiology, Etiology and Rational Treatment

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I am registered pharmacist from Pakistan and writing an article is my passion and creativity. I have Published a lot of articles in journals

Gout is an arthropathy characterized by recurrent acute attacks of urate crystals induced arthritis. It may also include the tophi ……deposits of monosodium urates in and around the joints and cartilage and in kidney causing urate stones (urate nephrolithiasis).

gout-pathophysiology-etiology-and-rational-treatment

Uric Acid Production and Excretion

  1. Uric acid is produced from the purines (Adenine and guanine) metabolism which are produced both from dietary and endogenous sources.
  2. An enzyme called Xanthine Oxidase which is responsible for the metabolism of the final step in purines metabolism converts hypoxanthine to xanthine and then xanthine to uric acid.
  3. Uric acid is excreted by both Kidneys (300-600mg/day) and a GI tract (100-300 mg/day).
  4. Uric has no known biological functions but some scientists believed that hyperuricemic people have fewer chances of Alzheimer’s disease.
  5. In hyperuricemic condition, urates may crystallize and in the joints and in kidneys.

Etiology

Hyperuricemia which causes gout may be primary or Secondary. Primary Hyperuricemia is caused by congenital deformities which lead to defect in purine metabolism or decreased uric acid secretion. Secondary hyperuricemia is caused by some diseases due to which secondarily the uric metabolism and excretions disturb. Secondary causes include:

Hematological Causes of Hyperuricemia and Gout are associated with increased nucleic turnover and breakdown to uric acid which may occur in cases like, Lymphoproliferative disorders, Myeloproliferative disorders, Certain Hemolytic anemias, and Hemoglobinopathies.

Other Diseases:- Diabetic ketoacidosis, psoriasis, and chronic Lead poisoning. Chronic Renal Failure:- In this condition, reduced renal clearance of uric acid can lead to hyperuricemia.

Drug-Induced:- Drug which competes with urates for renal tubular secretion are like Aspirin and other salicylates, diuretics (except spironolactone), Ethambutol, drugs which increase nucleic turnover like cytotoxic drugs, and drugs which increase purines (Adenine) catabolism like ethanol.

Pathophysiology

Gouty arthritis is the result of deposition of monosodium urate crystals in the synovium of the involved joints. Initially acute attacks occur in the toe called Podagra an in 75% of cases symptoms starts from the toe. The involved joint response is the inflammation of the joint and is characterized by redness, warmth, and tenderness. If the gout is left untreated this may lead to tophi formation in the joints. Tophi are the deposits of monosodium urate crystals which lead to joint deformity and disability, further untreated gout may lead to kidney involvement which can result in renal impairment.

Urolithiasis (stones in urinary system) is the complication of about 20% of the patients with Hyperuricemia and Gout. Urine acidosis and dehydration or low consumptions of fluid and water are the aggravating factors which can lead to urolithiasis. Nephropathy may also be the result of the urates deposition of urate crystals in the kidney leading to renal failure.

Clinical Features

Acute GoutIn some 75% of cases a first attack affects the big toe, and this form is called podagra. Other common sites are the ankles, knees, elbows, wrists, and fingers. An attack often starts overnight or a few hours after an acutely stressful episode, e.g. MI or major surgery. The joint becomes exquisitely painful and inflamed and the overlying skin may flake over the next few hours: this sign plus the symptoms is almost conclusive. The attack subsides spontaneously over a few days or weeks, though most sufferers seek treatment. There may be no recurrence, or a second attack may follow after a variable period ranging from days to years. Attacks tend to be more severe in younger patients, aged under 30 years.

Chronic GoutThis is uncommon, except in patients who are non-compliant with medication, or those with a metabolic abnormality. Acute episodes occur with increasing frequency, leading to tophus formation and permanent joint damage. Renal impairment increases with time and this is aggravated in about one-third of patients by associated hypertension, though the latter is probably by reflection of kidney damage rather than a cause.

gout-pathophysiology-etiology-and-rational-treatment

Diagnosis

Diagnosis of gout is done by the signs and symptoms mentioned above along with hyperuricemia. Usually moderately high ESR and leukocytosis finding in a serological analysis. Synovial fluids were taken from the involved joint and microscopy for a crystal of urates, but it is not possible for all joint and it is an impossibly painful process. Response to colchicine may provide the indications of Gout. Familial history of gout may provide clues for gout.

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 co-morbid conditions such as hypertension and hyperlipidemia. Pharmacological measures should be combined with non-pharmacological measures such as weight loss, changes in diet, increased exercise and reduced alcohol consumption.

Management of Acute Attack

An acute attack of Gout which is a worse painful event is managed by an analgesic agent and anti-inflammatory agents.
First line agents include NSAIDs. Where indomethacin is involved in patients with no Cardiovascular and GI bleedings or having concurrent but studies have shown it not to be superior in efficacy or safety when compared to other NSAIDs. Obviously, Aspirin use should be prevented as an analgesic agent because of its interference with the urates excretion in kidney tubules although low dose aspirin may be advised to CVS patients. Others like somewhat tolerated agents with fewer problems of GI Tract bleeding like Diclofenac, Ibuprofen, Naproxen, and Ketoprofen can be used as an analgesic at a high dose. Overall there is no convincing evidence to prefer one NSAID over the other in patients having gout without other concurrent disorders. Selective Cox2 agent may be preferred to prevent GIT problems in which etoricoxib is usually selected agent for treatment of Gout. But it should be kept in mind that there is no benefit of Cox2 selective agent (etoricoxib) use along with low dose Aspirin which is a non-selective Cox inhibitor. NSAIDs should be avoided in patients with heart failure, renal insufficiency and a history of gastric ulceration. Care should also be exercised in elderly patients with multiple pathologies. When prescribing an NSAID, the need for gastric protection should be considered in patients at increased risk of a peptic ulcer, bleed or perforation. In patients with heart failure losartan which has also concurrent uricosuric effect can also be initiated as a therapy.
Second line agent includes colchicine which is introduced in place of NSAIDs in patients having CVS problems and in patients with above-mentioned problems for NSAIDs. Colchicine should be started as soon as possible after the attack because of its slow onset of action. The mood of action of colchicine is not fully understood but it is thought to be arresting the microtubule assembly of microtubules in neutrophils and inhibit other cellular functions. Metabolism of colchicine is by enzymes CYP3A4 and has immense chances of drug interactions with drugs.
Third Line of Agents: are the first line of agents in monoarticular disease. They are corticosteroids in a patient who is resistant or have a contraindication for NSAIDs and Colchicine. They may be given systemically or locally (intrathecally). A common dose of Methylprednisolone for a large joint is 80mg such as a knee and 40mg of methylprednisolone or triamcinolone for smaller joint like wrist or elbow joint.

Management of Chronic Gout

The presence of hyperuricemia is not an indication to commence prophylactic therapy. 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. There are, however, some groups of patients where prophylactic therapy should be instigated after a single attack. These include individuals with uric acid stones, the presence of tophi at first presentation and young patients with a family history of renal or cardiac disease. The aim of the therapy is to maintain the monosodium urates level below the saturation point which is 300umol/L. prophylactic treatment should not be started in an acute attack, it should be started when the acute completely resolves almost 2-3 weeks after the symptoms resolution. But once started it should not be stopped even if another acute attack develops. Three classes of agents used in chronic Gout are:
Uricostatic AgentsUricostatic agents block the effect of xanthine oxidase and prevent the conversion of xanthine to uric acid. Blocking the enzyme reduces the production of the uric acid thus decrease the level of uric acid. Agent included is Allopurinol and Febuxostat.

Allopurinol is a prophylactic agent of choice in chronic gout. Allopurinol is inactive form activated by the liver to oxypurinol having a longer half-life 14-16h compared to 2 hours and both are secreted by renal clearance. To dose must be adjusted in renal impairment. In a patient with a normal renal function starting dose of 100mg/day is started with the increment of 100mg per 2-3 weeks until urate level is below 300 umol/day or maximum dose approaches which is 900mg/day. A decrease in serum urate will occur within a couple of days of introducing allopurinol therapy with a peak effect at 7–10 days. The dissolution of tophi may take up to 6–12 months with effective therapy. Azathioprine and mercaptopurine both are metabolized by xanthine oxidase so a dose of these agents should be decreased by up to one quarter.

Febuxostat is also xanthine oxidase inhibitor but more selective and more potent then Allopurinol. It is selective in terms that it has no effect on other enzymes involved in the metabolism of purines and pyrimidines. Recommended to the patients who are in tolerated to Allopurinol or in whom it is contraindicated.

Uricosuric AgentsIncrease uric acid excretion the urine by preventing the tubular absorption for the tubules in Kidneys. These agents should be avoided in patients with urate nephropathy or those who are overproducers of uric acid due to the high risk of developing renal stones. The uricosuric agent is required to maintain adequate fluid intake, and the need for alkalinization of urine should be considered to prevent urate precipitation. Agents included are Benzbromarone is withdrawn in the UK due to its association with hepatotoxicity, that’s why it is not the part of a discussion in here.

Sulphinpyrazone. Sulphinpyrazone is effective in reducing the frequency of gout attacks, tophi, and plasma urate levels at doses of 200–800 mg/day. It has the same mode of action on the kidney as benzbromarone and probenecid all of which inhibit URAT-1 transporter resulting in reduced urate re-absorption. However, in addition to this, sulphinpyrazone inhibits prostaglandin synthesis resulting in a similar adverse effect profile to NSAIDs, for example, gastrointestinal ulceration, acute renal failure, fluid retention, elevated liver enzymes, and blood disorders. The use of sulphinpyrazone is reserved for use in patients with adequate renal function who are underexcretion of uric acid and intolerant or resistant to treatment with allopurinol.

Probenecid is also not marketed in the UK. It is a week uricosuric agent compared to the above two, and it rarely is given alone. It is usually given as add-on agent along with Allopurinol monotherapy.
Uricolytic AgentUricolytic agent converts uric acid to allantoin through the action of uricase (urate oxidase). Uricolytic agents are given to a patient having tumor-associated secondary hyperuricemia. Rasburicase is the included drug in this class.

This content is for informational purposes only and does not substitute for formal and individualized diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed medical professional. Do not stop or alter your current course of treatment. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.

© 2019 Abid Hayat

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