Biochemical foundations and pathogenesis
The disease is based on a disorder of purine base metabolism. Normally, purines undergo a chain of biochemical transformations through intermediate stages (hypoxanthine, then xanthine) until they turn into the final metabolite — uric acid. In gout, the concentration of this substance in blood plasma pathologically increases, which is called hyperuricemia.
An increase in uric acid levels occurs through two main mechanisms:
- Decreased renal excretion. This is the leading factor, occurring in 90% of all clinical cases. The kidneys fail to cope with the elimination of the metabolite from the body.
- Excessive production. Metabolic disorders leading to hyperproduction of acid are observed in only 10% of cases.
Mechanism of acute attack development
The inflammatory reaction in gout develops as a strict logical chain where physicochemical processes trigger an immune response:
- Crystallization. Uric acid has poor solubility. At high concentrations, it precipitates in tissues (predominantly in joints), forming salts — urate crystals.
- Cellular activation. Urate crystals interact with toll-like receptors on the membranes of monocytes and synoviocytes.
- Phagocytosis. Immune cells engulf the crystals. Inside the cell, the enzyme caspase-1 is activated with the participation of inflammasomes.
- Cytokine cascade. Caspase-1 transforms the inactive precursor pro-IL-1β into active interleukin-1β (IL-1β). This specific cytokine is the key trigger of inflammation.
- Clinical result. Acute gouty arthritis develops.
> Pharmacological nuance: Based on the understanding of this mechanism, the drug anakinra (a selective IL-1β receptor blocker) is currently being investigated for the effective relief of acute attacks.
Pharmacotherapy strategy
Gout treatment is strictly divided into two directions depending on the stage of the disease. Drugs for relieving an attack are not suitable for prophylaxis, and vice versa.
A. Relief of an acute attack The main goal at this stage is to relieve pain and suppress inflammation.
- Nonsteroidal anti-inflammatory drugs (NSAIDs). Used systemically.
- Colchicine. A specific drug for terminating gouty inflammation.
- Glucocorticoids (GCs). In severe cases, their intra-articular administration is possible.
Important exception: Acetylsalicylic acid (ASA) is categorically not recommended. It impairs the renal excretion of uric acid, increasing its concentration in blood plasma and worsening the patient's condition.
B. Prophylaxis of attacks (urate-lowering therapy) The goal of chronic treatment is the systemic reduction of plasma uric acid levels to prevent the formation of new crystals. Two groups of drugs are distinguished:
- Uric acid synthesis inhibitors (uricostatic agents). Inhibit the formation of the metabolite. Representatives: allopurinol, febuxostat.
- Uricosuric agents. Increase the excretion of uric acid from the body. Representatives: sulfinpyrazone, benzbromarone.
Briefly: answers to topical questions
What is the mechanism of action of allopurinol?
The mechanism of action of allopurinol consists in the competitive inhibition of the enzyme xanthine oxidase.
The drug is a structural analogue of hypoxanthine, a precursor of uric acid. Due to its structural similarity, it inhibits xanthine oxidase and disrupts uric acid synthesis.
As a result of this action, the following pharmacodynamic effects are observed:
- Reduction of uric acid formation.
- Accumulation of precursors — an increase in the concentration of hypoxanthine and xanthine in blood plasma.
Hypoxanthine and xanthine have high solubility in plasma and do not form crystals.
What ismechanism of action of colchicine?
The mechanism of action of colchicine is based on the disruption of the interaction between $\alpha$- and $\beta$-tubulin, which leads to the destruction of cellular cytoskeleton microtubules.
The drug accumulates in leukocytes, where it blocks microtubule formation. The consequence of this process is the following cellular effects:
- Antimitotic action — inhibition of cell division and leukopoiesis.
- Impairment of motility — suppression of cell component migration and exocytosis of biologically active substances.
- Blockade of chemotaxis — leukocytes cease to migrate into the focus of inflammation.
- Impairment of phagocytosis — leukocytes do not engulf urate crystals.
As a result, the release of inflammatory mediators decreases, leading to the relief of the attack.
It is easy to remember the contraindication during an attack by the abbreviation ASA (Acetylsalicylic acid): Absolutely Sorry Candidate (or in Russian: *A*bsolutno *S*kverny *K*andidat). It impairs the renal excretion of uric acid, retaining it in the blood, so it will only make things worse.
Class and exam questions
Why do joints specifically become inflamed in gout?
Due to poor solubility, excess uric acid crystallizes in joint tissues in the form of salts (urates). Immune cells phagocytose these crystals, which leads to the activation of caspase-1, the release of interleukin-1β, and the initiation of a powerful inflammatory cascade.
What is the main cause of excess uric acid in the body?
In the overwhelming majority of cases (about 90%), hyperuricemia is caused by the kidneys reducing the excretion of uric acid. In only 10% of cases are metabolic disorders leading to its excessive production the cause.
Can acetylsalicylic acid be used to relieve pain in gout?
No, this is strictly contraindicated. Acetylsalicylic acid impairs the renal excretion of uric acid, which leads to an increase in its concentration in blood plasma and aggravates the severity of the attack.
What is the difference between allopurinol and benzbromarone?
Both drugs are used for attack prophylaxis, but they work differently. Allopurinol is a uricostatic agent (inhibits uric acid synthesis), while benzbromarone is a uricosuric agent (increases its excretion by the kidneys).
What else to study on this topic
- Biochemical cascade of purine base metabolism down to hypoxanthine and xanthine
- The role of inflammasomes and the enzyme caspase-1 in the intracellular activation of monocytes
- Mechanism of action of colchicine in relieving acute gouty arthritis
- Pharmacodynamics of uric acid synthesis inhibitors (allopurinol, febuxostat)
- Prospects for the use of targeted IL-1β receptor blockers (anakinra)
- Comparative characteristics of uricosuric agents (sulfinpyrazone and benzbromarone)
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