Uricostatic drugs

Allopurinol: pharmacokinetics and metabolism

Allopurinol (Allopurinolum) remains the baseline uricodepressive drug for lowering uric acid levels. When taken orally after meals, it exhibits high bioavailability, which varies widely from 50 to 90%. This means that a significant portion of the taken dose successfully reaches the systemic circulation.

Upon entering the body, the drug undergoes intensive biotransformation. In liver tissues, allopurinol is converted into its main active metabolite, oxypurinol. It is important to understand that this specific metabolite plays a decisive role in the clinical efficacy of the entire therapy.

The pharmacokinetics of these two substances differ cardinally. While the half-life of the parent substance (allopurinol) is only 1 to 3 hours, oxypurinol is eliminated from the body much more slowly. Its half-life reaches 12–30 hours. This pharmacokinetic feature guarantees a prolonged therapeutic effect and makes it possible to maintain a stable suppressing concentration of the active substance in the patient's blood throughout the day, preventing sharp fluctuations in uric acid levels.

Safety profile and adverse effects of allopurinol

The prescription of allopurinol requires strict monitoring by the physician due to its specific safety profile. The most insidious and frightening complication for the patient during the first weeks of therapy is paradoxical flare-up. It manifests as a classic acute gout attack. The mechanism of this paradoxical phenomenon is directly related to pharmacodynamics: against the background of a sharp decrease in uric acid synthesis, the concentration gradient changes, and urates actively exit from formed tissue depots back into the systemic circulation.

Among other adverse reactions, allergic manifestations lead the way. Most often, they occur in the form of skin rashes and dermatitis. Patients may also complain of gastrointestinal dyspeptic disorders, particularly diarrhea. Disorders such as persistent headaches and marked daytime sleepiness are occasionally recorded from the central nervous system.

The drug has strict contraindications for use. It is strictly contraindicated to prescribe it during an acute gout attack (so as not to exacerbate urate mobilization), as well as during pregnancy and breastfeeding. In addition, severe pathologies of the excretory and metabolic systems—hepatic failure and chronic renal failure—serve as a serious obstacle to therapy.

Febuxostat: a selective alternative

In clinical situations where the patient shows intolerance to allopurinol, or when it is necessary to achieve a faster and more powerful clinical response, febuxostat (Febuxostatum) becomes the drug of choice.

Its main pharmacological advantage lies in the high selectivity of action. Febuxostat works as a strictly selective xanthine oxidase enzyme blocker. Unlike its non-selective predecessors, it targetedly switches off the target enzyme and does not affect the complex metabolic processes of other purines and pyrimidines in the body at all. This reduces the risk of interfering with normal cellular nucleic acid metabolism.

The clinical efficacy of febuxostat in pronounced hyperuricemia is assessed by specialists as very high. Complete normalization of serum uric acid levels (reaching target values) is usually achieved within 28 days of regular drug intake.

Adverse reactions to febuxostat

Despite the high selectivity and modernity of the drug, febuxostat therapy requires careful monitoring of the patient's condition. A specific side effect of this uricodepressive agent is its effect on the hepatobiliary system. An asymptomatic increase in liver transaminases—specific liver enzymes—may be recorded in patients' biochemical blood tests, which requires periodic laboratory monitoring.

In addition to laboratory changes, clinical manifestations from the cardiovascular and central nervous systems are possible. In particular, patients sometimes note the appearance of tachycardia (rapid heartbeat) and dizziness attacks. The list of possible, albeit less frequent, side effects also includes myositis—inflammatory lesions of skeletal muscles accompanied by muscle pain.

Class and exam questions

What else to study on this topic

• Biochemical mechanism of allopurinol conversion to oxypurinol in hepatocytes.
• Pathophysiology of paradoxical flare-up: mechanisms of urate mobilization from tissue depots.
• Comparative characteristics of selective and non-selective xanthine oxidase inhibitors.
• The effect of uricodepressive drugs on liver transaminase levels and liver function monitoring.

Other topics in the section "Antigout drugs"

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