Pharmacology of Uricosuric Agents

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Questions and Answers

What is the primary therapeutic effect of allopurinol?

Stimulate purine production

Enhance the solubility of uric acid

Inhibit the enzyme xanthine oxidase (correct)

Increase the synthesis of uric acid

Which substances are elevated in the urine as a result of allopurinol administration?

Uric acid and xanthine

Xanthine and uric acid

Hypoxanthine and xanthine (correct)

Uric acid and hypoxanthine

In what conditions is allopurinol indicated for treatment?

Cardiovascular diseases

Bacterial infections

Only for hyperuricemia

Gout and malignancies like leukemia (correct)

Why are elevated plasma levels of hypoxanthine and xanthine not problematic after allopurinol treatment?

They are readily excreted and more soluble Signup and view all the answers

What happens to plasma urate levels when allopurinol inhibits uric acid synthesis?

They decrease and dissolve urate crystals Signup and view all the answers

What is the primary action of probenecid in the treatment of hyperuricemia?

It decreases the rate of urate crystal deposition. Signup and view all the answers

Which of the following metabolites of probenecid possess some uricosuric activity?

Glucuronide conjugates Signup and view all the answers

What is a contraindication for the use of probenecid?

Blood dyscrasias Signup and view all the answers

What is the main cause of acute gouty arthritis?

Accumulation of monosodium urate crystals Signup and view all the answers

What structural feature increases the uricosuric activity of compounds like probenecid?

Increased size of the alkyl group. Signup and view all the answers

What role do kidneys play in uric acid levels in the body?

They excrete about 70% of daily urate production Signup and view all the answers

Which compound has a similar uricosuric effect to probenecid?

Sulfinpyrazone Signup and view all the answers

What physiological pH condition influences the solubility of uric acid?

pH 5.7, where it forms monosodium salt Signup and view all the answers

Which of the following factors can trigger an acute gout attack?

Minor trauma or emotional stress Signup and view all the answers

What is the pKa value of sulfinpyrazone, and why is it significant?

2.8, indicating it is a strong acid that enhances uricosuric effect. Signup and view all the answers

Which property of sulfinpyrazone contributes to its uricosuric activity?

Acidic nature. Signup and view all the answers

What happens when sodium urate solubility limits are exceeded?

Urate crystals are deposited in joints Signup and view all the answers

What is a common underlying issue contributing to chronic gout?

Decreased excretion of uric acid Signup and view all the answers

What is the effect of sulfinpyrazone on human platelets?

It decreases platelet aggregation. Signup and view all the answers

Which enzyme is responsible for the formation of uric acid from xanthine?

Xanthine oxidase Signup and view all the answers

What is the typical uric acid concentration in males without gout?

1,000 to 1,200 mg Signup and view all the answers

What role does the urate anion transporter (URAT1) play in the human body?

It facilitates the reabsorption of uric acid in the renal proximal tubules. Signup and view all the answers

Which therapeutic agent is commonly used to control acute gout attacks?

Indomethacin Signup and view all the answers

What is a primary action of colchicine in the treatment of gout?

It reduces inflammation related to urate crystal deposition. Signup and view all the answers

What is the mechanism of action for probenecid in uric acid management?

It inhibits the URAT1 transporter. Signup and view all the answers

Which combination of treatments is often recommended for gout due to the limitations of colchicine?

Colchicine and probenecid Signup and view all the answers

What pH condition does colchicine induce in the synovial tissue and why is it beneficial?

Increased pH, increasing uric acid solubility. Signup and view all the answers

What therapeutic strategy is utilized to reduce uric acid formation in patients with gout?

Enzyme inhibitors Signup and view all the answers

Why is it essential to balance uric acid levels in the body?

To avoid gout attacks and related inflammation. Signup and view all the answers

Study Notes

Understanding Gout

Gout is an inflammatory disease marked by high plasma and urine uric acid levels, presenting in acute and chronic forms.
Acute gouty arthritis occurs from monosodium urate crystals accumulating in joints, generally triggered by trauma, stress, infections, or dietary indulgences.
Chronic gout leads to permanent joint deformities due to prolonged elevated uric acid levels.

Uric Acid Formation and Excretion

Uric acid is synthesized from purines (adenine and guanine) via xanthine oxidase, producing uric acid as an end product of metabolism.
Normal uric acid levels are 1,000-1,200 mg in males and about half in females; gout patients may have levels two to three times higher.
Uric acid solubility is low (~6 mg/100 mL), leading to deposition of crystals when levels exceed solubility limits, initiating gout attacks.

The Role of URAT1

URAT1, a urate anion transporter in the renal proximal tubules, is crucial for urate homeostasis and targeted by uricosuric drugs.

Therapeutic Strategies for Gout

Management includes:
- Controlling acute attacks with anti-inflammatory drugs (e.g., colchicine, NSAIDs like indomethacin).
- Increasing uric acid excretion with uricosuric drugs (e.g., probenecid, sulfinpyrazone).
- Inhibiting uric acid biosynthesis with xanthine oxidase inhibitors (e.g., allopurinol).

Acute Gout Treatment

Treatments focus on NSAIDs (indomethacin) and glucocorticoids.
Colchicine, derived from Colchicum, alleviates inflammation but does not lower uric acid levels; it may be paired with uricosuric agents like probenecid.

Colchicine Mechanism

Inhibits lactic acid production, enhancing uric acid solubility at higher pH levels; also reduces inflammation by blocking lysosomal enzymes during phagocytosis.

Chronic Gout Management

Two main drug classes:
- Uricosuric agents that enhance uric acid excretion (Probenecid, Sulfinpyrazone).
- Xanthine oxidase inhibitors that decrease uric acid formation (Allopurinol).

Probenecid Overview

Probenecid increases uric acid excretion by inhibiting URAT1 and reducing reabsorption in the kidneys.
Metabolized extensively; indicated for hyperuricemia management after acute gout attacks subside.

Sulfinpyrazone Characteristics

Functions similarly to Probenecid and has anti-platelet properties.
Strong acidic nature (pKa = 2.8) enhances uricosuric effect; indicated for chronic gout treatment.

Allopurinol Details

Originally intended as an antineoplastic, allopurinol inhibits xanthine oxidase, reducing uric acid production.
Its use results in increased urinary xanthine and hypoxanthine levels, which are more soluble and easily excreted.
Allopurinol is suitable for treating both primary and secondary gout conditions.

Summary

Gout management involves understanding uric acid metabolism, therapeutic drug targets, and appropriate treatment strategies to control acute and chronic manifestations effectively.

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Description

This quiz covers the pharmacological effects of uricosuric agents, particularly Probenecid. It discusses how these compounds help in decreasing plasma uric acid concentrations, their metabolic pathways, and the relationship between alkyl group size and uricosuric activity.