Evaluation of a Thiazide-Allopurinol Drug Interaction

doi:10.1097/00000441-198610000-00006

The American Journal of the Medical Sciences

Volume 292, Issue 4, October 1986, Pages 213-216

https://doi.org/10.1097/00000441-198610000-00006 Get rights and content

ABSTRACT

Allopurinol toxicity has been associated with the use of this drug in patients with renal insufficiency, a situation where the half-life of oxipurinol, the major metabolite of allopurinol, is prolonged. Allopurinol toxicity has also been associated with the concomitant use of allopurinol and thiazide diuretics. In the present study, the effect of hydrochlorothiazide administration on the renal clearance and serum half-life of oxipurinol has been studied in eight normal volunteers to determine if thiazides delay the clearance of oxipurinol. Oxipurinol’s renal clearance and serum half-life were measured in each volunteer during a control period and again while the volunteer was receiving 50 mg/day hydrochlorothiazide for 1 week. No change in renal oxipurinol clearance (21.1 ± 5.9 vs. 20.4 ± 8.7 ml/min) or serum oxipurinol half-life (23.7 ± 4.2 vs. 23.4 ± 4.4 hours) was noted with the addition of thiazides. The association previously noted between the use of thiazide diuretics and the development of allopurinol toxicity cannot be explained by alterations in oxipurinol pharmacokinectics.

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Cited by (18)

Management of hyperuricemia in asymptomatic patients: A critical appraisal
2020, European Journal of Internal Medicine
Citation Excerpt :
The estimated incidence of AHS is ̴1:1000 in the US with reported mortality of 20–25% [61]. While earlier literature suggested that high doses of allopurinol, diuretic use, and CKD increase the risk of SCARs [62,28], a large retrospective cohort study by Kim did not find any significant association with these variables. All SCARs requiring hospitalization occurred within 365 days from the start of treatment and were ten times more frequent in allopurinol initiators than non-users.
While there is consensus on starting urate-lowering therapy (ULT) in cases of symptomatic hyperuricemia, the frequent condition of asymptomatic hyperuricemia (AH) remains a challenge due to differences in the findings of studies that have addressed the issue. Uric acid has anti-oxidant properties, but high levels predispose to gout and may play a role in metabolic syndrome. We systematically evaluated randomized controlled trials (RCTs) addressing ULT in patients with AH, to assess the current evidence. We found broad heterogeneity among the studies (13 RCTs), in terms of study design and population, making findings challenging to interpret and generalize; hard end-points were not assessed. Allopurinol is often prescribed for AH despite the fact that its use is not backed by conclusive evidence from prospective RCTs, nor is it recommended by the guidelines. Its potential benefits, in terms of absolute risk reduction, must be weighed against its potential for harm since it can trigger severe adverse hypersensitivity reactions, sometimes even fatal. RCTs with hard end-points are needed to assess the risk/benefit of lowering uric acid in subjects with AH, particularly as secondary prevention for cardiovascular risk and in patients with different degrees of renal disease. To date, particularly after the result from the CARES trial, preventive treatment of asymptomatic and non-severe hyperuricemia is not recommended.
Pharmacological urate-lowering approaches in chronic kidney disease
2019, European Journal of Medicinal Chemistry
Citation Excerpt :
Furosemide increases serum level of oxypurinol without decreasing level of UA [47]. Similar phenomenon was observed on hydrochlorothiazide [48]. The exact mechanism is complex and remains unclear.
Chronic kidney disease (CKD) has become a global public health issue and uric acid (UA) remains a major risk factor of CKD. As the main organ for the elimination of UA, kidney owned a group of urate transporters in tubular epithelium. Kidney disease hampered the UA excretion, and the accumulation of serum UA in return harmed the renal function. Commercially, there are three kinds of agents targeting at urate-lowering, xanthine oxidoreductase inhibitor which prevents the production of UA, uricosuric which increases the concentration of UA in urine thus decreasing serum UA level, and uricase which converts UA to allantoin resulting in the dramatic decrement of serum UA. Of note, in patients with CKD, administration of above-mentioned agents, alone or combined, needs special attention. New evidence is emerging for the efficacy of several urate-lowering drugs for the treatment of hyperuricemia in patients with CKD. Besides, loads of novel and promising drug candidates and phytochemicals are in the different phases of research and development. As of today, there is insufficient evidence to recommend the widespread use of UA-lowering therapy to prevent or slow down the progression of CKD. The review summarized the evidence and perspectives about the treatment of hyperuricemia with CKD for medicinal chemist and nephrologist.
The teratogenicity of allopurinol: A comprehensive review of animal and human studies
2018, Reproductive Toxicology
Citation Excerpt :
Additional information on determinants linked to congenital abnormalities (e.g. paternal health and age, disease activity, nutritional and smoking status, socioeconomic and environmental factors) were not provided in these two cases. Furthermore, both mothers suffered from renal impairment which is linked to increased risk for allopurinol toxicity, what even might grow when allopurinol is combined with other drugs such as diuretics [58,59]. Another considerable significant determinant is that case #1 was of Mennonites descent on the paternal side, a population known for having an increased risk for unique genetic disorders like the Amish [60,61].
Allopurinol is widely used in the management of multiple disorders including gout, kidney stones and inflammatory bowel disease. Despite of long-term experience, its safety in pregnancy has been debated due to reports on possible teratogenicity. We aimed to review the literature on the safety of allopurinol in pregnancy and offspring. In animals, allopurinol induced species-specific reproductive toxicity. In humans, a total of 53 allopurinol exposed infants were reported in the literature. Major congenital malformations were reported in two cases with a comparable pattern of multiple abnormalities. Five other infants had minor birth defects. In conclusion, the association between allopurinol and teratogenicity appears to be weak and limited to two reports with uncertain causality. However, the available data are insufficient to make a certain judgement, and as allopurinol treatment evolves, report and prospective follow-up of all exposed infants (i.e. deviant and normal cases) should be encouraged.
Xanthine oxidase inhibitor treatment of hyperuricemia
2012, Gout and Other Crystal Arthropathies
Xanthine oxidase inhibitor treatment of hyperuricemia
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Diuretic drugs
1989, Side Effects of Drugs Annual
Against expectations, widespread controversy continues to be fed by speculation that the metabolic effects of thiazide diuretics predispose to myocardial infarction and sudden death. Both Khair and Kochar as well as Kaplan argue that, as a result, the role of diuretics in the management of hypertension has been undermined and that there is good reason to choose an alternative agent. The chapter discusses metabolic effects of potassium, magnesium, zinc, as well as severe hyponatremia, serum lipids, glucose tolerance, hyperuricema, and gout. Special problems like impotence, skin reactions, and interstitial pneumonitis have been explained. The chapter discusses specific drugs such as bemetizide, hydrochlorothiazide + amiloride (moduretic), metolazone, spironolactone, tienilic acid (ticrynafen), and triamterene.

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: Supported by the Veterans Administration and by NIH Grants ROl CA 26418 and RR 00095.

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Original ArticlesEvaluation of a Thiazide-Allopurinol Drug Interaction

ABSTRACT

Biochem Pharmacol

Biochem Pharmacol

Am J Med

J Am Acad Dermatol

Asymptomatic hyperuricemia: The case for conservative management

Ann Intern Med

Allopurinol

Original Articles
Evaluation of a Thiazide-Allopurinol Drug Interaction