Transplantation. Jul 27;66(2) Uricosuric effect of the angiotensin II receptor antagonist losartan in heart transplant recipients. Minghelli G(1). This agent promotes uric acid excretion via effects on the organic anion transport The AIIA losartan also produces a uricosuric effect in healthy volunteers. Uricosuric medications (drugs) are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule of the the uricosurics benzbromarone and losartan had no effect, suggesting these drugs act.
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The following search terms were used: Studies were excluded uricosjric did not explore fractional excretion or serum uric acid as an endpoint, if patients did not have a diagnosis of gout or hyperuricemia at baseline, or if they were non-English language. A total of eight studies met the inclusion criteria. Losartan demonstrated statistically significant reductions in serum uric acid levels or increases in fractional excretion of uric acid in all studies, whereas no other ARB reached statistical benefit.
The effect of ARBs on the occurrence of gout attacks or other clinical outcomes were not represented. Four studies evaluated safety effects of these agents indicating abnormalities such fefect minor changes in lab values.
In conclusion, losartan is the only ARB that has consistently demonstrated a significant reduction in serum uric acid levels, although the significance of impacting clinical outcomes remains unknown. Losartan appears to be a safe and efficacious agent to lower serum uric acid levels in patients with hyperuricemia. The presence of hyperuricemia has also been associated with poor health-related outcomes including myocardial infarction MIstroke and nephrolithiasis [ Zhu et al.
In addition, it is estimated that employed individuals diagnosed with gout miss 5 days more per year than their counterparts without the disease. In a population-based study from the United Kingdom inresults showed that the prevalence of gout has increased by This information highlights the current and growing number of individuals afflicted with this disease state and underscores the importance of identifying viable options for the treatment of gout. Gout is an arthritis classified commonly by uric acid crystallization that occurs within joints [ Choi et al.
Humans lack the enzyme uricase, which is responsible for breaking down ingested purines from dietary sources e. As urate levels increase, individuals are at a greater risk for saturation and formation of crystals. URAT1 serves as a urate—anion exchanger in the proximal tubule of the kidney yricosuric is a key target for uricosuric agents [ Choi et al.
In contrast, genetic mutations in GLUT9 can precipitate individuals to a defect in uric acid absorption leading to hypouricemia [ Dinour et al. Finally, when there is dysfunction of the urate transporter ABCG2, it has been found that there is the potential for both renal underexcretion of uric acid and a blockade of intestinal urate excretion, thereby leading to renal urate losartsn [ Matsuo et al.
One-third of urate elimination occurs in the uricoeuric tract, while the other two-thirds are eliminated through the uricsuric and excreted in the urine [ Choi et al. When excretion is impaired, hyperuricemia and uric acid crystallization can result, which predisposes individuals to gout and potentially painful gout attacks. First-line interventions include dietary modifications such as exercise and consuming a low purine diet [ Crittenden and Loeartan, ; Khanna et al.
While the use of nonsteroidal anti-inflammatory drugs NSAIDsoral glucocorticoids and colchicine are recommended for uricosuriic gout attacks, urate-lowering therapy is recommended uricosugic individuals with chronic gout consisting of multiple gouty attacks per year and eftect prespecified conditions as indicated by the treatment guidelines [ Khanna et al.
First-line urate-lowering agents are xanthine oxidase inhibitors such as allopurinol and febuxostat. Probenecid, a uricosuric agent that helps to promote excretion of uric acid, can be utilized second-line if xanthine oxidase inhibitor use is contraindicated.
Newer agents such as pegloticase have also emerged in treatment guidelines, but the use of these agents is only recommended in severe gout when uricosiric agents have failed [ Khanna et al. The ACR Guidelines endorse the use of additional uricosuric agents such as fenofibrate and losartan in combination with xanthine oxidase inhibitors if target urate levels are losartah met with first-line agents alone [ Khanna et al.
Uricosuric – Wikipedia
Asymptomatic hyperuricemia can occur and, treatment with urate-lowering therapy most commonly occurs only in high risk patients such as those with a history of multiple gout attacks [ Khanna et al. Uricosuric agents increase the urinary excretion of uric erfect, thereby decreasing serum uric acid levels.
This is thought to occur by inhibition of the URAT1 anion exchanger responsible for hricosuric reabsorption of filtered urate, which is located in the proximal tubule of the kidney [ Loartan et al. Many medication therapies have secondary uricosuric effects, and although used for alternate primary indications, can assist conventional agents in reducing serum uric acid levels.
High-dose salicylate and indomethacin have both been studied for their uricosuric effects [ Shin et al. ARBs inhibit the activity of angiotensin II, a potent vasoconstrictor that is formed through a conversion from angiotensin I by angiotensin-converting enzyme ACE [ Michel et al.
Angiotensin II is a vital regulator of homeostasis and is a primary component of the renin-angiotensin system. This vasoconstrictor not only plays a role in many tissues in the body, but also has several effects in the cardiac system including increased cardiac contractility and renal reabsorption of sodium.
Therefore ARBs play a significant role in the treatment of hypertension and as renoprotective agents [ Michel et al. While utilized for similar indications, the available ARBs differ widely in their chemical structures, which correlate to various differences in their pharmacodynamic and pharmacokinetic effects.
Overall, ARBs are well tolerated; however, the most common adverse effects include hypotension, hyperkalemia and increased serum creatinine levels [ Taylor et al. Bibliographies of relevant articles were reviewed for additional citations. Some duplicate citations were included in these results and were removed by comparing each result against the prespecified inclusion and exclusion criteria.
From those, eight studies met criteria [ Rayner et al.
Rayner and colleagues conducted an open-label, randomized, controlled, two-parallel group study [ Rayner et al. Individuals had to be maintained on a stable dose of diuretics for at least 12 weeks before study entry. Those with baseline use of steroids, NSAIDs, allopurinol, colchicine or with renal dysfunction were excluded. As the primary outcome, the uric acid levels of the losartan group decreased from 7.
Of note, in the losartan group, the uric acid levels decreased with no effect on serum creatinine, while in the candesartan group, there was no change in uric acid levels but there was a slight increase in serum creatinine. Both drugs were well tolerated; however, there was one serious adverse effect noted in the study that was not described by the authors [ Rayner et al.
Dang and colleagues conducted a multicenter study across 20 clinical institutions exploring the effects on serum uric acid levels after administration of losartan or irbesartan [ Dang et lsoartan. Study participants were excluded if they had a diagnosis of gout or renal lithiasis within the last 2 years. Losartan decreased serum uric acid levels from 7.
Irbesartan decreased serum uric acid levels from 7. Potassium and serum creatinine levels were reviewed and both lab values remained within accepted normal ranges throughout the study [ Dang et al. This study was a prospective, randomized, double-blind, crossover study design.
The patients then crossed over to receive the alternate therapy. From a baseline serum uric acid level of 9. Compared with the baseline uric acid level of 9.
Several gout attacks occurred through each phase of the study.
The effect of angiotensin II receptor blockers on hyperuricemia
Four individuals experienced an acute gouty attack after being switched from losartan back to enalapril therapy. Shahinfar and colleagues conducted a double-blind, placebo-controlled, parallel study with 63 patients to explore the safety and efficacy of losartan in individuals with thiazide-induced hyperuricemia [ Shahinfar et al.
Individuals with secondary hypertension, significant cardiac history including MI within the past year, and transient ischemic attack TIA or cerebrovascular attack CVA within the past 3 years were excluded. Patients were randomized into one of 4 treatment groups for 3 weeks: Outcomes included urine uric acid excretion, serum uric acid levels, urine pH and dihydrogen urate supersaturation.
Urine uric acid excretion increased at hours 2, 4 and 6 on day 1. There were no significant serum uric acid level increases at hours 2, 4 and 6 on day 1. Losartan was well tolerated and no participants experienced urate nephropathy [ Shahinfar et al. Khan and colleagues conducted a randomized, open-label, prospective, comparative study in which 60 patients with hyperuricemia ranging from 7.
Individuals with a history of secondary hypertension, history of gout and renal lithiasis in the last 2 years, history of malignant hypertension, history of CVA within the last 2 years and history of cardiac arrhythmia were all excluded from this study.
A total of 57 patients were analyzed at 12 weeks. In the hydrochlorothiazide monotherapy group, uric acid levels increased from 8. In the hydrochlorothiazide and losartan group, uric acid levels decreased from 8. In the losartan monotherapy group, uric acid levels decreased from 8. There was no safety analysis conducted in this study [ Khan et al.
The effect of angiotensin II receptor blockers on hyperuricemia
A follow-up study was conducted by the same study investigators which evaluated an additional outcome of urinary acid excretion [ Khan llsartan al. There was no safety analysis conducted in this follow-up study [ Khan et al.
From baseline, fenofibrate reduced serum uric acid levels from 7. Following combination therapy, the addition of losartan further decreased uric acid levels from 5. This represented an additional In addition, combination therapy with losartan, increased the fractional excretion of uric acid from 6. This study did not complete a safety analysis [ Elisaf et al. Losartan plus benzbromarone significantly decreased serum uric acid from 4.
Losartan plus allopurinol significantly decreased serum uric acid from 6. This study did not conduct a safety analysis [ Takahasi et al. This review explored the available literature for the urate-lowering effects of ARBs. Losaetan was the only ARB which was found to reduce serum uric acid levels uriclsuric to increase the excretion of uric acid in all the studies discussed in this review [ Rayner et al. Candesartan and irbesartan were the other ARBs found in the literature that were compared to losartan for their potential uricosuric effects.
Upon review of the three studies which looked at the uricosuric effects of candesartan and irbesartan, there was no significant benefit with use of these agents [ Dang et al. Efffect two of the studies, serum uric acid levels were not reduced with the use of candesartan or irbesartan and, in the final study, serum uric acid levels decreased with irbesartan, but this result was not found to be statistically significant [ Dang et al.
There are multiple explanations as to why candesartan and irbesartan do not have the same effects as losartan. There are differences in the chemical structures of the ARBs, there is potential for the ARB to be cis -inhibitory or trans -stimulating or both, and there is variability amongst ARBs to have inhibitory effects on the uptake of uric acid by the URAT1 receptor [ Iwanaga et al.
Further studies with additional ARBs could be beneficial in determining if any of the other agents within this class are able to exert similar effects to losartan. The presence of an active metabolite has not been shown to be the cause for differences between the ARBs in their uricosuric effects; however, many have postulated that it is the position in which the ARB binds to the URAT1 transporter [ Iwanaga et al.
It is unclear whether alternative ARBs other than those studied in this review have the same binding potential as losartan. Future studies would be needed to determine if uricoeuric is the case. Despite losrtan reduction in serum uric acid levels and increased excretion of uric acid from losartan therapy as evidenced by the studies reviewed, it would be beneficial to explore more clinically meaningful endpoints in the future, such as reduction in the number of gout attacks or hospitalizations associated with gout.
Furthermore, evaluating quality of life and gout attack free intervals would help quantify the relevance of incorporating losartan with xanthine oxidase inhibitors for gout management. It may also be necessary to conduct additional studies for longer periods of time to capture this clinical outcome. Although beyond the scope of this review, other clinically meaningful results unrelated to gout manifestations have been reported.
Losartan has demonstrated renoprotective effects directly related to the degree of serum uric acid lowering; however, these endpoints were not explored in the included studies that enrolled losarttan with baseline hyperuricemia or a gout diagnosis [ Ito et al.
In addition, hyperuricemia has been linked to an increase in cardiovascular events such as stroke, hypertension and heart failure [ Zhu et al. Many individuals with hypertension are treated with thiazide diuretics, which can cause hyperuricemia.