The thiazide diuretic, hydrochlorothiazide (HCTZ) remains one of the most widely prescribed and cost-effective antihypertensives available on the market.  This in part due to the numerous clinical trials and practice guidelines that support the use of thiazide diuretics as first line or add-on therapy for hypertension in a broad range of patients.1,2  Furthermore, HCTZ is overall well tolerated and contraindications or warnings against its use are few.  However, some patients are known to develop hyperuricemia or gout.3-5  This is known to occur in some patients since HCTZ and uric acid are both substrates for the organic anion transporter-1 (OAT1) located on the basolateral surface of the proximal renal tubule.  As such, HCTZ can compete, in part, with uric acid for transport across the cell surface membrane thereby decreasing the renal elimination of uric acid from the body.6-9   For a more detailed discussion about this and other proposed mechanisms please click here

Should patients with asymptomatic hyperuricemia while on HCTZ be treated with allopurinol?
If the patient develops asymptomatic increases in uric acid, allopurinol should not be started prophylactically.  While there are no known significant drug interactions between hydrochlorothiazide and allopurinol, we are not aware of any substantial evidence that doing this will decrease gout attacks and/or long-term complications in patients being maintained on HCTZ.10  The implementation of allopurinol is plausible given the fact that increased uric acid levels have been associated with reduction or blunting of cardiovascular benefits associated with blood pressure lowering by HCTZ.11 

Should patients with acute gout attacks associated with HCTZ by started on allopurinol?
No. First and foremost, allopurinol should not be used in the setting of acute gout attack as it can worsen the attack and/or increase the patients risk for recurrent exacerbations within a few days of the attack.  Furthermore, we are not aware of any studies that support this intervention as a preventive measure once the gout attack has resolved.  This is also generally recommended since there is some evidence that the implementation of allopurinol in these patients (especially if they have renal insufficiency) can predispose the patient to a greater risk of rash.12  Therefore, if a patient develops an acute gout attack after being initiated on HCTZ or during the dosage titration phase, the HCTZ should be discontinued until the attack has resolved.  Since it is known that HCTZ can cause a dose dependent increase in uric acid levels,13-15 it is possible that the patient could be restarted on HCTZ (after the resolution of the exacerbation) at a lower dose without further complications, but this must be weighed against the risks and the patients input into their treatment. 

Ultimately, the most effective intervention is prevention.  Avoiding the use of HCTZ in high risk patients with baseline hyperuricemia or a past medical history of gout attacks and/or the presence of tophi is preferred.  This is especially true knowing that there are other antihypertensive options, such as losartan, that are less concerning in this patient population.16

References:

1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group.  Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial  (ALLHAT).  JAMA.  2002;288:2981-2997. 
2. Rosendorff C, Black HR, Cannon CP, et. al.  Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention.  Circulation.  2007;115:2761-2788.  
3. Reyes AJ.  Cardiovascular drugs and serum uric acid.  Cardiovasc Drugs Ther  2003;17:397-414.  
4. Savage PJ, Pressel SL, Curb JD et al.  Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program.  SHEP Cooperative Research Group.  Arch Intern Med  1998;158:741-51.  
5. Carlsen JE, Kober L, Torp-Pedersen C.  Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects.  BMJ  1990;300:975-8.  
6. Mount DB.  Molecular physiology and the four-component model of renal urate transport.  Curr Opin Nephrol Hypertens  2005;14:460-3.  
7. Rafey MA, Lipkowitz MS, Leal-Pinto E et al.  Uric acid transport.  Curr Opin Nephrol Hypertens  2003;12:511-6.  
8. Srimaroeng C, Perry JL, Pritchard JB.  Physiology, structure, and regulation of the cloned organic anion transporters.  Xenobiotica  2008;38:889-935. 
9. Hasannejad H, Takeda M, Taki K et al.  Interactions of human organic anion transporters with diuretics.  J Pharmacol Exp Ther  2004;308:1021-9.  
10. De Vries JX, Voss A, Ittensohn A et al.  Interaction of allopurinol and hydrochlorothiazide during prolonged oral administration of both drugs in normal subjects. II. Kinetics of allopurinol, oxipurinol, and hydrochlorothiazide.  Clin Investig  1994;72:1076-81. 
11. Franse LV, Pahor M, Di Bari M et al.  Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Elderly Program (SHEP).  J Hypertens 2000;18:1149-54.  
12. Young JL Jr, Boswell RB, Nies AS.  Severe allopurinol hypersensitivity.  Association with thiazides and prior renal compromise.  Arch Intern Med  1974;134:553-8.  
13. Reyes AJ.  Cardiovascular drugs and serum uric acid.  Cardiovasc Drugs Ther  2003;17:397-414.  
14. Savage PJ, Pressel SL, Curb JD et al.  Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program.  SHEP Cooperative Research Group.  Arch Intern Med  1998;158:741-51.  
15. Carlsen JE, Kober L, Torp-Pedersen C.  Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects.  BMJ  1990;300:975-8.  
16. Shahinfar S, Simpson RL, Carides AD et al.  Safety of losartan in hypertensive patients with thiazide-type hyperuricemia.  Kidney Int  1999;56:1879-85.

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hydrochlorothiazide, HCTZ, gout, hyperuricemia, allopurinol, pharmacology weekly