Pearl of the Month

A couple of little known side effects of medications


A 46-year-old woman with diabetes and seizure disorder presents with nausea and fatigue. Her physical exam is unremarkable.

Dr. Douglas S. Paauw

Meds: Glyburide 5 mg daily, metformin 850 mg b.i.d., phenytoin 300 mg daily, topiramate 400 mg daily, pantoprazole 40 mg daily.

Labs: Na 133, K 3.9, Cl 112, HCO3 13, Glu 158, Bun 18, Cr 1.0.

What is the most likely cause of this patient’s acidosis?

A. Phenytoin

B. Topiramate

C. Metformin

D. Pantoprazole

The correct answer to this question is topiramate.

Metformin has had warnings about risk of lactic acidosis occurring in patients with kidney disease, but there is no evidence that metformin is associated with lactic acidosis or raised serum lactate levels in patients with diabetes with normal renal function.1Metformin is actually safer than previously believed in patients with chronic kidney disease (CKD), and its use may decrease CV risk in patients with stage 3 CKD.2 This patient has a non–anion gap acidosis (anion gap is 8).

Topiramate acts as a carbonic anhydrase inhibitor, which causes impairment of both the normal reabsorption of filtered HCO3 by the proximal renal tubule and the excretion of hydrogen ion by the distal tubule.3 Acidosis occurs in most patients who are treated with topiramate. Dr. Ture and colleagues did a cross-sectional study to assess the frequency of metabolic acidosis in patients who were taking topiramate.4 Eighty patients who were on topiramate for seizure prevention prior to elective craniotomy were studied. Metabolic acidosis was present in 71% of the patients. Patients treated with topiramate also have a higher risk for kidney stones and uric acid elevation.

A 60-year-old patient presents with right great toe pain. On exam he has warmth and erythema of the 1st MTP joint. Aspiration of the joint shows uric acid crystals. He has had BP’s of 150-160 mm Hg systolic on his home BP monitoring over the past 6 months. In clinic today BP is 156/90 mm Hg. Labs: Bun 10, Cr 1.0, K 3.8, Uric acid 7.4.

Which blood pressure medication would you recommend?

A. Hydrochlorothiazide

B. Chlorthalidone

C. Lisinopril

D. Losartan

E. Irbesartan

In a patient with gout, diuretics should be avoided if possible, as they increase uric acid levels. Of the other three options, losartan offers the added benefit of lowering uric acid levels. Losartan has uricosuric effects and lowers uric acid levels, a property that is unique to losartan of the angiotensin receptor blockers (ARBs) that have been studied.5-6 The uric acid lowering appears to be a probenecid-like effect. Losartan has also been evaluated to see whether using it in combination with a thiazide diuretic can reduce the rise in uric acid that occurs with thiazides. Dr. Matsumura et al. looked at data from the COMFORT trial, focusing on the effect of combining losartan with hydrochlorothiazide on uric acid levels.7 They looked at a group of 118 patients on an ARB other than losartan plus a diuretic, who were then randomly assigned to losartan 50 mg/hydrochlorothiazide 12.5 mg or continuation of another ARB plus a diuretic. Blood pressure control was the same between groups, but the patients who received the losartan combination had lower uric acid levels (P = .01).

Pearls: Topiramate acts as a cerbonic anhydrase inhibitor and can cause a non–anion gap acidosis. Losartan has a modest uricosuric effect and can modestly lower uric acid levels. This is a unique property of losartan and is not shared by other ARBs.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at


1. Salpeter SR et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010;4:CD002967.

2. Charytan DM et al. Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2019 Jan 22. doi: 10.1111/dom.13642.

3. Mirza N et al. Effect of topiramate on acid-base balance: extent, mechanism and effects. Br J Clin Pharmacol. 2009 Nov;68(5):655-61.

4. Ture H et al. The frequency and severity of metabolic acidosis related to topiramate. J Int Med Res. 2016;44(6):1376-80.

5. Würzner G et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60.

6. Puig JG et al. Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens. 1999 Jul;17(7):1033-9.

7. Matsumura K et al. Effect of losartan on serum uric acid in hypertension treated with a diuretic: the COMFORT study. Clin Exp Hypertens. 2015;37(3):192-6.

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