Case series show that hypokalemia following initiation of diuretic therapy occurs in most patients within 2 to 8 weeks. However, no studies are available that adequately predict the risk of this complex and multifactorial condition. Patients taking diuretics should have a potassium level checked in the first 2 to 8 weeks after initiating therapy. Mild hypokalemia (3.1 to 3.4 mmol/L) may be transient, so a repeat measurement may be considered before initiating potassium replacement. Dietary sodium restriction may also help to conserve potassium, because this will decrease urinary flow rate and potassium loss. The frequency with which to check potassium levels should be guided by the patients’ underlying clinical conditions and dietary potassium and sodium intake. (Grade of Recommendation: C, based on case series) The National Council on Potassium in Clinical Practice issued a set of guidelines for potassium replacement in September 2000.1 The authors recommend using thiazide diuretics at a low dose only (eg, 12.5-25 mg of hydrochlorothiazide daily) and adding a potassium-sparing diuretic drug when higher diuretic doses are needed. For patients with asymptomatic hypertension they recommend trying to maintain a serum potassium level of at least 4.0 mmol/L. The University of Iowa Family Practice Handbook2 states: “Maximal decrease in serum K+ concentration is usually seen after 7 days of treatment. Serum K+ concentration should be measured before initiation of a diuretic and 1 week after initiation of increase in dose of the diuretic.” Hypokalemia is defined as a serum potassium level less than 3.5 mmol/L (3.5 mEq/L); hypokalemia at levels between 3.1 and 3.4 mmol/L is considered mild. The incidence of hypokalemia reported for patients on diuretic therapy is broad (7.2% to 56%),3-6 and the time period required to develop hypokalemia varies (1 week6 to >1 year7). Factors including the type of diuretic used, dosage, duration of use, dietary potassium, and so forth, make predicting an individual patient’s progression nearly impossible. Widmer and coworkers5 found that the risk of hypokalemia was greatest with concomitant glucocorticoid use, polypharmacy (greater than 12 medications administered), and female sex. The latter risk factor may be related to a higher dose-to-weight relationship. Lemieux and colleagues8 followed 50 patients receiving a variety of diuretic regimens (hydrochlorothiazide 50 to 100 mg daily or every other day with or without reserpine 0.25 mg daily). Only 3 patients in this group had potassium levels below 3.5 mmol/L, and all decreases were only transient. Peters and coworkers6 documented potassium levels below 3.5 mEq/L in 6 of 19 patients taking hydrochlorothiazide 25 or 50 mg for 20 weeks. Three of these patients normalized without therapy. One of these transiently hypokalemic patients was also taking triamterene, a potassium-sparing diuretic. Potassium-sparing diuretics may not free the clinician from checking a potassium level, however. Penhall and coworkers9 found hypokalemia in 24 of 54 patients receiving a fixed-combination diuretic (hydrochlorothiazide 50 mg and potassium-sparing amiloride 5 mg). Note that the dose of hydrochlorothiazide was higher in this study than is generally used today. Most recent studies have found that hydrochlorothiazide in doses above 12.5 to 25 mg do not result in significantly lower blood pressure and only lead to more electrolyte abnormalities.10 Morgan and Davidson11 performed an analysis of the published data available in 1980. They found that the average fall in potassium is less for patients taking furosemide (0.3mmol/L) than on thiazide diuretics (0.6mmol/L) and that this fall was only slightly influenced by dose or duration of treatment. Allen F. Shaughnessy, PharmD Few hypertensive patients started on low-dose diuretics will become hypokalemic, and most of those who do will have serum levels greater than or equal to 3.0 mEq/L. In patients with heart failure or renal disease, potassium should be monitored shortly after the initiation of a diuretic because of potentially more rapid electrolyte and fluid shifts. However, many of these patients will also be taking an ACE inhibitor or spironolactone: 2 drugs that may increase serum potassium levels. In the absence of heart failure or renal disease checking a potassium level a month or so following initiation, as recommended by this review, seems reasonable. Triamterene is a medication used in the management and treatment of edematous states. It is in the potassium-sparing diuretics class of drugs. This activity outlines the indications, action, and contraindications for triamterene as a valuable agent in managing fluid retaining states and hypertension. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the management of patients with edematous states and associated conditions. Objectives:
Triamterene is a potassium-sparing diuretic that has been in use since 1964. Triamterene is used by physicians who treat patients with fluid retention states secondary to conditions such as congestive heart failure, nephrotic kidney disease, liver cirrhosis, secondary hyperaldosteronism, or even merely idiopathic edema; all of which are FDA approved indications.[1] When giving triamterene in the combination dosage form with hydrochlorothiazide, other FDA-approved indications of use include the management of hypertension or the treatment of edema in patients who develop hypokalemia secondary to hydrochlorothiazide monotherapy.[2] Of note, the use of triamterene can also be indicated for overcoming diuretic resistance in patients on only one full dose of a diuretic; by combining two types of diuretics such as triamterene with a loop diuretic, a diuretic synergism would successfully overcome the resistance and achieve the desired reduction in edema.[3] Among the potassium-sparing diuretics, triamterene was the second drug of this class to be FDA approved for use in the US following spironolactone. However, despite these two drugs being within the same class and achieving the same desired result, they have two distinct mechanisms of action. While spironolactone is an aldosterone receptor antagonist operating at the late distal tubule and collecting tubules of the nephron on the apical aspect of these sites, triamterene acts at the same region of the nephrons but specifically at the epithelial sodium channels (ENaC), which are on the luminal side. These channels are transmembrane channels that operate to increase sodium uptake in exchange for secreting potassium.[4] After the ENaC actively reabsorbs the sodium from the lumen of the nephron into the principal cells of the collecting tubule, the sodium is then transported out of the cell into the interstitium via a sodium-potassium exchange pump.[5] All this collective reabsorption of sodium out of the nephron and kidney back into the interstitium naturally causes water to passively follow suit in the pursuit of osmoregulation with sodium, creating a net gain of fluid retention. When triamterene is introduced to the ENaC, it inhibits this channel and thus exerts a strong diuretic and a limited natriuretic effect in the distal renal tubule and collecting tubule, decreasing the reabsorption of sodium for potassium and, as a result, effectively decreasing the passive reabsorption of water. Essentially, the action of triamterene is indirectly antagonistic to the role of aldosterone, an adrenal mineralocorticoid, but it is not a direct antagonist of aldosterone itself like the drug spironolactone is. Triamterene is administered only orally and can be administered either as a monotherapy or as a combination therapy, depending on the indication. It is available as a capsule in either a 50 mg or 100 mg cap as a monotherapy. In an adult patient with peripheral edema, 100 mg orally bid would be given with the max dose being 300 mg/day. In combination with hydrochlorothiazide, it is also available as a capsule; the dosage is 37.5 mg of triamterene with 25 mg of hydrochlorothiazide. For the treatment of patients with hypertension or peripheral edema, 1 to 2 caps PO daily would be prescribed. For the treatment of a patient with hypertension or peripheral edema, one tab orally each day would be prescribed. The major side effects of triamterene include dizziness, fatigue, headache, dry mouth, hyperkalemia, and dehydration.[1] Other common side effects include nausea, vomiting, rash, diarrhea, muscle cramps, weakness, xerostomia, azotemia, and hyperuricemia. Serious adverse effects include anaphylaxis, ventricular arrhythmias, hyperkalemia, drug-induced interstitial nephritis, acute renal failure due to nephrotoxicity, thrombocytopenia, megaloblastic anemia, and hepatotoxicity. Triamterene can also cause triamterene nephrolithiasis in patients with a history of previous kidney stones; these patients should avoid this drug.[6] Urolithiasis may also occur as a result of triamterene use.[7] Drug hypersensitivity is a common side effect to be aware of; this can co-occur with acute hepatic injury, rash, drug fever, and jaundice.[8] There are also several patient populations to be cautious in using this drug; these populations include the use of this drug in patients 65 years and older, in patients with diabetes mellitus, congestive heart failure, gout, patients on sodium restriction, and women that are breastfeeding.[9] Triamterene is most often given in combination with hydrochlorothiazide, and thus more contraindications exist due to the combination of these drugs. Contraindications include hyperkalemia, pregnancy, severe hepatic impairment, severe renal impairment, metabolic or respiratory acidosis, acute myopia, and secondary angle-closure glaucoma. For patients using triamterene, it is essential to monitor specific labs and blood pressure of patients taking this drug in either its sole or combination form with HCTZ. BUN/creatinine, blood pressure, urine output, serum uric acid, CBC, and electrolytes, in particular serum potassium, should be monitored at a baseline when first placed on the drug. Once findings indicate establishing a stable tolerance of the drug, it can be periodically monitored, specifically when dose changes are made and during illnesses. Potassium-sparing diuretics overdose is relatively rare, and there are no reports of deaths. With mild to moderate toxicity, there can be the development of nausea, vomiting, diarrhea, mild dehydration, and hyperkalemia. If there is severe toxicity, there can be the development of severe dehydration coupled with hyperkalemia, which may lead to dysrhythmias, tachycardia, hypotension, hyperactive deep tendon reflexes, and possibly changes in mental status. Acute renal failure may also develop due to the deposition of triamterene in the renal tubules.[10] Should there be any signs of toxicity, the clinician should immediately discontinue the drug. Patients taking triamterene or the combination form of triamterene/HCTZ should have close follow up with primary care physicians caring for them. Clinicians and other interprofessional healthcare team members should educate patients on possible side effects or adverse effects that the patient could experience while beginning treatment or having a dose change, having the patient be on the lookout for potential issues with the use of the drug. In the in-patient setting, hospitalists should be prudent to contact the patient's primary care physicians or pharmacies to obtain a history of the patient's adherence and tolerance to the medication. Collaborative decision-making between physicians, patients, pharmacists, and nurses, operating as an interprofessional team, is vital for creating the most effective outcomes and decreasing the likelihood of nonadherence.[11] Review Questions1. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Oct 13, 2021. Triamterene. [PubMed: 31643196] 2.Tu W, Decker BS, He Z, Erdel BL, Eckert GJ, Hellman RN, Murray MD, Oates JA, Pratt JH. Triamterene Enhances the Blood Pressure Lowering Effect of Hydrochlorothiazide in Patients with Hypertension. J Gen Intern Med. 2016 Jan;31(1):30-6. [PMC free article: PMC4700022] [PubMed: 26194642] 3.Hoorn EJ, Ellison DH. Diuretic Resistance. Am J Kidney Dis. 2017 Jan;69(1):136-142. [PMC free article: PMC5182087] [PubMed: 27814935] 4.Knauf H, Wais U, Albiez G, Lübcke R. [Inhibition of the exchange of Na+ for K+ and and H+ by triamterene (in epithelia)(author's transl)]. Arzneimittelforschung. 1976 Apr;26(4):484-6. [PubMed: 133688] 5.Horisberger JD, Giebisch G. Potassium-sparing diuretics. Ren Physiol. 1987;10(3-4):198-220. [PubMed: 2455308] 6.Ettinger B, Oldroyd NO, Sörgel F. Triamterene nephrolithiasis. JAMA. 1980 Nov 28;244(21):2443-5. [PubMed: 7431573] 7.Thürmann PA. [Influence of drugs on urological diseases]. Urologe A. 2016 Mar;55(3):401-9; quiz 410-1. [PubMed: 26908119] 8.Nolan PJ, D'Arcy G. Triamterene drug fever and hepatitis. Med J Aust. 1987 Sep 07;147(5):262. [PubMed: 3670184] 9.Drugs and Lactation Database (LactMed) [Internet]. National Library of Medicine (US); Bethesda (MD): 2006. Triamterene. [PubMed: 30000336] 10.Nasr SH, Milliner DS, Wooldridge TD, Sethi S. Triamterene crystalline nephropathy. Am J Kidney Dis. 2014 Jan;63(1):148-52. [PubMed: 23958399] 11.Corrêa NB, de Faria AP, Ritter AM, Sabbatini AR, Almeida A, Brunelli V, Calhoun DA, Moreno H, Modolo R. A practical approach for measurement of antihypertensive medication adherence in patients with resistant hypertension. J Am Soc Hypertens. 2016 Jun;10(6):510-516.e1. [PubMed: 27161936] |
Which drug would the nurse expect to be prescribed for a patient taking hydrochlorothiazide who develops hypokalemia?
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