Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Emerging

Effect and Mechanism of Action

Albuterol, administered by IM, IV, and SC routes, is associated with decreased levels of serum/plasma potassium, as well as of calcium, magnesium, and phosphate. ⁸

Research

In an experiment investigating nontherapeutic metabolic and cardiovascular effects of therapeutic doses of beta-2-adrenoceptor agonists, Phillips et al. ⁹ administered IV infusions of salbutamol (albuterol) and rimiterol to four healthy male subjects. In response to “equivalent molar amounts of salbutamol and rimiterol,” they observed “dose-related decreases in plasma potassium, phosphate and corticosteroids” as well as “significant” hypocalcemia, hypomagnesemia, hyperlactatemia, and ketonemia and dose-related increases in plasma glucose, renin activity, serum insulin, and heart rate. They noted that with either drug, “special care is required for patients who may have abnormal glucose tolerance, potassium depletion, or be predisposed to lactic acidosis,” and suggested that rimiterol “may be preferable for infusion because of its short plasma half-life.” ⁹ Spector ⁸ reported that “beta adrenergic agonists can lower serum potassium levels predominantly when they are administered by the parenteral route.” In particular he noted that dose-related hypokalemia has been demonstrated with albuterol given by the IM, IV, and SC routes, as well as with SC epinephrine. He further cautioned that comedication with agents such as corticosteroids, theophylline, diuretics, and digoxin could exacerbate potassium status and recommended further research into the “hypokalemic effect of all forms of beta agonists in view of their possible contribution toward arrhythmias and asthma deaths.” ⁸ Subsequently, in a study of the effects of oral albuterol on serum and skeletal levels of digoxin in four healthy subjects, Edner and Jogestrand ¹⁰ observed a parallel reduction in the serum potassium concentration (0.58 mmol/L) and serum digoxin concentration, compared with control measurements.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The possibility of adverse effects on potassium status from albuterol, rimiterol, or related beta-2-adrenergic bronchodilators has been consistently demonstrated, but evidence is lacking as to the frequency of this effect or the efficacy of interventions to prevent or diminish it. The observed adverse effects on potassium levels are less likely to occur with use of albuterol via oral inhalation, the most common form of administration, particularly with occasional application in acute episodes. Clinical trials are warranted to determine the clinical significance of these effects of albuterol on potassium status and whether supportive coadministration of potassium and other minerals is safe and efficacious, as well as the comparative effects of food versus supplemental/prescribed sources. Pending substantive research findings, physicians prescribing albuterol, particularly those administering it parenterally, are advised to monitor potassium levels and consider potassium coadministration if indicated by direct findings or other factors associated with increased risk.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Consensus

Effect and Mechanism of Action

Amiloride hydrochloride is an antikaliuretic-diuretic agent, which as a pyrazine-carbonyl-guanidine is unrelated chemically to other diuretics, including potassium-sparing agents. Because of its intended action of reducing urinary excretion of potassium, amiloride can produce a state of inappropriately elevated potassium levels, especially with concomitant angiotensin-converting enzyme (ACE) inhibitor therapy. ^11,12 Further, exogenous sources of potassium, including potassium-rich foods such as fruit or food seasoning containing potassium chloride, can contribute to potassium accumulation in the presence of amiloride. Except for hyperkalemia (serum potassium levels >5.5 mEq/L), amiloride is generally thought to be well tolerated, and reports of significant adverse effects are infrequent.

Research and Reports

Published research is lacking, and case reports of hyperkalemia are generally uncirculated because this interaction is considered axiomatic, and coadministration is always accompanied by cautions of inherent risk.

• Note:

  As a result of its potassium-sparing activity, amiloride is often prescribed in conjunction with medications, such as thiazides and amphotericin B, that cause electrolyte disturbances, especially potassium wasting, to mitigate these potentially dangerous adverse effects. These patterns of compensatory coadministration are discussed in the context of the respective medication(s) involved.

Clinical Implications and Adaptations

Amiloride is often prescribed because of demonstrated hypokalemia, but the risk of hyperkalemia warrants frequent monitoring when an ACE inhibitor and amiloride are administered concomitantly. Patient education is critical because potassium-rich foods are generally considered desirable for individuals wanting to enhance their cardiovascular health, and salt substitutes may be misconstrued as appropriate. Thus, despite good intentions, consuming even several pieces of fruit per day can be problematic for some individuals in the context of potassium-sparing agents such as amiloride. Regular monitoring and highly specific and practical dietary counseling are essential, with patients having even mildly compromised renal function at greatest risk.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Consensus

Effect and Mechanism of Action

Hypokalemia, as well as hypocalcemia, hypomagnesemia, and alkalosis, is a predictable outcome of renal tubular damage from aminoglycosides. Moreover, gentamicin-induced renal failure is potentiated by potassium depletion. Potassium administration may reduce the sequelae of aminoglycoside-induced hypokalemia but introduces significant risks in at-risk patient populations.

Research and Reports

Renal tubular damage is a well-established toxic effect of aminoglycosides, such as gentamicin, which has been demonstrated in animal studies and described in case reports. Clinically significant depletion of potassium (and magnesium) or other metabolic disturbances are assumed to be uncommon complications but are more likely to occur in elderly patients administered large doses over extended periods. ^13-17 Findings from clinical trials specifically investigating coadministration of potassium, alone or with synergistic nutrients, in the prevention or treatment of aminoglycoside toxicity are lacking in the published literature.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing aminoglycosides on a chronic or repeated basis are advised to monitor closely for depletion of potassium and magnesium and other metabolic disturbances resulting from renal tubular damage and to consider prophylactic or compensatory nutritional support for such individuals. Serum creatinine, blood urea nitrogen (BUN), and creatinine clearance should be measured before initiating therapy and should be monitored throughout treatment, along with serum potassium and magnesium levels. Only after such assessment should increased intake of potassium (from dietary or supplemental sources) be undertaken, and then only under close supervision.

Enhancing potassium levels in response to potential compromise by aminoglycosides may be necessary and appropriate but needs to be approached with caution and care. Potassium levels can most easily be increased through consumption of several pieces of fruit each day. Slow-K, Micro-K, and K-dur are typical examples of the potassium preparations prescribed by physicians. However, increasing potassium intake by any means is usually contraindicated and often dangerous in patients with reduced kidney function, especially those on dialysis. Magnesium may also be appropriate for its general role in cardiovascular health; its tendency to be depleted by aminoglycosides, other drugs, and their adverse effects; and its role in maintaining intracellular potassium. Similar precautions regarding renal function apply to magnesium as well as potassium.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Emerging

Effect and Mechanism of Action

Amphotericin B is a macrocyclic antifungal agent, similar in structure to nystatin, administered both systemically and topically for fungal infections. Amphotericin B is well known for inducing electrolyte disturbances. In particular, hypokalemia and potassium depletion (as well as magnesium wasting) are frequent complications of amphotericin B therapy, especially when combined with oral corticosteroids. ^18,19 Moreover, potassium depletion appears to potentiate amphotericin B–induced toxicity to renal tubules. ²⁰

Hyperkalemia from rapid infusion or high doses in renally compromised patients is also possible, with attendant risks and adverse effects.

Research

Early research demonstrated reversible concentration-dependent loss of intracellular potassium in vitro and hyperkalemic ventricular arrhythmias in dogs. ^21-26 Craven and Gremillion ²⁷ reported two episodes of ventricular fibrillation with progressive hyperkalemia (up to 8-8.4 mEq/L) in an anuric patient during rapid infusion of high-dose amphotericin B (1.4 mg/kg over 45 minutes). They subsequently conducted animal experiments investigating risk factors of ventricular fibrillation during rapid amphotericin B infusion. First, they noted that prolonged infusion (≥3 hours) and concurrent hemodialysis “each prevented the development of hyperkalemia and ventricular arrhythmia.” Thus, in trials involving two anuric patients receiving 4-hour infusions of amphotericin B during dialysis (0.7 and 1.0 mg/kg), they observed that peak amphotericin B concentrations in serum were lower and that serum potassium levels were maintained in the normal range. Likewise, in eight patients with normal renal function who received lower doses (0.7 ± 0.2 mg/kg) over 45 minutes, peak concentrations of amphotericin B in serum were also lower, with only slight increases in the serum potassium level. The authors thus recommended that “rapid infusion of amphotericin B not be used in patients with impaired potassium excretion unless accompanied by hemodialysis and careful potassium monitoring.” ²⁷

Findings from a rodent study conducted by Bernardo et al. ²⁰ suggest that “potassium depletion does not influence the acute renovascular effects of amphotericin B but potentiates its [renal] tubular toxicity.”

Although substantive evidence is minimal, in some cases amiloride is combined with amphotericin B to prevent or mitigate the adverse effects of amphotericin B–induced hypokalemia and hypomagnesemia, especially in patients at high risk for complications resulting from these electrolyte disorders. ²⁸ Other potassium-sparing agents might provide similar activity, but research is lacking.

Limited clinical research indicates the importance of regulating potassium, preventively or in response to observed hypokalemia, using amiloride and potassium coadministration. In a randomized clinical trial involving 20 neutropenic patients with various hematological disorders, Smith et al. ²⁹ compared the prophylactic use of oral amiloride, 5 mg twice daily, concomitantly with IV amphotericin B (vs. amphotericin B alone) and demonstrated a decrease in potassium wasting. “Patients receiving amiloride had a significantly higher plasma potassium (p <.01), a significantly lower urinary potassium loss (p <.01), and required significantly less potassium chloride supplementation to maintain their plasma potassium within the normal range.” ²⁹ Subsequently, Bearden and Muncey ³⁰ investigated the effect of amiloride (5-10 mg twice daily for 14.7 ± 12.6 days) in 19 oncology patients exhibiting marked electrolyte wasting from amphotericin B at 0.67 ± 0.30 mg/kg for a mean of 21.9 days (range, 7-57 days). They found that mean serum potassium concentrations increased in the 5 days before and after administration and reported a trend toward decreased potassium supplementation. Notably, these researchers adopted a more conservative approach than that of Smith et al., ²⁹ in that “amiloride was added to amphotericin B treatment only when patients began to exhibit excessive potassium requirements.” Nevertheless, they concluded: “Early utilization of amiloride may be considered in patients with underlying risk factors for hypokalaemia (i.e., leukaemia, cisplatin use, diuretics) in whom a prolonged course of amphotericin is anticipated…. This retrospective study suggests that amiloride may benefit patients by decreasing total potassium requirements and supplementation, as well as increasing serum potassium concentrations.” They also cautioned that the “addition of another medication to a patient population receiving multidrug therapy is not recommended in all instances, and should be considered on a case-by-case basis.” ³⁰

Pasic et al. ³¹ studied the safety and efficacy of liposomal amphotericin B (mean daily dose, 5 mg/kg; 2-6 mg/kg) in 15 pediatric patients receiving bone marrow transplants for primary immunodeficiency (PID). Of these, four developed mild hypokalemia, which resolved with increased potassium administration.

Reports

Hypokalemia is a frequently reported adverse effect of amphotericin B therapy, but hypokalemia-associated rhabdomyolysis tends to be a rare occurrence. Da Silva et al. ³² reported on a 10-year-old boy with hypokalemic rhabdomyolysis in the lower extremities after 1 week of amphotericin B therapy. Initial laboratory tests revealed a “serum potassium of 1.7 mEq/L and a serum creatinine phosphokinase of 3937 U/L plus myoglobulinuria.” The patient “progressed to achieve full regression of muscular weakness after one week” after fluid expansion and IV potassium replacement.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians administering amphotericin B, whether in standard or liposomal form, are advised to be watchful for electrolyte disturbances, particularly depletion of potassium and magnesium. Such events are common and can be predicted in many patients, especially with extended or repeated amphotericin therapy. Amphotericin is almost always administered in inpatient hospital settings. Careful and frequent monitoring of serum electrolytes is required in all patients. Coadministration of potassium and possibly magnesium as a preventive, or at least reactive, measure is fundamental to comprehensive and judicious care, particularly in patients at high risk for potassium depletion. Amiloride is sometimes coadministered during amphotericin B therapy to decrease potassium wasting and can be considered a therapeutic option. It is noteworthy that amphotericin-induced potassium depletion can cause serious complications through its secondary effects on other medication, such as a potential increase in digitalis toxicity.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Consensus

Effect and Mechanism of Action

The ACE inhibitors can increase serum levels of potassium in certain individuals, particularly those with diabetes or compromised renal function. ^33-35 The increased levels of intracellular potassium and magnesium associated with ACE inhibitor therapy may be an important mechanism by which ACE inhibitors reduce arrhythmias. ^36-38 Some ACE inhibitors, such as enalapril, can significantly inhibit plasma aldosterone concentration and urinary excretion of aldosterone. ³⁹ In general, these effects appear to be similar for long-acting ACE inhibitors such as enalapril and short-acting ACE inhibitors such as captopril.

The concomitant use of potassium with an ACE inhibitor drug increases the risk of hyperkalemia, especially with rapid introduction. ¹² Potassium levels may become further elevated with simultaneous use of potassium-sparing diuretics, potassium-based salt substitutes, very-low-calorie diets, and NSAIDs (which reduce renal excretion of ACE inhibitors). ^40-42 All these risks are amplified in the context of renal insufficiency.

Research

The concomitant use of ACE inhibitor and potassium-sparing diuretic therapy is a contraindication rather than a potassium interaction; in such cases, both potassium and potassium-sparing medications should be avoided. For example, Burnakis and Mioduch ⁴³ noted the significant risk of hyperkalemia in patients receiving combined therapy with captopril and potassium. Chiu et al. ¹² conducted a retrospective chart review of five patients, all with diabetes and older than 50, who were seen for hyperkalemia in emergency care after having amiloride HCl/hydrochlorothiazide added to an ACE inhibitor drug regimen 8 to 18 days before presenting. They stated that these findings “highlight the dangers of a precipitous rise in serum potassium levels in patients at risk for renal insufficiency, already receiving an angiotensin-converting enzyme (ACE) inhibitor, who are given a potassium-sparing diuretic.”

Ohya et al. ³⁹ administered enalapril (5 mg once daily) and captopril (12.5 mg three times daily) to 11 patients with mild essential hypertension and normal renal function for 1 week each in a crossover design, to compare effects of long-acting (enalapril) and short-acting (captopril) ACE inhibitors on serum electrolytes and circadian rhythm of urinary electrolyte excretion in relation to aldosterone status. Both agents “significantly decreased urinary K excretion” while “not significantly alter[ing] serum K level.” Notably, the amplitude of urinary K excretion was decreased by both drugs, although the circadian rhythm (acrophase) was not affected by either drug. Both enalapril and captopril “significantly reduced blood pressure” (to a similar degree) while enalapril, but not captopril, “significantly inhibited plasma aldosterone concentration and urinary aldosterone excretion.” Thus, although the primary finding of this trial was that “enalapril caused more sustained inhibition of aldosterone secretion” than captopril, they also noted that “both drugs showed similar effects on the K homeostasis in patients with mild essential hypertension.” ³⁹

Nevertheless, the effects of ACE inhibitor therapy on potassium and magnesium may play an important role in their therapeutic effect. O’Keeffe et al. ³⁶ investigated the effect of captopril therapy on lymphocyte potassium and magnesium concentrations in patients with congestive heart failure (CHF). They compared lymphocyte potassium and magnesium in 18 patients taking furosemide and potassium for CHF before and 3 months after the introduction of captopril to 32 healthy controls. Nine of the treatment subjects exhibited decreased baseline lymphocyte magnesium and potassium concentrations, despite similar plasma electrolyte levels. Notably, there was a “significant increase in both lymphocyte potassium and magnesium levels” after 3 months’ treatment with captopril and furosemide in these patients. Furthermore, nine patients “who had been taking a potassium-sparing combination diuretic also had an increase in lymphocyte magnesium” after the introduction of captopril. These authors concluded that “increased intracellular potassium and magnesium may be one mechanism whereby [ACE] inhibitors reduced arrhythmias and improve survival” in CHF patients. ³⁶ In contrast, however, some of these same researchers subsequently examined the effect of 6 months’ captopril (or nifedipine) therapy on lymphocyte magnesium and potassium levels in 28 patients treated for hypertension. They observed “no difference in serum or lymphocyte concentrations in the two groups compared to 45 healthy, normotensive controls.” ³⁷

Overall, as summarized by Shionoiri ⁴¹ in a review of pharmacokinetic drug interactions involving ACE inhibitors (1993): “When ACE inhibitors are given, hyperkalaemia may occur in patients with renal insufficiency, those taking potassium supplements or potassium-sparing diuretics, and in diabetic patients with mild renal impairment.”

Reports

Numerous case reports have been published describing hyperkalemia in patients undergoing ACE inhibitor therapy. ^35,44-46 Stoltz and Andrews ⁴⁰ described severe hyperkalemia during very-low-calorie diets and ACE inhibitor use. Ray et al. ⁴² reported two cases of severe hyperkalemia resulting from the concomitant use of salt substitutes (KCl) in hypertensive patients taking ACE inhibitors, in what they warned was “a potentially life threatening interaction.” Serum potassium stabilized in the normal range after cessation of the salt substitute in each case. The authors concluded that “without vigilance the contribution of the salt substitute to hyperkalaemia would have been overlooked and an ACE inhibitor erroneously withdrawn.” ⁴²

Clinical Implications and Adaptations

Health care professionals treating patients taking an ACE inhibitor are strongly encouraged to counsel these individuals to avoid unsupervised increases in potassium intake, in the form of supplements but also as high-potassium foods (e.g., fruit) or salt substitutes, on the basis of the increased risk for problematic reactions. A clinically significant increase in blood potassium levels represents an uncommon yet potentially serious adverse effect associated with ACE inhibitors. The importance of frank inquiry and detailed inventory of concomitant (or even occasional) medications, diet, nutrients and herbs cannot be overemphasized. Close supervision and regular monitoring are essential, particularly in individuals with compromised renal function. The prescription of potassium chloride or potassium-sparing medications is generally contraindicated during ACE inhibitor therapy.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid

Preliminary

Effect and Mechanism of Action

Nonselective beta blockers inhibit both beta-1-adrenergic and beta-2-adrenergic receptors. Carvedilol, celiprolol, and labetalol exhibit mixed antagonism of both beta-adrenergic and alpha-1-adrenergic receptors.

In general, beta-adrenergic blockers can cause moderate increase in serum potassium concentrations and may lead to hyperkalemia. Beta-adrenergic blockade can enhance the rise and prolong the elevation in serum potassium without decreasing urinary potassium excretion. ⁴⁷ “Beta-adrenergic mechanisms seem to be concerned in the extrarenal handling of the potassium-load,” and beta blockade in humans can particularly impair extrarenal disposal of an acute potassium load. ^47,48 This increase “cannot be explained by the retention of potassium in the organism, and is probably caused by the redistribution of potassium from intracellular to extracellular compartments.” Further, the action inhibited by beta-blockade appears to function “presumably by inducing an increased uptake of potassium in muscular cells and liver cells” through beta-adrenergic mechanisms that are “probably of the beta 2-type.”

Research

In contrast to beta-adrenergic agonists, which are often used to treat acute hyperkalemia, beta blockers can cause profound elevations of serum potassium. In an experiment involving nine healthy subjects, Rosa et al. ⁴⁷ investigated the role of catecholamines in the regulation of potassium homeostasis by administering IV potassium chloride (0.5 mEq/kg) in the presence and absence of propranolol. The initial potassium infusion elevated serum potassium by 0.6 ± 0.09 mEq/L, and the addition of propranolol “augmented the rise (0.9 ± 0.05 mEq per liter) and prolonged the elevation in serum potassium without decreasing urinary potassium excretion.” The authors concluded that “Beta-adrenergic blockade impairs … extrarenal disposal of potassium load” and that such findings “suggest that in patients with impaired potassium disposal, the risk of hyperkalemia may be increased when sympathetic blockade is induced.” ⁴⁷

In a review (1983) of the effect of adrenergic blockade on potassium concentrations in different conditions, Lundborg ⁴⁸ cautioned that in theory “there are several conditions in which it is important to have a defence against hyperkalaemia from exogenous or endogenous sources, for example, during heavy physical exercise, after a potassium-rich meal, or after traumatic tissue damage.” He concluded: “Available data indicate that non-selective beta-blockade increases serum potassium concentrations during and after heavy exercise and during coronary bypass.”

Reports

Arthur and Greenberg ⁴⁹ described the cases of three renal transplant recipients who “developed potentially life-threatening hyperkalemia” after IV administration of labetalol for postoperative hypertension.

Clinical Implications and Adaptations

Physicians prescribing beta-adrenergic blockers are advised to caution patients to avoid potassium in supplements, medications, and salt substitutes. Moreover, eating large servings of fruit rich in potassium, such as bananas, is generally contraindicated without prior discussion and ongoing monitoring. Nevertheless, enhanced potassium intake may be appropriate in certain patients comedicated with potassium-depleting diuretics or after an episode of vomiting or diarrhea. Close supervision and regular monitoring of potassium levels and other relevant clinical parameters are essential, especially with changes in medication regimens, diet, and intake of natural agents such as herbs or nutrients. Again, as noted by Lundborg, ⁴⁸ the risk of hyperkalemia is increased after heavy physical exercise, a potassium-rich meal, or traumatic tissue damage, all of which may cause a rapid elevation in circulating potassium levels, which can be exacerbated in patients taking beta-blocker medications.

See Licorice in Herb-Nutrient Interactions.

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Mixed

Effect and Mechanism of Action

The enzyme carbonic anhydrase catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid with attendant potassium loss. Agents with diverse mechanisms act as carbonic anhydrase inhibitors in the treatment of a variety of conditions, most of which involve fluid regulation, including those involving intraocular pressure. For example, acetazolamide achieves alkalinization of the urine and promotion of diuresis through its action on this reversible hydration-dehydration reaction in the kidneys and resultant renal loss of bicarbonate (HCO ^{3 −} ), along with sodium, water, and potassium. In high doses, all carbonic anhydrase inhibitors cause some decrease in renal blood flow and glomerular filtration rate. In general, with the exception of specific agents such as furosemide (which is also a loop diuretic) and acetazolamide, methazolamide and most other drugs in this class tend to have a weak and transient diuretic effect and are not used as systemic diuretics.

Research

Clinical trials investigating the systemic effect of carbonic anhydrase inhibitors on potassium status are lacking. Although acetazolamide is used for its diuretic action in the treatment and prevention of high-altitude pulmonary edema, and furosemide is well known as a loop diuretic, most agents in this class are used in the treatment of ocular conditions such as glaucoma. Consequently, the limited available data indicate that in most cases the degree of potassium loss is unlikely to be of clinical significance, even with chronic administration, barring other dominant influences or confounding factors.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing carbonic anhydrase inhibitors, with the significant exceptions of furosemide and acetazolamide for systemic cardiovascular conditions, can generally assume that adverse effects on potassium status are improbable in most patients not taking other potassium-depleting medications or otherwise compromised. As a cautionary suggestion, and for the benefit of overall nutritional status, health care professionals can reiterate support for the healthful practice of regularly consuming plentiful fresh fruits and vegetables and decreasing intake of salt (specifically sodium) and processed foods. Monitoring is important because excessive alkalinization of the urine and metabolic acidosis (resulting from decreases in plasma bicarbonate) may lead to a disequilibrium in carbon dioxide transport in the erythrocytes.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Bimodal or Variable Interaction, with Professional Management
	Minimal to Mild Adverse Interaction—Vigilance Necessary

Emerging to Consensus

Effect and Mechanism of Action

Cisplatin can induce renal functional damage and cause chronic tubulopathy, characterized by magnesium and potassium wasting, reduced calcium excretion, metabolic alkalosis, and a strong tendency to hypomagnesemia and hypokalemia. In this common complication an unrecognized and untreated magnesium depletion can lead to a potassium depletion that is refractory to repletion with potassium alone. ⁵⁰ The resulting hypokalemia can be corrected only with concomitant administration of magnesium with potassium. ⁵¹ Thus, this interaction demonstrates the critical role that magnesium plays in maintaining intracellular potassium.

Cisplatin and related chemotherapeutic agents cause renal toxicity to varying degrees. Coadministration of potassium, magnesium, or other nutrients adversely affected by these drugs is constrained by compromised urinary excretion and may be contraindicated in some patients with borderline renal function.

Research

Limited but consistent research findings parallel and confirm clinically based consensus regarding the effects of cisplatin in depleting potassium. Buckley et al. ⁵² documented hypomagnesemia in 66 patients receiving a five-drug combination chemotherapy regimen containing low-dose cisplatin. They observed that 38 (76%) of 50 patients receiving treatment every 4 weeks became hypomagnesemic during treatment, and that the incidence increased with the cumulative cisplatin dose, ranging from 41% after a single course to all patients receiving six cycles of therapy. Notably, patients receiving the combination at a longer interval (8 vs. 4 weeks) between cycles exhibited a lower incidence. The authors thus reported that the incidence and severity of hypomagnesemia was dose dependent. They also noted that the higher incidence of hypomagnesemia observed in this study might be related to an interaction of cisplatin with one or more of the drugs in the combined regimen. ⁵² Bianchetti et al. ⁵³ studied renotubular handling of potassium, sodium, calcium, phosphate, hydrogen ions and glucose, and urinary concentrating ability in three children (age 8-11 years) with renal magnesium loss, persisting for longer than 2 years after discontinuation of cisplatin treatment for neuroblastoma, and compared these findings with group of healthy children serving as controls. Apart from renal magnesium wasting, there was a clear tendency toward reduced calciuria associated with normal or slightly elevated plasma calcium, and plasma potassium levels “tended to be low” (3.4-3.7 mmol/L). Plasma chloride was normal, and plasma “creatinine levels, glucosuria and phosphaturia, and urinary concentrating capacity were adequate.” They noted that overall patterns in these children were similar to those observed in three children (age 4½-13 years) with primary renotubular hypomagnesemia-hypokalemia and hypocalciuria. Thus, the authors concluded that “cisplatin may induce renal functional damage identical to that found in primary renotubular hypomagnesaemia-hypokalaemia with hypocalciuria.” ⁵³

Reports

Rodriguez et al. ⁵⁰ described “two patients with hypomagnesemia-associated refractory hypokalemia following cisplatin therapy.” They found that potassium administration failed to correct the potassium deficit and “profound hypokalemia persisted until hypomagnesemia was recognized and corrected” after the eleventh and ninth days, respectively. Based on these clinical experiences, the authors recommended that “both serum K ion and Mg levels should routinely be assessed in patients who require cisplatin therapy.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians administering cisplatin will want to monitor electrolyte status closely and will usually need to coadminister a wide range of nutrients, including potassium, to mitigate adverse effects and optimize therapeutic outcome. In clinical practice, adverse effects on potassium status are considered a certainty with cisplatin. Carboplatin has considerably less renal toxicity (but more marrow suppression), and oxaliplatin also has less renal toxicity but more neurotoxicity. Given the high probability of renal damage with these agents, regular monitoring of renal function is obligatory, and nutrient administration can proceed only within the constraints of such systemic limitations, particularly resultant compromise of urinary excretion of potassium and magnesium. Thus, many oncologists treating with standard-dose cisplatin routinely include potassium and magnesium in the pre/post–IV hydration fluid.

In a review of the relationship between magnesium deficiency and potassium depletion refractory to repletion, Whang et al. ⁵¹ concluded by recommending that “(1) serum Mg be routinely assessed in any patients in whom serum electrolytes are necessary for clinical management and (2) until serum Mg is routinely performed, consideration should be given to treating hypokalemic patients with both Mg as well as K to avoid the problem of refractory K repletion due to coexisting Mg deficiency.”

Further research may be warranted to determine factors influencing degree of risk and adverse effects among patients treated with cisplatin and to develop clinical guidelines for integrative therapeutics incorporating nutritional support.

Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management

Consensus , though Preliminary

Effect and Mechanism of Action

Colchicine can impair absorption of potassium (and other nutrients) and may increase potassium loss (as well as loss of other minerals, e.g., calcium and magnesium). ^54,55 Depletion can be prevented or corrected with nutrient coadministration.

Research

For decades, colchicine has been widely viewed as likely to cause potassium loss. ⁵⁴ However, clinical trials specifically investigating and confirming this adverse effect are lacking.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing colchicine, especially for an extended period and in patients at greater risk for overall compromised nutritional status, are advised to monitor for imbalances and depletions in potassium and other nutrients. Colchicine is a potent anti-inflammatory often used as therapy in acute attacks of gout, which carries significant toxicity. It is sometimes used on a more chronic basis for rare disorders such as familial Mediterranean fever. Conservative practice also suggests consideration of preventive or corrective coadministration of potassium, as well as magnesium, calcium, and beta-carotene. Vitamin B ¹² may also be indicated if neuropathies develop. Dietary changes, especially restricting purine intake and reducing alcohol consumption, as well as adding cherry juice, can also be therapeutic in the treatment of individuals with gout.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Emerging

Effect and Mechanism of Action

Oral corticosteroids increase urinary excretion of potassium and can cause hypolkalemia. ^56-58 The mineralocorticoid action of cortisol causes a decrease in serum potassium concentration, together with stimulation of intestinal sodium absorption and an increase in serum sodium concentration, the combination of which can lead to water retention, weight gain, and increased risk of hypertension. Although used for its mineralocorticoid effects, fludrocortisone is classified as a glucocorticoid and an aldosterone agonist with physiological effects similar to but more potent than hydrocortisone. In general, these adverse effects vary with agent, dosage, duration, and comedications.

Potassium depletion may contribute to the mineralocorticoid-induced sodium retention. Conversely, potassium administration can augment urinary sodium excretion, attenuate mineralocorticoid-induced sodium retention, and reverse hyperaldosteronism. ^59-63

Research

The effects of oral corticosteroids on urinary excretion of potassium is well established, but consensus is lacking (and specific research absent) regarding the clinical significance of this influence. ⁵⁷ Nevertheless, there is risk of hypokalemia during prolonged, high-dose corticosteroid therapy. ^56,64

The role of external potassium balance in modulating mineralocorticoid-induced sodium retention in humans remains uncertain. However, in a small trial involving eight healthy subjects treated with fludrocortisone, Krishna and Kapoor ⁶¹ demonstrated that potassium administration can ameliorate mineralocorticoid-induced sodium retention and enhance urinary sodium excretion. Conversely, fludrocortisone is used to treat interdialytic hyperkalemia in dialysis patients or may be useful, in combination with spironolactone, to correct sodium and potassium losses in secretory diarrhea. ^65,66

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing oral corticosteroids, especially for an extended period and in patients at greater risk for overall compromised nutritional status, are advised to monitor for imbalances and depletions in potassium and other nutrients. The minimal available evidence suggests that clinically significant potassium depletion is possible in some patients depending on the patient's general health, including diet, exercise, and other key physiological influences, and the potency of the particular agent(s) applied. In patients whose potassium status may be at risk, the consumption of fruit, vegetables, and other foods rich in potassium is usually the simplest and most effective means of preventing or correcting potential potassium depletion associated with long-term steroid therapy.

See Trimethoprim-Sulfamethoxazole.

Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Emerging

Effect and Mechanism of Action

Cyclosporine, an inhibitor of calcineurin, can induce hyperkalemia through different mechanisms, most notably immunosuppressant-induced nephrotoxicity, and chronic progressive tubulointerstitial fibrosis/arteriopathy in particular. ⁶⁷ “Cyclosporin A (CsA)–induced hyperkalemia is caused by alterations in transepithelial K ⁺ secretion resulting from the inhibition of renal tubular Na ⁺ ,K ⁺ -ATPase activity.” ⁶⁸ An obvious cause, found in many cases, derives from CsA-induced nephrotoxicity, a well-known adverse effect, that “causes a reduction in glomerular filtration rate through vasoconstriction of the afferent glomerular arterioles and may result in acute renal failure.” ⁶⁹ “Calcineurin inhibitor-induced acute renal failure may occur as early as a few weeks or months after initiation of cyclosporin therapy.” ⁶⁷ Nevertheless, other individuals exhibiting adequate kidney function have developed hyperkalemia, possibly because of tubular resistance to aldosterone. ⁶⁹ Overall, dose-related renal tubule dysfunction, tubulointerstitial fibrosis/arteriopathy, and secondary hypoaldosteronism are considered the primary reasons for CsA-associated hyperkalemia, but no conclusive evidence has emerged to provide a comprehensive explanation for this phenomenon.

Reports and Research

Cyclosporin A and other immunosuppressive drugs are generally known to “induce either hypoaldosteronism or pseudo-hypoaldosteronism presenting with hyperkalemia and metabolic acidosis” after renal transplantation. ⁷⁰

Caliskan et al. ⁶⁹ reported four cases of cyclosporine-associated hyperkalemia in allogeneic blood stem cell transplant patients “despite adequate kidney function.” The authors proposed that hyperkalemia was caused by renal tubule dysfunction and secondary hypoaldosteronism. Takami et al. ⁷¹ reported the cases of two patients with advanced renal cell carcinoma who developed hyperkalemia during CsA therapy after allogeneic hematopoietic stem cell transplantation. They noted that this adverse effect occurred despite adequate renal function; both patients developed hyperkalemia, and cyclosporine, “the only pharmaceutical agent to which this electrolyte abnormality could be attributed,” contributed to “tubular resistance to aldosterone.” They also suggested that “the presence of a single functional kidney may be a risk factor for isolated hyperkalemia” resulting from cyclosporine.

In a 1995 study involving 24 renal transplant recipients 6 months after transplantation, Laine and Holmberg ⁷² investigated renal and adrenal mechanisms in cyclosporine-induced hyperkalemia observed in 11 of these patients. “The TTKGs [transtubular potassium concentration gradients] were low normal or reduced in both normo- and hyperkalaemic patients implying inhibition of K ⁺ secretion.” The hyperkalemic patients received more CsA, and serum potassium concentration correlated with CsA dose. Notably, adrenal function exhibited “no clear effect,” and the authors of this relatively early study concluded that hyperkalemia “was not fully explained by renal mechanisms.”

In a 1999 prospective study of 49 kidney allograft recipients who received transplants before age 5 years, Qvist et al. ⁷³ documented “excellent long-term graft survival and good graft function” 5 to 7 years after renal transplantation. Nevertheless, the authors noted that whereas “sodium handling remained intact, … hyperuricemia was seen in 43-67%; 17-33% showed abnormal handling of potassium; and most patients had a subnormal concentrating capacity.”

Higgins et al. ⁷⁴ studied and compared the frequency and severity of nephrotoxicities, hyperkalemia, and hyponatremia in renal transplant recipients treated with cyclosporine versus tacrolimus. In this retrospective study they investigated sodium and potassium handling in 125 patients initially treated with cyclosporine ( n= 80) or tacrolimus ( n= 45) during the first 90 days after renal transplantation. They observed that serum potassium levels were higher in patients treated with tacrolimus than in those treated with cyclosporine, noting that hyponatremia was more likely in subjects with hyperkalemia.

Dangerous disturbances in potassium status and concentrations in patients being treated with cyclosporine have been reported repeatedly, and polypharmacy using several different agents has been used to reverse these adverse effects. Thyroxine is known to enhance renal cortical Na ⁺ ,K ⁺ -ATPase activity. In a rodent experiment, You et al. ⁶⁸ found that coadministration of thyroxine “prevented CsA-induced hyperkalemia and reduced creatinine clearance, Na ⁺ ,K ⁺ -ATPase activity, and severity of the histologic changes in the renal tubular cells.” Limited research indicates that ACE inhibitors or angiotensin II type I receptor antagonists such as losartan may be effective and well tolerated in the treatment of hypertension in renal transplant recipients at heightened risk of hyperkalemia and hyperuricemia from decreased renal blood flow and glomerular filtration rate associated with a single kidney and concomitant cyclosporine use. ⁷⁵ One study noted that “in this high-risk population, the effects on serum potassium levels are less marked with losartan than with enalapril.” ⁷⁶ In a clinical trial involving 21 renal transplant patients under CsA therapy and 12 healthy controls, Heering et al. ⁷⁰ investigated the relationship between renal allograft function under CsA therapy and plasma aldosterone concentration, potassium and water homeostasis, and mineralocorticoid receptor (MR) expression level in peripheral leukocytes. They concluded that “aldosterone resistance in kidney transplantation is in part induced by a down-regulation of mineralocorticoid receptor expression.” They also noted that administration of fludrocortisone reversed hyperkalemia and metabolic acidosis without significant effect on MR expression. Similarly, Singer et al. ⁷⁷ described the prompt reversal of hyperkalemia and other “severe life-threatening complications” through administration of glibenclamide in three critically ill patients who developed “potassium-channel syndrome” after receiving cyclosporine or other drugs with K(ATP) channel-opening properties. Thus, although several strategies have been evaluated to attenuate cyclosporine-induced nephropathy, evidence of their efficacy remains preliminary.

Clinical Implications and Adaptations

Physicians treating allograft patients with cyclosporine will generally be monitoring for renal damage and associated hyperkalemia and other disturbances in electrolyte balance. Concomitant potassium in such patients is generally contraindicated, and frank inquiry as to lifestyle practices, including a thorough inventory of dietary and supplement intake, is essential to comprehensive management of such patients.

	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Bimodal or Variable Interaction, with Professional Management

Consensus

Effect and Mechanism of Action

The central role of potassium in maintaining proper function of cardiac (and other) muscles is a basic physiological precept in clinical medicine. The safe use of digoxin requires stable blood potassium levels because hypokalemia may predispose to digitalis toxicity and dangerous cardiac arrhythmias. However, digoxin impairs potassium transport from the blood into cells. ⁷⁸ Furthermore, potassium depletion, induced by concomitant diuretic use and often secondary to hypomagnesemia, is quite common among individuals treated with digoxin. Conversely, an overdose of digoxin can cause a potentially fatal hyperkalemia.

Reports and Research

As early as 1960, in a paper on the relationship between digitalis and potassium in the context of surgery, Lown et al. ⁷⁸ discuss impaired potassium transport from the blood into cells caused by digoxin. In reporting on correlations with serum digoxin level in five cases of suicidal and accidental digoxin ingestion, Smith and Willerson ⁷⁹ noted that potentially fatal hyperkalemia can result from an overdose of digoxin.

In 1985, Whang et al. ⁸⁰ published their findings on the frequency of hypomagnesemia in hospitalized patients receiving digitalis. In measuring serum sodium, magnesium, and potassium levels in 136 serum samples sent to the laboratory for digoxin assay, they found that hyponatremia occurred most frequently (21%), followed by hypomagnesemia in 19%, hypokalemia in 9%, and hypermagnesemia in 7%. They noted that the “twofold frequency of hypomagnesemia” compared to hypokalemia “indicates that clinicians are more attuned to avoiding hypokalemia than hypomagnesemia in patients receiving digitalis,” and added that their “observation suggests that hypomagnesemia may be a more frequent contributor than hypokalemia to induction of toxic reactions to digitalis.” Thus, they concluded that electrolyte monitoring, both of magnesium and potassium, is critical “in patients receiving digitalis, who often are also receiving potent diuretics.”

Schmidt et al. ⁸¹ found that the impairment of extrarenal potassium homeostasis by heart failure and digoxin treatment may be counterbalanced by exercise. Based on the finding that “extrarenal potassium handling is altered as a result of digoxin treatment,” the authors proposed that this is “likely to reflect a reduced capacity of skeletal muscle Na/K-ATPase for active potassium uptake because of inhibition by digoxin (similar to that seen with beta-blockers), adding to the reduction of skeletal muscle Na/K-ATPase concentration induced by heart failure per se.” Consequently, however, “in heart failure patients, improved haemodynamics induced by digoxin may … increase the capacity for physical conditioning.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing digoxin or related cardiac glycosides need to monitor for potassium (and magnesium) depletion. Unsupervised use of potassium supplements (or even high intake of potassium-rich foods) is generally contraindicated during digitalis therapy. However, when coadministration of potassium may be indicated, particularly in the context of potassium-depleting diuretics, oral preparations may not be as effective or as well tolerated as consistent dietary consumption of fruit and other foods rich in potassium. Education and support for a regular program of moderate exercise can be therapeutically valuable in most patients and consistent with broader knowledge of cardiovascular health and risk factors. Close supervision and regular monitoring are inherently appropriate in all digitalized patients.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Consensus

Effect and Mechanism of Action

Thiazide, loop, and similar diuretics are often referred to as “potassium depleting” because by definition they increase potassium excretion with diuresis; in practice, they concurrently deplete magnesium at the cellular level. ⁸² The diuretic-induced magnesium deficiency can lead to refractory potassium depletion but may not be detectable through routine serum magnesium determinations. ^51,83

Research

Potassium wasting with these medications is axiomatic, and hypokalemia is a common finding in those taking diuretic medications, especially the elderly. Avoiding hypokalemia is generally agreed to be beneficial in several cardiovascular disease states, including acute myocardial infarction, heart failure, and hypertension. Nevertheless, data from direct research into diuretic-induced hypokalemia are limited. Moreover, clinically significant differences in the severity of effects on potassium status between high-dose and low-dose diuretics, as well as oral versus intravenous administration, have been proposed. Furthermore, the available research does provide some important insights that depart from common assumptions.

Not all patients receiving treatment with “potassium-depleting” diuretics necessarily develop clinically significant (or at least readily detectable) decreases in potassium concentrations. In three yearly multicenter surveys involving 18,872 patients with initially normal baseline serum potassium, Zuccala et al. ⁸⁴ investigated older age and in-hospital development of hypokalemia in the 4035 patients who started receiving loop diuretics during their hospital stay. After adjusting for a number of variables, age and use of parenteral (but not oral) loop diuretics were associated with hypokalemia. The authors concluded that “older age is independently associated with the in-hospital development of hypokalemia, particularly among patients taking loop diuretics” and recommended monitoring of serum potassium levels “when older patients are treated with these agents.”

Franse et al. ⁸⁵ analyzed data of 4126 participants in a 5-year, randomized, placebo-controlled clinical trial of chlorthalidone-based treatment of isolated systolic hypertension in older persons to determine whether hypokalemia that occurs with low-dose diuretics is associated with a reduced benefit on cardiovascular events. They found that after “adjustment for known risk factors and study drug dose, the participants who received active treatment and who experienced hypokalemia had a similar risk of cardiovascular events, coronary events, and stroke as those randomized to placebo.” However, “within the active treatment group, the risk of these events was 51%, 55%, and 72% lower, respectively, among those who had normal serum potassium levels compared with those who experienced hypokalemia.” Thus, they concluded that subjects who had hypokalemia after 1 year of treatment with a low-dose diuretic “did not experience the reduction in cardiovascular events achieved among those who did not have hypokalemia.” Besides demonstrating that treatment with a thiazide diuretic led to a reduction in serum potassium levels in some participants, these findings indicate that patients exhibiting decreased potassium levels were also more likely to experience cardiovascular events, such as heart attacks, heart failure, sudden cardiac death, stroke, and aneurysm.

The interrelationship between potassium (K) and magnesium (Mg) depletion patterns is an important topic with significant implications for normal electrolyte balance and cardiac function. In a 1992 paper, Whang et al. ⁵¹ reviewed experimental and clinical observations supporting the view that uncorrected Mg deficiency impairs repletion of cellular K. “[C]onsistent with the observed close association between K and Mg depletion,” they found that concomitant “Mg deficiency in K-depleted patients ranges from 38% to 42%.” Although this refractory “K repletion due to unrecognized concurrent Mg deficiency can be clinically perplexing,” they note that it “may be operative in … patients receiving potent loop diuretics” as well as other medications. Based on these findings, they recommend that “(1) serum Mg be routinely assessed in any patients in whom serum electrolytes are necessary for clinical management and (2) until serum Mg is routinely performed, consideration should be given to treating hypokalemic patients with both Mg as well as K to avoid the problem of refractory K repletion due to coexisting Mg deficiency.” ⁵¹

The complications arising from the effects of potassium depletion have broad implications for an at-risk cardiovascular patient population. For example, low preoperative serum potassium levels can adversely influence perioperative outcomes in cardiac surgery patients. Wahr et al. ² conducted a prospective, observational, case-control study to determine the prevalence of abnormal preoperative serum potassium levels and whether such abnormal levels are associated with adverse perioperative events. Analyzing data gathered from 24 diverse U.S. medical centers in a 2-year period, they found that perioperative arrhythmias occurred in 1290 (53.7%) of 2402 patients and that “serum potassium level less than 3.5 mmol/L was a predictor” of serious perioperative arrhythmia, intraoperative arrhythmia, and postoperative atrial fibrillation/flutter, and “these relationships were unchanged after adjusting for confounders.” These authors concluded: “Although interventional trials are required to determine whether preoperative intervention mitigates these adverse associations, preoperative repletion is low cost and low risk, and our data suggest that screening and repletion be considered in patients scheduled for cardiac surgery.” ²

Ruml et al. ⁸⁶ conducted two clinical trials investigating the effect of varying doses of potassium-magnesium citrate on thiazide-induced hypokalemia and magnesium loss. In subjects first administered hydrochlorothiazide, 50 mg daily, these researchers found that three different “dosages of potassium-magnesium citrate significantly increased serum potassium concentration, with > 80% of subjects regaining normal values despite continued thiazide therapy.” They concluded that potassium-magnesium citrate “not only corrects thiazide-induced hypokalemia, but also may avert magnesium loss while providing an alkali load.” However, “higher dosages,” such as 70 mEq potassium, 35 mEq magnesium, and 105 mEq citrate per day, are “probably required for the prevention of magnesium loss and adverse symptoms of thiazide therapy.” ⁸⁷

Nutritional Therapeutics, Clinical Concerns, and Adaptations

In practice, it is generally advisable to coadminister both potassium and magnesium when prescribing any potassium-depleting diuretic, except in cases involving those with renal insufficiency. For long-term care, coadministration of potassium in the dosage range of several hundred milligrams to several grams per day is usually appropriate, depending on the individual's diet, age, genetic predisposition, medications, and other factors. Potassium deficiency status can be evaluated by monitoring RBC potassium levels or, more conventionally, serum potassium concentration. Assessment of potassium status may be appropriate but is often not essential, because low serum potassium is not required for patients to benefit from potassium coadministration. However, since administration of potassium (and/or magnesium) can be risky, and is usually contraindicated, in patients with renal insufficiency, kidney function tests are critical before initiating, and periodically through the course of, concomitant repletion therapy.

Administration of potassium, magnesium, or other electrolyte needs to be maintained for 6 months to compensate for any drug-induced tissue depletion pattern and throughout the duration of, and possibly after conclusion of, relevant diuretic therapy. A typical complementary magnesium dose for most individuals would be in the range of 300 to 500 mg per day, preferably as magnesium citrate, malate, gluconate, or glycinate. A multimineral formulation would add support against parallel depletions of other vulnerable minerals. Beyond potassium and magnesium, clinical care within an integrative setting might also emphasize a diet rich in minerals, vitamins, antioxidants, and essential fatty acids as part of an evolving and individualized approach to cardiovascular therapeutics involving health care professionals trained and experienced in multiple therapeutic disciplines.

See Ipecac in Herb-Nutrient Interactions.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect

Mixed and Preliminary

Effect and Mechanism of Action

Excessive or repeated use of any laxative can deplete potassium (and a wide range of other nutrients) through a variety of mechanisms, including impaired absorption and altered transit time. Short-term use of cathartic laxatives, as in the context of colon cleansing for radiological examinations, can cause acute drops in serum potassium that may be particularly dangerous in patients on diuretic or digitalis therapy and those with cardiac conditions or otherwise susceptible to arrhythmias. ⁸⁸ Among its several actions, docusate administration stimulates net secretion of potassium. ⁸⁹ Mineral oil, as a lipid solvent, may interfere with normal absorption of potassium and other nutrients and absorb many substances. Inherently, these factors are aggravated in the context of compromised nutritional intake and limited physical activity. Potassium coadministration, through dietary or supplemental prescription intake, can usually prevent or reverse any disturbances in potassium status.

Stimulant-type laxatives such as bisacodyl may both reduce potassium absorption and cause excessive potassium loss, as well as sodium depletion and hyperreninemia, most probably through two mechanisms: (1) loss of potassium as a result of stimulation of mucus secretion in intestinal mucosa and (2) a “dual effect of potassium on aldosterone secretion, with renin as a mediator.” ^90-93 Thus, hypokalemia can result from abuse or chronic bisacodyl use.

Reports and Research

Fleming et al. ⁹² reported the case of a patient “with marked chronic hypokalemia (potassium, 1.7 to 2;3 meq/litre) and sodium depletion secondary to laxative abuse and dietary inadequacy.”

Moriarty et al. ⁸⁹ used an intestinal perfusion technique to investigate the mechanism of action of docusate in the human jejunum and observed that it “stimulated net secretion of water, sodium, chloride and potassium and inhibited net absorption of glucose and bicarbonate.”

In a prospective study involving 320 patients, Ritsema and Eilers ⁸⁸ investigated the impact of colon cleansing before procedures on serum potassium concentrations and the efficacy of potassium administration in preventing serious hypokalaemia. Of the four subject subgroups, two were being treated with diuretics, and one of those also received potassium. “Hypokalaemia was present prior to cleansing in six (11%), and after cleansing in 20 (36%) of the 55 patients in the group 1 patients on diuretics but without potassium supplements. There was, after cleansing, no significant fall in serum potassium in the group 2 patients on diuretics who received potassium supplements.” Notably, no hyperkalemia resulted from potassium coadministration. Likewise, both subgroups not receiving diuretics, one of which received a 2-day preparation of 15 g magnesium sulfate and 10 mg bisacodyl twice daily and the other a 1-day preparation of 2.4 mg sennoside, exhibited a “significant fall of the mean level of serum potassium.” Thus, the authors concluded that “both 1 day and 2 days of cleansing with cathartics may result in a significant fall in serum potassium, which can be prevented by oral potassium supplements.” In particular, they noted that administration of 15 mL of potassium chloride with 0.9 mmol K/mL three times daily during the preparation “in patients on diuretics may be prudent to avoid the risk of cardiac arrhythmia.” ⁸⁸

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Individuals using laxatives or stool softeners on a regular basis, especially outside the context of professional supervision, should be encouraged to increase their consumption of fresh fruits and vegetables as a means of preventing or reversing nutrient depletion. Repeated use of laxatives, other than bulking fibers such as psyllium seed husks, for longer than 7 days should be discouraged and root causal factors addressed. Healthful dietary practices will reduce the likelihood and severity of constipation and the need for laxatives or stool softeners in most individuals, especially when combined with increased intake of healthy oils and whole grains and regular exercise. Acute prophylactic potassium administration is judicious in some clinical situations, such as short-term use of laxatives before diagnostic procedures. Regular use of a high-quality multivitamin/mineral formulation will often be indicated and beneficial in preventing and correcting multiple nutritional insufficiencies in individuals using these medications, especially the elderly, institutionalized, or otherwise nutritionally compromised individuals. In general, nutritional supplements are most effectively assimilated when taken separate from fiber, mineral oils, or other substances that may potentially impair their absorption.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Consensus

Effect and Mechanism of Action

Losartan and its active metabolite, E-3174, affect the renin-angiotensin system and reduce aldosterone activity by selectively blocking the binding of angiotensin II to angiotensin I receptors found in vascular smooth muscle and other tissues, causing vasodilation and inhibiting retention of sodium and water by the kidneys, thus decreasing blood volume. Neither losartan nor its active metabolite inhibits angiotensin converting enzyme, and, in fact, as these agents inhibit the pressor effect of angiotensin II the removal of the negative feedback of angiotensin II causes a significant rise in plasma renin activity, and a resultant rise in angiotensin II plasma concentration, in hypertensive patients. Consequently, losartan may cause increases in blood potassium levels that can be clinically significant. ⁹⁴ Increasing potassium intake (food, supplements, prescription, salt substitute) concurrent with an angiotensin II receptor antagonist may lead to hyperkalemia and the resulting adverse effects.

Research

As the first angiotensin II receptor antagonist (ARB) to be marketed for the treatment of hypertension, losartan has been the subject of more research than others drugs in this class. Nevertheless, “ARB-related hyperkalemia is class- and not compound-specific.” Thus, as summarized by Sica ⁹⁵ in a 2006 review of the effects of antihypertensive therapy on potassium homeostasis, that ARBs, as with ACE inhibitors, “will increase the serum K ⁺ value in virtually all treated subjects, but only to a degree (0.1-0.2 mEq/L) that is barely discernible clinically,” and proposed that hyperkalemia in such cases “remains highly definitional in nature.”

Hyperkalemia is a known adverse effect of losartan. In controlled hypertensive trials with losartan monotherapy and losartan-hydrochlorothiazide (Hyzaar), a serum potassium greater than 5.5 mEq/L occurred in 1.5% and 0.7% of patients, respectively. ⁹⁶ Nevertheless, in such research no patient discontinued losartan or losartan-hydrochlorothiazide therapy because of hyperkalemia. ⁹⁷ Moreover, in a study of the efficacy and tolerability of losartan in hypertensive patients with chronic renal insufficiency, Toto et al. ⁹⁸ reported that hyperkalemia (>6 mEq/L) requiring discontinuation of losartan occurred in only one patient (of 112 subjects). However, in another study focusing on patients with type 2 diabetes and proteinuria, significantly more patients in the losartan group developed hyperkalemia (losartan 24.2% vs. placebo 12.3%; p< 0.001). ⁹⁹

Reports

Numerous reports, published and unpublished, describe hyperkalemia in patients receiving losartan or other angiotensin II receptor antagonist drugs, particularly in the context of potassium-sparing diuretics and compromised renal status. ^100-105 Miyahara et al. ¹⁰⁶ reported a case of intraoperative hyperkalemia induced with administration of an angiotensin II receptor antagonist and intake of dried persimmons, a fruit high in potassium.

Clinical Implications and Adaptations

Health care professionals treating patients taking an angiotensin II receptor antagonist (ARB) are strongly encouraged to counsel these individuals to avoid unsupervised increases in potassium intake, in the form of supplements but also as high-potassium foods (e.g., fruit) or salt substitutes, on the basis of the increased risk for problematic interactions. A clinically significant increase in blood potassium levels represents an uncommon yet potentially serious adverse effect associated with ARB drugs. The importance of frank inquiry and detailed inventory of concomitant (or even occasional) medications, diet, nutrients, and herbs cannot be overemphasized. Close supervision and regular monitoring are essential, especially in individuals with compromised renal function. The prescription of potassium chloride or potassium-sparing medications is generally contraindicated during angiotensin II receptor antagonist therapy.

See Magnesium in Nutrient-Nutrient Interactions.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Emerging

Effect and Mechanism of Action

Many anti-inflammatory agents affect potassium metabolism, but through a variety of mechanisms with the potential to produce a range of different effects, including severe reactions of rapid-onset hyperkalemia in acute renal failure. The effects of NSAIDs on prostaglandin production appear central to many adverse reactions. For example, indomethacin inhibits renal prostaglandin synthesis, which in turn reduces renin-aldosterone levels and potassium excretion and subsequently elevates serum potassium levels, potentially causing hyperkalemia. Similarly, ibuprofen can impair renal function and thus elevate blood potassium levels, particularly in elderly persons or those with preexisting renal compromise. ¹⁰⁷ “Generally, the renal failure with NSAIDs is acute and reversible, though analgesic nephropathy with papillary necrosis and chronic renal failure are reported.” ¹⁰⁸

Research

In a prospective, randomized, crossover trial, Whelton et al. ¹⁰⁹ compared the renal effects of ibuprofen, piroxicam, and sulindac in patients with asymptomatic renal failure. “All three regimens suppressed renal prostaglandin production.” In contrast to the other two NSAIDs, they observed excessive elevations of serum potassium by the eighth day (beyond those tolerated in the study design) that required withdrawal of treatment in 3 of 12 subjects who received ibuprofen, 800 mg three times daily. Further, when these three patients were rechallenged with ibuprofen, 400 mg three times daily, “two again developed evidence of acute renal deterioration.” The authors concluded that “a brief course of ibuprofen, a compound widely used on a nonprescription basis, may result in acute renal failure in patients with asymptomatic, mild chronic renal failure.”

Reports

Poirier ¹⁰⁸ reported a “probable case of acute, reversible renal failure and hyperkalemia, after an increase in dose of ibuprofen.” After reviewing other cases of renal dysfunction associated with NSAIDs, the author concludes: “Electrolytes, blood urea nitrogen, and serum creatinine levels need to be monitored in high-risk patients with predisposing factors and for chronic, long-term use of drugs that inhibit prostaglandin synthesis.”

Clinical Implications and Adaptations

Potassium intake should be limited during NSAID therapy because potassium levels may rise in an unregulated manner, potentially reaching clinically significant hyperkalemia. Health care professionals treating patients using NSAIDs are strongly encouraged to counsel these individuals to avoid unsupervised increases in potassium intake, in the form of supplements but also as high-potassium foods (e.g., fruit) or salt substitutes, on the basis of the increased risk for problematic interactions. Although their use is widespread and largely unregulated, the high frequency of adverse reactions to NSAIDs is generally underestimated by patients and often forgotten by health care professionals. Apart from hepatotoxicity, which continues to be a major risk factor, the adverse effects of these agents on renal function need to be considered in all individuals with chronic use and even in some individuals with occasional use. A clinically significant increase in blood potassium levels represents an uncommon yet potentially serious adverse effect associated with NSAID therapy.

As previously noted, adverse reactions, although reversible, can be sudden and severe, particularly in those with compromised renal function. As summarized by Poirier ¹⁰⁸ : “Possible predisposing factors to renal deterioration include the amount of drug consumed, presence of compromised renal blood flow, underlying renal insufficiency, nephrotoxic drug combinations, and high urinary prostaglandin excretion.” Thus, regular monitoring is important in all patients using NSAIDs and close supervision may also be essential in those at high risk for adverse reactions. Principles of conservative practice recommend that health care professionals assess and correct the causes and aggravating factors involved in chronic inflammatory responses and educate patients to minimize use of anti-inflammatory medications.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Preliminary or Emerging

Effect and Mechanism of Action

The antiarrhythmic drugs with class 1A cardiac activity slow cardiac conduction and lengthen the QT interval. As with other antiarrhythmic drugs, quinidine may worsen cardiac rhythm disorders and increase the risk of death, especially in individuals with a history of a heart attack. More broadly, intracellular potassium and magnesium levels are intrinsic to electrical stability, and high and low levels of these anions, both within the cells and in the serum, predispose to cardiac rhythm disturbances; therefore, antiarrhythmic drugs of all classes (1A, 1C, and 3) can interact with medicines that affect potassium (and magnesium) levels.

Individuals with low blood levels of potassium (and magnesium), caused by diuretics, vomiting, or other stressors, may develop serious cardiac adverse effects, such as arrhythmias, in response to quinidine. In particular, quinidine causes torsades de pointes under certain conditions, particularly hypokalemia, hypomagnesemia, and other electrolyte abnormalities. Potent suppression of a potassium channel subunit current by quinidine is a likely contributor to torsades de pointes arrhythmias. ¹¹⁰ Thus, arrhythmias “may develop in hypokalemia due to enhanced normal automaticity, abnormal automaticity, or slowed conduction; moreover, hypokalemia is associated with enhanced digitalis toxicity, quinidine-related torsades de pointes, and interference with the antiarrhythmic activity of quinidine.” ¹¹¹

With simultaneous intake, direct adsorption by potassium or other mineral salts could theoretically result in decreased drug bioavailability, although not necessarily to a clinically significant degree. ¹¹²

Research

Hypokalemia, especially in the presence of hypomagnesemia or other electrolyte abnormalities, is associated with a range of adverse effects, including quinidine-related torsades de pointes, and interference with the antiarrhythmic activity of quinidine. Here, once again, the critical importance of the interrelationship between potassium and magnesium is a recurrent theme.

Mutations in a gene encoding a potassium channel subunit (HERG) can be related to the long-QT (LQT) syndrome characteristic of torsades de pointes, a polymorphic ventricular arrhythmia. Pharmacological suppression of repolarizing potassium currents is also a mechanism causing the acquired LQT syndrome. ¹¹⁰

Roden and Iansmith ¹¹¹ concluded their paper on the effects of low potassium or magnesium concentrations on isolated cardiac tissue by proposing that, in individuals with hypertension, “treatment that controls hypertension without causing electrolyte abnormalities is preferable for patients who are at risk of arrhythmias, or who are receiving drugs such as digitalis or quinidine.”

Further research into electrolyte function in cardiac tissue, related drug interactions and depletions, and individual genomic and pharmacogenomic variability is warranted and can benefit from an integrative approach to multidisciplinary therapeutic interventions.

Report

Teplick et al., ¹¹³ as well as other authors, ¹¹⁴ have reported cases of esophagitis caused by oral potassium chloride (“slow KCl” liquid and tablets) and quinidine tablets, separately. The concomitant use of these agents could theoretically increase the probability of adverse reactions. The authors noted that in “all reported cases caused by KCl tablets, left atrial enlargement was present as the result of mitral stenosis.” ¹¹³

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing quinidine or related antiarrhythmic drugs, especially in conjunction with potassium-depleting diuretics, are advised initially to assess and then periodically monitor potassium and magnesium status, keeping in mind that serum concentrations do not accurately reflect intracellular levels. Coadministration of potassium and other nutrients may prevent or correct nutrient depletion that could create or amplify adverse drug effects. In contrast to magnesium, rapid repletion of potassium by the IV route is not used in the treatment of acute arrhythmias.

Within a comprehensive therapeutic repertoire, quinidine, potassium, and magnesium represent important options appropriate for consideration in crafting a long-term program of care for individuals with arrhythmias, hypertension, and other cardiovascular conditions. Treatment using medications that do not deplete vital nutrients or otherwise introduce electrolyte abnormalities is preferable, especially patients who at risk of arrhythmias or receiving drugs such as quinidine. Regular monitoring and appropriate nutritional support are important therapeutic tools when recourse to more deleterious agents is deemed necessary. Low potassium and magnesium concentrations not only contribute to or cause cardiac arrhythmias, but deficiencies of these minerals can also interfere with the efficacy or enhance the toxicity of many drugs used to treat patients with heart disease. Clinical care within an integrative setting might also emphasize a diet rich in vitamins, minerals, and antioxidants and incorporate hawthorn (Crataegus oxyacantha),L-carnitine, coenzyme Q10, and other nutrients as part of an individualized and evolving approach to cardiovascular therapeutics.

	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Minimal to Mild Adverse Interaction—Vigilance Necessary

Consensus

Effect and Mechanism of Action

In contrast to potassium-wasting diuretics, spironolactone and triamterene, along with amiloride, constitute a drug class of diuretic agents that, by design, conserve potassium. Spironolactone inhibits the action of aldosterone and other mineralocorticoids, causing the kidneys to excrete sodium and fluid while retaining potassium. Triamterene achieves its diuretic effect by inhibiting the reabsorption of sodium in exchange for potassium and hydrogen ions in the distal renal tubule and thus maintains or increases sodium excretion and reduces loss of potassium, hydrogen, and chloride ions. Because triamterene is not a competitive antagonist of aldosterone, its dosing is determined by the kaliuretic effect of concomitantly administered drugs and the response of the individual patient, rather than being proportionate to the level of mineralocorticoid activity. Thus, triamterene can prevent diuretic-induced potassium loss comparable to 3.1 to 4.7 g (80-120 mmol) of potassium daily. Consequently, these medications are often used in combination with hydrochlorothiazide or other kaliuretic drugs to mitigate potassium wasting.

Conversely, increased potassium intake (foods, supplements, prescription, salt substitutes) could lead to excessive elevation of potassium levels in patients being treated with these medications, especially with concomitant ACE inhibitors or other medications that alter potassium metabolism. Arrhythmias and other adverse effects of hyperkalemia can be severe and are sometimes rapid in onset.

In addition to hypertension, potassium-sparing medications are used in the treatment of cirrhotic patients with ascites as well as those with Conn's, Bartter's, and Liddle syndromes and hirsutism.

Research

Spironolactone and triamterene intentionally reduce urinary excretion of potassium while enhancing sodium excretion. As potassium-sparing diuretics, these agents can produce a state of hyperkalemia (i.e., inappropriately elevated potassium levels). When used in combination with a thiazide diuretic, hyperkalemia (>5.4 mEq/L) has been reported as ranging from 4% in patients less than 60 years of age to 12% in patients 60 years and older, with an overall incidence of less than 8%. Arrhythmias and other cardiac irregularities are among the adverse effects associated with hyperkalemia. Conversely, concern has been raised about potential risks of hypokalemia among some patients using triamterene, even though hypokalemia is a less common occurrence with the use of triamterene than with non-potassium-sparing diuretics.

In a random crossover study, Jackson et al. ¹¹⁵ investigated the influence of spironolactone (50 and 100 mg daily), triamterene (100 and 200 mg daily), potassium chloride (32 and 64 mmol daily), and placebo on plasma potassium and other variables in nine hypertensive patients taking bendrofluazide, a thiazide diuretic (10 mg daily). They observed that spironolactone and triamterene had “significant and parallel dose-response curves for plasma potassium, with a relative potency for triamterene:spironolactone of 0.25:1, significantly lower than the accepted 0.5:1 ratio,” while also lowering serum sodium, bicarbonate, and body weight and increasing serum urea and creatinine levels. Potassium chloride “increased plasma potassium above placebo values, but the dose-response was not significant and was not parallel with those of the potassium-sparing drugs.” Notably, seven of nine patients “remained hypokalaemic despite treatment with 64 mmol potassium chloride daily.”

Sawyer and Gabriel ¹¹⁶ studied progressive hypokalemia in 80 elderly patients with heart failure taking three thiazide potassium-sparing diuretic combinations over 36 months. Compared with amiloride and spironolactone, the “triamterene-containing preparation was discontinued most frequently (6/44) because of hypokalaemia (plasma potassium less than 3.0 mmol/L).” The median fall in plasma potassium over 3 years in those patients not withdrawn because of hypokalemia was “similar in each case (P greater than 0.05) and possibly failed to reach significance because of the withdrawal rate (9%),” and the “trend was for a greater fall in those patients taking triamterene.” The authors concluded that the “spironolactone-containing preparation may be the least unsatisfactory of the three.”

In a randomized study, Schnaper et al. ¹¹⁷ evaluated the efficacy of three drug regimens (hydrochlorothiazide and 20 mmol potassium; hydrochlorothiazide and 40 mmol potassium; or hydrochlorothiazide and triamterene) in patients rendered hypokalemic by hydrochlorothiazide while maintaining blood pressure control. Among 447 hypertensive patients, most with a history of diuretic-induced hypokalemia, 252 developed diuretic-induced hypokalemia while receiving hydrochlorothiazide (50 mg/day). In all groups, mean serum levels of potassium increased within 1 week and “showed no further change thereafter.” Although each “regimen provided continued control of mild to moderate hypertension,” the hydrochlorothiazide/triamterene and hydrochlorothiazide plus 40 mmol of potassium combinations were “significantly more effective in restoring serum potassium levels” than was the combination of hydrochlorothiazide and 20 mmol of potassium. Furthermore, the authors reported that “significant increase in magnesium levels was observed only in the group treated with the hydrochlorothiazide/triamterene combination.”

Reports

In at least one case, reported by Stepan et al., ¹¹⁸ a patient has caused unintended hyperkalemia (and diarrhea) through surreptitious ingestion of potassium-sparing diuretics, with attendant decreased sodium absorption and elevated serum aldosterone levels.

Clinical Implications and Adaptations

Health care professionals treating patients with a potassium-sparing diuretic are strongly encouraged to counsel these individuals to avoid unsupervised increases in potassium intake, in the form of supplements but also as high-potassium foods (e.g., fruit) or salt substitutes, on the basis of the increased risk for problematic interactions. A clinically significant increase in blood potassium levels represents a potentially serious adverse effect associated with potassium-sparing diuretics. The importance of frank inquiry and detailed inventory of concomitant (or even occasional) medications, diet, nutrients, and herbs cannot be overemphasized. Close supervision and regular monitoring are essential, particularly when coadministered with an ACE inhibitor or in individuals with compromised renal function.

	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid

Emerging

Effect and Mechanism of Action

Trimethoprim or trimethoprim-sulfamethoxazole (TMP-SMX) may elevate potassium concentration, possibly to the point of hyperkalemia, which although reversible may be severe; these agents also can increase serum creatinine and BUN. ^94,119-121 “Trimethoprim (an organic cation) acts like amiloride and blocks apical membrane sodium channels in the mammalian distal nephron.” ¹²⁰ Inhibition of sodium channels in A6 distal nephron cells by trimethoprim appears to play a role in the drug's potassium-sparing diuretic activity. ¹²⁰ Consequently, the transepithelial voltage is reduced and potassium secretion inhibited, resulting in decreased renal potassium excretion and hyperkalemia.

Research

A small but consistent body of research findings indicates that trimethoprim or TMP-SMX can elevate potassium levels and tend to cause hyperkalemia, particularly in patients with compromised renal function or other major medical problems (e.g., AIDS).

Over several years, Velazquez, Alappan, Perazella, et al. ^120-123 have conducted a series of trials and published several papers examining the issue of hyperkalemia during TMP-SMX therapy. In conjunction with a rodent experiment, they investigated the effects of trimethoprim-containing drugs on sodium channels in the distal nephron and renal potassium excretion in 30 patients with acquired immunodeficiency syndrome (AIDS). They found that trimethoprim “increased the serum potassium concentration by 0.6 mmol/L (95% Cl, 0.29 to 0.95 mmol/L) despite normal adrenocortical function and glomerular filtration rate,” and that 15 of the 30 subjects exhibited serum potassium levels greater than 5 mmol/L during trimethoprim treatment. ¹²⁰ In a prospective chart review of 105 hospitalized patients with various infections, 80 of whom were treated with standard-dose TMP-SMX, they observed that serum potassium concentration in the treatment group increased about 5 days after TMP-SMX therapy was initiated. In contrast, the serum potassium concentration in the control group decreased nonsignificantly over 5 days. Thus, they reported that standard-dose TMP-SMX therapy used to treat various infections “leads to an increase in serum potassium concentration,” based on the findings that a “peak serum potassium concentration greater than 5.0 mmol/L developed in 62.5% of patients; severe hyperkalemia (peak serum potassium concentration > or = 5.5 mmol/L) occurred in 21.2% of patients.” They concluded that patients treated with standard-dose TMP-SMX “should be monitored closely for the development of hyperkalemia, especially if they have concurrent renal insufficiency (serum creatinine level > or = 106 μmol/L).” ¹²² Subsequently, in a prospective, randomized clinical study involving 97 outpatients, they investigated the effect of standard-dose TMP-SMX combination treatment on serum potassium concentrations. They observed that after 5 days, subjects receiving TMP-SMX (TMP, 320 mg/day; SMX, 1600 mg/day) “developed a statistically significant rise in the serum potassium concentration as compared with the control group,” who received other antibiotics. “However, severe hyperkalemia (K ⁺ ≥5.5 mmol/L) occurred in only 3 patients (6%) treated with trimethoprim-sulfamethoxazole,” and “none of the subgroups of treated patients developed clinically important hyperkalemia.” The authors interpreted these findings as suggesting that “outpatients, in contrast to [AIDS] patients and hospitalized patients with mild renal insufficiency, develop severe or life-threatening hyperkalemia less commonly when treated with this antimicrobial regimen.” Nevertheless, they cautioned that “outpatients having risk factors which may predispose to the development of hyperkalemia should be carefully monitored” when treated with TMP-SMX. ¹²³

Reports

Hyperkalemia has been reported in patients receiving high-dose trimethoprim as well as standard-dose TMP-SMX therapy. ^119,120,124 Velazquez et al. ¹²⁰ and Greenberg et al. ¹¹⁹ described increases in serum potassium concentration of 0.6 mmol/L and 1.1 mmol/L., respectively, in AIDS patients administered high-dose trimethoprim (20 mg/kg/day). Three other cases of hyperkalemia in elderly patients receiving standard-dose TMP-SMX therapy were subsequently reported. ^125-127 Koc et al. ¹²⁸ published a case report of severe hyperkalemia in two renal transplant recipients treated with standard-dose TMP-SMX.

Clinical Implications and Adaptations

Physicians prescribing trimethoprim or TMP-SMX are strongly encouraged to counsel these individuals to avoid unsupervised increases in potassium intake, in the form of supplements but also as high-potassium foods (e.g., fruit) or salt substitutes, on the basis of the increased risk for problematic interactions. A clinically significant increase in blood potassium levels represents a potentially serious adverse effect associated with trimethoprim or TMP-SMX therapy. The importance of frank inquiry and detailed inventory of concomitant (or even occasional) medications, diet, nutrients, and herbs cannot be overemphasized. Close supervision and regular monitoring are essential, particularly with long-term use in individuals with compromised renal function or other significant physiological burdens and those taking other medications that might alter potassium metabolism.

Acetylsalicylic acid (acetosal, acetyl salicylic acid, ASA, salicylsalicylic acid; Arthritis Foundation Pain Reliever, Ascriptin, Aspergum, Asprimox, Bayer Aspirin, Bayer Buffered Aspirin, Bayer Low Adult Strength, Bufferin, Buffex, Cama Arthritis Pain Reliever, Easprin, Ecotrin, Ecotrin Low Adult Strength, Empirin, Extra Strength Adprin-B, Extra Strength Bayer Enteric 500 Aspirin, Extra Strength Bayer Plus, Halfprin 81, Heartline, Regular Strength Bayer Enteric 500 Aspirin, St. Joseph Adult Chewable Aspirin, ZORprin); combination drugs: ASA and caffeine (Anacin); ASA, caffeine, and propoxyphene (Darvon Compound); ASA and carisoprodol (Soma Compound); ASA, codeine, and carisoprodol (Soma Compound with Codeine); ASA and codeine (Empirin with Codeine); ASA, codeine, butalbital, and caffeine (Fiorinal); ASA and extended-release dipyridamole (Aggrenox, Asasantin).

Similar properties: Salsalate (salicylic acid; Amigesic, Disalcid, Marthritic, Mono Gesic, Salflex, Salsitab).

High-dose aspirin may cause hypokalemia. ¹²⁹ The effects of chronic aspirin intake on potassium status have not been documented. Clinically significant adverse effects are improbable in otherwise-unmedicated individuals with a well-balanced diet rich in fruits and vegetables, but are possible in the context of other risk factors, such as declining function with physiological aging, diet poor in nutrients and high in processed foods, comedication with potassium-depleting medications, or individual pharmacogenomic variations affecting any of these influences.

Amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, dextroamphetamine sulfate; D-amphetamine, Dexedrine; combination drug: mixed amphetamines: amphetamine and dextroamphetamine (Adderall; dexamphetamine).

Amphetamine may theoretically disrupt potassium channels and thereby contribute to some of the adverse cardiac effects associated with these drugs. ^130,131 However, potassium channel function and dietary intake of potassium are not necessarily related. Focused research with well-designed clinical trials may be warranted to determine the existence, probability and circumstances, severity, and clinical significance of any such interaction.

Amlodipine (Norvasc); combination drug: amlodipine and benazepril (Lotrel); bepridil (Bapadin, Vascor), diltiazem (Cardizem, Cardizem CD, Cardizem SR, Cartia XT, Dilacor XR, Diltia XT, Tiamate, Tiazac), felodipine (Plendil); combination drugs: felodipine and enalapril (Lexxel); felodipine and ramipril (Triapin); gallopamil (D600), isradipine (DynaCirc, DynaCirc CR), lercanidipine (Zanidip), nicardipine (Cardene, Cardene I.V., Cardene SR), nifedipine (Adalat, Adalat CC, Nifedical XL, Procardia, Procardia XL); combination drug: nifedipine and atenolol (Beta-Adalat, Tenif); nimodipine (Nimotop), nisoldipine (Sular), nitrendipine (Cardif, Nitrepin), verapamil (Calan, Calan SR, Covera-HS, Isoptin, Isoptin SR, Verelan, Verelan PM); combination drug: verapamil and trandolapril (Tarka).

See also Angiotensin-Converting Enzyme (ACE) Inhibitors and Beta-Adrenoceptor Antagonists.

Calcium signaling appears to play a role in both renal and external handling mechanisms involved in potassium regulation. Both verapamil and nifedipine, at pharmacological doses, can impair aldosterone production, but chronic administration of verapamil (but not nifedipine) appears to attenuate aldosterone responsiveness to angiotensin II in vivo after potassium loading. Calcium channel blockers may improve extrarenal potassium disposal. In a review (1991) of the effects of calcium channel blockers on potassium homeostasis Freed et al. ¹³² noted: “Clinically, there are no reports of either hyperkalemia or hypokalemia with the routine therapeutic use of these agents given alone.” The authors concluded that review of the “data indicates that current evidence implicating this class of drugs in the pathogenesis of disordered potassium regulation remains equivocal.” The authors reported the “development of hyperkalemia in a patient with chronic renal failure following the initiation of therapy with the calcium channel blocker diltiazem: however, numerous other etiologies may also have contributed to the development of hyperkalemia in this case.”

Lavin et al. ³⁷ examined the effect of 6 months’ nifedipine (or captopril) therapy on lymphocyte magnesium and potassium levels in 28 patients treated for hypertension. They observed “no difference in serum or lymphocyte concentrations in the two groups compared to 45 healthy, normotensive controls.”

Ephedrine (Adrenaline, Epi; Adrenalin, Ana-Gard, AsthmaHaler, AsthmaNefrin, Bronchaid, Bronkaid Mist, Brontin Mist, Epifin, Epinal, EpiPen, Epitrate, Eppy/N, Medihaler-Epi, Primatene Mist, S-2, Sus-Phrine; epinephrine, injectable: Adrenalin Chloride Solution, EpiPen Auto-Injector.

Based on the function of epinephrine/adrenaline as a “stress hormone,” some secondary literature has suggested that elevated levels may reduce intracellular concentrations of potassium and magnesium and thus could be associated with hypokalemia. ¹³³ In some discussions, adrenaline and beta-adrenergic agonists are lumped together, even though adrenaline is both an alpha-adrenergic and a beta-adrenergic agonist. Moreover, patients almost never use adrenaline on an ongoing basis; it is almost exclusively used in allergic reactions and other acute care situations, with the possible exception of Primatene mist (inhaled adrenaline OTC drug), which has been linked to asthma deaths, presumably from arrhythmias. Evidence from clinical trials or qualified case reports is lacking, and proposed mechanisms have not been confirmed in relation to exogenous intake of epinephrine as a pharmaceutical agent.

Pending substantive research findings, it seems prudent that individuals using epinephrine on a repeated basis be counseled to maintain a diet high in potassium (as well as vitamin C and magnesium) or should consider regular use of a multinutrient formulation containing these nutrients. In general, close supervision and regular monitoring are warranted in patients prescribed adrenaline or related beta-adrenergic agonists, particularly with repeated use in individuals with compromised renal function, a history of cardiac irregularities or other significant physiological burdens, and taking other medications that might alter potassium metabolism.

Cinoxacin (Cinobac, Pulvules), ciprofloxacin (Ciloxan, Cipro), enoxacin (Penetrex), gatifloxacin (Tequin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), moxifloxacin (Avelox), nalidixic acid (Neggram), norfloxacin (Noroxin), ofloxacin (Floxin, Ocuflox), sparfloxacin (Zagam), trovafloxacin (alatrofloxacin; Trovan).

Several minerals can decrease the absorption of fluorinated quinolone antibiotics by chelating with these antibiotics when administered simultaneously. In such situations, the antimicrobials appear to be rendered inactive when the 3-carbonyl and 4-oxo functional groups characteristic of medications in this class form chelates with multivalent metal cations, particularly aluminum, magnesium, calcium, iron, and zinc, but also copper, manganese, and possibly sodium.

There is general agreement as to the pattern of interaction between fluoroquinolones and multivalent cations, as discussed in the monographs for several minerals. However, no published research (case reports or clinical trials) has specifically found that potassium acts in this way or adversely affects fluoroquinolone antibiotics by any other known mechanism.

Nevertheless, physicians prescribing fluoroquinolone antibiotics should instruct patients to take any mineral supplements (as well as related antacids) as far apart as possible from the medications, although a margin of at least 6 hours before or 2 hours after the antibiotics is usually adequate, to avoid the potential interaction. It is important to note that this interaction concern is only relevant to oral administration of both agents.

Haloperidol (Haldol)

Haloperidol has variously been observed to induce both hyperkalemia and hypokalemia. ^134,135 The clinical significance of changes in potassium concentrations due to haloperidol remains unclear, and specific evidence from relevant clinical trials is lacking.

Physicians prescribing haloperidol should consider disturbances in potassium metabolism and status among the potential adverse effects discussed with patients and monitored during therapy. Physicians should caution against rapid increases or decreases in potassium intake, from supplements, salt substitutes, or food sources (e.g., fruit), and any significant changes in potassium intake should be professionally supervised. The limitations of using serum potassium levels to detect intracellular potassium concentrations should be kept in mind when watching for adverse drug reactions.

Heparin (Calciparine, Hepalean, Heparin Leo, Minihep Calcium, Minihep, Monoparin Calcium, Monoparin, Multiparin, Pump-Hep, Unihep, Uniparin Calcium, Uniparin Forte).

Related but evidence lacking for extrapolation:

Heparinoids:Danaparoid (Orgaran), fondaparinux (Arixtra).

Heparin therapy may increase serum potassium levels and has been associated with hyperkalemia. ^94,136 Physicians administering heparin are advised to consider potential elevations in potassium levels and caution against rapid increases or decreases in potassium intake, from supplements, salt substitutes, or food sources (e.g., fruit). Any significant changes in potassium intake should be professionally supervised. Focused research with well-designed clinical trials may be warranted to determine the existence, probability and circumstances, severity, and clinical significance of any such interaction.

Animal-source insulin: Iletin; human analog insulin: Humanlog; human insulin: Humulin, Novolin, NovoRapid, Oralin.

Matsumura et al. ¹³⁷ reported the case of 47-year-old man with type 2 diabetes mellitus who experienced severe electrolyte disorders (including hypokalemia, hypophosphatemia, and hypomagnesemia) after attempting suicide by subcutaneously injecting a massive dose (2100 U) of insulin. Although this unique and extreme incident appears to carry minimal relevance to typical diabetic patients, this report has been mentioned as an example of a potential interaction between insulin and potassium. Pending well-qualified case reports or other scientific data indicating clinically significant interactions, further research does not seem warranted.

Notably, one of the standard treatments for life-threatening hyperkalemia is administration of glucose and insulin, which moves large amounts of potassium from the serum to the intracellular compartment to assist in rapidly lowering serum potassium.

Phenylpropanolamine (Acutrim, Dex-A-Diet, Dexatrim, Phenldrine, Phenoxine, PPA, Propagest, Rhindecon, Unitrol); combination drugs: Ami-Tex LA, Appedrine, Contac 12 Hour, DayQuil Allergy Relief, Dex-A-Diet Plus Vitamin C, Diadex Grapefruit Diet Plan, Dimetapp, Entex LA, Robitussin CF, Tavist-D, Triaminic-12.

Pseudoephedrine (Afrinol, Cenafed, Chlor Trimeton, Decofed, Dimetapp Decongestant, Drixoral, Efidac, Genaphed, PediaCare Infant Drops, Ridafed, Sudafed, Sudrine, Suphedrin, Triaminic A.M.).

Unsupported statements scattered through secondary literature mention the possibility of hypokalemia being associated with use of pseudoephedrine, phenylpropanolamine, and related decongestants. Published evidence from clinical trials is lacking to substantiate the occurrence of any such interaction, as is documentation of any proposed or proven mechanism of action.

The sympathomimetic effects of these medications may be similar to effects of the beta-2 agonists.

Demeclocycline (Declomycin), doxycycline (Atridox, Doryx, Doxy, Monodox, Periostat, Vibramycin, Vibra-Tabs), minocycline (Dynacin, Minocin, Vectrin), oxytetracycline (Terramycin), tetracycline (Achromycin, Actisite, Apo-Tetra, Economycin, Novo-Tetra, Nu-Tetra, Sumycin, Tetrachel, Tetracyn); combination drugs: chlortetracycline, demeclocycline, and tetracycline (Deteclo); bismuth, metronidazole, and tetracycline (Helidac).

Potassium may interact with tetracycline antibiotics in several ways. As with many minerals, but not as strongly as others, potassium may form chelates with tetracyclines, thereby impairing absorption of both agents. Tetracycline may interfere with the activity of potassium. Finally, self-limiting esophagitis and renal damage, adverse effects associated with tetracyclines, may be aggravated by concomitant potassium or may produce hyperkalemia from nephrotoxic effects, respectively. ^113,114,138

In 1965, Mavromatis ¹³⁹ published a case describing tetracycline-induced nephropathy confirmed by renal biopsy. This apparently unique report has germinated a concern that tetracycline might cause hypokalemia because of its nephrotoxic effects. Evidence to substantiate this as an adverse event of any frequency is lacking but reinforces the recurrent admonition to monitor renal function and watch for hyperkalemia in at-risk patients.

Teplick et al., ¹¹³ as well as other authors, reported several cases of esophagitis caused by oral potassium chloride (“slow KCl” liquid and tablets), tetracycline capsules, and doxycycline capsules, separately. ^114,138 The concomitant use of these agents could theoretically increase the probability of adverse reactions. The authors noted that in “all reported cases caused by KCl tablets, left atrial enlargement was present as the result of mitral stenosis.” ¹¹³

Only minimal evidence from clinical trials or qualified case reports is available documenting or substantiating these possible interactions. This lack of confirmation in the literature suggests that such interactions are rare and of minimal clinical significance.

Physicians prescribing tetracycline-class antibiotics for longer than 2 weeks are advised to monitor renal function closely in patients with compromised renal function. Clinically significant potassium depletion is improbable in most individuals with short-term use of these medications. It is generally recommended that tetracycline antibiotics be taken on an empty stomach, with a full glass of water, 1 hour before or 2 hours after ingestion of any supplements, food, or other drugs. However, separating intake of antibiotics from mineral intake may be particularly important given the propensity to chelation between minerals and many medications. Further, potassium chloride should generally be taken with plenty of water and an upright position maintained for at least 1 hour after ingestion to avoid esophageal irritation; other forms of potassium may be tolerated more readily.

Dyphylline (Dilor, Lufyllin), fenoterol (Berotec), oxytriphylline (Choledyl), salbutamol (Airomir, Apo-Salvent), terbutaline (Brethaire, Brethine, Bricanyl), theophylline/aminophylline (Phyllocontin, Slo-Bid, Slo-Phyllin, Theo-24, Theo-Bid, Theocron, Theo-Dur, Theolair, Truphylline, Uni-Dur, Uniphyl); combination drug: ephedrine, guaifenesin, and theophylline (Primatene Dual Action).

Although still unresolved after contentious debate for over 20 years, it appears that beta-2 sympathomimetic drugs can affect potassium status to the point of inducing hypokalemia, but that clinically significant adverse effects are improbable in most individuals. ¹⁴⁰ As summarized by Cayton ¹⁴¹ in a letter: “The beta2 receptor has an important role in potassium homoeostasis, and hypokalaemia is a physiologically and pharmacologically predictable consequence of treatment with beta2 sympathomimetic bronchodilator drugs, which has been well documented in normal and asthmatic subjects.”

In a clinical trial involving four groups of four healthy young subjects each, Haalboom et al. ¹⁴² investigated the effects on plasma potassium after inhalation of fenoterolin, a beta-2 agonist. Plasma potassium levels decreased significantly in subjects from the three groups who received fenoterol, whereas levels were unchanged in the placebo group. Based on these preliminary findings, the authors cautioned: “Inhalation of beta 2-agonists may be dangerous, especially in patients under stress—e.g., during an acute asthmatic attack, when the plasma potassium concentration would already be subnormal as the result of raised circulating adrenaline levels.” ¹⁴² However, in a series of published letters, Smith, Berkin, and others replied that although “it is not disputed that acute beta2 agonist administration lowers the plasma potassium, the clinical relevance of this is not established.” Citing prior research, they added: “Perhaps more importantly, the effect of chronic beta2 agonist dosing on plasma K appears to be negligible.” ^143-145

Physicians treating patients using beta-2 sympathomimetic bronchodilator drugs are advised to monitor potassium levels, keeping in mind that serum concentrations can reveal hypokalemia but do not accurately reflect intracellular levels, and to be watchful for indications of potassium deficiency. The risk of compromised potassium status is often already heightened in patients with asthma taking steroids or those being treated with digoxin/diuretics for congestive heart failure. Concomitant nutritional support with potassium and magnesium may be beneficial in many of these patients but requires professional supervision and regular monitoring, at least initially, and on a continued basis in any individuals with compromised renal function. Well-designed clinical trials investigating this potentially dangerous adverse effect may be warranted to determine the existence, probability and circumstances, severity, and clinical significance. Discovery, compilation, and analysis of qualified case reports are also warranted.

Thiorodazine (Mellaril).

Ventricular arrhythmias associated with use of thioridazine in alcohol withdrawal may be caused by alterations in electrical activity within the heart. ¹⁴⁶ Coadministration of potassium might reduce the incidence and severity of such adverse effects, but substantive evidence from clinical trials and qualified reports is lacking.

Magnesium carbonate combination drug: magnesium carbonate, aluminum hydroxide, alginic acid, and sodium bicarbonate (Gaviscon Extra Strength Tablets, Gaviscon Regular Strength Liquid, Gaviscon Extra Strength Liquid); magnesium hydroxide (Phillips’ Milk of Magnesia MOM); combination drugs: magnesium hydroxide and aluminum hydroxide (Advanced Formula Di-Gel Tablets, Co-Magaldrox, Di-Gel, Gelusil, Maalox, Maalox Plus, Mylanta, Wingel); magnesium hydroxide and calcium carbonate (Calcium Rich Rolaids); magnesium hydroxide, aluminum hydroxide, calcium carbonate, and simethicone (Tempo Tablets); magnesium trisilicate and aluminum hydroxide (Adcomag trisil, Foamicon); magnesium trisilicate, alginic acid, and sodium bicarbonate (Alenic Alka, Gaviscon Regular Strength Tablets).

Magnesium plays a critical role in potassium metabolism. The dynamic and interdependent relationship between potassium and magnesium is demonstrated throughout the literature examining the physiology, pharmacology, therapeutics, and interactions of these key minerals, most critically with regard to cardiac electrical activity. ¹⁴⁷ Magnesium depletion may be a cause of potassium deficiency, and magnesium coadministration is often necessary to correct refractory potassium repletion. ^51,148 However, administration of potassium may increase the need for magnesium intake. Conversely, increased magnesium intake may cause a fall in serum potassium concentrations unless potassium intake is also increased.

The risk of cardiac arrhythmias or adverse effects due to the depletion of or interaction between these electrolytes is heightened in individuals taking potassium-depleting diuretics or digoxin or otherwise at risk of developing potassium deficiency becasue of chronic diarrhea, vomiting, or other factors. ^80,104 Physicians treating individuals with such elevated risk, especially those with cardiac irregularities, are advised to encourage patients to maintain a regular and ample intake of foods rich in potassium, particularly fruits and vegetables, and to avoid changes in intake of either nutrient, especially rapid increases of supplemental forms, outside the context of medical supervision and regular monitoring.

Botanical agents with a diuretic action may or may not inherently deplete potassium or other nutrients, and some, such as dandelion leaf (Taraxacum),may actually enhance mineral levels. The plant part(s) used, preparation, dosage, and clinical context all influence the mechanism by which any single herb or botanical combination achieves diuresis and the degree of depletion of potassium or other electrolytes. In general, a huge gap exists between the collective clinical experience of trained prescribers of botanical medicines and the relevant scientific literature of well-designed, adequately powered clinical trials as well as qualified case reports. Nevertheless, such effects and the limitations in the available data are discussed here to a limited degree and more thoroughly in the monographs on the major plant medicines in clinical use.

Ipecac (Cephaelis ipecacuanha).

Repeated use of ipecac as an emetic can excessively lower serum potassium levels. ¹⁴⁹ Health care professionals treating individuals with eating disorders or engaged in unsupervised rapid weight loss programs should caution them regarding the potential adverse effects of electrolyte imbalances and potentially dangerous practices associated with bulimia and other eating disorders. Increased consumption of fruit and potassium-containing mineral formulations may be appropriate pending suspension of such behavior.

Licorice root (Glycyrrhiza glabra, G. uralensis, G. echinata, G. pallidiflora);carbenoxolone (CBX); deglycyrrhizinated licorice, DGL.

See also Licorice monograph.

Licorice root from several species has been used in various forms in the traditional practices of European, American, and Chinese herbal medicine for centuries, if not millennia, and has generally been regarded as safe with professional evaluation and supervision. Nevertheless, high-dose chronic intake of herbal products containing licorice with the glycyrrhizin constituent present can cause pseudoaldosteronism, in certain susceptible individuals, characterized by elevated blood pressure, hypokalemia, and fluid retention, resulting from mineralocorticoid activity. Intake of more than 1 g of glycyrrhizin daily, the amount in approximately 10 g of licorice root, is considered adequate to produce clinically significant adverse effects. ¹⁵⁰ Consequently, individuals with a history of or predisposition to hypertension are encouraged to use herbal medications containing non-deglycyrrhizinated (i.e., glycyrrhizin-containing) licorice (non-DGL) only under the supervision of health care professionals trained and experienced in herbal medicine and with active collaboration with the prescribing physician(s) whenever diuretics or cardiac medications are involved.

In contrast, licorice extracts that have been deglycyrrhizinated, and thus are typically labeled as “DGL,” do not induce these effects, nor do most of the “licorice” confectionary products, because they generally do not contain actual licorice root.

Senna ( Cassia senna, Cassia angustifolia;Black-Draught, Fletcher's Castoria, Gentlax, Senexon, Senna-Gen, Senokot, Senolax).

See Laxatives and Stool Softeners.