Replacing Magnesium and Potassium In Diuretic Therapy

Goal
     To update the clinician’s knowledge of the importance of replacing potassium and magnesium orally, in light of the latest recommendations that diuretics remain first-line therapeutic agents in treatment of hypertension.

Objectives
     Upon concluding this program, the clinician should be able to:

• Outline reasoning behind recommendations that diuretics be used as first-line agents in treatment of uncomplicated essential hypertension;
• List the cations likely to be depleted by such therapy and the consequences of depletion; and
• Design therapeutic diuretic and supplemental regimens appropriate for the hypertensive patient in order to maximize therapeutic efficacy and minimize potential complications.

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Introduction
     “Hypertension currently affects 50 million people in the United States. For those without hypertension who are 55-65 years of age, the lifetime probability of developing hypertension is 90%. Forty percent of the overall cost of $37 billion for hypertension is for drug therapy, currently taken by 24 million people.” 1     
     According to The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-299, thiazide-type diuretics (TTDs) were unsurpassed in reducing clinical events and lowering blood pressure and were as well-tolerated as calcium channel blocker (CCB) and angiotensin-converting enzyme inhibitor (ACE inhibitor) therapy in ALLHAT. Thus, diuretics continue to be recommended as initial therapy in hypertension. While the details of the study and its conclusions were considerably more complex than that; and treatment of hypertension in any given individual must be based on multiple parameters, it seems an undeniable assessment that diuretics will reasonably remain a cornerstone in the treatment uncomplicated hypertension. All this in spite of the facts that other classes of antihypertensive medication are more expensive and that the underlying mechanisms by which diuretics provide enduring lowering of blood pressure remain poorly understood – the theory and observation that they temporarily reduce blood volume doesn’t adequately explain their long-term effectiveness.1
     The ALLHAT study also seems to defy the logic of “you get what you pay for,” since the diuretics, most now available as generic formulations, represent some of the most economical of all therapeutic choices when treating hypertension; yet they have been demonstrated to provide superior protection against the advancement of cardiovascular disease (CVD) and incidence of both fatal and non-fatal myocardial infarction. The plain fact of it is that most hypertensive patients are just better-off in the long run for taking a diuretic than another more expensive option in the absence of another significant factor (like diabetes), especially since most cases of hypertension lack a single definable and reversible causative factor.
     Those patients insufficiently responsive to a single medication for hypertension and appropriate lifestyle changes should be considered for combination therapy to minimize the side effects of higher doses of a single therapeutic option and optimize clinical efficacy, and such combinations typically include a diuretic when the first choice was not a diuretic. As with many health problems, it is often rational to use small to moderate dosages of multiple medications to achieve blood pressure goals in order to reduce the incidence and severity of side effects.
     This also emphasizes that hypertension is merely a symptom of what is usually a function of multiple existing problems in metabolism and lifestyle (usually including extent of atherosclerosis as a function of age and lifestyle choices), tends to worsen over time without intervention, and eventually leads to other more severe problems that can include congestive heart failure, cardiovascular disease, myocardial infarction, and stroke, whose reduction in incidence and severity are the ultimate goal of antihypertensive efforts. It is important to note that the ALLHAT study compared usage of one agent in each of the three relevant classes of medication (chlorthalidone in the case of the thiazide-like diuretic), but that broad assumptions can be made from such large study results; and the importance of normalizing blood lipids in the process of minimizing developing cardiovascular disease cannot be ignored. 1

Cation Depletion
     The fact that diuretics continue to be considered first-line therapy in uncomplicated hypertension, though, highlights the necessity of addressing the problem of depletion of magnesium (Mg) and potassium (K) by the diuretics, and possibly even zinc, especially with long-term therapy. One of the most common and serious side effects of diuretic therapy is in increased urinary loss of K, and though less well-publicized and measured, excessive urinary loss of Mg can also be clinically significant. Significant depletion of other cations has yet to be sufficiently studied, but zinc depletion may also prove problematic. Diuretic effects on Calcium (Ca) and Sodium (Na) levels and metabolism, while certainly important, seem to be shadowed by effects on K and Mg, to the extent that if K and Mg levels are maintained, Ca and Na tend to be minor considerations that are more manageable in the proper environment provided containing stable and adequate amounts of K and Mg. The effects of diuretics on Mg and K metabolism should take into account site of action and duration of action of diuretics, duration of treatment and dosage used, concurrent drug therapy, underlying disease conditions, and dietary intake of Mg and K.
     Blood levels of chloride, calcium phosphates, bicarbonate, sodium, potassium, and magnesium, as cations, are basic measures of health that comprise the electrolyte panel. As such, they provide a range of normal or acceptable values, beyond which a variety of disease states may be contributory and problematic. While most such values are fairly rigid boundaries of normalcy within the blood, and more specifically in the serum, the body as a system tends to maintain them within normal limits at the expense of stores found in more substantial tissues like bone. An abnormal value taken alone may or may not signify dysregulation that may point to any of a variety of pathologies. Importantly, the serum level of potassium is fairly friable within limits, in that it tends to respond fairly rapidly to changes that might affect it. Magnesium, on the other hand, is present in smaller amounts and seems more carefully maintained by homeostatic systems; so by the time blood levels of magnesium are noticed, serious depletion of body stores may be well underway.
     Diuretics acting in the proximal tubule tend to have only minor effects on Mg excretion. Loop-blocking diuretics, though, cause major urinary losses of Mg, which have been demonstrated in numerous experimental and clinical studies, findings consistent with micropuncture studies in laboratory animals that implicate the loop of Henle as the major site of Mg reabsorption. The effects of thiazide-like diuretics on Mg excretion, then, are less well-established than those of loop-blocking diuretics. Experimental studies demonstrate that thiazides have little or no direct effect on Mg transport in the nephron, but some clinical studies indicate that thiazide treatment may still induce Mg loss as a function of alterations in the renin-angiotensin-aldosterone system and in the process of regulating calcium and parathyroid hormone and may also be affected by concurrent treatment with other medications and various underlying disease conditions. Potassium-sparing diuretics are often administered concomitantly with more potent diuretics in an effort to assuage diuretic-induced K depletion. These agents act in the late distal tubule and collecting duct; and evidence continues to accumulate that these agents may also exert some magnesium-sparing properties as well.
     Experimental and clinical investigations from various laboratories point toward a dose-response relationship of amiloride in reducing fractional excretion of Mg and K during furosemide-induced diuresis, with a net effect on Mg excretion less than on K excretion, an observation compatible with the different theoretic handling of K and Mg in the distal tubule and collecting duct. The effects of aldosterone antagonists on Mg excretion are less well-established than those of amiloride, and some recent studies indicate that angiotensin-converting enzyme inhibitors may also influence Mg and K metabolism, which may also have important therapeutic implications. At any rate, it should be clear that magnesium loss should be a serious consideration of any long-term diuretic therapy, as significant as loss of potassium. 2

Table 1: Consequences of depletion of various ions during potassium-sparing diuretic therapy. 3
     An increase in serum potassium levels may occur after coadministration of potassium-sparing diuretics and ACE inhibitors, resulting in hyperkalaemia especially in patients with renal insufficiency.
- Drug Saf 1995 May; 12(5): 334-47 -- ACE inhibitors. Drug interactions of clinical significance. -- Mignat C, Unger T.
      Its occurrence is dose dependent and can be corrected by potassium supplements, but potassium-retaining diuretics, which also correct the often associated fall in serum magnesium, are preferable. Many reports link hypokalaemia with cardiac arrhythmias, but some dispute this association in the absence of the concomitant use of digoxin. Hyponatraemia rarely occurs, but can be life threatening. Calcium excretion is markedly reduced, but unlike other electrolyte disturbances from diuretics, this may be valuable: some suggest diuretics have an anti-osteoporotic action. Diuretics increase glucose and insulin resistance and should be used sparingly in diabetics.
- Eur Heart J 1992 Dec; 13 Suppl G: 96-103 -- Adverse reactions to diuretics. -- Prichard BN, Owens CW, Woolf AS. Urinary zinc excretion was studied in a randomized trial in 9 patients during treatment with bendroflumethiazide, chlorthalidone and hydrochlorothiazide and in another 9 patients during treatment with bumetanide, furosemide and triamterene.
     During treatment with the thiazides, the zinc concentration rose by 30% and the total amount of zinc excretion increased by 60%. In contrast, during treatment with the loop-diuretics, urine zinc concentration diminished and the total amount of zinc excretion increased much less than during therapy with the thiazides.
- Acta Med Scand 1980; 208(3): 209-12 -- Urinary zinc excretion during treatment with different diuretics. -- Wester PO. May cause magnesium deficiency and potassium deficiency.
- Acta Med Scand Suppl 1986; 707:79-83 -- Potassium-sparing diuretics. -- Dyckner T, Wester PO. One of the most common and serious side effects of diuretic therapy is in increased urinary loss of potassium. Another, although less well publicized, side effect of diuretic therapy is excessive urinary loss of magnesium.
- Magnesium 1986; 5(5-6): 282-92 -- Magnesium and potassium-sparing diuretics. -- Ryan MP. In general, the multitude of nutrients required for optimum health are synergistic and interdependent. Thus, a depletion of one signifies a high likelihood of deficiencies in others. Many nutrients, for example, require the presence of either calcium or vitamin C for normal physiological utilization, and a deficiency of any of the B vitamins implies a deficiency in the B vitamins in general, as they occur together in nature. In this light, while symptoms of serum deficiency in any major cation would be expected to share a number of similarities, potassium deficiency (hypokalemia) is more widely-recognized than some others, easily and more reliably measured in blood and serum, clearly defined in its acute state, and characterized by muscle weakness, fatigue, mental confusion, irritability, weakness, increased vulnerability to arrhythmia, and disruptions in nerve conductivity and muscle contraction. Due to their close relationship, with few exceptions, what is true for potassium is also true for magnesium. A diet low in fresh fruits and vegetables but high in sodium can significantly contribute to a chronic potassium and magnesium deficiency, sometimes seen in elderly populations; and the impact of such deficiency can certainly be amplified in the presence of therapy with the digitalis glycosides, which enhance vulnerability to arrhythmia. 4 Both enjoy major stores in bone and can be mobilized extensively from bone by normal regulatory measures to maintain a narrow range of normal blood levels. Body stores of both generally increase in conditions of urinary retention (oliguria, anuria, urinary obstruction, renal failure, etc.) and decrease due to inadequate intake, excessive loss (as in diarrhea and vomiting), and movement into cells (as in conditions causing alkalosis). Dietary potassium deficiency, though, is less common than deficiency caused by excessive fluid loss from sweating, diarrhea, or urination, or the use of diuretics, laxatives, aspirin, and a few other medications. The amount of potassium normally lost in sweat is significant (up to 3 grams of potassium per day), especially during prolonged exercise in a warm environment. Those who regularly exercise have higher potassium needs, so a daily intake of at least 4 grams of potassium is recommended for such individuals. While particularly true for the elderly, athletes, and people with high blood pressure, patients who consume 4,000 mg. of potassium or more per day have a much lower incidence of all degenerative diseases including insulin resistance syndrome, hypertension, stroke, obesity, and adult onset diabetes. In addition to functioning as an electrolyte, potassium is essential for conversion of blood sugar into glycogen, the storage form of blood sugar in the muscles and liver. A potassium shortage results in lower levels of stored glycogen. Because exercising muscles use glycogen for energy, a potassium deficiency produces great fatigue and muscle weakness, the first signs of potassium deficiency. 4 Cells actually pump sodium out and potassium in via the "sodium-potassium pump" in the membranes of all body cells. One essential function is prevention of cellular swelling -- If sodium is not pumped out, water accumulates within the cell to cause cellular edema. The sodium-potassium pump also functions to maintain the electrical charge within the cell, which is particularly important to muscle and nerve cells. During nerve transmission and muscle contraction, potassium exits the cell and sodium enters, which results in an electrical charge change. This change causes a nerve impulse or muscle contractions. 4 While the systems of most patients can adequately cope with almost any excess of potassium, those with kidney disease are not capable of excreting excess and thus may easily suffer overload and toxicity, which not only affects muscles, but most significantly, the heart to cause arrhythmia. The diabetic patient is at risk even in the absence of known renal insufficiency. Potassium supplementation (unless closely supervised ) is contraindicated when using a number of medications, including digitalis glycosides, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and beta-blockers. 4, 5 Hyperkalemia (an excess of serum potassium) is a potentially life-threatening illness that can be difficult to diagnose and that can lead to sudden death due to arrhythmia, and the clinician must be alert to its possibility in patients at risk. The possibility of hyperkalemia requires immediate ECG to determine the presence of electrocardiographic signs of electrolyte imbalance and minute-to-minute levels of potassium are controlled by intracellular to extracellular exchange, mostly by the sodium-potassium pump that is controlled by insulin and beta2 receptors. A balance of GI intake and renal potassium excretion normally maintains long-term potassium balance. 5, 6