Role of Potassium in Hypertension: In light of Recent JNC 8 Guidelines

Hypertension: a disease of changing civilization

It is being increasingly recognized now-a-days that a mismatch between our ancient physiology and the western diet and lifestyle underlies many so-called diseases of civilization, such as hypertension, coronary heart disease, obesity, and type 2 diabetes.¹Carrera-Bastos P, Fontes-Villalba M, O’Keefe JH, et al. Research Reports in Clinical Cardiology 2011:2 15-35.   This makes a compelling case for possible causal role of diet and dietary behaviors in these diseases, with other lifestyle factors, such as physical inactivity, playing a contributory role in addition. Particularly, an inversion of the potassium and sodium concentrations in modern diet is a recent event in human evolutionary history that is believed to contribute to the rising prevalence of hypertension. This might be due to an increasing use of table salt, a high intake of processed foods (with added salt), and the displacement of potassiumrich foods (e.g., fruit and vegetables) by potassiumpoor foods, such as vegetable oils, refined sugars, whole grains, and dairy products that has apparently resulted in substantially lower average potassium content in our modern diets than its sodium content. In this review, we focus on this dietary inversion, and aim to identify the role of potassium in hypertension as a potential and enticing therapeutic target.

Potassium: an important nutrient in the body

Potassium is a major intracellular cation that is required for normal functions in the body.²Institute of Medicine (U.S.). Panel on Dietary Reference Intakes for Electrolytes and Water. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate / Panel on Dietary Reference Intakes for Electrolytes and Water, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board 2005. Available at: http:// www.nal.usda.gov/fnic/ DRI/DRI_Water/water_full_report.pdf [Accessed on 26.5.2014].  ^,3Delgado MC. Current Hypertension Reports 2004;6(1):31-35.   It maintains fluid volume inside/outside of cells, and thus normal cellular function, decrease markers of bone turnover and recurrence of kidney stones, and acts to blunt the rise of blood pressure (BP) in response to excess salt intake.⁴Dietary Reference Intakes: Electrolytes and Water. Available at: http://www.iom.edu/Global/News%20Announcements/~/me dia/442A08B899F44DF9AAD083D86164C75B.ashx [Accessed on 26.5.2014].   Deficiency of potassium consequently results in homeostatic alterations detrimental to the human health, dependent on the extent of potassium lost. While severe potassium deficiency is characterized by clinical hypokalemia (serum potassium concentration <3.5 mmol/L), resulting in various adverse consequences, such as cardiac arrhythmias, muscle weakness, and glucose intolerance; the effect of moderate potassium deficiency is more subtle, typically occurring without overt hypokalemia, and characterized by increased BP, increased salt sensitivity, increased bone turnover, and risk of kidney stones. These adverse effects can result from a deficiency of potassium, a deficiency of its conjugate anion, or both.

Identifying the impact on cardiac health – sodium and/or potassium?

An inadequate intake of dietary potassium is particularly linked with increased risk of hypertension, and cardiovascular disease (CVD), and this relationship is the subject of this review, not including consequences of overt hypokalemia. Evidence from epidemiological, experimental and clinical studies suggests potassium as an important regulator of BP, consistent with findings of surveys conducted in widely divergent geographic locations that extrapolate this negative association by indicating higher prevalence of hypertension in populations consuming diets low in potassium.⁵Krishna GG. J Am Soc Nephrol. 1990;1(1):43-52.  

This importance of potassium is also reinforced by the Dietary Guidelines for Americans 2010 Advisory Committee, which identifies potassium as one of the shortfall nutrient vital for human health. The committee made this conclusion based on a moderate body of evidence on association between potassium intake and BP reduction in adults, which in order influences the risk of CVD.⁶Weaver CM. Adv Nutr. 2013;4(3):368S-77S.   It is however the sodium-to-potassium intake ratio that is often cited as a better predictor of cardiovascular outcome than either nutrient per se – a high-sodium/low-potassium environment is supposed to significantly alter the central hemodynamics, leading

to potential target organ damage, this effect being largely mediated by altered renal sodium handling, impaired endothelium-dependent vasodilatation, and increased oxidative stress.

Nonetheless, potassium may be the element that could alternatively be more relevant in initial stages of hypertension. An evidence emerging through a study of arterial pressure and body content of electrolytes in 91 patients with essential hypertension and 121 normal controls points towards this prospect. Lever AF et al⁷, in this study, proposed three hypotheses to explain the mechanisms relating electrolytes and arterial pressure in essential hypertension – namely, a cell-salt hypothesis, a dietary salt hypothesis, and a kidney-salt hypothesis (Table 1); these are not necessarily independent or exclusive. It was concluded that two mechanisms probably operate in essential hypertension. In the early stages of the disease, BP is raised by an abnormal process related more closely to potassium than to sodium, with it being fundamental to BP regulation. A renal lesion develops later, possibly due to hypertension, characterized by resetting of pressure natriuresis and manifested by an abnormal relation between body sodium and arterial pressure and by susceptibility to increased dietary sodium intake. This possibly suggests that a potassium centered approach might be more prudent in initial hypertension.

Diet: an important variable to modulating potassium intake

The increased prevalence of hypertension and CVD is undoubtedly associated with the modern highsodium/ low-potassium diet.⁸Castro H, Raij L. Semin Nephrol. 2013;33(3):277-89.   In modern societies, wide interest towards Western diets have led to a decrease in potassium intake with reduced consumption of

fruits and vegetables and with an allied increase in sodium intake through increased consumption of processed foods.⁶Weaver CM. Adv Nutr. 2013;4(3):368S-77S.   This dietary modulation, operating on a genetic substrate of susceptibility, is postulated the prime factor in genesis and continuation of “essential” hypertension.⁹Meneely GR, Battarbee HD. Am J Cardiol. 1976;38(6):768-85.   The noxious effect perpetuates right from childhood with development of such dietary patterns and continuing in adulthood with increasing use of convenience and snack foods containing artificially high concentrations of sodium and low levels of potassium. As follows, the benefits of dietary potassium on cardiac health may therefore be primarily through its effect on BP (discussed below) as high dietary potassium is associated with a decrease in BP, particularly in context of a high-sodium diet. Table 2 gives recommended adequate dietary intakes of sodium and potassium for different age groups.⁴Dietary Reference Intakes: Electrolytes and Water. Available at: http://www.iom.edu/Global/News%20Announcements/~/me dia/442A08B899F44DF9AAD083D86164C75B.ashx [Accessed on 26.5.2014].  

Hypertension and initial antihypertensive medications

An understanding of hypertension and its initial management is desirable to more closely identify the impact of potassium on cardiac health. Hypertension is a major modifiable risk factor in the development of CVD, stroke, and end-stage renal disease, imposing immense socio-economic burden.1¹⁰Aburto NJ, Hanson S, Gutierrez H, et al. BMJ 2013;346:f1378.   It is in fact identified as the largest risk factor for cardiovascular mortality, followed by overweight/obesity, physical inactivity, high low-density lipoprotein (LDL)- cholesterol, smoking, high dietary salt, and high trans fatty acids. This may have wide socio-demographic and prognostic implications seeing that the world is aging with increasing life-expectancy, and adults older than 50 years of age have an almost 90% lifetime risk of developing hypertension¹¹Appel LJ, Brands MW, Daniels SR, et al; Hypertension. 2006;47(2):296-308.  ; with consequently increased risk of cardiac events, such as coronary heart disease (CHD) and stroke, which together are leading causes of mortality.⁶Weaver CM. Adv Nutr. 2013;4(3):368S-77S.   Importantly, this relationship between BP and these subsequent events is direct and progressive throughout the range of BP even including the non-hypertensive ranges of BP. As such, small changes in BP can have substantial effects on mortality; for instance, a 2-mmHg reduction in BP can reduce mortality attributable to stroke by 6% and CHD by 4% in adults.⁶Weaver CM. Adv Nutr. 2013;4(3):368S-77S.   Therefore, the intervention should begin as early as possible.

Initial antihypertensive treatment

In uncomplicated stage I hypertension (systolic BP of 140 to 159 mmHg, or diastolic BP of 90 to 99 mmHg), dietary changes serve as initial treatment before drug therapy; while in those already on antihypertensive drug therapy, lifestyle modifications can further lower the BP.¹¹Appel LJ, Brands MW, Daniels SR, et al; Hypertension. 2006;47(2):296-308.   General dietary recommendations for lifestyle modifications to prevent and treat hypertension include restriction of dietary sodium to 1500 mg per day in adults ≤ 50 years of age, to 1300 mg per day in adults 51 to 70 years of age, and to 1200 mg per day in adults > 70 years of age; besides other lifestyle and weight-reduction strategies.¹²Hackam DG, Khan NA, Hemmelgarn BR, et al; Can J Cardiol. 2010;26(5):249-58.  

For pharmacological management, treatment thresholds and targets are predicted based on patient’s global atherosclerotic risk, target organ damage and comorbid conditions.¹²Hackam DG, Khan NA, Hemmelgarn BR, et al; Can J Cardiol. 2010;26(5):249-58.   Antihypertensive therapy should be considered in all adult patients regardless of age, but with caution in elderly patients who are frail. The recommendations suggest that BP should be decreased to < 140/90 mmHg in all patients <60 years, and to 150/90 mmHg in hypertensive persons aged 60 years or older.

Generally, for adults without compelling indications for other agents, initial therapy should be monotherapy with one of the first-line drugs. The 2014 JNC-8 recommendations in this context suggest that in the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting-enzyme (ACE) – inhibitor or angiotensin receptor blocker (ARB); whilst in the general black population, including those with diabetes, a thiazide-type diuretic or CCB should be used as initial antihypertensive treatment.¹³James PA, Oparil S, Carter BL, et al. JAMA. 2014;311(5):507-20.  

This shows that, in most cases, use of thiazide-type diuretics is suggested, either as first-line therapy alone or in combination with another agent.¹⁴Brown A, Captain B. Am J Ther. 2011;18(6):e244-54.   Additional add-on drugs should be used if target BP levels are not achieved with standard dose monotherapy. Again, choices include one of the four first-line initial antihypertensive drugs mentioned above. A combination of two first-line agents may also be considered for initial treatment if systolic BP is 20 mmHg above target or if diastolic BP is 10 mmHg above target. However, a combination of ACE-inhibitors and ARBs should be avoided, due to risk of hyperkalemia,¹⁵Desai A. Circulation 2008;118: 1609-1611.   unless there are compelling indications to suggest consideration of such dual therapy. Agents that are appropriate for first-line monotherapy for isolated systolic hypertension include thiazide diuretics, longacting dihydropyridine CCBs or ARBs.

Diuretics’ position as monotherapy for initial hypertension

Diuretics have gained an important place in monotherapy for initial hypertension by rendering systolic and diastolic BP control in a large percentage of patients suffering from mild-to-moderate uncomplicated essential hypertension, reducing cardiovascular morbidity and mortality. And the effectiveness in adult and elderly hypertensive subjects is independent of the race. Administered alone or in combination with other agents, diuretics hence form the basis of therapy for majority of the hypertensive patients. Per se, as perceived through JNC-8, thiazides are the usual initial choice in most cases; while loop diuretics are generally reserved for those with resistant hypertension, heart failure, or

renal insufficiency.1¹⁶Shah U, Anjum S, Littler WA. Postgrad Med J 2004;80:271-276.  ^,17Reyes AJ. J Hum Hypertens. 2002;16 Suppl 1:S78-83.   Table 3 enlists some diuretics that are used to treat hypertension.

Limitations of diuretics

Despite the favorable position in initial treatment of hypertension (see above), initial diuretic monotherapy is not without concerns, given that both antihypertensive and unfavorable effects of these drugs increase as functions of the dose. Generally, the side effects of high dose diuretic therapy, for instance 25 mg hydrochlorothiazide (HCTZ) once daily, are not overly bothersome, but the hypokalemia, hypercholesterolemia, hyperinsulinemia, and worsening of glucose tolerance due to frequently prolonged high dose diuretic therapy can cause problems by affecting patient outcomes.¹⁶Shah U, Anjum S, Littler WA. Postgrad Med J 2004;80:271-276.  

These changes in part appear to limit the clinical utility and positive response of cardiovascular prognosis to antihypertensive treatment with classic doses of diuretics. Particularly, hypokalemia (reduced potassium level) offsets the cardiovascular benefit conferred by reduction in high BP caused by diuretics. Lower doses of diuretics are comparatively safer than classically used high dose formulations, and reduce high BP to the sought extent in many patients, but it would take approximately 12-14 weeks for a low dose antihypertensive diuretic, used as monotherapy, to attain final stable BP values after treatment initiation. Adding a potassium-sparing diuretic to the therapeutic regimen could be another possibility to prevent hypokalemia, but the recent updated JNC-8 recommendations somehow preclude this prospect by providing recommendation specific only for thiazide-type diuretics, including thiazide diuretics, chlorthalidone, and indapamide; and notincluding loop or potassium-sparing diuretics.¹³James PA, Oparil S, Carter BL, et al. JAMA. 2014;311(5):507-20.   As well, potassium sparing diuretics are rarely used alone because of their weak antihypertensive action; and are generally used in combination with thiazide or loop diuretics.¹⁶Shah U, Anjum S, Littler WA. Postgrad Med J 2004;80:271-276.  

The data hence clearly suggests that patients receiving diuretics are important candidates for higher intakes of potassium to offset the consequences of hypokalemia.

Mechanisms for antihypertensive effects of potassium

The exact mechanisms for antihypertensive effects of potassium are not completely clear, but may include several possible factors. Box 1 shows some of the possible mechanisms proposed for this putative antihypertensive effect of potassium^18-20Treasure J, Ploth D. Hypertension. 1983;5(6):864-72.
Singh RB, Singh NK. Acta Cardiol. 1987;42(2):103-13.
Haddy FJ, Vanhoutte PM, Feletou M. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R546-52.      making therapeutic implications of real antihypertensive activity of potassium great. Potassium mediated decrease in intravascular volume, in part through reduced sodium reabsorption, i.e., increased urinary sodium excretion, is not long-lasting; and hence cannot explain the long-term effects on BP. Increased levels of potassium in the plasma, reflecting dietary intakes, are associated with endothelium-dependent vasodilation through stimulation of Na⁺-K⁺ adenosine triphosphatase (ATPase) pump and opening of its potassium channels.⁶Weaver CM. Adv Nutr. 2013;4(3):368S-77S.   Other putative mechanisms of action for potassium include alterations in baroreflex sensitivity and sensitivity to receptors and hormones, which influence vascular smooth muscle and sympathetic nervous system cell function, and may be important to lowering the BP other than the natriuretic effects of potassium.

Potassium effect on nocturnal BP

Healthy individuals normally experience a “dip” in BP during the night, an absence of which is linked to increased risk for adverse cardiovascular events.²¹Gumz ML, Rabinowitz L. Semin Nephrol. 2013; 33(3): 229-236.   This suggests importance of maintaining this normal circadian pattern of BP, and correction of non-dipping BP, to cardiovascular health.²²Stow LR, Gumz ML. J Am Soc Nephrol. 2011;22(4):598-604.   In fact, many researchers have proposed the nighttime BP as particularly important, which may be a better predictor of outcomes and mortality than daytime BP. Nocturnal hypertension is thus a consistent target for antihypertensive treatment.

Several approaches exist to control the nocturnal hypertension, and include both lifestyle changes, such as sodium restriction and potassium supplementation, and pharmacological treatments, primarily through use of bedtime dosing of antihypertensive agents.²³Vij R, Peixoto AJ. Expert Rev Cardiovasc Ther. 2009;7(6):607-18.   Particularly, since renal salt handling has been linked to the regulation of this dipping phenotype, renal potassium handling may be critical too. Potassium supplementation has therefore been used as a therapy for hypertension²⁴Braschi A, Naismith DJ. Br J Nutr. 2008;99(6):1284-92.  , and studies have shown its positive effect in lowering of nocturnal BP. Interestingly, even normotensive non-dippers were found to benefit from increased potassium intake, which restored the dipping profile.²⁵Wilson DK, Sica DA, Devens M, et al. Blood Press Monit. 1996;1(6):447-455.   This latter finding could suggest favorable prognostic implications of potassium supplementation in the wider population of those at risk of hypertension or at initial stage of mild hypertension.

Potassium supplementation with thiazide diuretics

Amelioration of hypokalemia (serum potassium <3.5 mmol/L)²⁶Ben Salem C, Hmouda H, Bouraoui K. Curr Drug Saf. 2009;4(1):55- 61.   lowers BP in essential hypertensive patients receiving thiazide diuretics; and this can be achieved via potassium supplementation in those who continue to take a constant amount of diuretic.²⁷Svetkey LP, Yarger WE, Feussner JR, et al. Hypertension 1987;9(5):444-50.   While this positive effect has been shown in various randomized, double-blind trials²⁸Kaplan NM, Carnegie A, Raskin P, et al. N Engl J Med. 1985;312(12):746-9.  ^,29Patki PS, Singh J, Gokhale SV, et al. BMJ. 1990;301(6751):521-3.  ; a recent systematic review of literature and meta-analysis provides high quality evidence for this phenomenon by showing that increased potassium intake [90 mmol/day (3510 mg/day) to 120 mmol/ day (4700 mg/day)] reduces BP in people with hypertension (Figure 1 and 2), and has no adverse effect on blood lipid concentrations, catecholamine concentrations, or renal function in adults.¹⁰burto NJ, Hanson S, Gutierrez H, et al. BMJ 2013;346:f1378.  ^,30Geleijnse JM, Kok FJ, Grobbee DE. J Hum Hypertens. 2003;17(7):471-80.   Such increased potassium intake should benefit most people in most countries. Founded on this evidence, the World Health Organization (WHO) developed its first guideline on potassium intake.31 The guideline states that adults (≥16 years of age) without compromised renal handling of potassium should consume > 90 mmol potassium/day for beneficial effects on BP and the risk of related CVDs. For children (2-15 years of age), potassium intake of at least 90 mmol/day should be adjusted downward, based on energy requirements of children relative to those of adults.³¹Guideline: Potassium Intake for Adults and Children. Geneva: World Health Organization; 2012. Available at: http://www.ncbi. nlm.nih.gov/books/NBK132470/ [Accessed on 29/5/2014].  

Population subgroups benefiting the most

In the current context of role of potassium in hypertension, of substantial public health relevance are findings related to two subpopulations – blacks and older individuals – since they are especially sensitive to the BP-lowering effects of reduced salt intake and increased potassium intake. Incidentally, these identifiable large subgroups within the hypertensive population (elderly with isolated systolic hypertension and blacks with hypertension) are also the one for whom diuretic treatment as initial management may achieve the most benefit.³²Krakoff LR. Circulation. 2005;112:e127-e129.   It thus follows that these two population subgroups are candidates to benefit most from antihypertensive effects of potassium supplementation. In fact, in several studies, the effects of increased potassium intake in blacks have been particularly striking.¹¹Appel LJ, Brands MW, Daniels SR, et al; Hypertension. 2006;47(2):296-308.  ^,33Hedayati SS, Elsayed EF, Reilly RF. Kidney Int. 2011;79(10):1061-70.  

Diet as a source of additional potassium

Of the several lifestyle-related factors contributing to the development of high BP and hypertension, diet has remained an important variable.³³Hedayati SS, Elsayed EF, Reilly RF. Kidney Int. 2011;79(10):1061-70.   In current context, as potassium deficiency is inversely related to the level of arterial BP, promoting nutrient rich foods through behavior modification shall be feasible and desirable to increasing this shortfall nutrient.³⁴Siani A, Strazzullo P, Giacco A, et al. Ann Intern Med. 1991;115(10):753-759.   Dietary potassium intake has been demonstrated to significantly lower the BP in a dose responsive manner in both hypertensive and non-hypertensive patients.³⁵Houston MC. Curr Hypertens Rep. 2011;13(4):309-17.  ^,36Haddy FJ. J Am Coll Nutr. 1987;6(3):261-70.   A linear dose-response relationship of 1.0 mmHg reduction in systolic BP and a 0.52 mmHg reduction in diastolic BP per 600 mg per day increase in dietary potassium intake is seen in hypertensive patients, which is independent of the baseline potassium deficiency. Average reduction in BP with 4700 mg (the recommended adequate

intake) of dietary potassium per day is 8.0/4.1 mmHg, depending on relative intakes of other minerals, such as sodium, magnesium and calcium. And this may have prognostic value since increasing consumption of potassium to 4700 mg per day predicts estimated decreases of 6-11% in myocardial infarction (MI).³⁵Houston MC. Curr Hypertens Rep. 2011;13(4):309-17.  

Potassium is present in a wide-variety of fruits and vegetables, which can play important roles in protecting against hypertension and CVD. For instance, consumption of white vegetables has been associated with decreased risk of CVD, possibly related to their high potassium content. Particularly, potatoes are the highest source of dietary potassium, but addition of salt should be limited. Potassium in foods is present with phosphate, sulfate, citrate, and many organic anions including proteins.⁶Weaver CM. Adv Nutr. 2013;4(3):368S-77S.  

Limitation of the dietary approach

While increased intake of dietary potassium is clearly beneficial in lowering BP, with patients with excessive potassium losses (such as those receiving diuretic) possibly benefiting in particular; a lack of measures to know exactly if the required level of potassium is being supplemented or not can be a potential limitation to dietary potassium in real practice. Furthermore, some potassium-rich foods may have inappropriately high potassium content; while some containing high sodium, saturated and trans fatty acids and cholesterol, are often undesirable in those with co-existing diabetes and dyslipidemia.³⁷American Diabetes Association. Diabetes Care 2008;31(Suppl. 1):S61-S78.   This latter aspect is important since hypertension and diabetes frequently co-exist in many individuals. Hence, these natural sources may not always supplant the oral potassium supplements, which may be a better prospect as potassium from dietary source cannot be precisely quantified. Besides, dietary potassium is mostly coupled with phosphate, rather than with chloride; and is therefore not effective in correcting the potassium loss associated with chloride depletion, such as in diuretic therapy.³⁸Cohn JN, Kowey PR, Whelton PK, et al. Arch Intern Med. 2000;160:2429-2436.  

Need of potassium supplements

In conjunction with the limitations of dietary sources of potassium, even though it is projected that benefits to BP may occur at levels below existing recommendations for potassium intake, especially from diet, there is insufficient data from dose-response trials to confirm this. And it would therefore be difficult for most individuals to achieve adequate levels of potassium intake through diet only. Meanwhile, intakes considerably above current levels shall be needed for optimal health since studies evaluating small increases in fruit and vegetable intake on heart outcomes for short periods have had disappointing results.⁶Weaver CM. Adv Nutr. 2013;4(3):368S-77S.   In such setting, potassium supplements can be considered to provide optimal potassium content to most subjects as a measure to improve hypertension and CVD risk. Potassium supplementation can lower BP in normal and hypertensive patients; with response appearing in about four weeks.²⁰Haddy FJ, Vanhoutte PM, Feletou M. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R546-52.  ^,39Obel AO. J Cardiovasc Pharmacol. 1989 Aug;14(2):294-6.   The effect can be significant as shown in a meta-analysis of 19 supplement trials. The meta-analysis showed that oral potassium supplements significantly lowered systolic BP by 5.9 mmHg and diastolic BP by 3.4 mmHg.⁶Weaver CM. Adv Nutr. 2013;4(3):368S-77S.  ^,40Cappuccio FP, MacGregor GA. J Hypertens. 1991;9(5):465-73.   The magnitude of the BP lowering effect was greater in patients with high BP (-8.2 mmHg for systolic and -4.5 mmHg for diastolic BP) and appeared to be more pronounced the longer the duration of the supplementation. Likewise, in a later meta-analysis of 33 randomized, controlled trials involving 2609 participants, oral potassium supplementation was associated with a significant mean reduction of 3.11 mmHg and 1.97 mmHg for systolic and diastolic BP, respectively.⁴¹Whelton PK, He J, Cutler JA, et al. JAMA. 1997;277(20):1624-32.  

Thus, in general, clinical features associated with mild hypokalemia may be successfully treated with oral potassium supplements; even as exerting hypotensive effects of clinically significant degree in patients with mild hypertension. In hypokalemia, increasing potassium intake to replenish potassium levels shall be considered when serum potassium levels are between 3.5 and 4.0 mmol. Nonetheless, supplementation may be warranted even in asymptomatic patients with mild-to-moderate hypertension if serum potassium level is below 3.5 mmol.³⁸Cohn JN, Kowey PR, Whelton PK, et al. Arch Intern Med. 2000;160:2429-2436.  

In most clinical settings of hypokalemia, oral is the preferred route as oral potassium is readily absorbed, is easy to administer, and relatively large doses can be given safely. Thus, oral administration of potassium chloride may be suggested when potassium levels need to be replenished, and in patients with ongoing potassium loss (e.g., those on thiazide diuretics), when it must be maintained.⁴²Lederer E, Alsauskas ZC, Mackelaite L, et al. Hypokalemia Treatment & Management. Available at: http://emedicine. medscape.com/article/242008-treatment [Accessed on 29/5/2014].  

Why potassium chloride?

As mentioned earlier, dietary potassium that is mostly coupled with phosphate, rather than with chloride, is not effective in correcting the potassium loss associated with chloride depletion, such as in diuretic therapy.³⁸Cohn JN, Kowey PR, Whelton PK, et al. Arch Intern Med. 2000;160:2429-2436.   This could be one possible reason why potassium chloride is the usually preferred potassium supplement amongst different potassium salts – potassium chloride, potassium phosphate, and potassium bicarbonate. The choice is further supported by its unique effectiveness against the most common causes of potassium depletion. Moreover, hypochloremia may develop if citrate, gluconate, bicarbonate or another alkalinizing salt is administered, particularly in patients adhering to diets that restrict the chloride intake. Potassium chloride is available in liquid or tablet formulations. However, tablets have several characteristics, such as the size of medication, ease of swallowing, and rate of disintegration, which might limit their use; in contrast, liquid formulation is absorbed rapidly from the stomach, with peak absorption near the end of the first hour following administration, and thus has immediate effect. Potassium chloride preparations in liquid form are hence advisable where rapid absorption from the gastrointestinal tract is critical.⁴³Levene DL. The absorption of potassium chloride–liquid vs. tablet. Can Med Assoc J. Jun 23, 1973; 108(12): 1480-passim.  

Conclusion

The association of low potassium levels and high BP levels is well established. As potassium exhibits an inverse relationship with BP, and high potassium can be beneficial in reducing BP in hypertensives, potassium supplementation is quite an interesting strategy as a large number of subjects with subnormal and mild hypertension can benefit from this nondrug approach. Moderate daily supplements of potassium may therefore be a prospective alternative to pharmacological methods for controlling mild hypertension, especially in those not willing or able to restrict salt intake. The need is accentuated while considering the continuing potassium depleting effect of thiazide diuretics, which JNC-8 recommends for initial monotherapy in most patients with mild- moderate hypertension. This suggests that patients with mild-moderate hypertension being considered for initial thiazide monotherapy are also candidates for potassium supplementation. Collectively, a reduced intake of sodium and increased intake of potassium will possibly make important contribution to the prevention of hypertension, especially in populations with elevated BP.

Amongst various potassium supplements, potassium chloride is the usual choice for supplementation in most cases of mild hypokalemia due to its unique effectiveness against the most common causes of potassium depletion. A dosage of 20 mmol/d of potassium in oral form would generally be sufficient for prevention of hypokalemia.⁴⁴Cohn JN, Kowey PR, Whelton PK, et al. Arch Intern Med. 2000;160:2429-2436.   Dosage should however be individualized for each patient such that no more than 20 mmol is given in a single dose.

Benefits of Potassium Supplements in Hypertension⁴⁵Krishna GG. Am J Med Sci. 1994 Feb;307 Suppl 1:S21-5.  ^,46World Hypertension League. Bulletin of the World Health Organization 1992;70(6):685-690.  

• Potassium supplementation not only ameliorates diuretic-induced hypokalemia but also enhances the hypotensive effect of diuretics.
• Antihypertensive therapy with potassium supplements ensures good control of blood pressure without reducing the salt diet.
• High intake of potassium exerts desirable vascular protective effects that are independent of its effects on blood pressure.

References

1. Carrera-Bastos P, Fontes-Villalba M, O’Keefe JH, et al. Research Reports in Clinical Cardiology 2011:2 15-35.
2. Institute of Medicine (U.S.). Panel on Dietary Reference Intakes for Electrolytes and Water. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate / Panel on Dietary Reference Intakes for Electrolytes and Water, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board 2005. Available at: http:// www.nal.usda.gov/fnic/ DRI/DRI_Water/water_full_report.pdf [Accessed on 26.5.2014].
3. Delgado MC. Current Hypertension Reports 2004;6(1):31-35.
4. Dietary Reference Intakes: Electrolytes and Water. Available at: http://www.iom.edu/Global/News%20Announcements/~/me dia/442A08B899F44DF9AAD083D86164C75B.ashx [Accessed on 26.5.2014].
5. Krishna GG. J Am Soc Nephrol. 1990;1(1):43-52.
6. Weaver CM. Adv Nutr. 2013;4(3):368S-77S.
7. Lever AF, Beretta-Piccoli C, Brown JJ, et al. Br Med J (Clin Res Ed). 1981;283(6289):463-8.
8. Castro H, Raij L. Semin Nephrol. 2013;33(3):277-89.
9. Meneely GR, Battarbee HD. Am J Cardiol. 1976;38(6):768-85.
10. Aburto NJ, Hanson S, Gutierrez H, et al. BMJ 2013;346:f1378.
11. Appel LJ, Brands MW, Daniels SR, et al; Hypertension. 2006;47(2):296-308.
12. Hackam DG, Khan NA, Hemmelgarn BR, et al; Can J Cardiol. 2010;26(5):249-58.
13. James PA, Oparil S, Carter BL, et al. JAMA. 2014;311(5):507-20.
14. Brown A, Captain B. Am J Ther. 2011;18(6):e244-54.
15. Desai A. Circulation 2008;118: 1609-1611.
16. Shah U, Anjum S, Littler WA. Postgrad Med J 2004;80:271-276.
17. Reyes AJ. J Hum Hypertens. 2002;16 Suppl 1:S78-83.
18. Treasure J, Ploth D. Hypertension. 1983;5(6):864-72.
19. Singh RB, Singh NK. Acta Cardiol. 1987;42(2):103-13.
20. Haddy FJ, Vanhoutte PM, Feletou M. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R546-52.
21. Gumz ML, Rabinowitz L. Semin Nephrol. 2013; 33(3): 229-236.
22. Stow LR, Gumz ML. J Am Soc Nephrol. 2011;22(4):598-604.
23. Vij R, Peixoto AJ. Expert Rev Cardiovasc Ther. 2009;7(6):607-18.
24. Braschi A, Naismith DJ. Br J Nutr. 2008;99(6):1284-92.
25. Wilson DK, Sica DA, Devens M, et al. Blood Press Monit. 1996;1(6):447-455.
26. Ben Salem C, Hmouda H, Bouraoui K. Curr Drug Saf. 2009;4(1):55- 61.
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