Search

Objective: We aimed to review the English and Chinese literature on Pa Ping and to confirm by personal interview the story of how its pathogenesis was uncovered., Background: In 1930, Dr. Alexander Stewart Allen noticed a pattern of illness arising in the region of Kiating, China. Area residents began presenting to local hospitals with nausea, vomiting, and diarrhea, and what emerged was a clinical picture of a gradual ascending paralysis that could result in death, termed Pa Ping. All 3 patients observed by Dr. Allen were male, had no family history of the disease, and had recently eaten before the onset of paralysis. Pa Ping developed in Dr. Allen himself, but he survived., Methods: Medical literature was reviewed for primary sources. Interviews of living descendants and friends of the doctors in China and North America were conducted and information was corroborated by written records., Results: Dr. Huang, with the National Central University College of Medicine, noticed a striking similarity between Pa Ping and familial periodic paralysis in 12 patients and reported 2 patients with Pa Ping treated with potassium citrate who experienced a reversal of the paralysis. Dr. K.T. Du analyzed meals of patients with Pa Ping seen by Dr. Zhe Tung and found barium in concentrations as high as 25.7%. This finding was confirmed by administering barium chloride to animals, which recapitulated the human syndrome., Conclusions: Although Dr. Huang had correctly noticed an underlying potassium depletion in patients with Pa Ping, the observations of Dr. Zhe Tung and Dr. K.T. Du ultimately established barium-induced hypokalemia as the underlying cause.

The metabolic syndrome (MS) has been associated with hyperactivity of the renin-angiotensin-aldosterone system (RAAS). To assess the hypothesis that diuretic therapy in MS patients through further stimulation of RAAS would elicit greater potassium (K) depletion, two groups of hypertensive patients with (MS group [MSG]; n=20) and without (control group [CG]; n=19) MS were studied. Plasma renin activity (PRA), aldosterone (PA), and K levels were determined and an oral glucose tolerance test with plasma insulin determinations for calculation of homeostasis model assessment of insulin resistance (HOMA-IR), sensitivity (ISI), and secretion (HOMA-beta) was performed, both before and 12 weeks after hydrochlorothiazide (HCT; 25 mg/d) therapy. At baseline, higher HOMA IR and HOMA-beta and lower ISI and plasma K were found in the MSG than in the CG, with no differences in PA and PRA between groups. With therapy, PRA increased similarly in both groups while PA increased only in the MSG. However, greater reduction in plasma K occurred in the CG, and the 2 groups reached similar final K values. Impairment in glucose tolerance occurred in both groups, with no change in HOMA-beta in the CG and reduction in the MSG, suggesting that diuretic therapy increases insulin resistance and impairs insulin secretion independent of abdominal obesity. These alterations could not be attributed to hyperactivity of RAAS.

Objective: Several studies have suggested that hydration and sodium load might reduce nephrotoxicity related to amphotericin B-deoxycholate (AmB-d). However, a schedule of these nephroprotective measures has not been standardized until now. A protocol of hydration and electrolyte supplementation was used prospectively in patients with hematological malignancies receiving empirical AmB-d treatment to evaluate its effect on AmB-d-related renal toxicity., Patients and Methods: A total of 77 consecutive patients received AmB-d (1 mg/kg per day) in association with an initial intravenous hydration of at least 1 l/m2 body surface, containing at least 1 l of 0.9% saline daily. Hydration was increased when serum creatinine levels showed a 20% increase from baseline. Serum electrolytes were replaced when indicated., Results: The median duration of AmB-d therapy was 14 days. The mean intravenous hydration and the mean diuresis were 1530 and 1970 ml/m2 of body surface per day, respectively. Overall, 55 patients (71.4%) received a mean of 18.5 days of therapy without dose-limiting adverse events. Despite significant increases in mean creatinine serum levels and decreases in mean creatinine clearance observed early in the whole population, in only six patients (7.8%) was therapy discontinued due to renal failure, which always recovered after treatment discontinuation. In eight patients (10.4%) therapy was stopped due to infusion-related side effects. Seven patients died while under antifungal therapy without relevant signs of AmB-d-associated toxicity., Conclusions: Our prospective experience confirms that adequate hydration (about 1500 ml/m2 of body surface) and careful electrolyte supplementation are simple measures able to contain nephrotoxicity and to permit adequate antifungal therapy at least in the empirical setting.

The mitogen-activated protein kinase (MAPK) cascades are thought to be important mediators in the transduction of extracellular signals into cellular responses. The p38 kinase, a member of the MAPK superfamily, is activated by a wide variety of extracellular stimuli and has been implicated in neuronal apoptosis induced by glutamate. In this study we have examined the role of p38 kinase in the potassium deprivation model of apoptosis in rat cerebellar granule neurons (CGN). An increase in p38 kinase activity was observed with a 15-minute potassium deprivation when compared to the basal level. We also found that SB203580 and PD169316, specific p38 kinase inhibitors, significantly attenuated apoptosis in potassium-deprived cells in a dose dependent manner. A decrease in caspase-3 mediated DEVD-MCA, substrate hydrolysis and the appearance of the 120 kDa-spectrin breakdown product in cells treated with SB203580 further suggests that the p38 kinase acts upstream of caspase-3 in the apoptosis cascade. The data provides evidence for an essential role of p38 kinase in mediating apoptotic cell death in CGN and the inhibition of p38 kinase mimics the suppression of apoptosis provided by natural survival signals.

The group of drugs, so-called "potassium sparing diuretics" represent an important part of our modern therapeutic arsenal. Their "weak diuretic" properties are especially beneficial in cirrhotic patients with ascites, when highly effective loop diuretics may be hazardous. Potassium sparing diuretics have not only the advantage of avoiding potassium loss, but can potentiate the effects of diuretics acting in distal tubules and Henle's loop also. They may be combined by each other or ACE inhibitors too, taking the necessary precautions and laboratory monitoring. Their indications include the hypertension and special diseases as Conn's, Bartter's, Liddle syndromes and hirsutism. The broad clinical usefulness justifies the drug inventory ambition to develop new, more effective potassium sparing compounds without side effects. Authors overview their main clinicofarmacological properties, therapeutical indications alone or in combinations and their potential side effects.

Thiazides and loop diuretics facilitate the loss of K and Mg through the kidneys leading to deficiencies that may require treatment with supplements. These losses may be overlooked, however, because serum concentrations may remain normal even when the muscle concentrations are appreciably reduced. In 76 patients who had received diuretics for 1-17 years, the mean concentrations of K, Mg and Na,K-pumps in skeletal muscle biopsies were significantly lower than in those from an age- and sexmatched control group, and muscle Mg and K concentrations were significantly correlated. The serum concentrations, however, were only below the control range in a few patients. The fact that Mg,K deficiencies may often be overlooked emphasises the need for data on the contents of skeletal muscle. A recently developed simple biopsy needle procedure permitted the detection of disorders of electrolytes during long-term diuretic treatment despite normal serum concentrations. With the same technique it was possible to detect repletion of the muscle electrolytes after a Mg supplementation period. Oral Mg supplementation could reestablish normal Mg as well as K status in patients in long-term diuretic therapy, provided that the supplementation was maintained for 6 months. Moreover, the normalization of muscle Mg and K was accompanied by a restoration of the concentration of Na,K-pumps measured as the [3H]ouabain binding site capacity in skeletal muscle. Mg and K contents were closely correlated in human muscle biopsies from patients on diuretic treatment, but also in rat muscle which had been moderately Mg depleted in vivo or in vitro. In isolated soleus muscle, which had been moderately Mg-depleted in vitro, reduction in cellular K could not be ascribed to reduced Na,K-pump mediated K-influx. The reduced K content might rather be related to increased K efflux from the muscles. In rats, insufficient dietary supplies of K, Mg and Zn were characterized by inhibition of growth and protein synthesis. These effects could not readily be related to the loss of these elements from muscle tissue, but rather should be seen as a response to a general deficiency. The most marked evidence of deficiency was seen in the serum levels, which pointed to the serum concentration as a possible mediator for the regulation of tissue growth. IGF-I is a low molecular weight peptide possessing growth promoting properties in many tissues probably as an interplay of both autocrine/paracrine and endocrine actions. In both animals and man insufficient supplies of energy and protein are accompanied by growth retardation and a decrease in serum IGF-I.(ABSTRACT TRUNCATED AT 400 WORDS)

Renal papillary cytoplasmic granularity (RPCG) induced by carbonic anhydrase inhibitors (CAIs) in rats is characterized by the accumulation of dense secondary lysosomes in epithelial, endothelial, and interstitial cells and may be related to drug-induced potassium depletion. Female Sprague-Dawley rats were given the CAI, acetazolamide, by gavage. Half were supplemented with 1% potassium chloride in the drinking water. Two treated groups were allowed to recover for 1 or 2 mo. Potassium supplementation inhibited RPCG by 80% but produced little amelioration of the mild 13% decrease in serum potassium induced by 200 mg/kg/day acetazolamide for 28 days. Acetazolamide-induced RPCG is reversible because 1- and 2-mo recovery periods decreased the incidence by 75% and 80%, respectively. The results support the hypothesis that RPCG is related to potassium depletion secondary to carbonic anhydrase inhibition. Because supplementation of potassium chloride had little effect on serum potassium, these data suggest that depletion of renal medullary potassium content is important in the pathogenesis of RPCG as previously suggested by others. Other types of diuretics that produce hypokalemia as a side effect may not deplete medullary potassium since RPCG has not been reported in humans or animals given these drugs.

Echinocytes have been incriminated in the pathogenesis of exertional diseases in horses. To evaluate the hypothesis that echinocytes are dehydrated erythrocytes, we decreased blood sodium and potassium concentrations in 4 horses by administering furosemide (1.0 mg/kg of body weight, q 12 h) for 2 days and we monitored CBC, serum and erythrocyte sodium and potassium concentrations, and echinocyte numbers. Serum sodium concentration decreased progressively over the 48 hours of furosemide administration, then returned to near baseline concentration at 168 hours. A statistically significant decrease (P < 0.05) in serum potassium concentration was observed at 24, 48, and 72 hours after initial furosemide administration, and remained less than the baseline value at the end of the study. Mean erythrocyte potassium concentration decreased rapidly and remained low at the end of the study. Minimal changes were observed in erythrocyte sodium concentration during the first 72 hours after furosemide administration, but the value was significantly (P < 0.05) increased at 168 hours. Type-I and type-II echinocyte numbers increased by 4 hours after furosemide administration and persisted throughout the study. Type-III echinocytes were not seen in baseline samples, but numbers increased only modestly after furosemide administration. Administration of epinephrine to well-hydrated horses increased echinocyte numbers only minimally, indicating that splenic contraction was not the likely cause for the furosemide-associated increase. To determine whether the decrease in erythrocyte potassium concentration and increase in sodium concentration was caused by furosemide acting directly on the erythrocyte membrane, we quantified erythrocyte potassium and sodium concentrations before and after incubation with furosemide in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Hydrochlorothiazide (HCT), 25 or 50 mg a day, alone and in combination with triamterene (T), 50 and 100 mg, respectively, or amiloride (A), 2.5 and 5 mg, respectively, was examined for effects on daily urinary potassium and sodium excretion. Daily sodium excretion was increased 1.5-2-fold with a double dose of the combined drugs as compared with their single dose. T and A produced additive effects on the natriuretic action of HCT. Lower doses of HCT and T failed to prevent urinary potassium loss, but their potassium-sparing effect was shown with their double dose. This effect was largely displayed by A given in a single or double dose. Lower serum potassium levels were seen with all the drugs, but this was less marked with HCT combined with T or A than with HCT monotherapy. Their double dose reduced serum potassium levels to an insignificantly greater extent. In some cases, the elderly patients developed hyperkalemia during the combined therapy. Thus, with the routine dose ratios, A showed a slightly higher potassium-sparing effect than did T. Some patients taking HCT in combination with T showed reddish-brown crystals and casts in the urinary sediment, which may indicate its tubular interstitial damaging action. Consequently, use of the combined drugs is more preferable than HCT monotherapy, and HCT in combination with A is likely to be more preferable than that with T.

It is known that the myocardial necrosis of potassium depletion heals by reconstitution and not by scarring, when animals are replenished with potassium. In the course of studies on DOCA-induced myofibrillar degeneration, we found that a membrane-like structure persisted in the area where the disintegrating myofiber was being removed by macrophages. This structure resembled the basal lamina, and enclosed a space in which macrophages with phagosomes containing disintegrating myofibral constituents were seen in association with undifferentiated cells. We postulate that this basal lamina-like structure along with the undifferentiated cells, play a role in the reconstitution of the myocardium during the stage of potassium repletion, and that the scaffolding by basal lamina may be effective in myocardial reconstitution.

A survey of the causes, clinical manifestations and differential diagnosis of patassium deficiency is given. Intention is to point out that the potassium cation plays a significant part in a number of metabolic reactions and has an important influence on neuro-muscular physiology and kidney function. The supply of potassium can be of vital importance.

The action of the most common diuretics is reviewed with emphasis on precise indications in the case of cardiac deficiency, arterial hypertension and certain forms of angina pectoris. These drugs are judged extremely useful if the necessary precautions are taken at all times. Disturbances to the water-electrolyte balance may however occur during treatment and changes in the magnesium electrolyte are described in the light of recent developments in our knowledge of the physiopathology of diuretics.

There have been many studies which suggest that patients with heart failure were potassium depleted. This depletion has been attributed to the use of potent diuretics, and these are now given with either potassium supplements or potassium-retaining diuretics. A detailed examination of the studies suggests that the reported decrease in body potassium compared with the results in healthy persons is not due to the diuretics. It can be partly explained by a failure to match patients and controls in terms of age, and the remaining difference can be explained by muscle wasting. There is therefore no evidence of a potassium depletion in these patients with heart failure.

During diuretic treatment alterations in myocardial cellular excitability due to potassium-induced disturbances of the membrane potential may arise without obvious changes of total body K. This may be explained by coexisting disturbances of the acid/base balance and other ions such as magnesium, two factors which independently influence the transport of potassium across the cell membrane. The consequence may be cardiac arrhythmias, particularly in the presence of digitalis. On the other hand hypokalemia, induced by diuretics, may also be accompanied by a significant depletion of total body K, bringing about more general consequences. It must be considered essential to maintain a normal general electrolyte balance during diuretic therapy. Potassium supplements may be used if true depletion of total body K is suspected, e.g. in hypokalemia with acidosis. Its use may, however, otherwise be questioned, as it is only directed towards the potassium situation and neglects the influence of diuretics upon other ions, such as H+ and Mg++. The potassium-sparing agents amiloride and triamterene normalize the general electrolyte situation in the distal tubules and should thus be regarded as drugs of first choice. Spironolactone has identical properties concerning the electrolytes but more serious side effects. It should be preferred when a significant secondary hyperaldosteronism is suspected and/or a more intense diuresis or an accentuated antihypertensive action is desired. The role of captopril in this context has not yet been established.

Diuretic therapy is the most common cause of potassium deficiency. Although the extent of potassium deficiency usually does not exceed 200 or 300 mEq, under appropriate circumstances such modest deficiency may have important consequences. Factors that tend to increase the incidence or severity of potassium deficiency in patients who take diuretics include high salt diets, large urine volumes, metabolic alkalosis, increased aldosterone production, and the simultaneous use of two diuretics that act on different sites in the renal tubule. There are many serious complications of potassium deficiency, including cardiac arrhythmias, muscle weakness, rhabdomyolysis, glucose intolerance, and several complications that result directly from increased ammonia production, such as protein and nitrogen wasting and hepatic coma. Emphasized herein are those conditions that impose potential danger in patients with mild hypokalemia. Important factors that identify specific causes of potassium deficiency and its treatment are discussed briefly.

In a group of elderly patients with systolic hypertension the hypotensive efficacy and adverse effects were studied of hydrochlorothiazide given in daily doses of 25 mg in a year. A fall of systolic and diastolic arterial blood pressure was obtained in 86% of these patients. Adverse effects included reduced concentration of potassium and magnesium ions in the serum and lymphocytes, but this reduction was small and appeared mainly in the serum. The used doses of hydrochlorothiazide had no effect on plasma renin activity, and on the serum levels of aldosterone, glucose, uric acid, cholesterol and triglycerides.

Thiazides and loop diuretics, facilitate the loss of Mg and K resulting in increased excretion in the urine. Although serum-K and serum-Mg values in patients receiving long-term treatment for hypertension or incompensated heart disease usually are normal, muscle-Mg and muscle-K contents are reduced in around 50% of these patients. Mg deficiency increases K loss and K/Mg deficiencies are frequently observed simultaneously. K repletion is often difficult if the accompanying Mg deficiency is not corrected simultaneously. The K/Mg loss from the muscles is accompanied by reduced concentration of Na,K-pumps. These disturbances may produce muscle symptoms, increased sensitivity to digitalis, inhibition of growth and possibly arrhythmias. Evaluation of the K and Mg status during diuretic treatment should be preferentially based on tissue determinations. The muscle biopsy method is rapid, reliable and may reveal conditions of deficiency. In several cases, oral supplements of Mg have proved to be adequate to restore the normal K/Mg status.

Measurements of total body potassium (T.B.K.) were made by whole-body counting in four groups of patients receiving oral frusemide for one year. Patients in group 1 had essential hypertension and normal renal function and received 40 mg frusemide daily without potassium supplements. Patients in group 2 were similar but received oral potassium supplements for the first four months of treatment. Patients in group 3 had hypertension associated with renal disease and received 120 mg frusemide daily without potassium supplements. Patients in group 4 also had hypertension and renal impairment and in addition to 120 mg frusemide daily they received oral potassium supplements for four months. No evidence of depletion of T.B.K. was found in any of the groups after continuous treatment with frusemide for one year. It is questioned whether potassium supplementation in long term diuretic therapy with frusemide is necessary unless there is evidence of pre-existing potassium depletion or of some other factor such as cardiac failure, cirrhosis of the liver, or the nephrotic syndrome.

Animal studies have shown that potassium depletion induced by diuretics or potassium deficient fodder leads to a selective decrease in the concentrations of potassium and in the concentration of sodium-potassium pumps in skeletal muscle. In 25 patients who had received diuretics for 2-14 years the mean concentrations of potassium, magnesium, and sodium-potassium pumps were measured in skeletal muscle biopsy specimens and were significantly lower than in those from a group of age matched controls. The reductions in all three variables were significant in those patients receiving diuretics for arterial hypertension as well as in those being treated for congestive heart failure. In 14 patients the mean muscle potassium concentration was below the control range, but only one of those was hypokalaemic (3.4 mmol/l), and 13 were receiving potassium supplements. In 15 patients the mean muscle magnesium concentration was below normal, and the mean muscle potassium and magnesium concentrations showed a linear correlation. In 12 patients in whom the mean muscle potassium concentration was below 80 mumol/g wet weight there was a linear correlation between the cellular potassium:sodium ratio and the concentration of 3H-ouabain binding sites indicating that potassium deficiency also leads to a down regulation of sodium-potassium pumps in human skeletal muscle. In spite of potassium supplements long term treatment with diuretics may lead to potassium and magnesium deficiencies, which are not detectable using the standard methods of serum analysis. The changes in concentrations of electrolytes and sodium-potassium pumps associated with treatment with diuretics may impair muscle function and potassium homoeostasis and interfere with the distribution of digitalis glycosides.

A 69 year old man presented with painful proximal muscle weakness which clinically simulated polymyositis. Further evaluation revealed normal muscle enzymes and hypophosphatemia which resulted from unsuspected antacid abuse. "Pseudo-myopathy" is one example of the myriad of rheumatic diseases which may be mimicked by hypophosphatemia.

Extra potassium supplements, spironolactone or amiloride were given for 5 months to forty-nine patients with heart failure who were taking furosemide and were in a steady state. Plasma potassium increased with all three treatments but there was no significant increase in total body potassium or red cell potassium. These findings together with other studies suggest that patients with heart failure taking diuretics do not have a significant depletion of body potassium.

The clinical manifestations of drug-induced renal disease may include all the manifestations attributed to natural or spontaneous renal diseases such as acute renal failure, chronic renal failure, acute nephritic syndrome, renal colic, haematuria, selective tubular defects, obstructive nephropathy, etc. It is therefore vital in any patient with renal disease whatever the clinical manifestations might be, to obtain a meticulous drug and toxin inventory. Withdrawal of the offending drug may result in amelioration or cure of the renal disorder although in the case of severe renal failure it may be necessary to utilise haemodialysis or peritoneal dialysis to tide the patient over the period of acute renal failure. Analgesic nephropathy is an important cause of terminal chronic renal failure and it is therefore vital to make the diagnosis as early as possible. The pathogenesis of some drug-induced renal disorders appears to be immunologically mediated. There are many other pathogenetic mechanisms involved in drug-induced renal disorders and some drugs may under appropriate circumstances be responsible for a variety of different nephrotoxic effects. For example, the sulphonamides have been incriminated in examples of crystalluria, acute interstitial nephritis, acute tubular necrosis, generalised hypersensitivity reactions, polyarteritis nodosa and drug-induced lupus erythematosus.

Twelve patients with congestive heart failure receiving maintenance therapy with digoxin and potent diuretics were followed closely during development of hypokalemia and potassium loss. Cardiac arrhythmias compatible with digoxtin toxicity developed in 6 patients in the presence of stable, normal serum digoxin concentrations. The mechanisms involved in the development of the rhythm disturbances are discussed with regard to hypokalaemia, intracellular potassium loss, intra-/extracellular potassium gradients and digoxin, and the significance of maintaining a normal potassium balance in this setting is stressed.

The phenolic antioxidants BHT and BHA have been widely used for many years in small concentrations for foods, pharmaceutical preparations and cosmetic products to prevent oxidation of labile lipoid components. Recently, in an aggressive campaign, daily 2 g doses of these compounds have been recommended, without scientific grounds, to combat senescence, genital herpes and cancer. However, information in the bio-medical literature reveals that the recommended human dose of 2 g/day is simply one order of magnitude below the lethal dose in animals. Obviously, these high dose levels, if not immediately lethal for humans, must produce pathological effects. Physicians and health authorities should be familiar with the consequences of prolonged administration of large doses of BHT and BHA and forbid their use except as fat stabilizers for food and pharmaceutical products.