Hyperaldosteronism secondary

Potassium-sparing by diuretic agents, particularly spironolactone, enhances the effectiveness of other diuretics because the secondary hyperaldosteronism is blocked. This class of diuretics decreases magnesium excretion, eg, amiloride can decrease renal excretion of potassium up to 80%. The most important and dangerous adverse effect of all potassium-sparing diuretics is hyperkalemia, which can be potentially fatal the incidence is about 0.5% (50). Therefore, blood potassium concentrations should be monitored carehiUy. 

The use of CA inhibitors as diuretics is limited by their propensity to cause metabolic acidosis and hypokalemia. Their use can be indicated in patients with metabolic alkalosis and secondary hyperaldosteronism resulting for example from aggressive use of loop diuretics. Furthermore, CA inhibitors are effective dtugs to produce a relatively alkaline urine for the treatment of cysteine and uric acid stones as well as for the accelerated excretion of salicylates. Perhaps the most common use of CA inhibitors is in the treatment of glaucoma. 

Hyperaldosteronism is a syndrome caused by excessive secretion of aldosterone. It is characterized by renal loss of potassium. Sodium reabsorption in the kidney is increased and accompanied by an increase in extracellular fluid. Clinically, an increased blood pressure (hypertension) is observed. Primary hyperaldosteronism is caused by aldosterone-producing, benign adrenal tumors (Conn s syndrome). Secondary hyperaldosteronism is caused by activation of the renin-angiotensin-aldosterone system. Various dtugs, in particular diuretics, cause or exaggerate secondary peadosteronism. 

Edema Edema associated with CHF, hepatic cirrhosis, and the nephrotic syndrome steroid-induced edema, idiopathic edema, and edema due to secondary hyperaldosteronism. 

May be used alone or with other diuretics, either for additive diuretic effect or antikaliuretic (potassium-sparing) effect. It promotes increased diuresis in patients resistant or only partially responsive to other diuretics because of secondary hyperaldosteronism. 

Aldosterone stimulates the rates of Na+ reabsorption and K+ secretion. This is relevant to the action of spironolactone, a diuretic that is a competitive inhibitor of aldosterone (discussed later). It is also pertinent because administration of diuretics can cause secondary hyperaldosteronism, which may exaggerate the potassium wasting that is a consequence of the increased delivery of Na+ and enhanced flow through distal convoluted tubules and collecting ducts. 

Triamterene can be used in the treatment of congestive heart failure, cirrhosis, and the edema caused by secondary hyperaldosteronism. It is frequently used in combination with other diuretics except spironolactone. Amiloride, but not triamterene, possesses antihypertensive effects that can add to those of the thiazides. 

See Table 15-6. Potassium-sparing diuretics are most useful in states of mineralocorticoid excess or hyperaldosteronism (also called aldosteronism), due either to primary hypersecretion (Conn s syndrome, ectopic adrenocorticotropic hormone production) or secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome, or other conditions associated with diminished effective intravascular volume). Use of diuretics such as thiazides or loop agents can cause or exacerbate volume contraction and may cause secondary hyperaldosteronism. In the setting of enhanced mineralocorticoid secretion and excessive delivery of Na+ to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics of either type may be used in this setting to blunt the K+ secretory response. 

Salt and water retention mediated by secondary hyperaldosteronism can complicate hydralazine treatment, leading to weight gain and peripheral edema, loss of blood pressure control, and rarely cardiac failure (SED-8, 474). 

Secondary hyperaldosteronism Fluid retention is also promoted by elevated levels of circulating aldosterone. This secondary hyperaldosteronism results from the decreased ability of the liver to inactivate the steroid hormone and leads to increased Na+ and water reabsorption, increased vascular volume, and exacerbation of fluid accumulation (see Figure 23.3). 

Spironolactone, an aldosterone antagonist, is the drug of choice since secondary hyperaldosteronism often coexists in patients with hepatic ascites. Aldosterone is usually metabolised by the liver and is highly protein bound, therefore the free aldosterone levels are raised in cirrhosis. Spironolactone competes with aldosterone for receptor sites in the distal tubule, resulting in potassium retention and sodium and water loss. The initial dose of spironolactone is 100-200 mg and can be slowly increased according to response. There is a lag of 3-5 days between the beginning of spironolactone treatment and the onset of the natriuretic effect. 

Metoclopramide has been shown to significantly reduce spironolactone-induced diuresis in cirrhotic patients with ascites. When administered to patients with secondary hyperaldosteronism, metoclopramide significantly reduced urinary sodium excretion, with a corresponding increase in urinary potassium excretion and a significant increase in plasma aldosterone. This effect was not seen with domperidone. From this study it is recommended that metoclopramide is avoided during diuretic therapy in cirrhotic patients with ascites [15]. 

Spironolactone (see p. 534) is a competitive aldosterone antagonist which also blocks the mineralocorticoid effect of other steroids it is used in the treatment of primary hyperaldosteronism and as a diuretic, principally when severe oedema is due to secondary hyperaldosteronism, e.g. cirrhosis, congestive cardiac failure. 

Spironolactone antagonises the sodium-retaining effect of aldosterone and other mineralocorticoids. It is used to treat primary and secondary hyperaldosteronism (p. 538). 

Alkalosis and hypokalaemia (possibly caused by secondary hyperaldosteronism or use of diuretics) shift the dissociation constant towards free, toxic NH3. By contrast, ammonia is considered - in a process resembling a vicious circle - to be a secondary stimulus for aldosterone production. Thiazide diuretics in particular put an overload on the detoxification capacity of the scavenger cells. This is because of an insufficient supply of bicarbonate for carbamoyl phosphate synthetase reaction due to diuretic-induced inhibition of the mitochondrial carboanhydrase. 

However, resistance to loop diuretics can occur by various mechanisms (36). These include poor adherence to therapy, poor absorption, progressive worsening of heart failure, excess volume loss, renal insufficiency, secondary hyperaldosteronism, and hypertrophy of the tubular cells of the distal nephron. Resistance due to inadequate drug absorption—either its speed or extent—is common with furosemide, which is poorly absorbed (34). Once recognized, this hurdle to response can be overcome by using loop diuretics that are predictably well absorbed, such as bumetanide and torasemide or by giving intravenous furosemide (37). 

One complication of long-term diuretic therapy in otherwise healthy individuals is edema, and it has been suggested that surreptitious use of diuretics can explain some otherwise paradoxical cases of idiopathic edema presumably the diuretic induces a persistent increase in plasma renin activity and secondary hyperaldosteronism, and attempts to stop the diuretic intake can at first actually aggravate the condition (127). However, three studies have furnished strong evidence that diuretic abuse is not an important cause of idiopathic edema (128-130). 

The first dose of GM-CSF can be followed within 3 hours by flushing, hypotension, tachycardia, dyspnea, musculoskeletal pain, and nausea and vomiting (6). At very high doses (generally over 16 micrograms/kg/day), erythroderma, weight gain, and edema with pleuropericardial effusions and ascites have been reported (10). Renal symptoms have also been described (11,12), as have various biochemical abnormalities, possibly due to secondary hyperaldosteronism (13-15). 

Spironolactone has been used as a potassium-sparing diuretic in cardiac failure and in the management of ascites and edema associated with hepatic cirrhosis with secondary hyperaldosteronism. It is also used to treat hyperaldosteronism due to adrenal tumors or adrenal hyperplasia. It has a weak positive inotropic effect and a modest antihypertensive effect, in keeping with its natriuretic action. 

Like all diuretics, the thiazides can cause electrolyte abnormalities, such as hypokalemia and hyponatremia, and dehydration. These complications are uncommon in patients with uncomplicated hypertension, but are more common in patients with heart failure or decompensated hepatic cirrhosis with secondary hyperaldosteronism. Until a patient is accustomed to the effect of a diuretic, dizziness may be experienced. Serum lipid concentrations are slightly raised acutely and hyperglycemia can occur during long-term therapy. Rare effects are thrombocytopenia, rashes, drug fever, cholestatic jaundice, pancreatitis, and precipitation of hepatic... 

In humans, spironolactone is absorbed readily and is metabolized in the liver to active compounds called canrenones. It is these metabolites that compete with aldosterone for its cytosolic receptor therefore, the maximal natriuretic effect is not observed until 24-48 h after treatment has been initiated. Spironolactone is indicated for the treatment of primary hyperaldosteronism but is also used in refractory edema and in secondary hyperaldosteronism consequent to use of loop or thiazide-type diuretics (Martinez-Maldonado Cordova 1990, Rose 1989, 1991, Wilcox 1991). In one study, the administration of spironolactone via nasogastric tube (1 and 2mg/kg) to ponies more than doubled the urinary excretion of sodium and reduced the urinary excretion of potassium for a period of 72 h, although there was no difference in the volume of urine produced (Alexander 1982). This suggests that spironolactone is a potassium-sparing agent in horses however, to date, no pharmacokinetic studies have been published. 

Bilateral adrenal hyperplasia Secondary hyperaldosteronism Hyperreninemic hyperaldosteronism (hypertension) Congenital adrenal hyperplasia (due to adrenal enzyme deficiencies in cortisol production [11 3- or 17a-hydroxylase])... 

Secondary hyperaldosteronism plays a major role in the pathogenesis of edema in patients with cirrhosis. Therefore these patients should initially be treated with spironolactone in the absence of impaired GFR and hyperkalemia. Thiazides may then be added for patients with a creatinine clearance >50 mL/min. For those patients who remain diuretic resistant, a loop diuretic may replace the thiazide. Patients with impaired GFR (creatinine clearance of <30 mL/min) generally will require a loop diuretic, with addition of a thiazide in those who do not achieve adequate diuresis. Care should be taken to avoid hypokalemia, which may precipitate hepatic encephalopathy by increasing ammoniagenesis (Fig. 49-8). ... 

Henle (e.g., furosemide, bumetanide, and torsemide) and distal convoluted tubule (thiazides), have most commonly been associated with the generation of metabolic alkalosis. These agents promote the excretion of sodium and potassium almost exclusively in association with chloride, without a proportionate increase in bicarbonate excretion. Collecting duct hydrogen ion secretion is stimulated directly by the increased luminal flow rate and sodium delivery, and indirectly by intravascular volume contraction, which results in secondary hyperaldosteronism. Renal ammoniagenesis may also be stimulated by concomitant hypokalemia, further augmenting net acid excretion. 

Excess aldosterone is categorized as either primary or secondary hyperaldosteronism. " ... 

Secondary hyperaldosteronism results from stimulation of the zona glomerulosa by an extra-adrenal factor, usually the renin-angiotensin system. Excessive potassium intake can create a physiologic increase in aldosterone, as can oral contraceptive use, pregnancy (10 times normal by the third trimester), and menses. Congestive heart failure, cirrhosis, renal artery stenosis, and Bartter s syndrome also can lead to elevated aldosterone concentrations. 

Hypokalemia is common in the patient with liver failure who has normal renal function. Poor nutritional intake and vomiting may initiate this disorder. Severe vomiting may lead to volume contraction metabolic alkalosis, with increased renal excretion of potassium. Secondary hyperaldosteronism, seen in the liver failure patient with intravascular depletion, also increases renal excretion of potassium. Loop diuretic therapy causes increased renal excretion of potassium, whereas diarrhea from lactulose therapy increases fecal excretion of potassium. All these conditions can lead to profound hypokalemia. Therefore, potassium requirements in the liver failure patient receiving specialized nutritional support often are increased substantially. 

Secondary hyperaldosteronism is common and is associated with renal, heart or liver disease. 

Spironolactone is useful in treating edema resulting from primary hyperaldosteronism and refractory edema associated with secondary hyperaldosteronism. 

Hydralazine is used in combination w-ith a -blocker and diuretic. Side-effcct.s inchide reflex tachycardia, which may provoke angina, headaches and fluid retention (as a result of secondary hyperaldosteronism). in slow aceiyluiors in particular, hydralazine may induce a lupun syndrome resulting in fever, arthralgia, malai.se and hepatitis. 

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