TRIPASS XR تري باس

 

107,108

Triamterene is absorbed incompletely from the GI tract. The drug has a short halflife of 1.5 to 2.5 hours. The total body clearance is high because of rapid and

extensive hepatic metabolism. Both the parent compound and the metabolite undergo

biliary and renal excretion. As with spironolactone, the hepatic metabolism of

triamterene can be altered in patients with cirrhosis.

109 The diuretic effect of

triamterene begins within 2 to 3 hours of administration, with a maximal duration of

12 to 16 hours.

Amiloride does not undergo hepatic metabolism; approximately 50% of amiloride

is excreted in the urine unchanged and the remainder is recovered in the stool as

unabsorbed drug or through biliary excretion. Serum amiloride concentrations peak 3

hours after oral ingestion, and the half-life is 6 hours. Although commonly

administered doses are in the range of 2.5 to 10 mg, diuresis increases over a much

greater range. The onset of action is 2 hours, with maximal effects at 4 to 6 hours.

Duration of action is dose dependent and ranges from 10 to 24 hours. Amiloride does

not undergo hepatic metabolism, and the drug can accumulate in patients with renal

insufficiency.

The maximal amount of filtered sodium that can be excreted through the action of

potassium-sparing diuretics is approximately 1% to 2%. Their natriuretic activity,

therefore, is relatively limited compared with the thiazide and loop diuretics. These

agents are often used concurrently with thiazide and loop diuretics to reduce

potassium loss. Spironolactone is especially useful in patients with liver cirrhosis

and ascites, who are likely to have high levels of aldosterone.

Acetazolamide

Acetazolamide inhibits carbonic anhydrase, an enzyme that mediates the excretion of

sodium, bicarbonate, and chloride ions in the proximal tubule. Use of the drug will

increase urine pH owing to the increased excretion of bicarbonate ion. The net

diuretic and natriuretic effects are limited, similar to those of the potassium-sparing

diuretics. Because of the drug’s proximal site of action, the sodium ions that are not

reabsorbed will subsequently be reclaimed in Henle’s loop and the distal tubule. In

addition, metabolic acidosis associated with the use of acetazolamide diminishes its

diuretic effect.

Osmotic Diuretics

Osmotic diuretics are nonresorbable solutes in the kidney tubule. They act primarily

in the proximal tubule, where the osmotic pressure they generate impedes the

reabsorption of water and solutes. Unlike other diuretics, the amount of water loss

exceeds the concurrent loss of sodium and potassium. Mannitol has been used in the

early treatment of oliguric postischemic acute renal failure to increase urine output.

Urea, another osmotic diuretic, and mannitol are used to reduce intracranial pressure

through cellular dehydration.

Complications of Diuretic Therapy

Disturbances in fluid, electrolyte, and acid–base balance are common side effects

associated with diuretic therapy. These side effects, including hypokalemia, are

discussed in detail in Chapter 9, Essential Hypertension; Chapter 14, Heart Failure;

and Chapter 45, Gout and Hyperuricemia. Two complications, hyponatremia and

metabolic alkalosis and acidosis, are, however, discussed in the subsequent section

because of their specific relevance to fluid balance.

HYPONATREMIA

Thiazides induce diuresis by inhibiting sodium and water reabsorption in the kidney

tubule. Because both sodium and water are lost, overdiuresis per se is not expected

to cause hyponatremia. Instead, hyponatremia represents a dilution of plasma sodium

by excess free water caused by volume-depletion–induced ADH activity. The

enhanced ADH secretion increases free-water reabsorption, resulting in

hyponatremia. Large doses of diuretic, excessive water drinking, and severe sodiumintake restriction all will accentuate the hyponatremia. Elderly patients are

particularly susceptible to this diuretic-induced complication because of the age-

associated loss of nephrons and consequent impairment of sodium–potassium

exchange.

METABOLIC ALKALOSIS AND ACIDOSIS

Metabolic alkalosis often occurs in conjunction with potassium depletion secondary

to diuretic use. The diuretic-induced contraction of ECF volume stimulates the

secretion of aldosterone, which promotes the absorption of sodium and the retention

of hydrogen ions in the kidney tubule. The net urinary loss of hydrogen ions into the

urine results in metabolic alkalosis. Generally, reducing the dose of the diuretic will

restore the acid–base balance.

Acetazolamide causes metabolic acidosis by inhibiting carbonic anhydrase, which

results in urinary excretion of sodium bicarbonate. Spironolactone, amiloride, and

triamterene can cause hyperchloremic metabolic acidosis because of their ability to

decrease potassium and hydrogen ion tubular secretion. Patients with renal

dysfunction or those taking potassium supplements or angiotensin-converting enzyme

inhibitors, which reduce aldosterone secretion, are at increased risk for developing

hyperkalemia and metabolic acidosis.

POTASSIUM

Homeostasis

The total amount of potassium stored in the body is approximately 45 to 55 mEq/kg

and varies with age, sex, and muscle mass. Lower total body potassium is found in

older adults, females, and individuals

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with a low lean-body-mass to fat ratio. Potassium is distributed unevenly between

the intracellular and extracellular compartments; 98% of the total body potassium

resides in the intracellular compartment, predominantly the muscle, and only 2% is

found in the extracellular space.

34,110 The disproportionate intracellular distribution

of potassium is maintained by the Na

+

/K+ ATPase pump, which transports sodium out

of the cell in exchange for potassium.

110–113 The cell membrane resting potential is

determined by the ratio of intracellular/extracellular potassium concentrations. As

this ratio increases, hyperpolarization of the cell membrane occurs. Conversely,

cellular depolarization results when the ratio decreases. In both situations, generation

of the action potential is impaired.

The plasma potassium concentration is maintained within a narrow range of 3.5 to

5.0 mEq/L. Although the plasma potassium concentration can be affected by the total

body potassium store, total body potassium excess or deficit cannot be estimated

accurately based solely on the plasma concentration. In fact, a normal plasma

potassium concentration does not imply normal total body potassium because

multiple factors affect the plasma potassium concentration independent of total body

potassium.

111

Potassium homeostasis is maintained by both renal and extrarenal processes. The

renal process regulates total body potassium by matching potassium excretion to

dietary intake (external balance),

114 whereas the extrarenal process regulates

potassium distribution across cell membrane (internal potassium balance).

111–112

The normal daily intake of potassium ranges between 50 and 100 mEq.

Approximately 90% of the ingested potassium is eliminated by the kidneys and

approximately 10% is eliminated via the GI tract.

114 Potassium is filtered freely

through the glomerulus and then reabsorbed. By the time the filtrate reaches the distal

convoluted tubule, greater than 90% of filtered potassium has already been

reabsorbed. The amount of potassium excreted is determined by distal tubular

potassium secretion in the principal cells of the cortical collecting duct, which is

under the influence of aldosterone. Hyperkalemia, increased potassium load, and AT2

can all stimulate aldosterone secretion.

111

Factors that affect renal potassium excretion include tubular flow, sodium delivery

to the distal segments of the nephron, the presence of poorly absorbable anions that

increase luminal electronegativity, acid–base status, and aldosterone activity.

114

Potassium excretion increases during hyperkalemia and decreases during potassium

depletion. Excretion of an acute potassium load is a slow process, with only half the

potassium load excreted in the first 4 to 6 hours. Lethal hyperkalemia would ensue

were it not for the extrarenal process that regulates intracellular/extracellular

potassium distribution.

111

The Na

+

/K+ ATPase pump, which extrudes sodium from the cell in exchange for

potassium, is pivotal in maintaining internal potassium balance.

114 Different hormonal

factors regulate the activity of the Na

+

/K+ ATPase pump, namely insulin,

catecholamines, and aldosterone. Insulin, the most important regulator, enhances

potassium uptake by muscle, liver, and adipose tissue by stimulating Na

+

/K+

ATPase.

115

Indeed, basal insulin secretion is essential for potassium homeostasis.

111

Whereas β2

-adrenergic agonists activate the Na

+

/K+ ATPase pump via cyclic

adenosine monophosphate and cause hypokalemia, α-adrenergic stimulation promotes

hepatic potassium release and causes hyperkalemia.

116 Epinephrine, an α-agonist and

β-agonist, causes a transient increase in plasma potassium (α-agonism) followed by a

more sustained decrease in plasma potassium (β-agonism).

116,117 Besides its

kaliuretic effect and enhanced potassium secretion in the colon, aldosterone also

stimulates Na

+

/K+ ATPase.

Other factors that affect the transcellular distribution of potassium include systemic

pH, plasma tonicity, and exercise.

111,113 The effect of acid–base balance on potassium

distribution is not readily predictable and depends on both the nature and the

direction of the underlying disorder. The concomitant effect of the acid–base

disorder on renal potassium excretion further complicates the relationship between

plasma potassium concentration and pH.

111,118

In acute inorganic acidosis, plasma

potassium concentration increases by 0.2 to 1.7 mEq/L per 0.1-unit decrease in pH.

Chronic inorganic metabolic acidosis usually is associated, however, with

hypokalemia because of urinary potassium loss associated with both proximal (type

2) and distal (type 1) renal tubular acidosis.

111,118

In contrast, organic acidosis

commonly has no effect on potassium distribution.

119

Other associated factors in organic acidosis may, however, affect cellular

potassium distribution.

118 For example, hyperglycemia in diabetic ketoacidosis may

increase the serum potassium concentration because of the hypertonic effect of

glucose.

120 Hypertonicity causes cell shrinkage and increases the intracellular to ECF

potassium gradient, favoring potassium egress. Acute metabolic alkalosis only

modestly decreases the plasma potassium concentration: 0.3 mEq/L for each 0.1-unit

pH increment.

111,118 As with chronic metabolic acidosis, chronic metabolic alkalosis

causes profound renal potassium wasting and is associated with hypokalemia.

Respiratory acid–base disorders usually are associated with less significant changes

in plasma potassium concentration than are metabolic acid–base disorders.

118

Exercise often causes an increase in the serum potassium concentration to a degree

that varies with the intensity of the exercise.

121

Hypokalemia

ETIOLOGY

CASE 27-8

QUESTION 1: J.P., a 60-year-old woman, presents to the ED with complaints of malaise, generalized

weakness, nausea, and vomiting for 3 days. Her medical history includes hypertension for 20 years. J.P.’s

current medications include hydrochlorothiazide 25 mg/day and nifedipine XL 30 mg/day. She has not been able

to take her medications in the past few days, however, because of vomiting. J.P. denies recent diarrhea or use

of laxatives. Her BP is 130/70 mm Hg with a pulse of 80 beats/minute while sitting, and 120/70 mm Hg with a

pulse of 95 beats/minute on standing. Physical examination reveals a thin, older woman with poor skin turgor,

dry mucous membranes, and a flat jugular vein. T-wave flattening is noted on the electrocardiogram (ECG).

Laboratory tests show the following:

Serum Na, 138 mEq/L

K, 2.1 mEq/L

Cl, 100 mEq/L

Bicarbonate, 32 mEq/L

BUN, 30 mg/dL

Creatinine, 1.2 mg/dL

Glucose, 100 mg/dL

ABG shows pH, 7.50; PCO2

, 45 mm Hg; and PO2

, 70 mm Hg at room air. Urine electrolytes are sodium, 30

mEq/L; potassium, 60 mEq/L; and chloride, less than 15 mEq/L. The patient’s presentation is consistent with

gastroenteritis. What are the causes of J.P.’s hypokalemia?

When evaluating hypokalemia, the clinician should determine whether the

hypokalemia is a result of low intake, increased cellular uptake of potassium, or

excessive loss of potassium via the kidneys, GI tract, or skin.

34,122 History and

physical evidence of potassium depletion, medication history (including use of overthe-counter medicines), and assessment of the patient’s BP, extracellular volume, and

concurrent acid–base status can provide clues to the causes of hypokalemia.

34,122

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