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Which drugs cause metabolic alkalosis?

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7 min read

Metabolic alkalosis is a common acid-base disorder seen in hospitalized patients, and it involves an elevated blood pH due to an increase in bicarbonate. Understanding which drugs cause metabolic alkalosis is crucial, as many therapeutic agents can alter the body's electrolyte balance and kidney function, leading to this condition.

Quick Summary

An elevation in blood pH due to excess bicarbonate can be triggered by several medications. Common culprits include loop and thiazide diuretics, mineralocorticoids, certain antacids, and chronic laxative abuse. The underlying mechanisms often involve volume depletion, hypokalemia, and enhanced renal bicarbonate reabsorption.

Key Points

  • Diuretics Cause Contraction Alkalosis: Loop diuretics (furosemide) and thiazide diuretics (hydrochlorothiazide) are major culprits, causing fluid loss that concentrates bicarbonate and activates renal compensatory mechanisms.

  • Mineralocorticoid Excess Stimulates H+ Loss: Drugs or substances that mimic aldosterone, such as licorice, increase the kidney's excretion of hydrogen and potassium ions, leading to alkalosis and hypokalemia.

  • Bicarbonate Loading is a Risk: Direct alkali administration, for instance, in severe antacid overuse or aggressive sodium bicarbonate therapy, can cause metabolic alkalosis, especially with reduced kidney function.

  • Laxative Abuse Causes Dehydration: Chronic laxative abuse can result in significant fluid and electrolyte loss, leading to volume depletion and triggering secondary hyperaldosteronism, which in turn causes metabolic alkalosis.

  • Hypokalemia Enhances Alkalosis: Low potassium levels contribute to metabolic alkalosis by causing a shift of hydrogen ions into cells and promoting increased renal acid secretion.

  • Management Depends on the Cause: Treatment strategies range from discontinuing the causative agent and fluid replacement (for chloride-responsive cases) to specific medications like aldosterone antagonists or carbonic anhydrase inhibitors.

In This Article

Metabolic alkalosis is a condition defined by an elevation in the serum bicarbonate concentration and an arterial pH above 7.45. While there are several physiological causes for this acid-base disturbance, numerous medications can induce or exacerbate the condition. Drug-induced metabolic alkalosis often results from mechanisms involving fluid and electrolyte disturbances, primarily affecting the kidneys' ability to manage bicarbonate excretion. Understanding these mechanisms is key to both prevention and treatment. The disorder can be categorized as 'chloride-responsive' or 'chloride-resistant,' a distinction that helps guide the diagnostic approach and management.

Diuretics

Diuretics, commonly known as 'water pills,' are one of the most frequent causes of drug-induced metabolic alkalosis. They are used to treat conditions such as hypertension, congestive heart failure, and edema by promoting diuresis, but this effect can disturb the body's acid-base balance. The primary mechanism involves volume contraction, activation of the renin-angiotensin-aldosterone system (RAAS), and renal loss of hydrogen and chloride ions.

Loop and Thiazide Diuretics

  • Loop Diuretics: Medications like furosemide, bumetanide, and torsemide work by inhibiting the sodium-potassium-chloride cotransporter (NKCC2) in the thick ascending limb of the loop of Henle. This inhibition leads to increased urinary excretion of sodium, potassium, and chloride. The resulting volume depletion activates RAAS, which in turn boosts the effect of aldosterone in the distal nephron. Aldosterone promotes potassium and hydrogen ion excretion in exchange for sodium reabsorption, thereby generating new bicarbonate and causing metabolic alkalosis. Loop diuretics can cause a more severe alkalosis than thiazides.
  • Thiazide Diuretics: Drugs such as hydrochlorothiazide and chlorothiazide inhibit the sodium-chloride cotransporter (NCC) in the distal convoluted tubule. Their mechanism is similar to loop diuretics, causing volume contraction and secondary hyperaldosteronism, but the effect on potassium and hydrogen excretion is less pronounced, resulting in a milder metabolic alkalosis.

Mineralocorticoid Excess

Excessive mineralocorticoid activity, either from natural overproduction or certain medications, can lead to metabolic alkalosis. Mineralocorticoids, especially aldosterone, play a critical role in regulating sodium and potassium balance. Excess levels cause increased sodium reabsorption in the collecting ducts while promoting the secretion of potassium and hydrogen ions, leading to hypokalemia and metabolic alkalosis.

Drugs Mimicking Mineralocorticoids

  • Licorice: The active ingredient in licorice, glycyrrhizin, inhibits the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11βHSD2). This enzyme normally deactivates cortisol. When inhibited, cortisol acts on mineralocorticoid receptors, producing a pseudo-aldosteronism state that leads to hypertension, hypokalemia, and metabolic alkalosis.
  • Exogenous Steroids: Some corticosteroids can have mineralocorticoid effects, especially at high doses or in specific conditions, leading to similar electrolyte imbalances.

Bicarbonate Administration

Direct or indirect administration of bicarbonate can lead to metabolic alkalosis, particularly when renal function is impaired. The kidneys are normally capable of excreting excess bicarbonate, but this capacity can be overwhelmed or compromised.

Sources of Bicarbonate

  • Sodium Bicarbonate: Overzealous or prolonged intravenous administration of sodium bicarbonate to correct metabolic acidosis can overshoot its target, leading to metabolic alkalosis. This is particularly common in the setting of rapidly corrected chronic hypercapnia, where the kidneys' high compensatory bicarbonate levels persist even after carbon dioxide has normalized.
  • Antacids (Milk-Alkali Syndrome): The chronic, excessive intake of calcium-containing antacids, like calcium carbonate, can lead to a condition known as milk-alkali syndrome. This causes hypercalcemia and can impair renal function, making it difficult for the kidneys to excrete the alkali load.

Laxative Abuse

Laxative abuse, especially with stimulant laxatives, can lead to chronic diarrhea and metabolic alkalosis, though it can also cause metabolic acidosis. The mechanism for metabolic alkalosis in this context is complex but often involves significant fluid and potassium loss. This results in volume contraction, triggering secondary hyperaldosteronism and subsequent renal hydrogen ion secretion. The resulting hypokalemia also shifts hydrogen ions into cells, further contributing to the alkalosis.

Other Medications

Several other classes of medications and substances can contribute to metabolic alkalosis through various mechanisms:

  • Carbenicillin and Penicillin: High-dose administration of these antibiotics can lead to metabolic alkalosis. These agents contain non-reabsorbable anions, which increase the delivery of sodium to the distal tubules. This promotes sodium reabsorption in exchange for enhanced potassium and hydrogen excretion, leading to hypokalemia and alkalosis.
  • Excessive Chloride Loss: Beyond diuretics, medications or conditions causing significant chloride depletion can lead to metabolic alkalosis. Chloride depletion stimulates renal bicarbonate reabsorption.

Comparison of Drugs Causing Metabolic Alkalosis

Drug Class Examples Primary Mechanism Associated Electrolyte Imbalances
Loop Diuretics Furosemide, Bumetanide Volume contraction, secondary hyperaldosteronism Hypokalemia, hypochloremia
Thiazide Diuretics Hydrochlorothiazide Volume contraction, secondary hyperaldosteronism Hypokalemia, hypochloremia
Mineralocorticoids / Mimics Aldosterone, Licorice Enhanced renal sodium reabsorption, increased H+ secretion Hypokalemia
Alkali Administration Sodium Bicarbonate, Calcium Carbonate (in excess) Bicarbonate loading Hypercalcemia (Milk-Alkali), hypokalemia (rebound)
Laxative Abuse Stimulant Laxatives Volume contraction, hypokalemia Hypokalemia, hypochloremia
Anion Antibiotics Carbenicillin, Penicillin Increased delivery of sodium and non-reabsorbable anion to distal nephron Hypokalemia

Management and Clinical Considerations

Recognizing the potential for drug-induced metabolic alkalosis is crucial for patient safety. The appropriate treatment depends on the underlying cause. Often, simply removing or reducing the dosage of the offending medication is sufficient.

  • Diuretic-Induced: Management typically involves fluid resuscitation with isotonic saline to correct volume depletion and repletion of potassium chloride. In cases where diuretics must be continued, adding a potassium-sparing diuretic like spironolactone or amiloride, or a carbonic anhydrase inhibitor like acetazolamide, can help.
  • Excess Mineralocorticoid: Aldosterone antagonists, such as spironolactone, are the treatment of choice for mineralocorticoid-induced alkalosis.
  • Severe Alkalosis: For severe cases (e.g., pH > 7.55), especially in patients with advanced renal failure, more aggressive measures like intravenous hydrochloric acid or dialysis may be necessary under specialized care.

It is important for clinicians to maintain a high index of suspicion, especially in patients with unexplained electrolyte imbalances and in those with underlying conditions like heart failure or kidney disease. A thorough review of a patient's medication history, including over-the-counter products and supplements, is an essential diagnostic step. The pathophysiology of metabolic alkalosis can be complex, involving both generation and maintenance phases, with volume depletion and hypokalemia being key factors in its persistence.

Conclusion

Numerous drugs, from commonly prescribed diuretics to antacids and abused laxatives, have the potential to cause metabolic alkalosis. This condition arises from disturbances in fluid and electrolyte balance that alter the kidneys' acid-base regulation, often leading to increased bicarbonate levels. By understanding the specific pharmacological mechanisms—such as volume contraction, secondary hyperaldosteronism, and direct alkali loading—clinicians can identify the cause and implement appropriate management strategies. Proper diagnosis requires a comprehensive patient history, including medication use, and targeted treatment often involves addressing the root cause and correcting underlying volume and electrolyte deficiencies, particularly potassium and chloride, to resolve the imbalance..

Key takeaways

  • Diuretics are a primary cause: Both loop (furosemide) and thiazide (hydrochlorothiazide) diuretics can induce metabolic alkalosis through volume contraction and secondary hyperaldosteronism.
  • Mineralocorticoid excess is a key mechanism: Excess aldosterone, or mimicking substances like licorice, enhances renal hydrogen and potassium excretion, leading to alkalosis and hypokalemia.
  • Bicarbonate loading is a direct cause: Exogenous administration of bicarbonate, or excessive antacid use (milk-alkali syndrome), can overwhelm the kidneys' ability to regulate pH.
  • Laxative abuse triggers volume depletion: Chronic laxative use causes fluid and potassium loss, leading to volume contraction and secondary hyperaldosteronism, which promotes metabolic alkalosis.
  • Hypokalemia contributes to persistence: A common feature of many drug-induced cases, low potassium levels shift hydrogen ions intracellularly and enhance renal acid secretion, perpetuating the alkalosis.
  • Anion antibiotics are a minor cause: Certain high-dose antibiotics like carbenicillin can act as non-reabsorbable anions, increasing the excretion of hydrogen and potassium ions.

Faqs

  • What are the most common medications that cause metabolic alkalosis? The most common medications are loop diuretics (like furosemide) and thiazide diuretics (like hydrochlorothiazide), as they cause fluid and electrolyte depletion.
  • How do diuretics cause metabolic alkalosis? Diuretics induce volume contraction and activate the renin-angiotensin-aldosterone system. This promotes the kidneys to excrete hydrogen and potassium while reabsorbing bicarbonate, raising blood pH.
  • Can excessive use of antacids lead to metabolic alkalosis? Yes, particularly absorbable antacids containing sodium bicarbonate or calcium carbonate. This is a risk for individuals with impaired kidney function who cannot excrete the excess alkali.
  • What is milk-alkali syndrome and how does it relate to metabolic alkalosis? Milk-alkali syndrome results from the chronic intake of large amounts of calcium (often from calcium carbonate antacids) and absorbable alkali. It causes hypercalcemia, which can impair kidney function, and an increase in bicarbonate, leading to metabolic alkalosis.
  • Does laxative abuse cause metabolic alkalosis or acidosis? Laxative abuse can cause either. While it typically causes metabolic acidosis due to bicarbonate loss in diarrhea, it can also cause metabolic alkalosis through significant volume and potassium depletion, which triggers renal mechanisms that retain bicarbonate.
  • Why is hypokalemia (low potassium) often associated with metabolic alkalosis? Hypokalemia causes hydrogen ions to shift from the blood into cells in exchange for potassium. This intracellular shift, along with enhanced renal acid excretion triggered by aldosterone, contributes to the elevation of blood pH.
  • How is medication-induced metabolic alkalosis typically treated? Treatment focuses on addressing the underlying cause, which often means discontinuing the offending drug. Volume depletion is corrected with intravenous saline, and potassium is replaced. Other medications like acetazolamide or potassium-sparing diuretics may be used in specific cases.

Citations

Frequently Asked Questions

Yes, many medications used for heart failure can cause metabolic alkalosis. Diuretics, particularly loop diuretics like furosemide, are a common component of heart failure treatment and can lead to fluid and electrolyte imbalances that result in alkalosis.

The primary mechanism is volume contraction, which stimulates the renin-angiotensin-aldosterone system (RAAS). Aldosterone then increases the kidneys' secretion of hydrogen ions into the urine, leading to an increase in blood bicarbonate and pH.

Yes, certain over-the-counter medications can cause it, including antacids containing calcium carbonate or sodium bicarbonate when consumed in excessive amounts, particularly by individuals with pre-existing kidney conditions.

Licorice contains glycyrrhizin, which inhibits an enzyme that deactivates cortisol. This leads to an apparent excess of mineralocorticoid activity, causing increased renal secretion of hydrogen ions and resulting in metabolic alkalosis.

Contraction alkalosis occurs when a large volume of fluid is lost, concentrating the remaining bicarbonate and raising blood pH. It is a common result of diuretic use, where volume depletion is a primary therapeutic effect.

Treatment varies depending on the cause but generally involves stopping the offending medication, correcting fluid volume with saline solution, and replacing lost electrolytes like potassium and chloride. Specific medications like carbonic anhydrase inhibitors or potassium-sparing diuretics may also be used.

Correcting hypokalemia is crucial because low potassium levels drive hydrogen ions into cells, further increasing the alkalosis. Addressing the potassium deficiency helps normalize the intracellular-extracellular ion balance and supports the resolution of the alkalosis.

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    USMLE Step 1 prep: Woman has shortness of breath, weight gain
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    Complications from the Misuse of Laxatives & Diuretics | ACUTE
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Related Topics:

#drug side effects #diuretics #hypokalemia #laxative abuse #Acid-base Balance #aldosterone #metabolic alkalosis #medication induced alkalosis

Medical Disclaimer

This content is for informational purposes only and should not replace professional medical advice.