Pharmacology of Magnesium Hydroxide

Introduction/Overview

Magnesium hydroxide is an inorganic compound with the chemical formula Mg(OH)₂, widely utilized in clinical medicine for its dual therapeutic roles as an antacid and an osmotic laxative. Its historical use dates back centuries, with its modern pharmaceutical formulation often referred to as “milk of magnesia” due to its suspension’s milky white appearance. As a cornerstone of over-the-counter gastrointestinal therapeutics, its pharmacology represents a fundamental topic for understanding the management of common acid-peptic disorders and constipation.

The clinical relevance of magnesium hydroxide stems from its efficacy, general safety profile, and widespread accessibility. It occupies a significant position in formulary management for conditions such as dyspepsia, gastroesophageal reflux disease (GERD), and occasional constipation. Its importance is further underscored by its role as a prototype for understanding the pharmacodynamics of non-systemic antacids and saline cathartics, providing a basis for comparing other agents within these classes.

Learning Objectives

• Describe the chemical properties and pharmaceutical classifications of magnesium hydroxide.
• Explain the detailed molecular and physiological mechanisms of action underlying its antacid and laxative effects.
• Analyze the pharmacokinetic profile, including absorption, distribution, and excretion pathways.
• Evaluate the approved therapeutic applications, common adverse effects, and significant drug interactions.
• Apply knowledge of special population considerations to guide safe and effective clinical use.

Classification

Magnesium hydroxide is systematically categorized within multiple therapeutic and chemical classification systems, reflecting its diverse pharmacological actions.

Therapeutic Classification

Primarily, magnesium hydroxide is classified as an antacid. Antacids are agents that neutralize gastric hydrochloric acid, thereby raising the intragastric pH. Within the antacid subclass, it is considered a non-systemic or minimally absorbed antacid, as its active moiety, the magnesium cation (Mg²⁺), exhibits limited absorption from the gastrointestinal tract under normal conditions. Concurrently, it is classified as a laxative. Specifically, it falls under the category of saline or osmotic laxatives. These agents promote defecation by drawing water into the intestinal lumen via an osmotic gradient, increasing intraluminal pressure, and stimulating peristalsis.

Chemical Classification

Chemically, magnesium hydroxide is an inorganic base, specifically a divalent metal hydroxide. It is poorly soluble in water, with a solubility of approximately 0.00064 g/100 mL at 20°C, which corresponds to a saturated solution pH of about 10.5. This low solubility is a critical determinant of its pharmacokinetic and pharmacodynamic behavior. In pharmaceutical preparations, it is often formulated as a suspension in water, typically at concentrations ranging from 7% to 8.5% w/v for antacid use and higher concentrations (e.g., 30-40% w/v) for laxative purposes. It may also be combined with other agents, such as aluminum hydroxide, to balance laxative and constipating effects in combination antacid products.

Mechanism of Action

The therapeutic effects of magnesium hydroxide are mediated through two distinct but concurrent mechanisms: local chemical neutralization in the stomach and osmotic activity in the intestines.

Antacid Action: Acid Neutralization

The primary mechanism for its antacid effect is a straightforward acid-base neutralization reaction. Upon ingestion, magnesium hydroxide reacts with hydrochloric acid (HCl) in the gastric lumen. The chemical reaction proceeds as follows:

Mg(OH)₂ (s) + 2HCl (aq) → MgCl₂ (aq) + 2H₂O (l)

Each mole of magnesium hydroxide neutralizes two moles of hydrochloric acid. The magnesium chloride (MgCl₂) formed is a soluble salt. The neutralization capacity of an antacid is typically expressed in milliequivalents (mEq), representing the number of milliequivalents of HCl that can be neutralized by a specific dose of the agent. Magnesium hydroxide has a high acid-neutralizing capacity (ANC), approximately 30-35 mEq per 400 mg. Raising the gastric pH to above 3.5 not only alleviates pain associated with acid irritation but also reduces the proteolytic activity of pepsin, which is largely inactive at pH >5. Furthermore, an elevated pH may promote the healing of gastroduodenal mucosa by creating a more favorable environment.

Laxative Action: Osmotic Effect

The laxative action is independent of its antacid effect and is primarily osmotic in nature. The poorly absorbed magnesium and hydroxide ions create an osmotic gradient within the lumen of the small and large intestines. Magnesium hydroxide itself is not readily absorbed; however, the small fraction that dissociates yields Mg²⁺ and OH^– ions. These ions, particularly Mg²⁺, are poorly absorbed from the intestinal tract. Their presence in the lumen increases the osmolarity of the intestinal contents. In accordance with the principles of osmosis, water moves passively from the plasma and intestinal tissues into the lumen to equilibrate the osmotic gradient.

This influx of water results in several physiological consequences: distension of the intestinal wall, an increase in intraluminal pressure, and stimulation of stretch receptors. These events trigger the activation of the peristaltic reflex, mediated by the enteric nervous system, leading to enhanced propulsive motility. Additionally, the increased fluid volume softens the fecal mass, facilitating its passage. The onset of action for the laxative effect is typically between 30 minutes and 6 hours, depending on the dose and individual gastrointestinal transit time.

Cellular and Receptor Interactions

Unlike many pharmacologic agents, magnesium hydroxide does not exert its effects through specific receptor agonism or antagonism, enzyme inhibition, or direct modulation of cellular signal transduction pathways. Its actions are predominantly physicochemical. However, the magnesium ion itself is a cofactor for over 300 enzymatic reactions in the body, including those involved in ATP metabolism, nucleic acid synthesis, and neuromuscular function. Systemic absorption of magnesium from therapeutic doses is generally insufficient to significantly influence these enzymatic processes, but excessive absorption, as in cases of overdose or renal impairment, can lead to hypermagnesemia with systemic effects.

Pharmacokinetics

The pharmacokinetic profile of magnesium hydroxide is characterized by minimal systemic absorption, with its activity confined almost entirely to the gastrointestinal lumen.

Absorption

Absorption of intact magnesium hydroxide is negligible due to its very low solubility in water at neutral pH. However, upon reaction with gastric acid, it is converted to soluble magnesium chloride (MgCl₂). A small but variable fraction (typically 5-30%) of the resulting magnesium ions (Mg²⁺) may be absorbed from the small intestine. The extent of absorption is influenced by several factors: the dose administered, the presence of food, gastrointestinal motility, and the individual’s magnesium status. Absorption occurs via both passive paracellular diffusion and active transport mechanisms. The active transport is saturable and is more prominent when magnesium intake is low. The hydroxide ion is largely converted to water and carbonate/bicarbonate during the neutralization process and is not absorbed as a distinct entity.

Distribution

Systemically absorbed magnesium is distributed throughout the body. Magnesium is primarily an intracellular cation, with approximately 99% of total body magnesium located within cells or bone. The intracellular compartment, particularly within skeletal muscle, liver, and other soft tissues, holds about 20-30% of total body magnesium. Bone serves as the major reservoir, containing 60-70% of the body’s magnesium in a surface-limited exchangeable pool and a deeper crystalline lattice. The remaining 1-2% is found in the extracellular fluid, with a normal serum concentration ranging from 0.70 to 1.05 mmol/L. Serum magnesium exists in three forms: approximately 55% as free, ionized Mg²⁺ (the physiologically active form); 30% bound to proteins (mainly albumin); and 15% complexed with anions such as citrate, phosphate, and sulfate.

Metabolism

Magnesium hydroxide does not undergo hepatic metabolism in the classical cytochrome P450 sense. The compound itself is chemically transformed in the stomach via the neutralization reaction. The magnesium ion, once absorbed, is not metabolized but exists as an essential electrolyte. Homeostatic regulation of serum magnesium levels is controlled primarily by renal excretion and, to a lesser extent, by intestinal absorption.

Excretion

The primary route of elimination for unabsorbed magnesium is fecal excretion. The magnesium that remains in the intestinal lumen contributes to the osmotic laxative effect and is eliminated in the stool. Systemically absorbed magnesium is excreted almost exclusively by the kidneys via glomerular filtration. Approximately 70-80% of serum magnesium is filtered at the glomerulus. The renal tubules, particularly the thick ascending limb of the loop of Henle and the distal convoluted tubule, reabsorb about 95-99% of the filtered load under normal conditions. Renal handling is the key regulator of magnesium balance. Excretion increases with elevated serum magnesium levels and decreases in states of magnesium deficiency. The elimination half-life (t_1/2) of systemically absorbed magnesium is not a fixed pharmacokinetic parameter for the drug itself but is governed by the body’s homeostatic mechanisms, typically resulting in a biphasic elimination with a rapid initial phase (hours) and a slower terminal phase related to bone turnover (days to weeks).

Dosing Considerations

Dosing is highly indication-specific. For antacid use, typical adult doses range from 400 mg to 1.2 g (5 mL to 15 mL of a standard suspension), administered between meals and at bedtime. The maximum daily dose for antacid purposes is often limited to avoid significant laxation. For use as a laxative, higher single doses are employed, commonly 2.4 g to 4.8 g (30 mL to 60 mL of suspension). Dosing frequency for laxative use is generally once daily, and it is not recommended for prolonged daily use without medical supervision due to the risk of electrolyte disturbances and dependence.

Therapeutic Uses/Clinical Applications

Magnesium hydroxide is employed for well-established indications rooted in its dual mechanisms of action.

Approved Indications

Symptomatic Relief of Hyperacidity: This is the primary antacid indication. It is effective for the temporary relief of heartburn, acid indigestion, sour stomach, and upset stomach associated with these conditions. It is used in the management of dyspepsia and as an adjunct in gastroesophageal reflux disease (GERD). Its rapid onset of action makes it suitable for as-needed relief.

Occasional Constipation: As an osmotic laxative, magnesium hydroxide is indicated for the short-term relief of occasional constipation. It produces a bowel movement that is typically semi-solid or watery, which is useful for alleviating acute symptoms. It is not intended for the management of chronic constipation without investigation of the underlying etiology.

Preparation for Certain Medical Procedures: In some clinical protocols, magnesium hydroxide may be used as part of a bowel cleansing regimen prior to colorectal surgery or endoscopic procedures, although it has largely been superseded by more effective and standardized osmotic purgatives like polyethylene glycol solutions.

Off-Label Uses

Management of Magnesium Deficiency: While not the first-line treatment for hypomagnesemia (where intravenous or other oral magnesium salts like magnesium oxide or chloride are preferred), magnesium hydroxide can contribute to the repletion of magnesium stores in mild, asymptomatic deficiency, given its partial absorption.

Adjuvant in Urinary Alkalinization: The systemic absorption of a small amount of the hydroxide moiety may contribute to a mild alkaline load. This property has been utilized historically as an adjunct in regimens aimed at alkalinizing the urine, such as in the management of certain drug overdoses (e.g., salicylates, barbiturates) or to promote excretion of uric acid, though its role here is minor and not standard.

Topical Applications: Formulations of magnesium hydroxide are sometimes used topically for dermatological conditions, such as to soothe minor skin irritations or as a drying agent, leveraging its mild alkaline and absorbent properties.

Adverse Effects

The adverse effect profile of magnesium hydroxide is generally mild and related to its local gastrointestinal actions or, less commonly, to systemic absorption.

Common Side Effects

The most frequent adverse effects are gastrointestinal and are often an extension of its pharmacologic activity.

• Diarrhea and Cramping: This is the most common side effect, resulting directly from its osmotic laxative action. Even at antacid doses, some individuals, particularly those with sensitive bowels, may experience loose stools or diarrhea. Abdominal cramping can occur due to the rapid distension and increased peristalsis.
• Nausea and Vomiting: These may occur, especially with higher laxative doses or in sensitive individuals, possibly due to gastrointestinal irritation or reflex mechanisms.
• Altered Taste: The chalky texture and taste of the suspension can be unpleasant for some patients.

Serious/Rare Adverse Reactions

Serious adverse effects are uncommon with appropriate use in individuals with normal renal function but can be significant.

• Hypermagnesemia: This is the most serious potential adverse effect. It occurs when the rate of magnesium absorption exceeds the kidney’s excretory capacity. Risk factors include renal impairment (even mild), excessive dosage, prolonged use, and concomitant use of other magnesium-containing products. Symptoms of mild hypermagnesemia (1.5-2.5 mmol/L) include nausea, flushing, headache, and lethargy. As levels rise (2.5-5.0 mmol/L), hypotension, bradycardia, drowsiness, and diminished deep tendon reflexes occur. Severe hypermagnesemia (>5.0 mmol/L) can lead to muscle paralysis, complete heart block, respiratory depression, cardiac arrest, and coma.
• Electrolyte and Acid-Base Disturbances: Profuse diarrhea can lead to fluid loss, hypokalemia, and hypochloremia. The loss of acidic gastric contents via neutralization and potential systemic absorption of alkali can very rarely contribute to a metabolic alkalosis, often referred to as “milk-alkali syndrome,” though this is more classically associated with large doses of calcium carbonate.
• Hypophosphatemia: Chronic use of antacids containing magnesium or aluminum can bind dietary phosphate in the gut, forming insoluble complexes and leading to increased fecal phosphate excretion and subsequent hypophosphatemia.
• Allergic Reactions: True IgE-mediated allergic reactions are exceedingly rare but could theoretically present as rash, urticaria, or anaphylaxis.

There are no black box warnings mandated by regulatory agencies for magnesium hydroxide when used according to labeled directions.

Drug Interactions

Magnesium hydroxide can interact with a wide range of orally administered drugs, primarily through physicochemical mechanisms in the gastrointestinal tract.

Major Drug-Drug Interactions

Absorption Interactions (Complexation/Adsorption): The magnesium cation can form insoluble or poorly absorbable complexes with several drugs, significantly reducing their bioavailability.

• Tetracycline and Fluoroquinolone Antibiotics: Chelation occurs between Mg²⁺ and the carbonyl and hydroxyl groups on these antibiotics, forming insoluble chelates. This can reduce antibiotic absorption by over 50%. Administration should be separated by at least 2-4 hours.
• Iron Supplements: Magnesium hydroxide can decrease the absorption of oral iron (ferrous salts), potentially worsening anemia. Separating administration by several hours is recommended.
• Bisphosphonates (e.g., alendronate, risedronate): Divalent cations like Mg²⁺ can complex with bisphosphonates, drastically reducing their already low absorption. These drugs must be taken with plain water on an empty stomach, and other medications, including antacids, should be delayed for at least 30 minutes (and longer for some agents).
• Thyroid Hormones (Levothyroxine): Calcium and magnesium-containing products can adsorb levothyroxine, impairing its absorption. Dosing should be separated by at least 4 hours.
• Mycophenolate Mofetil: Antacids containing magnesium and aluminum can reduce the absorption of the active metabolite, mycophenolic acid.

pH-Dependent Interactions: By raising gastric pH, magnesium hydroxide can alter the dissolution and ionization of other drugs.

• Azole Antifungals (e.g., ketoconazole, itraconazole): These drugs require an acidic environment for optimal dissolution and absorption. Elevated gastric pH can cause a clinically significant decrease in their bioavailability.
• Protease Inhibitors (e.g., atazanavir): The absorption of some HIV protease inhibitors is pH-dependent, and concurrent antacid use may reduce their plasma concentrations.
• Enteric-Coated Formulations: Premature dissolution of enteric coatings, which are designed to resist stomach acid, may occur in a less acidic stomach, potentially leading to gastric irritation or degradation of the drug.

Pharmacodynamic Interactions:

• Other Laxatives: Concomitant use with other laxatives may potentiate the laxative effect, increasing the risk of diarrhea and electrolyte imbalance.
• Neuromuscular Blocking Agents: In the setting of hypermagnesemia, the effects of non-depolarizing neuromuscular blockers (e.g., rocuronium, vecuronium) can be potentiated and prolonged due to magnesium’s own neuromuscular blocking properties at the neuromuscular junction.
• Cardiac Glycosides (Digoxin): Hypokalemia and hypomagnesemia (from diarrhea) can potentiate digoxin toxicity. Conversely, hypermagnesemia may enhance the cardiac effects of digoxin, potentially leading to bradycardia and heart block.

Contraindications

Absolute contraindications to the use of magnesium hydroxide include:

• Severe renal impairment (e.g., creatinine clearance < 30 mL/min) due to the high risk of hypermagnesemia.
• Known hypersensitivity to magnesium hydroxide or any component of the formulation.
• Symptoms of appendicitis, acute abdominal pain, nausea, or vomiting where the cause is undiagnosed, as a laxative may exacerbate conditions like bowel obstruction or perforation.
• Severe electrolyte disturbances, particularly hypermagnesemia.

It is also contraindicated in patients with ileostomy or colostomy, as the liquid stool may be difficult to manage.

Special Considerations

The use of magnesium hydroxide requires careful evaluation in specific patient populations due to altered physiology or increased risk.

Pregnancy and Lactation

Pregnancy: Magnesium hydroxide is generally considered a Category B drug in some historical classification systems, meaning animal reproduction studies have not demonstrated a fetal risk, but there are no adequate and well-controlled studies in pregnant women. It is commonly used occasionally during pregnancy for heartburn or constipation, as systemic absorption is minimal. However, chronic or high-dose use is not recommended due to theoretical risks of electrolyte imbalance and the potential to alter uterine activity in cases of severe hypermagnesemia. It is considered preferable to some other laxatives (e.g., stimulant types) for occasional use in pregnancy.

Lactation: Magnesium is a normal constituent of breast milk. The amount of magnesium excreted into breast milk following maternal ingestion of magnesium hydroxide is not expected to differ significantly from baseline physiological levels and is unlikely to affect the nursing infant. Therefore, occasional use is generally considered compatible with breastfeeding.

Pediatric Considerations

Use in children requires caution and appropriate dosing. Magnesium hydroxide is sometimes used in pediatric populations for constipation under medical guidance. Dosing is typically weight-based (e.g., 0.5 mL/kg of a standard suspension, up to a maximum). It is crucial to avoid dehydration and electrolyte disturbances, as children are more susceptible to fluid shifts. It should not be used in very young infants without specific pediatrician instruction. The antacid use in children for conditions like GERD is less common and should be supervised, as symptoms in children may indicate a different underlying pathology.

Geriatric Considerations

Older adults may be at increased risk for adverse effects. Age-related decline in renal function, even in the absence of overt renal disease, can impair magnesium excretion and predispose to hypermagnesemia. Concomitant use of other medications that affect renal function or electrolyte balance (e.g., diuretics, ACE inhibitors, NSAIDs) is common. Constipation is a frequent complaint in the elderly, but the cause should be investigated before initiating laxative therapy. Chronic use of osmotic laxatives like magnesium hydroxide can lead to dependence and electrolyte abnormalities. A lower dose may be effective and should be initiated.

Renal and Hepatic Impairment

Renal Impairment: This is the most critical special consideration. The kidney is the sole regulator of systemic magnesium balance. In renal impairment, the ability to excrete absorbed magnesium is diminished, leading to accumulation. The risk correlates with the degree of renal dysfunction.

• Mild to Moderate Impairment (CrCl 30-90 mL/min): Use with caution. Short-term, occasional use at low doses may be acceptable, but serum magnesium levels should be monitored if used repeatedly.
• Severe Impairment (CrCl < 30 mL/min) or End-Stage Renal Disease: Magnesium hydroxide is generally contraindicated due to the high and potentially fatal risk of hypermagnesemia. Alternative agents for acid suppression (e.g., H2-receptor antagonists, proton pump inhibitors) and constipation (e.g., lactulose, polyethylene glycol) are preferred.

Hepatic Impairment: No specific dose adjustment is required for hepatic impairment alone, as magnesium is not metabolized by the liver. However, patients with advanced liver disease (e.g., cirrhosis) often have associated conditions such as renal dysfunction (hepatorenal syndrome), ascites, and electrolyte imbalances, which would necessitate the same cautions as for renal impairment and fluid/electrolyte disorders.

Summary/Key Points

Bullet Point Summary

• Magnesium hydroxide is a dual-purpose agent functioning as a non-systemic antacid and an osmotic laxative via chemical neutralization and osmotically-driven water influx, respectively.
• Its pharmacokinetics are defined by minimal and variable absorption of the magnesium ion, with excretion of the unabsorbed fraction in feces and renal elimination of any absorbed magnesium.
• Primary therapeutic indications include the symptomatic relief of hyperacidity (dyspepsia, GERD) and the short-term management of occasional constipation.
• The most common adverse effect is dose-related diarrhea. The most serious risk is hypermagnesemia, which is predominantly a concern in patients with renal impairment.
• It participates in numerous drug interactions, primarily through gastrointestinal complexation (e.g., with tetracyclines, fluoroquinolones, bisphosphonates) and by altering gastric pH (e.g., affecting azole antifungals).
• Special caution is required in populations with reduced renal excretory capacity, including the elderly and those with renal disease, where use may be contraindicated.

Clinical Pearls

• When used as an antacid, advise patients to take doses 1 hour after meals and at bedtime for optimal duration of effect, separating administration from other oral medications by 2-4 hours to avoid absorption interactions.
• For laxative use, recommend adequate fluid intake to support the osmotic effect and prevent dehydration, and emphasize that it is for occasional use only.
• Always assess renal function, either estimated or measured, before recommending regular or high-dose use, particularly in older adults.
• Inquire about the use of other magnesium-containing products (e.g., supplements, laxatives, antacids) to prevent cumulative magnesium intake.
• Recognize that the onset of laxative action can vary; lower doses may take several hours, while higher doses may act within 30-60 minutes, necessitating appropriate timing of administration.

References

1. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
6. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.