How does stomach acid pH affect the absorption of d-amphetamine (dextroamphetamine)?

Interaction Between D-Amphetamine and Stomach Acid pH

Gastric pH significantly affects d-amphetamine absorption, with alkaline conditions increasing absorption and acidic conditions decreasing it—therefore, avoid co-administration with antacids or proton pump inhibitors, as these agents can substantially alter amphetamine bioavailability and clinical effects. 1

Mechanism of pH-Dependent Absorption

D-amphetamine is a weak base with a pKa of 9.9, making its absorption highly dependent on gastric and urinary pH 1:

• In acidic environments (low pH): Amphetamine becomes more ionized, reducing gastrointestinal absorption and increasing urinary excretion 1
• In alkaline environments (high pH): Amphetamine remains non-ionized, enhancing gastrointestinal absorption and decreasing urinary excretion 1

This pH sensitivity creates clinically significant drug interactions with agents that alter gastric acidity 1.

Specific Drug Interactions to Avoid

Gastrointestinal Alkalinizing Agents

Co-administration of d-amphetamine with gastrointestinal alkalinizing agents such as antacids should be avoided 1:

• Sodium bicarbonate and similar antacids increase amphetamine absorption 1
• These agents increase blood levels and potentiate amphetamine's actions 1
• The enhanced absorption can lead to excessive sympathomimetic effects and potential toxicity 1

Proton Pump Inhibitors

Co-administration of d-amphetamine with proton pump inhibitors should be avoided 1:

• PPIs block gastric acid production, reducing gastric acidity 1
• In the presence of a PPI, the median Tmax of amphetamine formulations was shortened from 5 hours to 2.75 hours 1
• This accelerated absorption alters the pharmacokinetic profile and can lead to unpredictable clinical effects 1

Urinary pH Modifiers

Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of non-ionized amphetamine, decreasing urinary excretion and increasing blood levels 1. Conversely, urinary acidifying agents (ammonium chloride, sodium acid phosphate) increase urinary excretion and lower blood levels 1.

Clinical Algorithm for Managing pH Interactions

When prescribing d-amphetamine:

1. Screen for concurrent medications:

   • Identify any antacids, PPIs, H2-receptor antagonists, or urinary pH modifiers 1
   • Review over-the-counter medications, as antacids are freely available 2

2. Avoid co-administration:

   • Do not prescribe gastrointestinal alkalinizing agents or PPIs with amphetamine 1
   • If acid suppression is necessary, consider H2-receptor antagonists with caution, though these have less dramatic effects than PPIs 3

3. Timing considerations if separation is attempted:

   • For drugs that cannot be discontinued, spacing administration by at least 4 hours may reduce interaction severity 2
   • However, given amphetamine's extended pharmacokinetic profile and the prolonged effects of acid-suppressing agents, complete avoidance is preferable 1

4. Monitor for altered efficacy:

   • Patients inadvertently taking alkalinizing agents may experience enhanced amphetamine effects 1
   • Patients taking acidifying agents may experience reduced therapeutic response 1

Common Pitfalls and Caveats

Over-the-counter antacid use: Patients may not report OTC antacid use, which is increasingly common as these products are freely available 2. Specifically ask about antacid, calcium supplement, and heartburn medication use 2.

Combination OTC products: Recent trends show combination formulations of antacids with H2-receptor antagonists, which create dual mechanisms for interaction—both pH-dependent and cation-mediated chelation 2. These pose particular risk.

Food effects: While food prolongs Tmax by approximately 2.5 hours for d-amphetamine, it does not affect the extent of absorption 1. This is distinct from pH-altering medications, which do affect total drug exposure 1.

Renal function considerations: Since amphetamine elimination is highly pH-dependent and involves both hepatic metabolism and renal excretion, any decrease in renal function combined with pH alterations can result in prolonged exposures 1. This is particularly relevant when urinary pH is altered by medications or diet 1.

Weak base drug class effect: D-amphetamine's pH sensitivity is characteristic of weak base drugs generally 4, 5. Understanding this principle helps predict interactions with other medications that alter gastric pH 4, 6.