Acid-Base Properties of Drugs

Study Notes

Drugs are classified as acids or bases.
Acid-base properties influence drug biodistribution and partitioning.
An acid is a proton donor.
A base is a proton acceptor.
Un-ionized acids (e.g., carboxylic acids) donate protons to form ionized conjugate bases (e.g., carboxylate).
Ionized acids (e.g., ammonium compounds) donate protons, yielding un-ionized conjugate bases (e.g., amine derivatives).
Un-ionized bases accept protons and form ionized conjugate acids.
Ionized bases accept protons and form un-ionized conjugate acids.

Water is amphoteric; it can act as both an acid and a base in biological systems.
Water can accept protons from acidic drugs (forming hydronium ions) or donate protons to basic drugs (forming hydroxide ions).

pKa is a measure of acid strength.
pKa is the negative logarithm of the modified equilibrium constant (Ka).
A lower pKa indicates a stronger acid.
Strong acids (low pKa) have equilibria that favor the formation of products (conjugate acid and base).
Weak acids (high pKa) have equilibria that favor the reactants (un-ionized acid).
A pKa for a base is the pKa of its conjugate acid.
A pKa for an acid is the pKa of its conjugate base.

Specific examples of acid-base reactions involving various compounds (hydrochloric acid, sodium hydroxide, dihydrogen phosphate, ammonium chloride, acetic acid and its conjugate base, indomethacin, saccharin, ephedrine HCl).

Percent ionization is calculated using equations.
The equations for percent ionization vary depending on whether it's an HA acid (e.g., carboxylic acids) or a BH⁺ acid (e.g., amines).
The % ionization of a drug can be influenced by the pH of the surrounding environment.
pH = pKa indicates 50% ionization. Increasing pH one unit from pKa will cause increased ionization for HA acids (up to 90.9% ionized) but decreases for BH⁺ acids (down to 9.1% ionized).

Understanding the pKa is important for drug solubility and biodistribution.
Ionized (polar) drugs tend to dissolve in water, while un-ionized (nonpolar) drugs tend to dissolve in lipids.
The pKa of a drug determines which form (ionized or un-ionized) predominates at a given pH.
Adjusting pH can influence the ionization state of a drug, thus its solubility.

Drug distribution (e.g., in the blood, tissues, across biological membranes, including gastric mucosa and intestinal tract ) is influenced by ionization.
Unionized forms of drugs cross membranes more readily than ionized forms.
Ionized forms are more water soluble.
Factors like pH, pKa, protein binding can influence these effects.