Learning Objective

To understand how the ionization of weak acids and weak bases depends on pH and pKa, and how ionization influences membrane permeation, lipid solubility, and renal excretion.

Ionization

Many drugs are weak acids or weak bases and exist in both ionized and nonionized forms depending on the pH of the environment and their pKa—the pH at which the drug is 50% ionized and 50% nonionized. The degree of ionization determines how a drug behaves within the body, particularly its ability to cross cell membranes and its route of elimination.

Key Principles

• Only the nonionized (uncharged) form crosses biomembranes, because it is lipid soluble.
• The ionized form is more water-soluble, making it more easily renally excreted.
• A drug becomes more ionized when the environmental pH shifts away from its pKa.

Activity

Weak Acids and Weak Bases

Weak Acid

R–COOH ⇋ R–COO⁻ + H⁺

• R–COOH (nonionized) → lipid soluble → crosses membranes
• R–COO⁻ (ionized) → water soluble → better cleared

Weak acids are nonionized in acidic environments (low pH) and ionized in basic environments.

Weak Base

R–NH₃⁺ ⇋ R–NH₂ + H⁺

• R–NH₂ (nonionized) → lipid soluble → crosses membranes
• R–NH₃⁺ (ionized) → water soluble → better cleared

Weak bases are nonionized in basic environments (high pH) and ionized in acidic environments.

Note

• Ionized = water soluble = better renal excretion
• Nonionized = lipid soluble = crosses membranes

Activity