Mechanism of weak electrolyte diffusion
Most drugs are weak electrolytes by chemical nature — weak acids (e.g., Acidum acetylsalicylicum) or weak bases (e.g., Atropinum).
To enter the systemic circulation or tissues, a molecule must cross cellular membranes. The primary condition for successful diffusion across the lipid bilayer is lipophilicity. Only the non-ionized form of the substance meets this requirement. Ionized molecules become hydrophilic and are repelled by the lipids of cell membranes.
Effect of the environment and pKa on the degree of ionization
The degree of drug ionization is a variable value. It depends on two parameters:
- Environmental pH where the drug is located (stomach, intestines, blood, urine).
- pKa (the negative logarithm of the dissociation constant Ka), an individual characteristic of the substance. The physical meaning of pKa is that when the environmental pH equals the drug's pKa, exactly half (50%) of the molecules are in an ionized state, and the other half are non-ionized.
There is a general equilibrium rule:
- Weak acids actively ionize in an alkaline environment (and are poorly absorbed there). The lower the pKa of an acid, the easier it releases a proton and ionizes even at low pH values.
- Weak bases ionize more strongly in an acidic environment (by capturing a proton), which also impedes their absorption.
Clinical significance: GI tract absorption
Knowing a substance's pKa allows predicting its absorption in different parts of the digestive tract.
- Stomach (acidic environment, pH 1–2). Here, weak acids (e.g., aspirin, pKa = 3.5) are predominantly in the non-ionized form, so their absorption begins at this stage already. Weak bases are heavily ionized in the stomach and practically unabsorbed (unless they have an extremely low pKa, like diazepam with pKa = 3.0).
- Intestines (alkaline environment, pH from 5–6 to 9–11). This is an ideal environment for the absorption of weak bases as they convert to the lipophilic non-ionized form. Interestingly, despite the pH shift, the intestine remains the main site of absorption for weak acids as well (with pKa > 3.0). This is due to the huge absorptive surface area of the small intestine, which compensates for the unfavorable pH level.
Managing renal drug excretion
Knowledge of ionization laws is applied in toxicology for the accelerated elimination of poisons or in drug overdoses. The physician's goal is to prevent reabsorption of the substance from the renal filtrate back into the blood.
- In weak acid poisoning: the urine is artificially alkalinized (e.g., by administering Natrii hydrocarbonas). In an alkaline environment, weak acids convert to the ionized form, lose the ability to cross the lipid membranes of the renal tubules, and are excreted in the urine.
- In weak base poisoning: the urine is acidified (e.g., using Ammonii chloridum). In an acidic environment, bases actively ionize and become "trapped" within the tubular lumen, after which they are excreted.
Briefly: answers to topical questions
What equation is used to calculate the exact ratio of the ionized and non-ionized fractions of a drug?
The exact ratio of the ionized and non-ionized drug fractions is calculated using the Henderson–Hasselbalch equation. This mathematical foundation of electrolyte membrane permeability links the substance's ionization constant ($pK_a$), environmental $pH$, and the concentrations of the protonated and unprotonated forms. The formula allows predicting the ability of medicinal substances to cross histohematic barriers depending on the $pH$ gradient between various body fluids.
Through which types of membrane transport are ionized and non-ionized molecules absorbed?
Absorption and passage of molecules through biological membranes differ depending on their physicochemical properties:
- Non-ionized molecules (non-ionized) — possess high lipophilicity and easily cross the lipid bilayer via passive diffusion (transcellularly).
- Ionized molecules (ionized) — hydrophilic compounds repelled by membrane lipids. They cannot cross the lipid bilayer and can be transported through water pores or intercellular clefts (filtration / passive diffusion through pores) if they match in size.
How does the degree of ionization affect the ability of a medicinal substance to cross the blood-brain barrier?
The degree of ionization affects the ability of a drug substance to cross the blood-brain barrier (BBB), since biological membranes are permeable predominantly to non-ionized lipophilic forms.
- Non-ionized / lipophilic forms cross the membranes of BBB endothelial cells via passive diffusion.
- Ionized / hydrophilic / polar forms cross membranes poorly; paracellular transport across the BBB is impossible due to tight junctions. Their penetration is only possible via specific pathways, such as transport proteins or receptor-mediated endocytosis.
Acids ionize in alkali, bases in acid. That is, like is absorbed by like (does not ionize), while opposites ionize and are excreted.
Class and exam questions
What is the difference between non-ionized and ionized drug forms?
The non-ionized form is lipophilic and easily penetrates cell membranes (is absorbed). The ionized form is hydrophilic, does not cross membranes, but is readily excreted by the kidneys.
What does the pKa value mean?
This is the environmental pH value at which exactly 50% of the molecules of a given medicinal substance are in the ionized state.
Why is ascorbic acid (pKa = 11.5) well absorbed at pH 4.5?
At pH 4.5, which is significantly lower than its pKa, ascorbic acid remains almost entirely in the non-ionized (lipophilic) form, facilitating its passage through membranes.
Why is urine alkalinized in aspirin poisoning?
Aspirin is a weak acid. In alkaline urine, it converts into the ionized form, which is incapable of being reabsorbed back into the blood, accelerating its elimination.
What else to study on this topic
- Calculation of the degree of ionization using the Henderson–Hasselbalch equation
- Graphical analysis of ionization dependence on pH (S-shaped curves)
- Examples of weak acids (furosemide, levodopa, paracetamol) and their pKa
- Examples of weak bases (adrenaline, morphine, lidocaine) and their pKa
- Features of absorption in the small intestine
Master the entire topic in the «Pharmacology» course
This is a summary. The course covers everything tested in classes and exams.
- Complete study guide on "Ionization of Medicinal Substances" and another 5,304 pages of the subject
- Assignments and quizzes after every topic — just like in a colloquium
- AI tutor answers questions on the topic anytime
- 116 video lessons on the subject
Other topics in "General Pharmacology"
Free video lessons: pharmacologyShort lessons with study notes — no registration required.
Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.