Main pathways of passive diffusion
The diffusio passiva process is implemented in the organism via two independent pathways, each imposing specific requirements on the chemical and physical properties of the molecules.
- Transcellular diffusion (through the lipid bilayer). The molecule dissolves directly into the lipid matrix of the cell membrane and passes through it. To successfully overcome the barrier, the substance must possess high lipophilicity (marked affinity for fats) and no electrical charge, meaning it must be in a non-ionized form. This is the baseline pathway for the majority of pharmacological agents.
- Paracellular diffusion (through aqueous pores and channels). In this scenario, the substance bypasses lipids, moving through intercellular clefts or specialized aqueous channels. This pathway is open only to hydrophilic compounds with very small molecular sizes—their diameter must be smaller than the pore itself. Classical examples of substances utilizing this pathway include water, ions, and small water-soluble molecules such as urea (urea).
The role of lipophilicity and amphiphilicity
The rate at which a substance penetrates the lipid bilayer of the membrane is directly dependent on its lipophilicity. The universal measure of this property in pharmacology is the partition coefficient in the standardized organic solvent (octanol)–water system. The higher this indicator, the more easily the molecule embeds into the lipid structure of the cell wall, whereas a low coefficient indicates hindered penetration.
However, there is a serious issue of absolute lipophilicity. If a molecule has excessive affinity for fats, it may simply "get stuck" inside the lipid phase of the membrane, losing the ability to transition into the aqueous medium of the intracellular fluid (cytosolum) or extracellular space.
Consequently, to successfully exit the membrane, a molecule must possess amphiphilicity—a delicate balance of lipophilicity and water solubility. Chemically, this ability is provided by the presence of electronegative atoms (oxygen, nitrogen, or sulfur) in the substance's structure. They interact with water molecules, forming hydrogen bonds and guaranteeing the required degree of hydrophilicity.
Fick's law and rate factors
The kinetics of passive diffusion is mathematically and conceptually described by Fick's law. The rate of the process ($dQ/dt$) is calculated by the following principle: the concentration difference is multiplied by the surface area and the diffusion coefficient, after which the result is divided by the membrane thickness.
Diffusion transport rate is influenced by the following key factors:
- Concentration gradient ($C_1 - C_2$): acts as the primary driving force of the process.
- Surface area: a direct proportionality is observed (the larger the available area, the faster the diffusion).
- Diffusion coefficient: a parameter determined predominantly by the lipophilicity of a specific substance (the octanol/water coefficient).
- Membrane thickness: characterized by inverse proportionality (thickening of the barrier naturally slows down the process).
- Molecular mass: the transport rate is inversely proportional to the square root of the molecular mass, which is why larger structures move significantly slower.
- Additional parameters: the intensity of the process is also affected by the spatial shape of the molecule and the ambient temperature.
Limitations for charged molecules and filtration
The lipid bilayer is a formidable barrier for charged particles and polar compounds. Ions cannot freely penetrate the membrane for two reasons. First, they are counteracted by the cell membrane potential. Second, the hydration phenomenon applies: in an aqueous environment, charged particles are immediately surrounded by a dense shell of water molecules, which physically excludes their close contact with lipids. Polar hydrophilic substances also practically fail to penetrate the bilayer due to extremely low solubility in fats.
An alternative pathway for them is filtration—passive diffusion in an aqueous medium through water pores (aquaporinae) formed by membrane glycoproteins.
However, this pathway has strict anatomical limitations. The diameter of aqueous pores ranges within 0.3–0.4 nm, making them permeable only to water and small molecules (e.g., glycerin — glycerinum). At the same time, the vast majority of hydrophilic medicinal substances have a molecular diameter exceeding 1 nm. The main pharmacokinetic conclusion is that hydrophilic drugs physically do not pass through the pores and cannot enter the cell via simple filtration, which is why this pathway is of no significant importance for most drugs.
Briefly: answers to topical questions
What mechanisms of drug transport across cell membranes exist besides passive diffusion?
Besides passive diffusion, the following mechanisms of drug transport across cell membranes exist:
- Facilitated diffusion (diffusio facilitata) — bidirectional transport involving carriers (e.g., the SLC superfamily).
- Primary active transport — unidirectional transfer of substances using ATP hydrolysis energy (e.g., the ABC superfamily).
- Secondary active transport — carried out by solute carriers.
- Pinocytosis — a mechanism for the transfer of hydrophilic substances (e.g., across the placental barrier).
What parameters determine the degree of ionization of a drug molecule in the body?
The degree of ionization of a drug molecule in the body is determined by two main parameters: the pH of the medium and the ionization constant ($K_a$ or $pK_a$). The Henderson–Hasselbalch equation is used to accurately calculate the ratio of ionized and non-ionized forms. The difference between the pH and $pK_a$ values determines the shift in equilibrium toward the formation of ions or non-ionized molecules.
How does the pH of the medium affect the passive diffusion of weak acids?
The pH of the medium determines the fraction of the non-ionized weak acid, which directly dictates its capacity for passive diffusion. In an acidic environment, weak acids exist predominantly in a non-ionized (lipophilic) form, allowing them to easily penetrate biological membranes. In an alkaline environment, the equilibrium shifts toward anion formation: weak acids become ionized, turn hydrophilic, and practically fail to cross the lipid bilayer, which impairs their absorption and accelerates excretion.
Which specific proteins form aqueous pores (channels) in the cell membrane?
Aqueous pores (channels) in the cell membrane are formed by integral proteins spanning the entire thickness of the lipid bilayer. These include:
- Aquaporins (aquaporinae) — specialized membrane glycoproteins forming channels for the transport of water and small hydrophilic molecules dissolved in it (such as urea and glycerin).
- Ion channels — complex spiral-shaped integral proteins forming pore walls for the simple diffusion of ions down their concentration gradient.
To recall Fick's law, use the "numerator and denominator" rule: Area, Gradient, and Lipophilicity (coefficient) are in the numerator—they "accelerate" the process. Membrane thickness and Molecular mass are in the denominator—they "slow it down".
Class and exam questions
Is ATP energy consumption required for passive diffusion?
No, this process occurs absolutely without the expenditure of ATP energy. The movement of molecules happens exclusively due to the physical concentration difference on both sides of the membrane.
Why can't hydrophilic drugs be absorbed via filtration through pores?
The diameter of membrane water pores is only 0.3–0.4 nm. Since the molecular size of most hydrophilic drugs exceeds 1 nm, they are physically incapable of passing through these narrow channels.
What happens if a drug molecule has absolute (excessive) lipophilicity?
Such a compound easily embeds into the cell membrane, but gets "stuck" in its lipid phase. To leave the membrane and enter the aqueous environment inside the cell, the substance requires minimal hydrophilicity (amphiphilicity).
What else to study on this topic
- Facilitated diffusion and the role of membrane transporters
- Active transport: differences from passive diffusion
- Effect of medium pH on the degree of molecule ionization
- Structure and functions of aquaporins (aquaporinae)
- The concept of bioavailability and its relationship with lipophilicity
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 "Passive diffusion" 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.