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General Principles Of Pharmacology:Passive diffusion

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Passive diffusion involves the movement of drug molecules down a concentration or electrochemical gradient without the expenditure of energy. The rate is directly proportional to the gradient; it is not saturable and so other drugs cannot inhibit it unless the physical properties of the drug or membrane are affected in some way. Drug movement over short distances by diffusion is rapid, but diffusion across membranes may be slow. The important types of membranes are:

• Single (e.g., blood cells)
• Porous (e.g., capillary walls)
• Multiple (e.g., epithelial cell layers)
• Complex (e.g., blood-brain barrier)

Rate of diffusion (Fick’s law)

Fick’s Law of Diffusion relates the rate of penetration of a drug across a membrane to the concentration gradient: The greater the permeability constant, the faster the equilibrium and vice-versa. K, the partition coefficient, is the most important determinant of the speed of transfer across membranes and the equilibrations. Highly lipid soluble drugs may equilibrate with tissues during a single passage of blood-the rate of drug uptake by tissues is then determined by the rate of blood flow

pH partitioning

Many drugs are organic acids or bases. A general rule is that only nonionized (lipid soluble) drugs pass quickly through membranes. Ionized species are too polar to pass easily. Thus, the rate of permeation of organic acids and bases will be determined by the gradient for the nonionized form. This will be governed by the pK and by the ambient pH. This is the "pH partition hypothesis" and is based on the Henderson-Hasselbalch equation.

Henderson-Hasselbalch equation

Consider a weak acid, such as acetic acid, which will be partially ionized:

Rearranging:

Taking the log of both sides and rearranging:

This leads directly to the Henderson-Hasselbalch equation:

The same is true for a weak base, such as ammonia:

Thus, in general:

In the case of weak acids:

In the case of weak bases:

Note that when [ionized] = [nonionized] , the pH = pK.

pH Partition Theory

The pK not only has a marked effect upon what is absorbed and what is not absorbed, it also determines equilibrium positions across the membranes. This is particularly true when the pH values on opposite sides of the membrane are very different (e.g., stomach lumen vs.. plasma or plasma vs.. renal tubule lumen).

Absorption of the drug across a membrane will continue until the driving force is zero. Since most drugs only cross membranes when they are nonionized, this means that zero driving force is achieved when the nonionized drug concentrations on the two sides are equal. This means that, in practice, the total drug concentrations on each side may be very different even at equilibrium.

The movement of a drug is not always affected by pH. Very weak acids and bases are essentially completely nonionized at physiological pH values and so their transfer is generally rapid and independent of pH. In contrast, strong acids and bases are completely ionized and so their transfer is usually slow and pH-independent. Sensitivity to pH is likely to be seen only with drugs whose nonionized fraction changes substantially within the normal physiological range of pH values. Such drugs include acids within the pK range 3 to 7.5 and bases in the pK range 7 to 11. Finally, the nonionized species must be lipid soluble.

Next Page: Facilitated Diffusion
Previous Page: Introduction:Pharmacology and its Branches

This is a free Pharmpedia textbook Author Prof.A.N.Nagappa

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