This chapter answers parts from Section B(ii) of the 2023 CICM Primary Syllabus, which expects the exam candidate to "Describe the absorption of drugs and factors that influence this". Of the factors that will influence this, some of the most important surely must be the characteristics of the drug and the membranes which it must cross on its way to its site of action.
The transport of a drug across a membrane depends on the following factors:
- Physicochemical properties of the drug:
- Molecular size
- Concentration gradient
- Properties of the membrane
- Surface area
- Permeability (drug-specific)
- Solution pH on either side of the membrane
- Type of transport
- Paracellular, in which case it diffuses through extracellular fluid
- Diffusion through membranes
- Active transport by facilitated diffusion or transport proteins
The discussion of this specific topic has never taken place in the CICM Primary Exam, but it may well arise at some stage in some sort of a viva setting. Any discussion of drug absorption from any site is going to have to start with the discussion of these issues. Moreover the topic touches on some fundamental concepts which are probably going to be common with cell physiology, particularly where transport of molecules in and out of cells is concerned.
The official textbook of the college (Pharmacokinetics Made Easy by Birkett) barely touches on this subject; on page 45 "physico-chemical properties" are mentioned in a table discussing the factors which influence absorption, but otherwise nothing further is said. Goodman & Gilman's textbook however has a whole section dedicated to "Physicochemical Factors in Transfer of Drugs Across Membranes", which serves as the major inspiration for this revision chapter. For the reader with institutional access, nothing beats Schanker's 1962 classic article in terms of sheer exhaustive detail. They don't write 'em like that any more.
This subject matter is vaguely reminiscent of early school-level biology. Painful recollections of textbooks may be elicited by childish diagrams, such as the following:
In summary, there are only a few ways for a drug to make its way through a living organism:
I.e. the drug can diffuse passively along the fluid-filled cavities in the body, it can cross membranes (whether through gaps or by diffusion). It can penetrate directly into cells by diffusing across the lipid bilayer, or it can be transported actively into the cells by means of facilitated diffusion, active uptake, pinocytosis or whatever else. In essence, apart from active pump-mediated transport all of these methods depend on diffusion in some way, and therefore are affected by all the usual factors which influence diffusion of anything through anything.
In general terms, diffusion can be usefully described by Fick's First Law of Diffusion, which states that "the molar flux due to diffusion is proportional to the concentration gradient". The complete equation is actually somewhat more complex:
where J is "diffusive flux", the magnitude and direction of the flow of a substance from one compartment to another; dφ is the concentration difference and dx is the distance for diffusion (or the thickness of the membrane). This distance variable is present in the one-dimensional application of the equation, and more clinically relevant models end up also including the surface area. D is a diffusion coefficient which is influenced by solution temperature, viscosity of the fluid, and the size of the molecules.
Diffusion through lipid and aqueous solutions will be slightly different, depending on drug properties. Specifically, the pH and pKa of the drug will influence the lipid-water partition coefficient of a drug. The higher the partition coefficient, the more drug can cross the membrane. The pKa and pH interplay also determines whether or not the drug will be ionised, and therefore whether it will be influenced by electrochemical gradients on top of concentration gradients.
Because the viscosity of human extracellular fluid is fairly stable and the temperature does not fluctuate by more then a couple of degrees, we can now narrow down the list of things which influence drug diffusion to a short list:
Special scenarios clearly change things somewhat. For instance, viscosity of extracellular fluid is usually fairly stable but the viscosity of bacterial slime might vary, not to mention the viscosity of gastric secretions, empyema pus, and so on. Things get even more weird when one considers the diffusion of drugs through non-standard media like bone, stratum corneum, the polymer of endotracheal tube cuffs, ECMO oxygenator materials, etc etc.
Rather than go into too much detail here, it would probably suffice to say that drugs might need to cross all sorts of solid and liquid barriers on their way to their site of action, and of these the solid barriers can be described as "membranes", for lack of a better term. These membranes are of two major types. These can be cellular membranes or extracellular membranes. It is easy to discuss cellular membranes because they are recogniseable from the vantage of high school-level biology, and because they tend to have fairly uniform drug permeability properties. The extracellular membranes however are a heterogeneous collection of substances ranging from the 40-nanometre layer of connective tissue on the surface of an alveolar epithelial cell all the way to the hydroxyapatite matrix in the petrous portion of the temporal bone.
Paracellular and transmembrane diffusion takes forever, and few drugs have access to a handy active transporter. The body is made of cells, they are enveloped in lipid, and this lipid becomes the most important factor in limiting drug diffusion. Ergo, lipid solubility of drugs (and the factors which influence it) becomes the most important consideration in drug absorption and penetration to the site of action. The lipid solubility of drugs is determined by the degree to which they are ionised in the body fluid, which in turn depends on their pKa and on the pH of the body fluid. Though the temptation to go full Animal on the concept pKa in this chapter is extreme, the author will stow it until the opportunity presents itself in the chapter on buffers and buffering power.