This chapter answers parts from Section B(ii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "Describe absorption and factors that will influence it". If one were asked to name the most important among these factors that will influence it, one would have to name the lipid-water partition coefficient, which is determined by the pKa of the drug and the pH of the body fluids.
Put simply, in solution the weak acids and bases will be present in some combination of ionised and non-ionised forms. Of these incompletely ionised substances, the non-ionised forms will be lipid soluble, whereas the ionised forms will not. The proportion of the ionised to non-ionised molecules is determined by the pH of the solution and the pKa of the drug (pKa being the pH at which concentration of ionized and non-ionised forms is equal).
To put it even more simply:
A substance will become more lipid soluble in a solution with a pH similar to its own pH.
The determined exam candidate looking for detailed published literature on this subject will usually find a satisfactory depth in any major pharmacology textbook. Goodman and Gilman dedicate about half a page to the subject. Birkett's Pharmacology Made Easy does not approach this subject, except in the section on renal clearance (p.67) where the interplay of pKa and pH is discussed in context of renal clearance. Of published articles, the most comprehensive overview available appears to be "Acidic and basic drugs in medicinal chemistry" by Charifson and Walters (2014), from whom this chapter borrows extensively.
To be more scientific about it, the ratio of polar dissociated molecules to non-polar undissociated ones is described by the Henderson-Hasselbalch equation:
The higher the pKa, the stronger the acid ( the more dissociated into protons). A weak acid will be neutral until it dissociates into a negatively charged ion (anion) and a proton. While it hangs onto its proton, it is still neutral and thus lipid-soluble. In an alkaline environment, there are few protons, and the acid will tend to donate them, becoming ionised and losing its lipid-solubility.
For an excuse to play with Illustrator, this relationship can be presented as a series of translucent fluid-filled tubes. This diagram depicts the effect of a change in pH on the lipid solubility of a weak acid.
Seeing as many drugs are either weak acids or weak bases, they will either be charged or uncharged in solutions with different pH. Generally speaking the pH of extracellular fluid is always going to be within some decimal fractions of 7.4, and so drugs with a pKa under 7 (i.e. weak acids) will usually be water-soluble. Weakly basic drugs with a pKa closer to 8 will usually be lipid-soluble and will therefore find it easier to negotiate the barrier membranes on their way to their target.
This concept of pH and pKa being related to lipophilicity and the rate/extent of membrane peneration is called the "pH-partition theory". However, it does not describe all possible cases. For instance, zwitterions (hermaphroditic neutral molecules with both positive and negative polar groups) penetrate lipid bilayers by presenting themselves "side-on" to the hydrophobic membrane, thus appearing as neutral non-polar molecules while they pass. It is thought that fluoroquinolones gain intracellular access in this manner (Cramariuc et al, 2012). Moreover, some ionised substances are present in such high concentrations that they are able to cross the lipid bilayer purely by the brute force of their concentration gradient (the classic example of this is water: the concentration of water in pure water is 55.5 mol/L).
Charifson and Walters (2014) present an excellent graph (reproduced below with no permission whatsoever) to demonstrate the distribution of pKa values across the commonly used substances. They selected all available drugs in ChEMBL and DrugBank, provided they were made up of at least 10 "heavy atoms", had a molecular weight under 1000 and contained a reasonably conventional bunch of elements (no lanthanides or anything). The final data set ended up being a collection of 1778 drugs.
The authors went further yet by analysing the pKa distrubition according to drug class, route of administration, clearance mechanisms, and so forth. Beautifully colourful graphs were produced. The curious exam candidate with infinite time resources is directed to the original paper for more details, but the basic findings consisted of several broad trends:
Acidic drugs tend to...
Basic drugs tend to...
Generally, it was found that there are more basic drugs among those agents which target membrane receptors and transporters, whereas those which target enzymes and ion channel tend to be more neutral.
For amusement, a short table of common basic and acidic drugs can be constructed:
Weak acid (pKa)
Weak base (pKa)
Trapping effects take place when drugs cross a lipid membrane and enter an area with a significantly different pH to the one they previously occupied. The change in pH may suddenly render the drug more ionised and therefore less lipophilic. Unable to cross the membrane in the opposite direction, ionised drug molecules will become concentrated in this ionising solution, a phenomenon known as "ion trapping".
The use of this in toxicology is probably the most interesting clinical application of the concept. It is a method of increasing drug clearance which depends on the premise that alkaline urine favors excretion of weak acids and acid urine favors excretion of weak bases. In this fashion, we are instructed to alkalinise the urine to promote the excretion of weak acids such as salicylate and urate.
Its not just urine. Native body fluid pH of vaginal/prostatic secretions, stomach juice and breast milk can all cause a trapping effect, concentrating drug molecules. Also, acidic environments of abscesses can interfere with polarity of local anaesthetics, making them less lipid soluble and thus less effective.
Again for no reason other than amusement, the author will conclude with a list of body fluids and their respective pH values so that inquisitive minds can create thought experiments exploring the ion trapping effects which might take place at the interface of blood, saliva, gastric acid, semen and vitreous humour. Depending on who is sampled and which textbook you read, these values may be slightly different.
Acidic body fluids (pH)
Alkaline body fluids (pH)
Charifson, Paul S., and W. Patrick Walters. "Acidic and basic drugs in medicinal chemistry: a perspective." Journal of medicinal chemistry 57.23 (2014): 9701-9717.
Cramariuc, Oana, et al. "Mechanism for translocation of fluoroquinolones across lipid membranes." Biochimica et Biophysica Acta (BBA)-Biomembranes 1818.11 (2012): 2563-2571.
Hogben, C. Adrian M., et al. "Absorption of drugs from the stomach. II. The human." Journal of pharmacology and experimental therapeutics 120.4 (1957): 540-545.