Ionisation weakly acidic/basic drugs

Ionisation determines the partitioning of drugs across membranes. Unionised molecules can easily cross and reach an equilibrium across a membrane, while the ionised form cannot cross. When the pH is different in the compartments separated by the membrane the total (ionised + unionised) concentration will be different on each side. An acidic drug will become concentrated in a compartment with a high pH and a basic drug in one with a low pH. This is known as ion-trapping, and occurs in the stomach, kidneys, and across the placenta. Urinary acidification accelerates the excretion of weak bases, such as pethidine, while alkalinisation increases the excretion of acidic drugs, such as aspirin. As an example consider pethidine (pKa 8.6) with an unbound plasma concentration of 100 (arbitrary units). At pH 7.4 only 6% of the pethidine will be unionised so that at equilibrium the concentration of unionised pethidine in the urine will be 6 units. In urine at pH 6.5 only 0.8% of the pethidine will be unionised so that the total concentration in the urine will be 744 units. 

Rgure 3.6 Percentage ionisation of weakly acidic and weakly basic drugs as a function of pH. 

We have considered above the effect on the ionisation of a dmg of buffering the solution at given pH values. When these weakly acidic or basic drugs are dissolved in water they will, of course, develop a pH value in their own right. In this section we examine how the pH of dmg solutions of known concentration can be simply calculated from a knowledge of the plC, of the dmg. We will consider the way in which one of these expressions may be derived from the expression for the ionisation in solution the derivation of the other expressions follows a similar route and you may wish to derive these for yourselves. 

When a weakly acidic or basic drug is administered to the body, the drug will ionise to a greater or lesser extent depending on its piCa and the pH of the body fluid in which it is dissolved. The pH of the body varies widely, but the most important biological solution is the blood, which, as stated above, normally has a pH of 7.4. An equation can be derived that will predict the extent to which the drug ionises, and, as is often the case, the starting point for the derivation is the Henderson-Hasselbalch equation (1.7). 

The situation becomes (even) more complicated if the drug ionises at the pH of the body compartment. For weak acids and weak bases, the aqueous and lipid solubility of the compound will depend on the extent to which the drug is ionised, which in turn will depend on the pK3 of the acidic and basic groups involved and the pH of the surroundings. 

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