Ionised drugs

Partition coefficient of the un-ionised drug The compound is highly water soluble and cannot be extracted to any great extent into an organic solvent since it is ionised to some extent at all pH values. 

The effect of pH on the HPLC retention time of an ionisable basic drug. Bupivacaine, which has a piSa of 8.1 is analysed by chromatography on ODS silica gel with a mobile phase consisting of acetonitrile/TRIS buffer pH 8.4 (40 60) at a flow rate of 1 ml/min. The t for the column at a mobile phase flow rate of 1 ml/min is 2.3 min. The retention time of bupivacaine at pH 8.4 is 17.32. If jJf app is the apparent capacity factor Of the partially ionised drug, then for a base ... 

Ambient pH in the extracellular fluid (ECF) is approximately 7.4 but the value varies and this determines the proportions of ionised and unionised local anaesthetic drug. A decrease in ambient pH will increase the amount of ionised drug and reduce the unionised fraction available for transfer across the cell membrane. A common example of this is when infection or inflammation reduces the ambient pH. In the case of lidocaine (lignocaine), a fall in tissue pH from 7.4 to 7.0 will halve the amount of unionised drug. This has obvious implications for efficacy. Similar effects occur following repeated administrations of acidified local anaesthetic solutions. 

Alkalinisation of local anaesthetic solution with sodium bicarbonate (NaHC03) increases the pH of the solution to a value near its pKa. This results in an increased proportion of unionised drug available for neural penetration and thereby reduces the onset time. Carbonation is a term used to describe the acidification of a local anaesthetic solution with carbon dioxide. Following injection, the carbon dioxide diffuses into the axoplasm causing a decrease in the pH. This results in a higher proportion of ionised drug within the cell. In theory this should enhance the Na-i- channel block but in practice the results are disappointing. 

Figure 19.1 Schematic of the influence of fetal pH on the maternal-fetal distribution of bupivacaine across the placenta. With fetal acidosis (pH 7.0) the total amount of drug increases due to an increase in the amount of ionised drug (cation).

Ion-exchange interactions - in which ionised drugs interact with opposites charged resins... 

The mass of ionised drug in the water phase = total mass X fraction ionised, which is 60 X 0.666 = 40 mg. 

Some ionised drug molecules can traverse the lipophilic gut membrane by combining with an ion of opposite charge (a counter ion) to form an ion pair. The ion pair, although composed of two ionic species, behaves as a neutral molecule with a high partition coefficient and can cross biomembranes effectively Quaternary ammonium compounds, which are charged at all values of pH, may be absorbed into the body in this way ... 

Urinary alkalinisation increases the urine elimination of certain poisons by shifting the urine pH above 7.5 [1,21,79]. It is achieved by intravenous injection of a sodium bicarbonate solution. Raised pH of urine facilitates elimination of acidic drugs such as salicylates and barbiturates as they become ionised. The rate of reabsorption of an ionised drug into the blood is significantly lower than that of a non-ionised drug [1, 79]. In all cases however AC administration is more efficient than urinary alkalinisation [1,80]. It should be also kept in mind that WBI and urinary alkalinisation are relatively slow procedures which may cause delay with AC administration. 

Reymond, F.,Transfer mechanism and hpophihcity of ionisable drugs, in Liquid interfaces in chemical, biological and pharmaceutical applications f Volkov, A. G. Eds, Marcel Dekker, New York, 2001, p. 729. 

Reymond, F, V. Chopineaux-Courtois, G. Steyaert, G. Bouchard, P. A. Carrupt, B. Testa, and H. H. Girault, Ionic partition diagrams of ionisable drugs pH-hpophUicity profiles, transfer mechanisms and charge effects on solvation, J Electroanal Chem, Vol. 462,(1999) p. 235. 

Figure 8.6 ionised and un-ionised drug in aqueous and organic phases. 

Figure 8.7 Un-ionised drug in an organic iayer in equiiibrium with un-ionised and ionised drug in an aqueous iayer.

Only un-ionised drugs cross the BBB. One could ask, if the tertiary amines are all protonated, when they access their receptor, i.e. at physiological pH, how come they still can cross the BBB This is because most, but not all, the molecules are protonated. For instance, at pH = 7.4, physostigmine pKa = 8.2) will be only 86% protonated and 14% unprotonated. This ratio is always constant. The unprotonated lipophilic form will cross the BBB and disrupt the balanced status, leading to production of new unprotonated molecules which will, in turn, cross BBB and so on. 

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