Weakly acidic and basic drugs

Dissociation of weakly acidic and basic drugs and their salts... 

Weakly acidic and basic drugs can exist in ionized (charged) and nonionized (uncharged) forms, depending on their pKa values and the pH of the medium (eg, blood, urine). Because nonionized forms are capable of reabsorption across tubular membranes, the renal elimination of acids and bases can be influenced by changes in urinary pH. If the renal clearance of a drug does not change when urinary pH increases, then the compound must be a nonelectrolyte. 

This equation applies to both acidic and basic drugs. Inspection confirms that the lower the pH relative to the pKa, the greater will be the fraction of drug in the protonated form. Because the uncharged form is the more lipid-soluble, more of a weak acid will be in the lipid-soluble form at acid pH, whereas more of a basic drug will be in the lipid-soluble form at alkaline 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). 

Weak acidic and neutral drugs may be absorbed from the stomach, but basic drugs are not. 

The evidence of the importance of dissociation in drug absorption is found in the resuit of studies in which pH at the absorption site is changed (Tabies 9.1 and 9.2). Tabie 9.2 cieariy shows the decreased absorption of a weak acid at pH 8.0 compared to pH 1.0 (13). On the other hand, an increase to pH 8.0 promotes the absorption of a weak base with practicaiiy nothing absorbed at pH 1.0. The data in Tabie 9.2 aiso permits a comparison of intestinai absorption of acidic and basic drugs from buffered soiutions ranging from pH 4.0 to 8.0 (14). These resuits are in agreement with the pH-partition hypothesis. 

Another approach to increase dissolution rates of poorly water-soluble acidic and basic drugs is to use microenvironmental pH modifiers (Badawy and Hussain 2007 Phuong et al. 2011 Tran et al. 2009). Generally, weak organic acids, such as ascorbic, adipic, citric, fumaric, glutaric, succinic, malic, tartaric acids, are used to decrease microenvironmental pH of weakly basic drugs. Various weak bases, such as sodium carbonate, sodium bicarbonate, magnesium oxide, calcium carbonate, potassium... 

Excretion of drugs will be affected by the pH of the urine. If the urine is acidic, weak bases are ionized and there will be poor re-absorption. With basic urine, weak bases are non-ionized and there is more re-absorption. The pH of the urine can be artificially changed in the range 5-8.5 oral administration of sodium bicarbonate (NaHCOs) increases pH values, whereas ammonium chloride (NH4CI) lowers them. Thus, urinary acidification will accelerate the excretion of weak bases and retard the excretion of weak acids. Making the urine alkaline will facilitate the excretion of weak acids and retard that of weak bases. 

In this system, weakly acidic drugs (barbiturates), as well as neutral and basic drugs, are extracted together at pH 9. Phenobarbitone extraction is poor (recovery approximately 20%), but is still sufficient to allow detection of the drug in dependent patients. 

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

Since passive diffusion is the primary driving force behind dermal absorption, physicochemical factors such as molecular weight and structure, lipophilicity, pKa, ionization, solubility, partition coefficients, and diffusivity can influence the dermal absorption of various classes of chemicals. In addition penetration of acidic and basic compounds will be influenced by the skin surface, which is weakly acidic (pH 4.2-5.6), since only the uncharged moiety of weak acids and bases is capable of diffusing though the lipid pathway. Several of these factors (e.g., molecular weight, and partition coefficients) have been used to predict absorption of various drug classes [24-26],... 

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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