EFFECTS OF pH DRUG KINETICS

Three examples concerning the importance of pH:

1. Aspirin is readily absorbed in the acidic stomach, but not in the alkaline large intestine.

2. Antibiotics are not excreted in acidic urine, but be reabsorbed in the kidney… in alkaline urine, antibiotics are excreted.

3. An injection of local anesthetics into a low pH, infected gingival environment, you won’t get a nerve block (with the exception of benzocaine).

Many drugs can exist in either an ionized (charged) form or unionized (uncharged) form. These drugs are either weak acids or weak bases. These molecules can exist as either protonated or unprotonated forms. The difference between a weak acid and weak base is that a weak acid is known as a proton donor, while a weak base is called a proton acceptor.

Notation: AH = free acid (neutral proton donor; associated, protonated)

B = free base (neutral proton acceptor; dissociated, deprotonated)

1. = ionized acid (negatively charged; dissociated, deprotonated)

BH⁺= ionized base (positively charged; associated, protonated)

AH  B + H^{+ *If you add more protons, both equations will be driven to the left}

BH⁺ B + H⁺

(As we go through the subject, the weak acid and the weak base will be treated together, just so that we’ll understand both of them at the same time)

Don’t confuse weak acids/bases with strong acids/bases. Strong acids such as HCl (for example) are never found associated together, HCl is such a strong acid that its always dissociated. Weak acids, however, are partially in the AH form and the A^- form.

The proton concentration in solution is given by pH, which is equal to –log [H⁺].

An example of a weak acid that shows up a lot is a drug molecule having a carboxyl group: -COOH  -COO^- + H⁺

A typical weak base group is a drug molecule having an amino group:

-NH₃⁺  -NH₂ + H⁺

The first concept in talking about pharmacokinetics is that some forms permeate membranes easily, and some don’t. Neutral forms (AH and B) can go through membranes easily, whereas charged or ionized forms (A^- and BH⁺) cannot.

Why is this true? Ions/ charged molecules are very strongly hydrated; water sticks to them very strongly. So if they are in the blood, they won’t go through membranes of capillary walls because these are hydrophobic inside. If a molecule is strongly hydrated, it is thus hydrophilic. In the film, they called this a low partition coefficient. The reason why this happens is because water is a polar molecule, arranged in a tetrahedral formation. Water has a strong dipole (charge separation), but it is neutral as a whole. Because the charges are separated, the water molecule can be attracted to ions.

When a molecule has no charge associated to it, water is actually pushed away from it, making these molecules hydrophobic. Thus these molecules can go through membranes very easily and are called PERMEANT.

Category: Pharmacology Notes