Re: drug excretion and pKa

Ka (a is a subscript) is simply the affinity constant or binding strength 
of a substrate to an enzyme, a hormone to a receptor or a drug to whatever 
protein (usually a protein) it may interact with.  Units are usually molar. 
 It measures the concentration of drug/chemical/hormone required for half 
maximal effect (if an inhibitor, half maximal inhibition).  The "p" in pKa 
simply means the negative log (base 10) of Ka.  Thus if the Ka is 10^-7 
Molar (0.0000001 Molar), the pKa is 7.  It is exactly analogous to pH where 
H is the proton (H+) concentration.

pKa is relevant to drug excretion because 
1) Drug metabolism makes drugs more polar, i.e., more water soluble, and 
this usually equates to making the drug more charged.
2)  The metabolized drug (or if already polar or charged) then travels from 
the liver (site of most drug metabolism) throught the blood to the 
kidney.
3)  Most elimination of blood components via the kidney (including drugs) 
is by filtration into the tubule of the kidney.  Many substances are 
reabsorbed back into the blood in the kidney.  That's why, unless you're 
diabetic, you don't lose glucose from your blood to urine.
4) However, charged polar substances are reabsorbed through specialized 
transport systems that move particularly anions.
5) If the pKa of the substance to be reabsorbed is far different from the 
pH of the urine, then the substance may become either more charged or 
almost completely uncharged while in the urine.  This affects whether or 
not it can be absorbed.  It depends on the drug and the relative pKa and pH 
as to what happens with each drug.
6)  Thus some drugs are reabsorbed very well in the kidney at normal pH.  
Others are not.  However, particularly in cases of overdose, it is often 
useful to make the urine more alkaline (give bicarbonate orally or iv).  
This sometimes will enhance or speed up secretion of some drugs thus 
shortening or minimizing toxicity of the drug.