Lecture 2: Ionization of Drugs Flashcards
Ionization state
-impacts solubility, absorption, binding to receptor
Charged molecules
more soluble, less likely to cross lipid membranes
pH
affects ionization
HA –> A- + H+
BH+ –> B + H+
Ionizable functional groups
-weak acids and bases
Ionizable groups with pKa < 7
-arylcarboxylic acid
-arylamine
-aromatic amines
-alkylcarboxylic acid
ionizable groups with pKa > 7
-alkyl amines
-phenol
-guanidine
nonionizable groups
-alkyl alcohol
-alkyl aldehyde
-ether
-ester
-ketone
-amide
-quarternary amine
Drug examples
SLIDE 6
Henderson-Hasselbach equation
pH= pKa + log [A-]/[HA]
when pH < pKa
[A-] < [HA]
-protonated
when pH > pKa
[A-] > [HA]
-deprotonated
when [A-]/[HA]
[HA] = [A-]
Acetaminophen
STRUCTURE
Water
-polar solvent that dissolves polar molecules
-H bond donors and acceptors
-ionic groups
Solubility
-like dissolves like
-can be improved by changing pH
1g Procaine
needs 200mL water
1g procaine-HCl
needs 1 mL water
At pH 7.4, what is the ratio of ibuprofen in the acid form (neutral) to
that in the base form (negatively-charged)? pKa= 4.4
1:1000
Membrane permeability
-GI tract, blood brain barrier, lipid membranes
-most drugs absorbed by passive diffusion
Absorption rate
related to the drugs liphophilicity
lipopholic drugs
absorbed more efficiently
Transport across membrane
-intercellular junctions
-lipid cell membranes
-transporters
-endo and exocytosis
Passive diffusion of ionizable drugs (cant cross lipid bilayer)
-more efficient at pH where drug is neutral
-even while mostly ionized it still moves through bilayer slowly
-equilibrium
diffusion rate
proportional to amount of neutral drug
Location of absorption
-most in jejunum (pH 5-7)
-acidic drugs in stomach (pH 1-3)
A drug is an organic base (RNH2) with a pKa of 9.0. Assume the
stomach has a pH of 1.5, and the small intestine has a pH of 6.5.
Where will the drug be preferentially absorbed?
Small Intestine
Can a drug with a permanent charge (e.g. quaternary amine) be
absorbed?
No
Which of the following drugs is negatively charged at pH 7.4?
drugs with pKa<7.4
Most drugs are absorbed from the GI tract to the blood stream by _______________.
passive diffusion
Which of the following statements is most accurate about passive diffusion of
Eventually, the concentrations of the drug become equal in both sides of the membrane.
At pH 7.5, what is the ratio of this drug (pKa = 9.5) in the acid form (neutral) to that in the base form (negatively-charged)?
100:1
Which of the following shows a functional group whose ionization status is not affected by the pH?
quarternary amine
