Lecture 4

Question 1

Acid/Base + Human Body Properties

Answer 1

• Human body averages 70-75% water
• Average drug molecule has a MW of ~200
• 20 mg drug is diluted to a 2 um solution
• DEALING WITH EXTREMELY DILUTE SOLUTIONS
• Weak acid/bases have an equilibrium
• Acids are hydrogen donors and bases are hydrogen acceptors

Question 2

pKa & pH Information

Answer 2

• pKa TELLS YOU NOTHING ABOUT IF THE COMPOUND IS AN ACID OR A BASE
• pKa tells the strength of acids and bases
• pH < 7 is acidic, pH > 7 is basic, pH = 7 is neutral
• low pH = high [H+] and high pH = low [H+]
• pH = -log[H+]

Question 3

Common Acid Groups and pKa

Answer 3

• Sulfonic Acids - 1
• Carboxylic Acids - 5
• Imide - 9
• Phenols - 10

Anions are stabilized by resonance of the negative charge onto the oxygens of carbonyl groups

Question 4

Common Base Groups and pKa

Answer 4

• Alkylamines - 10

- Arylamines - 4

Question 5

Conjugates

Answer 5

Acid: HA (Acid) <=> H+ + A- (conjugate base)
Base: BH+ (conjugate acid) <=> H+ + B (base)

Question 6

Ka for Acids and Bases

Answer 6

Acid Ka: Ka = [H+][A-]/[HA]
Dissociation constant of acid

Base Ka: Ka = [B][H+]/[BH+]
Dissociation of the base’s conjugate acid (BH+)

General Formula: Ka = [H+][conj. base]/[conj. acid]
Dissociation constant for dissociations yielding H+

Question 7

Henderson-Hasselbalch Equations

Answer 7

pKa = pH + log([acid form]/[base form])
pH = pKa + log([base form]/[acid form])

Amount of unionized form available is dependent on pKa & pH of surrounding fluid

Question 8

Acids + pH

Answer 8

• As pH increases, unionized % of acids decreases

- pH < pKa: more unionized form available to cross barrier

Question 9

Bases + pH

Answer 9

• As pH increases, unionized % of bases increases

- pH > pKa: more unionized form available to cross barriers

Question 10

Ion Trapping

Answer 10

• Weak acids enter the blood in acidic environments like the stomach where they favor being unionized
• Once they enter more basic or neutral environments they favor becoming ionized
• This transition from unionized to ionized as the pH increases traps the drug on the side of the membrane with the higher pH so that it can’t backtrack

Question 11

Weak Acid Drug Transfer

Answer 11

• primarily absorbed in the stomach
• little absorption in the small intestine (more ionized)
• Want more drug in unionized state

pH Partition Theory: Organic acids are better absorbed in acidic environments

Question 12

Weak Base Drug Transfer

Answer 12

• primarily absorbed in the intestine (pH = 8.4)
• Less absorbed in blood and practically none in the stomach
• Want more drug in ionized state
• *Need to take drug early enough to consider the need to travel to the intestine before it takes affect**

pH Partition Theory: Organic amines (bases) are better absorbed in basic environments

Question 13

Limitations to pH Partition Theory?

Answer 13

• Most drugs are still absorbed via the intestine
• Increased surface area helps
• Absorption follows the law of mass action, even if only 1% of the compound is neutral in the intestine that will be diffused into the blood where no drug is via passive diffusion
• This then allows more drug to enter the neutral state to reestablish the equilibrium which will then also be absorbed (quite effectively)

Question 14

Ionization

Answer 14

• Protonization or deprotonization resulting in charged molecules
• About 85% of drugs are ionized

Question 15

Acidity/Bascity control… (3)

Answer 15

1. Absorption and transportation to the site of action (by extension, bioavailability, solubility, absorption, volume of distribution, etc.)
2. Binding to action site (unionized via hydrogen bonding, ionized via strength of salt bridges or hydrogen bonding)
3. Elimination of compounds (bile, renal, P450 metabolism)