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ANSWERS TO CASE STUDIES
Chapter 2: Drug Design and Relationship of Functional Groups to
Pharmacologic Activity
Absorption/Acid-Base Case (p. 42)
Question #1:
Drug Functional groups present
Hydrophilic/ hydrophobic characteristics
Effect on absorption
Effect on ability to cross BBB Aromatic hydrocarbon Hydrophobic โ^ โ Halogenated aromatic hydrocarbon
Hydrophobic โ^ โ
Tertiary amine Hydrophilic โ^ โ Ether Hydrophilic โ^ โ
Cetirizine
Carboxylic acid Hydrophilic โ^ โ Hydrocarbon Hydrophobic โ^ โ Clemastin e
Aromatic hydrocarbon Hydrophobic โ^ โ
Halogenated aromatic hydrocarbon
Hydrophobic โ^ โ
Tertiary amine Hydrophilic โ^ โ Ether Hydrophilic โ^ โ Hydrocarbon Hydrophobic โ^ โ
Cetirizine is a second-generation H 1 -antagonist and is purported to be nonsedating. Clemastine is a first-generation H 1 -antagonist and is considered to be a sedating antihistamine. Based on the structure evaluation process, both cetirizine and clemastine contain several hydrophobic functional groups that would facilitate their crossing the blood-brain barrier. Both molecules contain an ionizable amine that will be predominantly ionized in the plasma. A key structural difference between these drug molecules is the presence of a carboxylic acid Cetirizine. This functional group is
hydrophilic and will be predominantly ionized in the plasma and therefore, may limit the extent of absorption across the blood-brain barrier. In order to limit the degree of drowsiness, it would be appropriate to recommend cetirizine (Zyrtec) for this patient.
Question #2:
Olopatadine hydrochloride is water soluble due to the solubilizing properties of the ion- dipole interaction between water and the ionized amine hydrochloride.
Questions #3:
Assumptions: pKa (tertiary amine) = 9. pKa (carboxylic acid) = 3.
pH=1 (stomach pH) pH=10 (intestinal pH) Tertiary amine (basic) ionized close to 50/50% ionized/unionized Carboxylic acid (acidic) unionized ionized
Cetirizine: In both compartments there will be at least one ionized functional group. In the intestine roughly 50% of the time there will be two functional groups ionized, which will limit the extent of absorption from this site. Cetirizine is probably absorbed from both sites but is probably absorbed from the stomach to a greater extent.
Clemastine: Absorbed best in the intestine where it is in its unionized form.
Question #4:
If the truck driver takes Cetirizine at the same time that he takes his TUMs, then the pH of the stomach will be elevated to 3.5 from pH=1. At this pH the carboxylic acid will become ionized and the extent of absorption from the stomach may be decreased to a limited extent. The truck driver may not receive the full antihistaminergic effect if he takes these two medications at the same time.
amount of hydrophobic character (aromatic hydrocarbon, cycloalkane, alkene). For a drug to be water soluble it must be able to interact with water via hydrogen bonding or an ion/dipole interaction, which are characteristic of polar functional groups. Considering the structural features of both agents, Penicillin V Potassium will be more water soluble due to the presence of several polar functional groups, including an ionized functional group.
The ionized form of codeine is more water soluble than the free base form because it can participate in ion/dipole interactions with water (a strong interaction).
Question #3:
If these two salts are mixed into the same IV bag, then it is anticipated that the salts will dissociate. As individual agents, the free forms of the drugs (Penicillin V Potassium is an acid in its free form and Codeine Phosphate is a base in its free form) may not be as water soluble as their salt forms and it is possible that one or both of these agents could precipitate out of solution. When mixed together, it is certainly possible that these drugs (acid + base) could form a complex (ionic). This complex is not likely to be particularly water soluble and may form a precipitate in the IV bag.
Absorption/Binding Interactions Case (p. 45)
Question #1:
Those functional groups that are hydrophobic in character will facilitate the absorption of this medication into the skin.
Characteristics of functional groups present in Terbinafine:
Aromatic hydrocarbon - Hydrophobic, โ Penetration of skin.
Alkene - Hydrophobic, โ Penetration of skin.
Alkane - Hydrophobic, โ Penetration of skin.
Alkyne - Hydrophobic, โ Penetration of skin.
Tertiary amine - Hydrophilic, Hydrophobic, โ Penetration of skin.
Questions #2:
Selection of the amino acids is based on the types of interactions that are possible with the particular functional group. With the tertiary amine it is essential to consider the ionization of this functional group prior to pairing with an amino acid. For the ion/dipole interaction, it is important to determine whether the drug is participating as the ion or the dipole when coupling potential amino acids to this type of functional group.
Functional groups in Binding interactions Amino acids that Terbinafine possible with enzyme could interact with group
Aromatic Hydrophobic staking Phenylalanine hydrocarbon interactions Tyrosine
Alkene Hydrophobic Isoleucine Leucine Valine Alanine Methionine Alkane Hydrophobic Isoleucine Leucine Valine Alanine Methionine Alkyne Hydrophobic Isoleucine Leucine Valine Alanine Methionine Tertiary amine H-bonding Serine Dipole/dipole Threonine Ion/dipole Cysteine Ionic Tyrosine Glutamic acid etc.
Ketone a. H-bonding a. Cysteine b. Dipole/dipole b. Lysine c. Ion/dipole c. Glutamic acid (ionized form)
Ester a. H-bonding a. HiSerine b. Dipole/dipole b. Threonine c. Ion/dipole c. Arginine (ionized form)
Alkene Hydrophobic Isoleucine
Functional groups in Binding interactions Amino acids that Salmeterol possible with enzyme could interact with group
Aromatic hydrocarbon a. Hydrophobic a. Phenylalanine b. Stacking interactions b. Tyrosine
Alkane Hydrophobic Leucine
Ether a. H-bonding a. Serine b. Dipole/dipole b. Threonine
Secondary amine a. H-bonding a. Histidine b. Dipole/dipole b. Glutamine c. Ion/dipole c. Cysteine d. Ionic (amine salt) d. Aspartic acid (ionized form)
Phenol a. H-bonding a. Tyrosine b. Dipole/dipole b. Threonine c. Ion/dipole c. Cysteine
d. Ionic (amine salt) d. Lysine (ionized form)
Alcohol a. H-bonding a. Glutamic acid b. Dipole/dipole b. Glutamine c. Ion/dipole c. Arginine (ionized form)
Water/Lipid Solubility Case (p. 47)
Structural feature in Meclizine Physical property
Aromatic hydrocarbon Hydrophobic Halogenated aromatic hydrocarbon Hydrophobic Tertiary amine Hydrophilic
Binding Interactions/Solubility Case (p. 48)
Question #1:
Functional groups in Phenylephrine Interactions possible with water contributing to water solubility
Secondary alcohol H-bonding, Dipole-dipole, Ion-dipole Secondary amine H-bonding, Dipole-dipole, Ion-dipole Phenol H-bonding, Dipole-dipole, Ion-dipole
Functional groups in Guaifenesin Interactions possible with water contributing to water solubility
Primary and secondary alcohol H-bonding, Dipole-dipole, Ion-dipole Ether H-bonding, Dipole-dipole, Ion-dipole
Question #2:
Functional groups in: Characteristics of group:
Phenylephrine Alkane Hydrophobic Aromatic hydrocarbon Hydrophobic
Chlorpheniramine Alkane Hydrophobic Aromatic hydrocarbon Hydrophobic Halogenated aromatic hydrocarbon Hydrophobic
Guaifenesin Alkane Hydrophobic Aromatic hydrocarbon Hydrophobic
The agent that has the most hydrophobic character is the one that is most likely to cross the lipophilic blood-brain barrier and have an effect on the childโs alertness. Of these agents, chlorpheniramine has the most hydrophobic character (see list of structural features in question 1 and 2). The only hydrophilic group present in chlorpheniramine is the tertiary amine.
Question #3:
Functional groups in Binding Interaction possible Chlorpheniramine with target of drug action
Aromatic hydrocarbon Hydrophobic stacking Halogenated aromatic hydrocarbon Hydrophobic stacking Alkane Hydrophobic van der Waal Tertiary amine H-bonding
Case Study p. 65.
Amine/Guanidine Ketone Carboxylic Acid Amide Which drug(s) contain this functional group?
Famotidine Enalapril Amlodipine
None Enalapril Enalapril
Hydrophobic or Hydrophilic in character?
Hydrophilic Hydrophilic Hydrophilic Hydrophilic
Acidic, basic, or neutral as drawn? Basic Neutral Acidic Neutral Types of interactions possible with target for drug action
Ionic (if ionized) Ion/dipole Dipole/dipole H-bonding
H-bonding Dipole/dipole Ion/dipole
Ionic (if ionized) Ion/dipole Dipole/dipole H-bonding
Ion/dipole Dipole/dipole
Is this group a H- bond donor, H- bond acceptor, both or neither?
Both H-bond acceptor only
H-bond donor and acceptor (as drawn)
Neither (as drawn)
Question #2:
Pepcid, in its hydrochloride salt form, is the conjugate acid of a weak base and is considered to have acidic character. At pH=1, Pepcidโs guanidine group will be ionized in the stomach (pKa=10.5; the pH of the environment is less than the pKa of the basic drug, therefore the functional group will be ionized). At pH=3.5, the guanidine group will still be ionized (same rationale).
Question #3:
Enalapril: Amine: ionized at pH=1 and at pH=3. Carboxylic acid: unionized at pH=1, slightly more than 50% ionized at pH=3.
Amlodipine: Amine: ionized at pH=1 and at pH=3.
Both drugs will have at least one structural component in its ionized form at both pHs.
Question #4:
These agents will have ionic character at both pHs. This ionic character will increase the ability of the drug to be soluble in the aqueous contents of the stomach but will decrease its ability to be absorbed across the lipophilic lining of the stomach. In the presence of famotidine, the carboxylic acid in enalapril will be somewhat greater than 50% ionized, which may further hamper absorption from the stomach. To be on the safe side, the famotidine should be separated from at least the enalapril dose.
Question #5:
The products of hydrolysis of enalapril:
Acid/Base Chemistry, Solubility, and Absorption Case Study (p. 66)
Question #1:
Acid/base character of Latanoprost as drawn: Neutral
Question #2:
Acid/base character of Timolol as drawn: Basic
