Page 203 - Medicinal Chemistry Self Assessment

192 Medicinal Chemistry Self Assessment

6. Lidocaine suffers from CNS-based toxicities largely due to production of the N-dealkylated metabolic
product monoethylglycinexylidide once the parent drug has crossed the blood–brain barrier.
a. Provide a structural rationale for why lidocaine is able to cross the blood–brain barrier.
Answer
Based on the information in the structure evaluation grid, we know that lidocaine has a fair
amount of hydrophobic character (aromatic hydrocarbons with aliphatic substituents, aliphatic
alkane substituents on amine) that enhance absorption across lipophilic membranes. At pH=7.4,
the tertiary amine will be predominantly ionized. Because an equilibrium between the ionized
and unionized forms of lidocaine exists, a very small percentage of the drug will be in its union-
ized form at any given time. The blood–brain barrier is highly selective. To cross this membrane
via passive diffusion, drugs typically must be in their unionized form and be highly lipophilic.
Because of the presence of the ionizable amine, only very small amounts of lidocaine will cross
the blood–brain barrier and then undergo oxidative N-dealkylation to produce an N-dealkylated
metabolic byproduct—monoethylglycinexylidide, the cause of the CNS-based toxicity observed.
1.19 and 2.19 – remove bold from label
b. Interestingly, neither tocainide nor tolycaine demonstrates similar CNS-based toxicities. Provide a

structural rationale for why these two local anesthetics are devoid of CNS-based side effects.

Tolycaine Tolcainide

Answer
1.25 and 2.25 – remove bold from label
From a structural perspective tolycaine is structurally identical to lidocaine with the exception

of the presence of a methyl ester instead of a benzylic methyl group. This methyl ester readily
A
undergoes enzyme catalyzed ester hydrolysis, a phase I metabolic transformation, to the corresponding
carboxylic acid. The resulting metabolic product will be ionized at physiological pH via two
B
C
functional groups, the carboxylic acid and the tertiary amine. Even though tolycaine can undergo
oxidative N-dealkylation to produce an N-dealkylated product that closely resembles mono-
D
ethylglycinexylidide, it is highly unlikely that this drug will cross the blood–brain barrier due to
the presence of these two ionizable functional groups. Again, although an equilibrium exists
between the ionized and unionized forms of both the carboxylic acid and the tertiary amine
functional groups, there is only a very small fraction of the drug that is completely unionized at
any point in time.
Sitagliptin

Tocainide contains several of the same functional groups found in lidocaine, but does not contain

an alkylated amine. The hydrophobic character afforded by the substituted aromatic hydro-

carbon and the presence of an amine-substituted aliphatic alkane will certainly contribute to the
2.25 – remove bold from label
ability of the drug to cross the blood–brain barrier. The primary amine will also be predominantly

ionized at pH=7.4 and, therefore, only a fraction of the time will it be available in its unionized

form. These structural characteristics are similar to lidocaine so it is possible for tocainide to cross
the blood–brain barrier. Unlike lidocaine, tocainide cannot undergo oxidative N-dealkylation, and
the metabolic byproducts that cause CNS-based toxicity are not formed.

Sitagliptin phosphate