One final anecdote involving 1,4-DHP Ca2+channel blockers concerns their role in
the discovery that grapefruit juice can markedly increase oral absorption of drugs, even
to potentially toxic levels. Unlike other citrus fruit juices, grapefruit juice can partici-
pate in a food–drug interaction that causes a drug to be absorbed in concentrations
much greater than anticipated. This observation was first noted for felodipine and then was
extended to all of the 1,4-DHP-type Ca^2 +channel blockers. In addition to the 1,4-DHPs,
grapefruit juice can affect a variety of other medications including antihistamines
(e.g., loratidine), AIDs drugs (e.g., saquinavir), lipid-lowering agents for atherosclero-
sis (e.g., simvastatin, lavastatin, atorvastatin), neurological drugs (e.g., carbamazepine,
diazepam, midazolam), and immunosuppressants (e.g., cyclosporine, tacrolimus).
Grapefruit juice contains furanocoumarins such as 6′,7′-dihydroxybergamottin that are
natural product inhibitors of intestinal enzymes such as CYP3A4, which oxidizes a
broad spectrum of drugs within the small intestine.
7.4.7 Ion Channel Active Agents: Symptomatic but not Curative DrugsOver the past several decades, drugs developed to be antagonists to voltage-gated ion
channels have heralded significant therapeutic advances. Na+and Ca^2 +channel antago-
nists have demonstrated considerable clinical utility in the treatment of cardiovascular
and neurological disorders. Although they have been useful, their value has been more
“symptomatic” than “curative” or even “disease stabilizing.” Ion channel active agents
for cardiac arrhythmias suppress the arrhythmia but do not prevent the development of
arrhythmias following cardiac injury. Likewise, ion channel active agents for seizures
suppress seizures but do not prevent the development of epilepsy after a brain injury.
This observation presents challenges for the selection of druggable targets when one is
designing drugs for a particular disorder. Should the drug designer select a target with
a higher chance of success, such as electrically excitable tissue, which will enable the
development of symptomatic agents, or should the designer target a receptor with a
lower likelihood of success, which may afford a curative approach? Recent research in
the area of epilepsy has begun to address this drug design dilemma.
The currently available anticonvulsant drugs are “symptomatic” agents that suppress
the symptoms of epilepsy (i.e., seizures) while failing to contend with the underlying
pathological process that initially caused (or continues to cause) the predisposition to
seizures. After an injury such as a depressed skull fracture with associated brain hem-
orrhage, there is a significant probability of developing epilepsy approximately 1.5–3 years
after the injury. The currently available anticonvulsant, if administered at the time of
the injury, will do nothing to prevent the ultimate development of epilepsy some two
years later. The drug can simply be used to suppress the seizures once they have
occurred.
These failings of traditional anticonvulsant drugs to influence the natural history of
epilepsy have been demonstrated repeatedly. As shown by various well-controlled post-
traumatic epilepsy studies, neither phenytoin nor carbamazepine prophylaxis has any
influence on the later development of epilepsy after head trauma. Thus the currently
available drugs do not seem to prevent the progressive pathology that underlies a devel-
oping seizure disorder. Indeed, limited evidence suggests that these drugs may be
achieving quite the contrary. Phenytoin prophylaxis, for instance, has been associated
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