indications. Antihistamines are usually the first drugs used to treat allergic reactions.
They are very effective at reducing the “runny nose and itchy eyes” (allergic rhinitis and
allergic conjunctivitis) of allergies. However, since they are effective at reducing the
runny nose of allergies, antihistamines are frequently used in “cold remedies.” The
nasal congestion of a cold (viral upper respiratory tract infection) arises via a different
mechanism from the nasal congestion of allergies; thus, the use of antihistamines in
over-the-counter cold remedies is questionable at best. Regrettably, the antihista-
mines are usually listed as one of several active agents within a “shotgun” cold remedy.
A person taking such a medication may be taking the antihistamine unknowingly. This
can cause problems. Since H 1 receptors are diffusely located throughout the brain, cold
remedies can cause drowsiness (a danger to those operating moving equipment) and
may, rarely, even trigger seizures in a person with a predisposition to epileptic seizures.
The same molecules used to treat allergies and “cold symptoms” have many other
uses. Antihistamines are particularly effective as antiemetics in suppressing nausea
associated with gastrointestinal illnesses. They can also be used to treat the symptoms
of motion sickness or even vestibular disturbances (vertigo). Because of their ability to
induce sedation, antihistamines are widely used in over-the-counter sleep aids.
4.7 INHIBITORY AMINO ACID NEUROTRANSMITTERS:
γ-AMINOBUTYRIC ACID (GABA)GABA is the most comprehensively studied inhibitory neurotransmitter, and there are
many reviews of its biochemistry and pharmacology. The reason for this great interest
is the discovery that the most popular drugs of the 1970–1980s, the benzodiazepine
tranquilizers or “anxiolytics,” as well as the previously popular barbiturates, act on the
GABAergic neuronal system.
4.7.1 Neuronal Systems and GABA MetabolismThere are numerous GABAergic neuronal pathways in the CNS. γ-Aminobutyric acid
is found in high concentrations in the cerebellum, is also found in the hypothalamus,
thalamus, and hippocampus, and occurs in low concentrations in practically all brain
structures as well as in the spinal cord. The amounts present are relatively high—on a
μmol/g order of magnitude—rather than the nanomolar quantities seen with most major
neurotransmitters.γ-Aminobutyric acid also occurs in glial cells, where its role is less
well defined.
The biosynthesis of GABA occurs only in the neurons, since it cannot penetrate the
blood–brain barrier, and no peripheral precursor is known. The synthesis is tied to the
Krebs cycle through α-ketoglutarate. γ-Aminobutyric acid is formed by the decarboxy-
lation of L-glutamate, catalyzed by glutamic acid decarboxylase (GAD), an enzyme
found only in the mammalian CNS and in the retina. This reaction is irreversible. The
cofactor of GAD is pyridoxal phosphate (vitamin B 6 ). Since GAD is the rate-determining
enzyme, GABA metabolism can be regulated by the manipulation of this enzyme, the
manipulation of pyridoxal, or both.
270 MEDICINAL CHEMISTRY