Page 596 - Basic _ Clinical Pharmacology ( PDFDrive )

582 SECTION V Drugs That Act in the Central Nervous System

GABA. Because of such backward signaling, endocannabinoids binding sites. The protein that contains a high-affinity binding
are called retrograde messengers. In the hippocampus, release site (1 μM) for GHB has been cloned, but its involvement in the
of endocannabinoids from pyramidal neurons selectively affects cellular effects of GHB at pharmacologic concentrations remains
inhibitory transmission and may contribute to the induction of unclear. The low-affinity binding site (1 mM) has been identified
synaptic plasticity during learning and memory formation. as the GABA receptor. In mice that lack GABA receptors, even
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Exogenous cannabinoids, eg, in marijuana, which when smoked very high doses of GHB have no effect; this suggests that GABA
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contains thousands of organic and inorganic chemical compounds, receptors are the sole mediators of GHB’s pharmacologic action.
exert their pharmacologic effects through active substances includ- GHB was first synthesized in 1960 and introduced as a general
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ing Δ -tetra-hydrocannabinol (THC), a powerful psychoactive anesthetic. Because of its narrow safety margin and its addictive
substance. Like opioids, THC causes disinhibition of dopamine potential, it is not available in the USA for this purpose. Sodium
neurons, mainly by presynaptic inhibition of GABA neurons in the oxybate can, however, be prescribed (under restricted access rules)
VTA. The half-life of THC is about 4 hours. The onset of effects of to treat narcolepsy, because GHB decreases daytime sleepiness
THC after smoking marijuana occurs within minutes and reaches a and episodes of cataplexy through a mechanism unrelated to the
maximum after 1–2 hours. The most prominent effects are eupho- reward system. Before causing sedation and coma, GHB causes
ria and relaxation. Users also report feelings of well-being, grandi- euphoria, enhanced sensory perceptions, a feeling of social close-
osity, and altered perception of passage of time. Dose-dependent ness, and amnesia. These properties have made it a popular “club
perceptual changes (eg, visual distortions), drowsiness, diminished drug” that goes by colorful street names such as “liquid ecstasy,”
coordination, and memory impairment may occur. Cannabinoids “grievous bodily harm,” or “date rape drug.” As the latter name
can also create a dysphoric state and, in rare cases following the use suggests, GHB has been used in date rapes because it is odorless
of very high doses, eg, in hashish, result in visual hallucinations, and can be readily dissolved in beverages. It is rapidly absorbed
depersonalization, and frank psychotic episodes. Additional effects after ingestion and reaches a maximal plasma concentration
of THC, eg, increased appetite, attenuation of nausea, decreased 20–30 minutes after ingestion of a 10–20 mg/kg dose. The elimi-
intraocular pressure, and relief of chronic pain, have led to the nation half-life is about 30 minutes.
use of cannabinoids in medical therapeutics. The justification of Although GABA receptors are expressed on all neurons of the
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medicinal use of marijuana was comprehensively examined by the VTA, GABA neurons are much more sensitive to GHB than are
Institute of Medicine (IOM) of the National Academy of Sciences dopamine neurons (Figure 32–3). This is reflected by the EC s,
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in its 1999 report, Marijuana & Medicine. Today, medical use of which differ by about one order of magnitude, and indicates the dif-
botanical marijuana has been legalized in 25 states and the District ference in coupling efficiency of the GABA receptor and the potas-
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of Columbia. Nevertheless this continues to be a controversial issue, sium channels responsible for the hyperpolarization. Because GHB
mainly because of the fear that cannabinoids may serve as a gateway is a weak agonist, only GABA neurons are inhibited at the concen-
to the consumption of “hard” drugs or cause schizophrenia in indi- trations typically obtained with recreational use. This feature may
viduals with a predisposition. underlie the reinforcing effects of GHB and the basis for addiction
Chronic exposure to marijuana leads to dependence, which to the drug. At higher doses, however, GHB also hyperpolarizes
is revealed by a distinctive, but mild and short-lived, withdrawal dopamine neurons, eventually completely inhibiting dopamine
syndrome that includes restlessness, irritability, mild agitation, release. Such an inhibition of the VTA may in turn preclude its
insomnia, nausea, and cramping. The relative risk for addiction is 2. activation by other addictive drugs and may explain why GHB
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The synthetic Δ -THC analog dronabinol is a US Food might have some usefulness as an “anticraving” compound.
and Drug Administration (FDA) -approved cannabinoid agonist
currently marketed in the USA and some European countries.
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Nabilone, an older commercial Δ -THC analog, was recently LSD, MESCALINE, & PSILOCYBIN
reintroduced in the USA for treatment of chemotherapy-induced
emesis. Nabiximols is a botanical drug obtained by standard extrac- LSD, mescaline, and psilocybin are commonly called hallucino-
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tion. Its active principles are Δ -THC and cannabidiol. Initially gens because of their ability to alter consciousness such that the
only marketed in the United Kingdom, it is now widely available to individual senses things that are not present. They induce, often in
treat symptoms of multiple sclerosis. In the USA, nabiximols is in an unpredictable way, perceptual symptoms, including shape and
phase III testing for cancer pain. The cannabinoid system is likely color distortion. Psychosis-like manifestations (depersonalization,
to emerge as an important drug target in the future because of its hallucinations, distorted time perception) have led some to clas-
apparent involvement in several therapeutically desirable effects. sify these drugs as psychotomimetics. They also produce somatic
symptoms (dizziness, nausea, paresthesias, and blurred vision).
Some users have reported intense reexperiencing of perceptual
GAMMA-HYDROXYBUTYRIC ACID effects (flashbacks) up to several years after the last drug exposure.
Hallucinogens differ from most other drugs described in this
Gamma-hydroxybutyric acid (GHB, or sodium oxybate for its chapter in that they induce neither dependence nor addiction.
salt form) is produced during the metabolism of GABA, but the However, repetitive exposure still leads to rapid tolerance (also
function of this endogenous agent is unknown at present. The called tachyphylaxis). Animals do not self-administer hallucino-
pharmacology of GHB is complex because there are two distinct gens, suggesting that they are not rewarding to them. Additional