Page 595 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 32 Drugs of Abuse 581

Flashbacks of altered perception can occur years after LSD use. tolerance and dependence. The withdrawal syndrome may be very
Moreover, chronic use of PCP may lead to an irreversible schizo- severe (except for codeine) and includes intense dysphoria, nausea
phrenia-like psychosis. or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis,
piloerection, sweating, diarrhea, yawning, and fever. Beyond the
withdrawal syndrome, which usually lasts no longer than a few
■ BASIC PHARMACOLOGY OF days, individuals who have received opioids as analgesics only
rarely develop addiction. In contrast, when taken for recreational
DRUGS OF ABUSE purposes, opioids are highly addictive. The relative risk of addic-
tion is 4 out of 5 on a scale of 1 (nonaddictive) to 5 (highly
Since all addictive drugs increase dopamine concentrations addictive).
in target structures of the mesolimbic projections, we classify
them on the basis of their molecular targets and the underlying
mechanisms (Table 32–1 and Figure 32–2). The first group Treatment
contains the opioids, cannabinoids, f-hydroxybutyric acid The opioid antagonist naloxone reverses the effects of a dose of
(GHB), and the hallucinogens, which all exert their action morphine or heroin within minutes. This may be life-saving in
through G protein-coupled receptors. The second group the case of a massive overdose (see Chapters 31 and 58). Naloxone
io
includes nicotine, alcohol, the benzodiazepines, dissocia- administration also provokes an acute withdrawal (precipitated
tive anesthetics, and some inhalants, which interact with abstinence) syndrome in a dependent person who has recently
ionotropic receptors or ion channels. The last group comprises taken an opioid.
cocaine, amphetamines, and ecstasy, which all bind to mono- In the treatment of opioid addiction, a long-acting opioid
amine transporters. The nonaddictive drugs are classified using (eg, methadone, buprenorphine, morphine sulphate) is often
the same criteria. substituted for the shorter-acting, more rewarding, opioid (eg,
heroin). For substitution therapy, methadone is given orally
DRUGS THAT ACTIVATE once daily, facilitating supervised intake. Using a partial agonist
G -COUPLED RECEPTORS (buprenorphine) and the much longer half-life (methadone,
IO
morphine sulphate, and buprenorphine) may also have some
OPIOIDS beneficial effects (eg, weaker drug sensitization, which typically
requires intermittent exposures), but it is important to realize
Opioids may have been the first drugs to be abused (preceding that abrupt termination of methadone administration invari-
stimulants) and are still among the most commonly used for ably precipitates a withdrawal syndrome; that is, the subject
nonmedical purposes. on substitution therapy remains dependent. Levomethadone, a
preparation containing only the active enantiomer, has similar
kinetics and effects as methadone, but lower side effects, par-
Pharmacology & Clinical Aspects ticularly when cardiac repolarization is perturbed (long QT
As described in Chapter 31, opioids comprise a large family of interval in the electrocardiogram). Some countries (eg, Canada,
endogenous and exogenous agonists at three G protein-coupled Denmark, Netherlands, United Kingdom, Switzerland) even
receptors: the μ-, κ-, and δ-opioid receptors. Although all three allow substitution of medical heroin for street heroin. A follow-
receptors couple to inhibitory G proteins (ie, they all inhibit ade- up of a cohort of addicts who received heroin injections in a
nylyl cyclase), they have distinct, sometimes even opposing effects, controlled setting and had access to counseling indicates that
mainly because of the cell type-specific expression throughout addicts under heroin substitution have an improved health status
the brain. In the VTA, for example, μ-opioid receptors are selec- and are better integrated in society. Abuse of prescription opioids
tively expressed on GABA neurons (which they inhibit), whereas has soared in the USA over the last 10 years, and the National
κ-opioid receptors are expressed on and inhibit dopamine neu- Institute on Drug Abuse (NIDA) estimates that more than
rons. This may explain why μ-opioid agonists cause euphoria, 2 million individuals are dependent on these substances, some
whereas κ agonists induce dysphoria. of whom may become heroin addicts.
In line with the latter observations, the rewarding effects of
morphine are absent in knockout mice lacking μ receptors but
persist when either of the other opioid receptors are ablated. In CANNABINOIDS
the VTA, μ opioids cause an inhibition of GABAergic inhibitory
interneurons, which leads eventually to a disinhibition of dopa- Endogenous cannabinoids that act as neurotransmitters include
mine neurons. 2-arachidonyl glycerol (2-AG) and anandamide, both of which
The most commonly abused μ opioids include morphine, bind to CB receptors. These very lipid-soluble compounds are
1
heroin (diacetylmorphine, which is rapidly metabolized to mor- released at the postsynaptic somatodendritic membrane, and dif-
phine), codeine, and oxycodone. Meperidine abuse is common fuse through the extracellular space to bind at presynaptic CB 1
among health professionals. All of these drugs induce strong receptors, where they inhibit the release of either glutamate or