Page 600 - Basic _ Clinical Pharmacology ( PDFDrive )

586 SECTION V Drugs That Act in the Central Nervous System

Cocaine is an alkaloid found in the leaves of Erythroxylum of the newborn, and the mothers faced harsh legal consequences.
coca, a shrub indigenous to the Andes. For more than 100 years, The follow-up of the children, now adults, does not confirm a
it has been extracted and used in clinical medicine, mainly as a drug-specific handicap in cognitive performance. Moreover, in
local anesthetic and to dilate pupils in ophthalmology. Sigmund this population, the percentage of drug-users is comparable to
Freud famously proposed its use to treat depression and alcohol controls matched for socioeconomic environment.
dependence, but addiction quickly brought an end to this idea. Susceptible individuals may become dependent and addicted
Cocaine hydrochloride is a water-soluble salt that can be after only a few exposures to cocaine. Although a withdrawal
injected or absorbed by any mucosal membrane (eg, nasal snort- syndrome is reported, it is not as strong as that observed with
ing). When heated in an alkaline solution, it is transformed into opioids. Tolerance may develop, but in some users, a reverse
the free base, “crack cocaine,” which can then be smoked. Inhaled tolerance is observed; that is, they become sensitized to small
crack cocaine is rapidly absorbed in the lungs and penetrates doses of cocaine. This behavioral sensitization is in part context-
swiftly into the brain, producing an almost instantaneous “rush.” dependent. Cravings are very strong and underlie the very high
In the peripheral nervous system, cocaine inhibits voltage- addiction liability of cocaine. To date, no specific antagonist is
gated sodium channels, thus blocking initiation and conduction available, and the management of intoxication remains support-
of action potentials (see Chapter 26). This mechanism, underlying ive. Developing a pharmacologic treatment for cocaine addiction
its effect as a local anesthetic, seems responsible for neither the is a top priority.
acute rewarding nor the addictive effects. In the central nervous
system, cocaine blocks the uptake of dopamine, noradrenaline,
and serotonin through their respective transporters. The block AMPHETAMINES
of the dopamine transporter (DAT), by increasing dopamine
concentrations in the nucleus accumbens, has been implicated Amphetamines are a group of synthetic, indirect-acting sympa-
in the rewarding effects of cocaine (Figure 32–4). In fact, the thomimetic drugs that cause the release of endogenous biogenic
rewarding effects of cocaine are abolished in mutant mice with a amines, such as dopamine and noradrenaline (see Chapters 6 and 9).
cocaine-insensitive DAT. The activation of the sympathetic ner- Amphetamine, methamphetamine, and their many derivatives
vous system results mainly from blockage of the norepinephrine exert their effects by reversing the action of biogenic amine trans-
transporter (NET) and leads to an acute increase in arterial pres- porters at the plasma membrane. Amphetamines are substrates of
sure, tachycardia, and often, ventricular arrhythmias. Users typi- these transporters and are taken up into the cell (Figure 32–4).
cally lose their appetite, are hyperactive, and sleep little. Cocaine Once in the cell, amphetamines interfere with the vesicular
exposure increases the risk for intracranial hemorrhage, ischemic monoamine transporter (VMAT; see Figure 6–4), depleting syn-
stroke, myocardial infarction, and seizures. Cocaine overdose aptic vesicles of their neurotransmitter content. As a consequence,
may lead to hyperthermia, coma, and death. In the 1970s, when levels of dopamine (or other transmitter amine) in the cytoplasm
crack-cocaine appeared in the USA, it was suggested that the drug increase and quickly become sufficient to cause release into the
is particularly harmful to the fetus in addicted pregnant women. synapse by reversal of the plasma membrane DAT. Normal vesicu-
The term “crack-baby” was used to describe a specific syndrome lar release of dopamine consequently decreases (because synaptic

Cocaine Amphetamine

VMAT

Amph
DA

DAT
DAT
DAT
DA DA DA
DA
Cocaine Amph

FIGURE 32–4 Mechanism of action of cocaine and amphetamine on synaptic terminal of dopamine (DA) neurons. Left: Cocaine inhibits
the dopamine transporter (DAT), decreasing DA clearance from the synaptic cleft and causing an increase in extracellular DA concentration.
Right: Since amphetamine (Amph) is a substrate of the DAT, it competitively inhibits DA transport. In addition, once in the cell, amphetamine
interferes with the vesicular monoamine transporter (VMAT) and impedes the filling of synaptic vesicles. As a consequence, vesicles are
depleted and cytoplasmic DA increases. This leads to a reversal of DAT direction, strongly increasing nonvesicular release of DA, and further
increasing extracellular DA concentrations.