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Chapter: Basic & Clinical Pharmacology : Drugs of Abuse

Drugs that Bind to Transporters of Biogenic Amines

The prevalence of cocaine abuse has increased greatly over the last decade and now represents a major public health problem world-wide.



The prevalence of cocaine abuse has increased greatly over the last decade and now represents a major public health problem world-wide. Cocaine is highly addictive (relative risk = 5), and its use is associated with a number of complications.

Cocaine is an alkaloid found in the leaves of Erythroxylon coca, a shrub indigenous to the Andes. For more than 100 years, it has been extracted and used in clinical medicine, mainly as a local anesthetic and to dilate pupils in ophthalmology. Sigmund Freud famously proposed its use to treat depression and alcohol depen-dence, but addiction quickly brought an end to this idea.

Cocaine hydrochloride is a water-soluble salt that can be injected or absorbed by any mucosal membrane (eg, nasal snort-ing). When heated in an alkaline solution, it is transformed into the free base, “crack cocaine,” which can then be smoked. Inhaled crack cocaine is rapidly absorbed in the lungs and penetrates swiftly into the brain, producing an almost instantaneous “rush.”

In the peripheral nervous system, cocaine inhibits voltage-gated sodium channels, thus blocking initiation and conduction of action potentials . This effect, however, seems responsible for neither the 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 of the dopamine transporter (DAT), by increasing dopamine concentrations in the nucleus accumbens, has been implicated in the rewarding effects of cocaine (Figure 32–5). In fact, the rewarding effects of cocaine are abolished in mice with a cocaine-insensitive DAT. The activation of the sympathetic ner-vous system results mainly from blockage of the norepinephrine transporter (NET) and leads to an acute increase in arterial pres-sure, tachycardia, and often, ventricular arrhythmias. Users typi-cally lose their appetite, are hyperactive, and sleep little. Cocaine exposure increases the risk for intracranial hemorrhage, ischemic stroke, myocardial infarction, and seizures. Cocaine overdose may lead to hyperthermia, coma, and death.

Susceptible individuals may become dependent and addicted after only a few exposures to cocaine. Although a withdrawal syn-drome is reported, it is not as strong as that observed with opioids. Tolerance may develop, but in some users a reverse tolerance is observed; that is, they become sensitized to small doses of cocaine. This behavioral sensitization is in part context-dependent. Cravings are very strong and underline the very high addiction liability of cocaine. To date, no specific antagonist is available, and the management of intoxication remains supportive. Developing a pharmacologic treatment for cocaine addiction is a top priority.


Amphetamines are a group of synthetic, indirect-acting sympath-omimetic drugs that cause the release of endogenous biogenic amines, such as dopamine and noradrenaline. Amphetamine, methamphetamine, and their many derivatives exert their effects by reversing the action of biogenic amine trans-porters at the plasma membrane. Amphetamines are substrates of these transporters and are taken up into the cell (Figure 32–5). Once in the cell, amphetamines interfere with the vesicular mono-amine transporter (VMAT; see Figure 6–4), depleting synaptic vesicles of their neurotransmitter content. As a consequence, levels of dopamine (or other transmitter amine) in the cytoplasm increase and quickly become sufficient to cause release into the synapse by reversal of the plasma membrane DAT. 

Normal vesicu-lar release of dopamine consequently decreases (because synaptic vesicles contain less transmitter), whereas nonvesicular release increases. Similar mechanisms apply for other biogenic amines (serotonin and norepinephrine).

Together with GHB and ecstasy, amphetamines are often referred to as “club drugs,” because they are increasingly popular in the club scene. They are often produced in small clandestine laboratories, which makes their precise chemical identification difficult. They differ from ecstasy chiefly in the context of use: intravenous administration and “hard core” addiction is far more common with amphetamines, especially methamphetamine. In general, amphetamines lead to elevated catecholamine levels that increase arousal and reduce sleep, whereas the effects on the dop-amine system mediate euphoria but may also cause abnormal movements and precipitate psychotic episodes. Effects on sero-tonin transmission may play a role in the hallucinogenic and anorexigenic functions as well as in the hyperthermia often caused by amphetamines.

Unlike many other abused drugs, amphetamines are neuro-toxic. The exact mechanism is not known, but neurotoxicity depends on the NMDA receptor and affects mainly serotonin and dopamine neurons.

Amphetamines are typically taken initially in pill form by abusers, but can also be smoked or injected. Heavy users often progress rap-idly to intravenous administration. Within hours after oral ingestion, amphetamines increase alertness and cause euphoria, agitation, and confusion. Bruxism (tooth grinding) and skin flushing may occur. Effects on heart rate may be minimal with some compounds (eg, methamphetamine), but with increasing dosage these agents often lead to tachycardia and dysrhythmias. Hypertensive crisis and vasoconstriction may lead to stroke. Spread of HIV and hepatitis infection in inner cities has been closely associated with needle sharing by intravenous users of methamphetamine. With chronic use, amphetamine tolerance may develop, lead-ing to dose escalation. Withdrawal consists of dysphoria, drowsi-ness (in some cases, insomnia), and general irritability.


Ecstasy is the name of a class of drugs that includes a large variety of derivatives of the amphetamine-related compound methylene-dioxymethamphetamine (MDMA). MDMA was originally used in some forms of psychotherapy, but no medically useful effects were documented. This is perhaps not surprising, because the main effect of ecstasy appears to be to foster feelings of intimacy and empathy without impairing intellectual capacities. Today, MDMA and its many derivatives are often produced in small quantities in ad hoc laboratories and distributed at parties or “raves,” where it is taken orally. Ecstasy therefore is the prototypi-cal designer drug and, as such, is increasingly popular.

Similar to the amphetamines, MDMA causes release of bio-genic amines by reversing the action of their respective transport-ers. It has a preferential affinity for the serotonin transporter(SERT) and therefore most strongly increases the extracellularconcentration of serotonin. This release is so profound that there is a marked intracellular depletion for 24 hours after a single dose. With repetitive administration, serotonin depletion may become permanent, which has triggered a debate on its neurotoxicity. Although direct proof from animal models for neurotoxicity remains weak, several studies report long-term cognitive impair-ment in heavy users of MDMA.

In contrast, there is a wide consensus that MDMA has several acute toxic effects, in particular hyperthermia, which along with dehydration (eg, caused by an all-night dance party) may be fatal. Other complications include serotonin syndrome (mental status change, autonomic hyperactivity, and neuromuscular abnormalities) and seizures. Following warnings about the dangers of MDMA, some users have attempted to compensate for hyper-thermia by drinking excessive amounts of water, causing water intoxication involving severe hyponatremia, seizures, and even death.

Withdrawal is marked by a mood “offset” characterized by depression lasting up to several weeks. There have also been reports of increased aggression during periods of abstinence in chronic MDMA users.

Taken together, the evidence for irreversible damage to the brain, although not completely convincing, implies that even occasional recreational use of MDMA cannot be considered safe.


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