Pharmacokinetics

The nature of the stimulant effects of cocaine and amphetamines depends on the route of administration. These drugs can be smoked (crack) or administered intravenously (shooting up), intranasally (snorted), or orally. As noted above, intravenous or inhaled freebase preparations produce intense, pleasurable sensations characterized as a “rush” that users have likened to sexual orgasm. Such extreme euphoria has been shown to be a powerful motivational factor for abusing these drugs. The intravenous doses that produce these subjective effects are approximately 8–16 mg cocaine and 10 mg of D-amphetamine. Peak cocaine levels in the bloodstream after intravenous administration appear almost immediately and rapidly decrease over the next 2 h (Figure 4.8). Smoked cocaine in the freebase form is absorbed into the bloodstream at a rate very similar to intravenous administration, and 50 mg of freebase produces cardiovascular effects approximately equivalent to 32 mg cocaine administered intravenously. Intranasal doses of 20–30 mg cocaine produce euphoric and stimulant effects that are short-lived and last for approximately 30 min. Cocaine levels in the blood after intranasal administration start low, build quickly, and then slowly taper off. Cocaine administered orally has less powerful effects than cocaine administered intravenously, presumably because of a much slower absorption rate. Peak blood levels after oral administration occur after about 60 min. South American Indians have used an oral coca leaf preparation combined with ash for centuries to promote absorption. They recognized that coca leaves were effective as a stimulant to reduce hunger and fatigue, and chewing the leaves (or drinking tea preparations) did not have any obvious major negative physical or psychic effects. Intranasal or oral administration of D-amphetamine in the dose range of 2.5–15 mg produces stimulant effects which are similar to cocaine. People report feelings of alertness, energetic vitality, confidence, assertiveness, and decreases in appetite and fatigue. Intranasal absorption is faster than oral administration and has more intense effects (Box 4.8). Compared with cocaine’s effects, which last for about 30 min, the stimulant effects of amphetamines last much longer – up to 4–6 h.

Figure 4.6 Effects of psychostimulants on performance. The figure shows hypothetical inverted U-shaped functions that relate the dose of psychostimulant to performance, depending on the complexity of the task. For a more complex task, the entire dose-effect function shifts to the left (think of a neurosurgeon or watch maker doing a delicate task). For simpler tasks (like chopping wood), the dose–effect function shifts to the right. [From: Hart CL, Ksir C, Ray O. Drugs, Society and Human Behavior, 13th edn. McGraw-Hill, Boston, 2009.]

Figure 4.7 Photographs of two types of benzedrine inhaler, first introduced to the market in 1932 by Smith, Kline & French Co.

TABLE 4.4

Weight Loss (in Pounds) Induced by Benzphetamine and D-Amphetamine

*Benzphetamine, a phenylalkylamine, is chemically and pharmacologically related to amphetamine. [Taken with permission from Simkin B, Wallace L. A controlled clinical comparison of benzphetamine and D-amphetamine in the management of obesity. American Journal of Clinical Nutrition, 1961, (9), 632–637.]

Figure 4.8 Cocaine plasma levels in blood after administration via intravenous, smoked, intranasal, and oral routes. These data show that the route of cocaine administration determines the profile of absorption over time. Notice that the peak levels of cocaine in the blood are delayed with oral administration compared with intravenous and smoked cocaine and that the peak levels in the blood are higher for intravenous and smoked cocaine. Notice also that the profile of absorption of intravenous cocaine is virtually identical to smoked cocaine. [From: Fischman MW. Behavioral pharmacology of cocaine. Journal of Clinical Psychiatry, 1988, 49(2 suppl): 7–10.] © 1988, Physicians Postgraduate Press. Reprinted by permission.

BOX 4.7

HOW DOES ONE EXPLAIN THE SEEMING PARADOX THAT PSYCHOSTIMULANTS SUCH AS AMPHETAMINES AND METHYLPHENIDATE CAN TREAT ADHD?

Although seemingly counterintuitive, psychostimulants are indeed one of the primary treatments for attention-deficit/hyperactivity disorder (ADHD). One may question this paradox: How does a stimulant drug treat someone who already appears to be highly stimulated? The answer lies in the fact that psychostimulants not only increase arousal; they also focus attention. A person with ADHD has difficulty controlling impulsive behavior – that is, their attention can rapidly shift from one thing to another. A psychostimulant, such as Adderall, helps focus attention and tune out distractions that would otherwise cause the person to lose focus on the task at hand.

Amphetamine is metabolized in the liver, and approximately 30% is excreted unchanged in urine. Amphetamine has a relatively long half-life of approximately 12 h, but the half-life can depend on the pH of urine (for a definition of “half-life,” see Introduction to the Neuropsychopharmacology). Alkaline urine can extend the half-life to over 16 h; acidic urine can shorten it to just 8 h. Methamphetamine’s metabolism and excretion are similar to amphetamine. Methamphetamine has a half-life of 11 h for the smoked route and 12 h for the intravenous route. Cocaine, in contrast, is rapidly and efficiently metabolized (half-life of just 48–75 min), and less than 10% is excreted unchanged in urine.

BOX 4.8

WHICH ROUTE OF ADMINISTRATION PRODUCES THE FASTEST ACCESS TO THE BRAIN?

Intravenous administration produces the quickest, nearly instantaneous, psychopharmacological effects, paralleled by smoking, the effects of which appear within seconds. The intranasal route is also very fast, with effects beginning to appear almost immediately and peak effects occurring after about 20 min. The oral route, similar to all drugs of abuse, is the slowest because of the time needed for absorption.

BOX 4.9

BEHAVIORAL MECHANISM OF ACTION

In this book, a “behavioral mechanism of action” refers to a unifying and integrating principle of order and predictability at the behavioral level for a given drug. Although the addiction process for each drug class has certain common neurobiological elements, each class of drugs is also unique and engages the addiction cycle at different points. Each drug class has different behavioral effects that define a phenotype. This behavioral mechanism may derive from medical use or behavioral pathology that informs medical use.
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