Historical Perspective

Amphetamine was first synthesized by Alles in 1897, but its stimulant effects were not recognized until 1929. Alles wanted to find a synthetic substitute for the recently banned ephedrine, a compound isolated from the Ephedra vulgaris plant in 1925. Amphetamine increases energy, elevates mood, prevents fatigue, increases vigilance and prevents sleep, stimulates respiration, and causes electrical and behavioral arousal from natural or drug-induced sleep. It was rapidly shown to be a safer and cheaper alternative to ephedrine as a stimulant. In World War II, amphetamine was supplied to paratroopers and commandos. British troops alone were issued 72 million tablets. In Japan, methamphetamine, initially used for munitions factory workers, flooded the civilian market at the end of the war; 5% of the Japanese population between the ages of 16 and 25 years became dependent on the drug. More than 50 “amphetamine” preparations containing amphetamine or derivatives, alone or in combination with other drugs (most notably barbiturates), were on the market after World War II.

Narcolepsy was probably the first condition for which amphetamine was used clinically. It revolutionized therapy for the condition, although it was not curative. The piperazine derivative of amphetamine, methylphenidate, was introduced in 1959 by Yoss and Daly.¹ The use of amphetamine in treatment of parkinsonism dates to 1937, when it was first used to alleviate muscle rigidity and postencephalitis parkinsonism. By 1968, its use in the treatment of this condition was largely suspended because of more effective dopaminergic agents. Until the dangers of amphetamine dependence and abuse became recognized, amphetamine was widely used in the treatment of obesity. It was also prescribed in the treatment of sedative abuse and alcoholism to offset sleepiness and lethargy.

Bradley and Bowen² were the first to report on the use of amphetamine to modify antisocial behavior in children: “when children are withdrawn or lethargic, the amphetamine tended to make them more alert, more accessible to persons and the environment.” A paradoxical calming effect was also noted in some children and aggressive adults. Most notably, a selected group of children who were “hyperactive” tended to move more quietly, to be calmer, and to be less quarrelsome after being treated with amphetamine. In 1958, methylphenidate was introduced to treat hyperactivity in children (see reference 3). These observations preceded reports on the effects of amphetamine and methylphenidate in the hyperkinetic child (children diagnosed with what is now called attention-deficit/hyperactivity disorder [ADHD]).

Although no controlled trials have investigated the use of stimulants in depression, many case series suggest effectiveness in some treatment-resistant cases. The use of stimulants with monoamine oxidase inhibitors is generally not advised but has not been reported to induce significant hypertension or hyperthermia. The combination of amphetamines with low (anticataplectic) doses of tricyclics is often prescribed in narcolepsy-cataplexy without any problem, and combining these substances in depression has been shown to be effective although not recommended because of the risk of dependence and abuse. Part of the beneficial effects of amphetamine on depression may be due to a reduction of fatigue and apathy rather than to a genuine antidepressant effect.

From a historical perspective, the number of indications for amphetamine stimulants has narrowed considerably over the years to primarily include narcolepsy, ADHD, and treatment-resistant depression. The rationale for this change has been the realization of the risk of abuse and dependence with these compounds. The introduction of other effective therapies for these conditions (e.g., modafinil for narcolepsy, atomoxetine for ADHD) has also led to narrower indications, although many new formulations and isomer-specific preparations have been recently developed and are increasingly used, mostly for the treatment of ADHD.

Structure-Activity Relationships and Major Chemical Entities

It is helpful to the understanding of the pharmacology of stimulant drugs to distinguish potency and efficacy; these terms are too often used incorrectly in colloquial language. Efficacy refers to the therapeutic effects that can be achieved by a drug, whereas potency describes the amount of the drug needed to achieve therapeutic effects. In general, potency correlates with the affinity of the drug for its target, whereas efficacy reflects how much maximal effect can be achieved when the targets are fully occupied. These two characteristics are uncorrelated.

Phenylisopropylamine (amphetamine) has a simple chemical structure resembling endogenous catecholamines (Fig. 44-1). This scaffold forms the template for a wide variety of pharmacologically active substances. Although amphetamine possesses strong central stimulant effects, minor modifications can result in agents with a broad spectrum of effects, including nasal decongestion, anorexia, vasoconstriction, and antidepressant effects (for the monoamine oxidase inhibitor tranylcypromine), and hallucinogenic properties (MDMA [methylenedioxymethamphetamine] and MDA [methylenedioxyamphetamine]).

Figure 44-1 Chemical structures of amphetamine-like stimulants, cocaine, modafinil, armodafinil, and caffeine (a xanthine derivative) compared with dopamine and norepinephrine.

The phenylisopropylamine molecule can be divided into three structural components: (1) an aromatic nucleus, (2) a terminal amine, and (3) an isopropyl side chain. Substitution on the aromatic nucleus generally produces less potent if not entirely inactive stimulants.⁴ The substitution of two or more methoxy groups plus addition of ethyl, methyl, or bromine groups on the aromatic nucleus creates hallucinogens of various potencies. Ecstasy (MDMA) is built on a methamphetamine backbone, with a dimethoxy ring extending from the aromatic group. If a similar compound is synthesized with a primary amine (without the methyl group), it creates Love (MDA). Substitution at the amine group is the most common alteration. Methamphetamine, which is characterized by an additional methyl group attached to the amine (a secondary substituted amine), is more potent than amphetamine, probably because of increased CNS penetration. An intact isopropyl side chain appears to be needed to maintain stimulant efficacy. Changing the propyl to an ethyl side chain, for example, creates phenylethylamine, an endogenous neuroamine that has mood- and energy-enhancing properties but is less potent and has a much shorter half-life than amphetamine.

The pharmacologic effects of most amphetamine derivatives are isomer specific. These differential effects occur at both the pharmacokinetic level (absorption, brain penetration, metabolism, distribution volume, elimination) and the pharmacodynamic profile level (actual pharmacologic effects). D-Amphetamine, for example, is a far more potent stimulant than the L-derivative. In electroencephalographic (EEG) studies, D-amphetamine is four times more potent than L-amphetamine in inducing wakefulness.⁵ The relative effects of the D and L isomers of amphetamine on norepinephrine and dopamine transmission explain some of these pharmacodynamic differences (for details, see the pharmacology section for each compound). Not all effects are stereospecific, however. For example, both enantiomers are equipotent at suppressing rapid eye movement (REM) sleep in humans and rats and at producing amphetamine psychosis.

Amphetamine-like compounds, such as methylphenidate, pemoline, and fencamfamin, are structurally similar to amphetamines; all compounds include a benzene core with an ethylamine group side chain (see Fig. 44-1). Both methylphenidate and pemoline were commonly used for the treatment of EDS in narcolepsy, but pemoline has been withdrawn from the market in several countries because of liver toxicity (Table 44-1). The most commonly used commercially available form of methylphenidate is a racemic mixture of both a D and L enantiomer. In this preparation, the D-methylphenidate mainly contributes to its clinical effects, especially after oral administration. This is due to the fact that L-methylphenidate, but not D-methylphenidate, undergoes a significant first-pass metabolism (by deesterification to L-ritalinic acid). A single isomer form of D-methylphenidate is also marketed under the brand name of Focalin.

Table 44-1 Commonly Used Pharmacologic Compounds for Excessive Daytime Sleepiness

* Dosages recommended by the American Sleep Disorders Association are listed in parentheses (usual starting dose and maximal dose recommended).

† Methamphetamine is reported to have more central effects and may predispose more to amphetamine psychosis. The widespread misuse of methamphetamine has led to severe legal restriction on its manufacture, sale, and prescription in many countries. L-Amphetamine (dose range, 20 to 60 mg) is not available in the United States but probably has no advantage over D-amphetamine in the treatment of narcolepsy (slightly weaker stimulant).

‡ The half-life of s-enantiomer of modafinil is short at 3-4 hours, and thus the half-life of racemic modafinil mostly reflects the half-life of armodafini (r-enantiomer).

§ Caffeine can be bought without prescription in the form of tablets (NoDoz, 100 mg; Vivarin, 200 mg caffeine) and is used by many patients with narcolepsy before diagnosis.

Cocaine also mediates its psychostimulant effects by blocking catecholamine reuptake (mainly dopamine), but its structure is different from that of amphetamine-like compounds (see Fig. 44-1). The fact that cocaine and some dopamine transporter inhibitors are drugs of abuse is responsible for schedule labeling of such drugs by the Food and Drug Administration.

Amphetamines are highly lipid soluble molecules that are well absorbed by the gastrointestinal tract. Peak levels are achieved approximately 2 hours after oral administration, with rapid tissue distribution and brain penetration. Protein binding is highly variable, with an average volume of distribution of 5 L/kg.

Both hepatic catabolism and renal excretion are involved in the inactivation of amphetamine. Amphetamine can be metabolized in the liver by either aromatic or aliphatic hydroxylation, yielding parahydroxyamphetamine or norephedrine, respectively, both of which are biologically active. The metabolism of amphetamine and amphetamine-like compounds is pH dependent. Amphetamine is metabolized into benzoic acid (23%), which is subsequently converted to hippuric acid or to parahydroxyamphetamine (2%). This in turn is converted to parahydroxynorephedrine (0.4%). Thirty-three percent of the oral dose is excreted unchanged in the urine. Urinary excretion of amphetamine and many amphetamine-like stimulants is greatly influenced by urinary pH. At urinary pH 5.0, the elimination half-life of amphetamine is short, about 5 hours; but at pH 7.3, it increases to 21 hours. Sodium bicarbonate will delay excretion of amphetamine and prolong its clinical effects, whereas ammonium chloride will shorten amphetamine action (and can possibly induce toxicity).

Methylphenidate is almost totally and rapidly absorbed after oral administration. Methylphenidate has low protein binding (15%) and is short acting; effects last approximately 4 hours, with a half-life of 3 hours. The primary means of clearance is through the urine, in which 90% is excreted.

Molecular Targets of Amphetamine Action

The molecular targets mediating amphetamine-like stimulant effects are complex and vary according to the specific analogue or isomer used and the dose administered. Amphetamine increases catecholamine (dopamine and norepinephrine) release and inhibits reuptake from presynaptic terminals. This results in increase in catecholamine concentrations in the synaptic cleft and enhances postsynaptic stimulation. The presynaptic modulations by amphetamines are mediated by specific catecholamine transporters⁶ (Fig. 44-2). Axelrod and colleagues first demonstrated that epinephrine can be rapidly and selectively taken up by the heart, spleen, and glandular organs, each of which has significant sympathetic innervation. It was subsequently discovered that norepinephrine-containing neurons bind and take up norepinephrine against a concentration gradient, suggesting the existence of selective norepinephrine transporters. Further experiments also found that these transporters not only can carry catecholamine back into nerve terminals but also can release catecholamines by reverse efflux.

Figure 44-2 A, Schematic representations of dopaminergic terminal neurotransmission in relation to mode of action of dopamine (DA) reuptake inhibitors and amphetamine. The DA transporter (DAT) is one of the most important molecules located at the dopaminergic nerve terminals and regulates dopaminergic neurotransmission. (1) Amphetamine interacts with the DAT carrier to facilitate DA release from the cytoplasm through an exchange diffusion mechanism (see C). At higher intracellular concentrations, amphetamine also (2) disrupts vesicular storage of DA and (3) inhibits the monoamine oxidase (MAO). Both these actions increase cytoplasmic DA concentrations. (4) Amphetamine also inhibits DA uptake by virtue of its binding to and transport by the DAT. These mechanisms all lead to an increase in DA synaptic concentrations, and these are independent of the phasic activity of the neurons. Increased synaptic concentration of DA stimulates postsynaptic DA receptors (D₁ type [1, 5] and D₂ type [2, 3, 4] receptors). AADC, aromatic acid decarboxylase; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; COMT, catechol-O-methyltransferase; D1-D5, dopamine receptors 1 through 5; DA, dopamine; DAT, dopamine transporter; DOPA, 3,4-dihydroxyphenylalanine; DOPAC, dihydroxyphenylacetic acid; G_i, G_o, and G_s, protein subunits; HVA, homovanillic acid; MAO, monoamine oxidase; 3-MT, methroxytyramine; TH, tyrosine hydroxylase; VMAT, vesicular monoamine transporter. B, Effects of dopamine reuptake inhibitors and amphetamines at the dopaminergic nerve terminal. Sodium and chloride bind to the DAT to immobilize it at the extracellular surface. This alters the conformation of the DA binding site on the DAT to facilitate substrate (i.e., DA) binding. DAT reuptake inhibitors bind to DAT competitively and inhibit DA-DAT bindings, resulting in increasing DA concentrations in the synaptic cleft. C, Amphetamine, in competition with extracellular DA, binds to the transporter. Substrate binding allows the movement of the carrier to the intracellular surface of the neuronal membrane, driven by the sodium and amphetamine concentration gradients, resulting in a reversal of the flow of DA uptake. Amphetamine dissociates from the transporter, making the binding site available to cytoplasmic DA. DA binding to the transporter enables the movement of the transporter to the extracellular surface of the neuronal membrane, as driven by the favorable DA concentration gradient. DA dissociates from the transporter, making the transporter available for amphetamine and thus another cycle.

The molecules responsible, the dopamine transporter (DAT) and the norepinephrine transporter (NET), have now been cloned and characterized. The DAT and NET proteins are about 620–amino acid proteins with 12 putative membrane-spanning regions. Amphetamine derivatives are known to inhibit the uptake and to enhance the release of dopamine, norepinephrine, or both by interacting with the DAT and the NET. These transporters normally move dopamine and norepinephrine from the outside to the inside of the cell. This process is sodium dependent; sodium and chloride bind to the dopamine or norepinephrine transporter to immobilize it at the extracellular surface and to alter the conformation of the dopamine or norepinephrine binding site so that it facilitates substrate binding. Substrate binding allows movement of the carrier to the intracellular surface of the neuronal membrane, driven by sodium concentration gradients. Interestingly, in the presence of some drugs such as amphetamine, the direction of transport appears to be reversed (see Fig. 44-2). Dopamine and norepinephrine are thus moved from the inside of the cell to the outside through a mechanism called exchange diffusion, which occurs at low doses (1 to 5 mg/kg) of amphetamine. This mechanism, rather than a simple inhibition of monoamine reuptake, is involved in the enhancement of extracellular catecholamine release by amphetamine. It explains why amphetamine in particular is more potent than expected on the basis of its relatively low binding affinity for DAT and NET.^7,8 A recent in vitro experiment has shown that amphetamine transport causes an inward sodium current. As intracellular sodium ions become more available, a DAT-mediated reverse transport of dopamine occurs, producing dopamine release through the DAT transporter.

At higher dose, other effects are involved. Increased serotonin (5-HT) release is also observed. Moderate to high doses of amphetamine (>5 mg/kg) also interact with the vascular monoamine transporter 2 (VMAT2; see reference 6). The vesicularization of the monoamines (dopamine, norepinephrine, serotonin, and histamine) in the CNS is dependent on VMAT2; VMAT2 regulates the size of the vesicular and cytosolic dopamine pools. Amphetamine is highly lipophilic and easily enters nerve terminals by diffusing across plasma membranes. Once inside, amphetamine depletes vesicular monoamine stores by several mechanisms. First, it binds directly, albeit with low affinity, to VMAT2, thereby inhibiting vesicular uptake. Second, amphetamine, a weak base, diffuses across the vesicular membrane in its uncharged (lipophilic) form and accumulates in the granules in its charged form (because of the lower pH of the synaptic vesicle interior). As vesicular amphetamine concentration increases, the buffering capacity of the catecholamine-containing vesicle is lost. The vesicular pH gradient diminishes, a loss of the free energy necessary for monoamine sequestration occurs, and vesicular monoamine uptake decreases. In addition, the collapse of the gradient purportedly results in a competition for protons between the native monoamines and amphetamine, thereby increasing uncharged vesicular neurotransmitter concentrations. All these mechanisms lead to a diffusion of the native monoamines out of the vesicles into the cytoplasm along a concentration gradient. Amphetamine can therefore be viewed as a physiologic VMAT2 antagonist that releases the vascular dopamine or norepinephrine loaded by VMAT2 into the cytoplasm. The high doses of amphetamine also inhibit monoamine oxidase activity. These mechanisms, as well as the reverse transport and the blocking of reuptake of dopamine or norepinephrine by amphetamine, lead to an increase in norepinephrine and dopamine synaptic concentrations (see reference 6), and these are independent on the phasic activity of the neurons.

Various amphetamine derivatives have slightly different effects on all these systems. For example, methylphenidate also binds to the NET and DAT and enhances catecholamine release. However, it has less effect on the VMAT granular storage site than native amphetamine does. Similarly, D-amphetamine has proportionally more releasing effect on the dopamine versus the norepinephrine system compared with L-amphetamine. MDMA (Ecstasy) has more effect on 5-HT release than on catecholamine release. Of note, other antidepressant medications acting on monoaminergic systems, including dopamine, norepinephrine, and 5-HT (e.g., bupropion or mazindol, see later), tend to exert their actions by simply blocking the reuptake mechanism.

Some but not all amphetamines have neurotoxic effects on monoaminergic systems. This is well established for MDMA and serotonergic systems in both humans and animals. Similarly, amphetamine derivatives with strong effects on monoamine release (typically methamphetamine and less so derivatives with simple monoamine reuptake inhibition effects, for example, methylphenidate) have neurotoxic effects on dopamine systems at high dose in animal studies, especially in the context of repeated administration mimicking binges of stimulant abuse administration.

Presynaptic Modulation of the Dopaminergic System Primarily Mediates the EEG Arousal Effects

How amphetamines and other stimulants increase EEG arousal has been explored by use of a canine model of the sleep disorder narcolepsy and DAT knockout mice models. Canine narcolepsy is a naturally occurring animal model of the human disorder.⁸ Similar to human patients, narcoleptic dogs are excessively sleepy (i.e., shorter sleep latency), have fragmented sleep patterns, and display cataplexy.⁸ Although amphetamine-like compounds are well known to stimulate catecholaminergic transmission, the exact mechanism by which they promote EEG arousal is still uncertain. Stimulation of either adrenergic or dopaminergic transmission or both has been suggested to play a role.

In narcoleptic and control Dobermans, the effects of ligands specific for the dopamine (GBR-12909, bupropion, and amineptine), the norepinephrine (nisoxetine and desipramine), or both the dopamine and norepinephrine (mazindol and nomifensine) transporters, as well as amphetamine and a nonamphetamine stimulant, modafinil, were studied to dissect wake-promoting mechanisms.⁹ The result indicated that prototypical dopamine uptake inhibitors, such as GBR-12909 and bupropion, dose dependently increased EEG arousal in narcoleptic dogs; nisoxetine and desipramine, two potent norepinephrine uptake inhibitors, had no effect on EEG arousal at doses that almost completely suppressed REM sleep and cataplexy (Fig. 44-3; see reference 9). Furthermore, the EEG arousal potency of various dopamine uptake inhibitors correlated tightly with in vitro DAT binding affinities (see Fig. 44-3), whereas a reduction in REM sleep correlated with in vitro NET binding affinities,⁹ suggesting that dopamine uptake inhibition is critical for the EEG arousal effects of these compounds.

Figure 44-3 Effects of various dopamine and norepinephrine uptake inhibitors and amphetamine-like stimulants on the EEG arousal of narcoleptic dogs and correlation between in vivo EEG arousal effects and in vitro dopamine transporter binding affinities. A and B, The effects of various compounds on daytime sleepiness were studied by 4-hour daytime polygraphic recordings (10:00 to 14:00) in narcoleptic animals (n = 4-5). Two doses were studied for each compound. All dopamine uptake inhibitors and CNS stimulants dose dependently increased EEG arousal and reduced slow-wave sleep (SWS) compared with vehicle treatment. In contrast, nisoxetine and desipramine, two potent norepinephrine uptake inhibitors, had no significant effect on EEG arousal at doses that completely suppressed cataplexy. Compounds with both adrenergic and dopaminergic effects (nomifensine, mazindol, D-amphetamine) were active on both EEG arousal and cataplexy. The effects of the two doses studied for each stimulant were used to approximate a dose-response curve; the drug dose that increased the time spent in wakefulness by 40% above baseline (vehicle session) was estimated for each compound. The order of potency of the compounds obtained was mazindol > (amphetamine) > nomifensine > GBR-12909 > amineptine > (modafinil) > bupropion. C, In vitro DAT binding was performed with [³H]-WIN 35428 onto canine caudate membranes. Affinity for the various dopamine uptake inhibitors tested varied widely between 6.5 nM and 3.3 mM. In addition, it was also found that both amphetamine and modafinil have low but significant affinity (same range as amineptine) for the DAT. A significant correlation between in vivo and in vitro effects was observed for all five dopamine uptake inhibitors and modafinil. Amphetamine, which had potent EEG arousal effects, has a relatively low DAT binding affinity, suggesting that other mechanisms, most probably monoamine releasing effects or monoamine oxidase inhibition, are also involved. In contrast, there was no significant correlation between in vivo EEG arousal effects and in vitro norepinephrine transporter binding affinities for dopamine and norepinephrine uptake inhibitors. These results suggest that presynaptic enhancement of dopamine transmission is the key pharmacologic property mediating the EEG arousal effects of most wake-promoting CNS stimulants.

D-Amphetamine has a relatively low DAT binding affinity but potently (i.e., need for a low dose) promotes alertness (see Fig. 44-3). It is also generally considered more efficacious (i.e., can produce more alertness with high dose) than pure DAT reuptake inhibitors in promoting wakefulness. As described in the pharmacology section, D-amphetamine not only inhibits dopamine reuptake, it also enhances dopamine release (at lower dose by exchange diffusion and at higher dose by antagonistic action against VMAT2) and inhibits monoamine oxidation to prevent dopamine metabolism. The dopamine releasing effects of amphetamine are likely to explain the unusually high potency and efficacy of amphetamine in promoting EEG arousal.

The effects of various amphetamine analogues (D-amphetamine, L-amphetamine, and L-methamphetamine) on EEG arousal and their in vivo effects on brain extracellular dopamine levels in narcoleptic dogs were compared¹⁰ to dissect wake-promoting effects of amphetamine. In vitro studies have demonstrated that the potency and selectivity for enhancing release or inhibiting uptake of dopamine and norepinephrine vary between amphetamine analogues and isomers.¹¹ Amphetamine derivatives thus offer a unique opportunity to study the pharmacologic control of alertness in vivo. Hartmann and Cravens⁵ previously reported that D-amphetamine is four times more potent than L-amphetamine in inducing EEG arousal but that both enantiomers are equipotent at suppressing REM sleep in humans and rats. Enantiomer-specific effects have also been reported with methamphetamine; L-methamphetamine is much less potent as a stimulant than either D-methamphetamine or L– or D-amphetamine (see reference 11). Similarly, in canine narcolepsy, D-amphetamine is 3 times more potent than L-amphetamine and 12 times more potent than L-methamphetamine in increasing wakefulness and reducing slow-wave sleep (Fig. 44-4A).¹⁰

Figure 44-4 Effect of amphetamine (AMP) derivatives on sleep parameters during 6-hour EEG recording. A, Typical effects of amphetamine derivatives on sleep architecture in a narcoleptic dog (600 nmol/kg intravenously). Representative hypnograms with and without drug treatment are shown. Recordings lasted for 6 hours, beginning at approximately 10:00 AM. Vigilance states are shown in the following order from top to bottom: cataplexy, wake, REM sleep, drowsy, light sleep (LS), and deep sleep (DS). The amount of time spent in each vigilance state (expressed as percentage of recording time) is shown on the right side of each hypnogram. D-AMP was found to be more potent than L-AMP, and L-methamphetamine (L-mAMP) was found to be the least potent, whereas all isomers equipotently reduced REM sleep. B and C, Local perfusion of amphetamine derivatives: effects on caudate dopamine (DA) and cortex norepinephrine (NE) levels. Local perfusion of D-AMP (100 µM) raised dopamine levels nine times above baseline. L-AMP also increased dopamine levels up to seven times above baseline, but this level was obtained only at the end of the 60-minute perfusion period. L-mAMP did not change dopamine levels under these conditions. In contrast, all three amphetamine isomers had equipotent enhancements on norepinephrine release. These results suggest that the potency of these derivatives on EEG arousal correlated well with measurements of dopamine efflux in the caudate of narcoleptic dogs, whereas effects on norepinephrine release may be related to REM suppressant effects.

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