Amphetamine

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The term amphetamines refers to the group of stimulants that includes amphetamine, meth-amphetamine, methylenedioxyamphetamine, and methylenedioxymethamphetamine. These low molecular weight basic drugs are sympathomimetic phenethylamine derivatives possessing central and peripheral stimulant activity. Amphetamines suppress appetite and produce CNS and cardiovascular stimulation. These effects are mediated by increasing synaptic concentrations of norepinephrine and dopamine either by stimulating neurotransmitter release or inhibiting uptake. Clinical uses of amphetamine and methamphetamine include chronic administration for the treatment of narcolepsy in adults and attention deficit hyperactivity disorder in children.1

These drugs are abused for their stimulant effect. The effects are usually longer lasting than those of cocaine and may prevent fatigue. The latter factor has led to their study in athletes and in military field situations. It is postulated that the disturbances in perception and psychotic behavior, which may occur at high doses, may be due to dopamine release from dopaminergic neurons and also serotonin release from tryptaminergic neurons located in the mesolimbic area of the brain.

Amphetamine and methamphetamine occur as structural isomers and stereoisomers. Structural isomers are compounds with the same empirical formula but a different atomic arrangement, e.g., methamphetamine and phentermine. Stereoisomers differ in the three-dimensional arrangement of the atoms attached to at least one asymmetric carbon and are nonsuperimposable mirror images. Therefore, amphetamine and methamphetamine occur as both d- and l-isomeric forms. The two isomers together form a racemic mixture. The d-amphetamine form has significant stimulant activity, and possesses approximately 3 to 4 times the central activity of the l-form. It is also important to note that the d- and l-enantiomers may not only have different pharmacological activity but also varying pharmacokinetic characteristics.

When indicated for therapeutic use, 5 to 60 mg or 5 to 20 mg of amphetamine or methamphetamine, respectively, are administered orally. An oral dose of amphetamine typically results in a peak plasma concentration of 110 ng/mL.2 When abused, ampetamines may be self-administered by the oral, intravenous, or smoked route. The latter route of administration is common for methamphetamine. With heavy use, addicts may ingest up to 2000 mg per day.

3.6.1.1 Absorption

Limited data is available on the G.I. absorption of amphetamine in humans. Beckett et al.3 reported serum concentrations of amphetamine in two healthy volunteers after a 15 mg oral dose of the d-isomer. Peak serum concentrations of 48 and 40 ng/mL were achieved at 1.25 h when the volunteers' urine was acidified. Slightly higher serum concentrations were observed (52 and 47 ng/mL) if the urine pH conditions were not controlled. Rowland4 observed a peak blood concentration of 35 ng/mL, 2 h after a 10 mg oral dose of d-amphetamine to a healthy 66 kg adult. The half-life for the d-isomer was 11 to 13 h compared with a 39% longer half life for the l-isomer. If the urine was acidified, excretion was enhanced and the half-lives of both

Phenylacetone

Phenylacetone

Benzoic Acid q,

c-n-ch2cooh o h

Hippuric Acid ho

Benzoic Acid q, c-n-ch2cooh o h

Hippuric Acid

— NH2 p-Hydroxyamphetamine ho

— NH2 p-Hydroxyamphetamine

3.6.2.2A. Metabolic pathway of amphetamine and methamphetamine.

isomers were reduced to approximately 7 h.5 Amphetamine demonstrates a linear one compartment open model over the dose range 20 to 200 mg.

3.6.1.2 Distribution

The plasma protein binding of amphetamine in humans is approximately 16 to 20% and is similar in drug dependent and naive subjects.6 Research by Rowland4 and Franksson and Anggard6 indicated that there was a difference in the volume of distribution between non-users (3.5 to 4.6 L/kg) and drug dependent individuals (6.1 L/kg). It has been suggested that the larger Vd observed in drug dependent subjects may be due to a higher tissue affinity for amphetamine in these individuals. Evidence to support this suggestion is found in studies with amphetamine dependent animals in which higher tissue concentrations of amphetamine were found.7

3.6.1.3 Metabolism and Excretion

Amphetamine is metabolized by deamination, oxidation, and hydroxylation. Figure 3.6.2.2A illustrates the metabolic scheme for amphetamine. Deamination produces the inactive metabolite, phenylacetone, which is further oxidized to benzoic acid and then excreted in urine as hippuric acid and glucuronide conjugates. In addition, amphetamine is also converted to norephedrine by oxidation and then this metabolite and the parent compound are p-hydroxylated. Several metabolites, including norephedrine, its hydroxy metabolite, and hydroxyamphetamine, are pharmacologically active. The excretion of amphetamine depends on urinary pH. In healthy men who were administered 5 mg of isotopically labeled d,l-amphetamine, approximately 90% of the dose was excreted in the urine within 3 to 4 days.8 Approximately 70% of the dose was excreted in the 24-h urine with 30% as unchanged drug. This was increased to 74% under acidic conditions and reduced to 1% in alkaline urine. Under normal conditions, <1% is excreted as phenylacetone, 16 to 28% as hippuric acid, 4% as benzoylglucuronide, 2% as norephedrine, <0.5% as p-hydroxynorephedrine, and 2 to 4% as p-hydroxyamphetamine.9 l-Amphetamine is not as extensively metabolized as the d-isomer. When volunteers were orally administered 5 to 15 mg of d- or l-amphetamine, the mean excretion of unchanged d-amphetamine was 33% of the dose and that of the l-isomer was 49% of the dose.2

The metabolism of amphetamine has been studied in those presenting with amphetamine pyschosis. In the presence of acidified urine, the renal elimination of amphetamine increased significantly. The intensity of the psychosis was found to correlate with the amount of basic polar metabolites excreted in the urine, such as norephedrine and p-hydroxyamphetamine, and not with the plasma amphetamine concentration. This suggests that these metabolites may play an important role in the development of paranoid pyschosis in chronic amphetamine users.6

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