Amphetamine Chemistry and Pharmacology

Study Notes

Amphetamines are derived from the Chinese medicine herb Ma huang.
Edeleanu synthesized alpha-methylphenethylamine (AMPH) to treat asthma.
Amphetamine potency increases from L-amphetamine to D-amphetamine to methamphetamine.

Amphetamine's structure is similar to neurotransmitters, allowing it to bind to their transporters.
AMPH is phenylethylamine, similar to dopamine (DA) and norepinephrine (NE), which are catecholamines.

Methamphetamine can be synthesized using the Nagai or Leuckart synthesis methods.

Amphetamines can be taken orally (70% bioavailability), injected, snorted (80% bioavailability), or smoked (70-99% bioavailability). Smoking is the fastest route of administration.
Ice, the smokable form of methamphetamine hydrochloride, has a half-life of 12 hours, resulting in a longer-lasting high than cocaine.
The distribution half-life is 30 to 120 minutes.
Amphetamines are metabolized more slowly, with CYP2D6 primarily responsible for metabolizing methamphetamine (half-life 12+ hours, duration 10-20 hours) and amphetamine (half-life ~11 hours, duration 3-12 hours).
Amphetamines are excreted in the urine, sweat, and saliva, eliminating active metabolites such as norephedrine and 4-hydroxyamphetamine.

Increase in norepinephrine release causes sympathomimetic effects.
Increased serotonin (5HT) release leads to delusional parasitosis and perceptual disturbances.
Increased dopamine release results in increased locomotor activity, such as punding.
Adverse effects include poisoning from contaminants and enhanced stimulatory effects due to polypharmacy.

Amphetamines increase the availability of dopamine, norepinephrine, and serotonin without requiring the firing of dopamine neurons.
They enter the synapse via dopamine transporter (DAT) or diffusion.
Amphetamines block reuptake by DATs, NETs (norepinephrine transporter), and SERTs (serotonin transporter).
- They form a complex with the transporter (AMPH-TAAR) and cause intracellular dopamine to build up, reversing the DAT.
- Leakage into the synapse occurs.
- The spike in dopamine can activate postsynaptic cells.
Amphetamines increase the release of dopamine, norepinephrine, and serotonin into the synapse.
They also inhibit monoamine oxidase (MAO) at high concentrations.
Amphetamines cause a dopamine surge in the basal ganglia, but their small size allows the transporter to complete its cycle, so they do not completely block the transporter.

Tolerance develops due to neurotransmitter depletion through displacement of serotonin, dopamine, and norepinephrine.
Amphetamines inhibit tyrosine hydroxylase, reducing dopamine and norepinephrine synthesis.
Acute dosing can reduce dopamine transporter function.
Reverse tolerance targets motor function ganglia.

Amphetamine withdrawal presents both physical and psychological symptoms.
These include cravings, depression, lethargy, muscle pain, abnormal sleep patterns, anhedonia, and emotional volatility.