Amphetamines Flashcards
What are amphetamines?
- Amphetamines are a large class of stimulants
originally based on the naturally occurring
ephedrine
When was amphetamine synthesized?
- Amphetamine first synthesized in 1887, brought
to market in 1930s as Benzedrine as a
decongestant
Why is amphetamine important?
Parent compound to the class
of substituted
amphetamines, both
synthetic and naturally
occurring.
Describe pharmacokinetics of amphetamines
Amphetamine and methamphetamine are used
interchangeably in clinical context
- Methamphetamine is more potent and has higher
BBB permeability and is preferred for illicit use - Methamphetamine HCl is preferred for smoking
(crystal meth) - As with cocaine – oral route is slowest, least
susceptible for abuse - Most common therapeutic route
- Much longer half-life than cocaine
- 7-30 hours
Describe psychosis
- Drug-induced, particularly in chronic users
- Indistinguishable from schizophrenia
- Use precipitates psychosis in schizophrenia
- Can persist beyond periods of intoxication
Describe punding
stereotyped behaviours
* Useless repetitive tasks
* Abstain from eating, drinking, bathroom breaks
* Irritated or angry if interrupted
Describe formication
Feeling of insects crawling on skin
* Common to pick at skin as a result
Describe amphetamine’s mechanism of action
- Amphetamines act at catecholaminergic nerve terminals
- Dopamine
- Norepinephrine
- Lesser effects on 5-HT (exception being the enactogenic amphetamines)
- Like cocaine, amphetamines are reinforcing through effects on dopamine and are stimulant and
sympathomimetic through effects on norepinephrine - Amphetamines increase catecholamine release through four mechanisms
- Competitive inhibition of DAT/NET
- Exchange transport at VMAT
- Altered catecholamine transport via TAAR1 signalling
- MAO inhibition
Describe amphetamine’s competitive inhibition at DAT/NET
At dopaminergic
terminals amphetamine
transport competes with
dopamine transport
leading to elevated
synaptic dopamine.
Describe exchange transport at VMAT
Amphetamines are
transported through VMAT
by exchange with
intravesicular dopamine,
resulting in transport of
dopamine out of vesicles
into the synaptic terminal.
Describe the activation of TAAR1
Amphetamines bind an
intracellular receptor (GPCR
coupled to Gs/Gq) involved in
monoamine regulation – trace
amine-associated receptor 1
(TAAR1).
TAAR1 signalling activates
protein kinase C (PKC) which
phosphorylates DAT.
Phosphorylated DAT reverses
the direction of dopamine
transport (dopamine efflux
transport) and is internalized
(non-competitive reuptake
inhibition).
Describe clinical uses of amphetamines
Largely discontinued as decongestants
after abuse potential was discovered
- Pseudoephedrine in common use
- Still can be used to treat narcolepsy
- Amphetamines most common treatment
for attention-deficit/hyperactivity
disorders (ADHD) - Widely used (illicit) as nootropic drugs
- High use among University students to
improve studying
Describe the link between amphetamines and ADHD
- ADHD characterised by increased
locomotor activity and distractibility - Inattentive subtype – characterised by
extreme difficulty in sustained attention - Impulsive-hyperactive subtype –
characterised by high impulsivity and
excessive motor activity - Why are psychomotor stimulants
effective in treating ADHD? - ADHD is dominated by an attentional
deficit - Hyperactivity manifests from distractability
- ADHD may occur through excessive
DAT activity resulting in dopamine
insufficiency - DAT density increased in ADHD adults
- Genetic evidence links some cases with a
polymorphism in the DAT gene
Describe Shulgin and enactogenic amphetamines
Alexander Shulgin synthesized MDMA in 1965
while at Dow and first tested the psychoactive
effects in 1976 after hearing about recreational
use from a grad student
- MDE, MDA also included
MDMA (amphetamine and hallucinogen) caused clients to become more
communicative, introspective, and empathic
Describe the drug effects of enactogens
- Drug effects:
- Euphoria
- Increased wakefulness
- Increased endurance
- Sense of well-being, sociability, and
extraversion - Sense of closeness, tolerance, and
empathy to others - Sexual arousal
