Amphetamines Flashcards
Amphetamines
large class of stimulants
originally based on the naturally occurring
ephedrine
Amphetamine first market product
Benzedrine as a
decongestant
Benzedrine came into regular use in
WWII for it’s
stimulant and performance
enhancing effects
Use became regulated in
60’s and 70’s as
addictive potential emerged
Remain in use in military
Canada’s first losses in Afghanistan were in
a friendly-fire incident blamed partly on the
US pilots use of amphetamines
amphetamines Typically taken
orally
in cases of abuse how in amphetamine taken
IV or smoking
Amphetamine and methamphetamine are used
interchangeably in clinical context
Methamphetamine
more potent and has higher
BBB permeability and is preferred for illicit use
Methamphetamine HCl
l is preferred for smoking
(crystal meth)
As with cocaine – oral route is
slowest, least
susceptible for abuse
amphetamine is metabolized in the
Liver
Much longer half-life than cocaine
7-30 hours
Susceptible to binge use
typically IV or inhalant
Susceptible to binge use – typically IV or inhalant
Often combined with depressants to limit anxiety
(mixed with barbiturates or heroin – ‘speedball’)
Behavioural effects (6)
- Euphoria
- Heightened alertness
- Increased confidence
- Reduced fatigue
- Improved performance on repetitive
psychomotor tasks - Enhanced athletic performance
Psychosis (3)
- Indistinguishable from schizophrenia
- Use precipitates psychosis in schizophrenia
- Can persist beyond periods of intoxication
Punding – stereotyped behaviours (3)
- Useless repetitive tasks
- Abstain from eating, drinking, bathroom breaks
- Irritated or angry if interrupted
Formication
- Feeling of insects crawling on skin
- Common to pick at skin as a result
Amphetamines act at
catecholaminergic nerve terminals
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 1
Competitive inhibition of DAT/NET
Amphetamines increase catecholamine release through four mechanisms 2
Exchange transport at VMAT
Amphetamines increase catecholamine release through four mechanisms 3
Altered catecholamine transport via TAAR1 signalling
Amphetamines increase catecholamine release through four mechanisms 4
MAO inhibition
Competitive inhibition of
DAT/NET
Dopamine and
amphetamine are both
substrates for the
dopamine transporter
At dopaminergic
terminals amphetamine
transport
competes with dopamine transport leading to elevated synaptic dopamine
Exchange transport at
VMAT
Once inside the cell, amphetamines is a substrate for the vesicular monoamine transporters (VMAT/VMAT2)
Amphetamines are
transported through VMAT
by
exchange with intravesicular dopamine, resulting in transport of
dopamine out of vesicles into the synaptic terminal.
Activation of TAAR1
increase the concentration of the associated monoamines in the synaptic cleft, causing the increased postsynaptic receptor binding.
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).
Amphetamine competitively inhibits
reuptake through DAT
Amphetamine increases
cytosolic dopamine.
Amphetamine increases DAT
internalization and
d induces dopamine
efflux by activating TAAR1.
Additionally at higher doses amphetamines
inhibit
MAO, decreasing intracellular
dopamine breakdown.
Prolonged amphetamine use can lead to
psychosis
In animals methamphetamine doses
result in long-lasting decreases in
DA, tyrosine hydroxylase, and DAT in the
striatum
In animals methamphetamine doses
result in long-lasting decreases in DA,
tyrosine hydroxylase, and DAT in the
striatum - Histology shows degeneration of
DA fibers
In animals methamphetamine doses
result in long-lasting decreases in DA,
tyrosine hydroxylase, and DAT in the
striatum - * Damage to 5-HT fibers in
neocortex, hippocampus, and striatum
Methamphetamine HCl (crystal meth) is highly
acidic
Smoking causes degradation of
tooth enamel * ‘Meth mouth’
‘Meth mouth’ Exacerbated by
sympathomimetic and
stereotypic effects
‘Meth mouth’ Exacerbated by y sympathomimetic and
stereotypic effects
Decreased salivation
Dehydration
Teeth grinding
Clinical uses of amphetamines decongestants
Largely discontinued as decongestants
after abuse potential was discovered
- Pseudoephedrine
decongestant
amphetamines still used to treat
narcolepsy
Amphetamines most common treatment
for
attention-deficit/hyperactivity
disorders (ADHD)
Widely used (illicit) as
nootropic drugs
Widely used (illicit) as nootropic drugs
High use among University students to
improve studying
ADHD characterised by
increased
locomotor activity and distractibility
inattentive ADHD subtype
– characterised by
extreme difficulty in sustained attention
Impulsive-hyperactive ADHD subtype
characterised by high impulsivity and
excessive motor activity
Combined ADHD subtype incorporates both
inattentiveness and impulsive-hyperactivity
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 foe ADHD links some cases with
polymorphism in the DAT gene
Enactogenic Amphetamines
MDMA, MDA, MDE
MDMA became popular among psychotherapists
in the late 70’s and early 80’s
MDMA caused clients to become more
communicative, introspective, and empathic
Pharmacokinetics of enactogens
Readily absorbed from GI
* Plasma levels peak after 2 hours
* Half-life of 8 hours
* Liver metabolism
Pharmacokinetics of enactogens - drug effect (6)
Euphoria
Increased wakefulness
Increased endurance
sociability
empathy
Sexual arousal
Mechanism of action -MDMA functions as
amphetamines but has increased
activity at
seratonergic neurons
Enactogenic effects are modulated
by effects on
5-HT
Sympathomimetic and stimulant
effects modulated by
NE
Reinforcing effects modulated by
DA
amphetamines have a high affinity for
TAAR1 and VMAT
Affects 5-HT, NE, and DA levels at
synapses
Weak agonist at postsynaptic
5-HT1 and 5-
HT2
receptors
MDA has more potent effects at
5-HTR
MDMA found to increase
oxytocin levels in
healthy volunteers
Oxytocin increase correlated with
subjective social effects
Adverse effects (6)
Increased heart rate
* Tremors
* Sweating
* Hyperthermia
Trismus
Bruxism
Hyperthermia
potentially fatal
Exacerbated by physical activity (i.e.
dancing)
Trismus
(tightening of jaw muscles)
Bruxism
(grinding teeth)
Considered a stereotyped behaviour
Bruxism
Withdrawal
No medically serious withdrawal syndrome
Withdrawal Some effects persist briefly after cessation (crash similar to cocaine) (8)
Trismus
* Depression
* Anxiety or paranoia
* Irritability
* Impulsiveness
* Restlessness – insomnia
* Memory impairment
* Anhedonia
Anhedonia
reduced ability to experience pleasure.
Persistent effects
Evidence in animals of persistent
damage to DA and 5-HT systems
Drug classification is based partly on
demonstrations of 5-HT damage
Persistent effects in humans chemical effects
Decreased 5-HIAA in CSF
* Decreased 5-HT transporter binding capacity
* Decreased hormone response to seratonergic signaling
Persistent effects in humans cognitive effects
Memory, visual processing, sleep
Persistent effects in humans Interpretations
No demonstration of effects of casual use
* Confounded by coincident drug use
* Impurities / adulterants in illicit drugs
