Amphetamines Flashcards
Ma huang
traditional Chinese medicine herb
has been used therapeutically for 5000 years
Lazar Edeleanu
synthesized alpha-methylphenethylamine in 1887 to treat asthma
amphetamine
stereochemistry of amphetamines
1-phenyl 2-propanamine
(benzene + propyl + amine)
L-amphetamine and D-amphetamine differ by the orientation of the methyl group
L-amphetamine
raises blood pressure
opens nasal passages
causes headache
least potent
D-amphetamine
same effects as L-form: raises bp, opens nasal passages, causes headache
also elevates mood, enhances energy
more potent than L-form
Benzedrine
racemic mixture of L- and D- enantiomers
equal proportions
methamphetamine
added methyl group (to nitrogen)
= hydrophobic
increased lipid solubility = easier to cross BBB → faster distribution to brain = increased potency and brain effects (psychoactive)
most potent
meth synthesis
Nagai synthesis
Reductive amination
Leuckart synthesis
dangerous → synthesis creates by-products (reactive oxygen species)
Nagai synthesis
addition of chemicals (hydriodic acid; red phosphorus) to pseudoephedrine or ephedrine
over the counter decongestants
contains contaminants
Reductive amination
add methlamine (methyl + amine) to commercial phenylacetone
Leuckart synthesis
add N-methylformamide (CH3NHCHO) to commercial phenylacetone
chemical similarity to catecholamines
methamphetamine and amphetamines contain a phenyl group (benzene + side chain)
similar to endogenous chemicals dopamine and norepinephrine (both have 2 OH groups attached to benzene ring - catecholamine structure)
allows amphetamines to bind to neurotransmitter transporters
Meth = drug of choice
extra methyl group
slower metabolism → extended duration of action; longer half-life
CNS-intensive effects, euphoria
smokeable form = cheap
absorption
ingestion (rx - avoid euphoria, slower delivery)
injection
snorted
smoking → fastest onset
Ice
HCl salt
smokeable meth
12 hour half-life
→ Ice = crack
70-100% bioavailability
meth vs cocaine
meth high lasts much longer than cocaine
peaks ~ 20min, lasts for 90+
metabolism
liver CYP2D6
amphetamine is metabolized to 4-hydroxyamphetamine and norephedrine
meth is metabolized to amphetamine = active metabolite
norephedrine
metabolite of amphetamine
stimulant
4-HA
metabolite of amphetamine
stimulant
activates TAAR, stimulates NE release, and inhibits MAO
TAAR
trace amino associated receptor
intracellular GPCR
MAO
monoamine oxidase
degrades monoamine neurotransmitters - dopamine, norepinephrine, and serotonin
CYP2D6*10
allele of CYP2D6 enzyme
reduces rate of metabolism of Meth/AMPH = prolonged effects of euphoria
in 10% of caucasians
in 75% of East + SE Asians → higher rates
excretion
kidneys
sweat
saliva
distribution
brain
lungs
liver
kidneys
spleen
onset 30-120 min
acute effects of AMPHs
euphoria, high energy levels, aggression, grandiosity, decreased appetite
sympathomimetic effects
delusional parasitosis; perceptual disturbances
locomotor activity
increased NE release
sympathomimetic effects
increased 5-HT release
increased serotonin → reroute sensory information
delusional parasitosis
perceptual disturbances
increased dopamine
affected locomotor activity
- punding
too much dopamine in basal ganglia (control of selection of action) = less selectivity → no inhibition of execution of behaviours
punding
repetitive meaningless behaviours
common in Parkinson’s patients
mechanism of action
elevates dopamine, NE, 5HT availability in synapses
- blocks reuptake
- increases release of dopamine into the synapse
- at high concentrations, inhibits MAO
- reverses transporter
amph enters nerve terminals
by dopamine transporter and diffusion
DA transporter
AMPH binds DAT → transported into terminal
competes with dopamine = stays in synapse
smaller structure than cocaine = not blocked, transport is completed
VMAT
vesicular monoamine transporter
transports amph into storage vesicles = replaces dopamine
→ dopamine is displaced from vesicles into synapse
MAO inhibition
amph binds MAO so it cannot degrade dopamine
AMPH-TAAR complex
activation of TAAR → activates phosphorylation-dependent signaling → phosphorylates DAT
= reverse transport
dopamine moves back into synapse
differences between amphetamine and cocaine
AMPH does not require dopaminergic neuron firing, unlike cocaine
smaller structure = does not block transporter
+ activation of TAAR
DA spike in synapse
= post-synaptic cell activation
AMPHs → dopamine surge in basal ganglia
microdialysis in rats shows that there is a greater increase in dopamine in the nucleus accumbens, compared to the caudate nucleus
NE and 5-HT
similar effects cause increased synaptic availability
adverse effects
poisoning from contaminants
polypharmacy - combining with other drugs can enhance stimulant effects
- ex. MAO inhibitors facilitate effects of meth = greater release of monoamines
tolerance
dopamine, serotonin, and norepinephrine depletion
burn out circuits by displacement from terminals
inhibition of tyrosine hydroxylase enzyme reduces synthesis of dopamine and norepinephrine → shut off biosynthetic pathway
acute dosing reduced DAT function
meth - reverse tolerance
similar to cocaine, behavioural sensitization
withdrawal
both physical and psychological
cravings, depression, lethargy, muscle pain, abnormal sleep patterns, anxiety
→ depressant symptoms (opposite - neural compensation)
anhedonia, emotional volatility
degree and length depend on dosing - can last 12 months
dependence
chronic use → reduced cell-surface expression of transporters for dopamine and NE
TAAR activation occurs upstream of reduced transporter expression
TAAR1 knockout mice
more sensitive to DA activation
TAAR1 agonists
reduce effects of AMPHs
compete for binding
excessive NE symptoms
activation of alpha1 receptors on blood vessels = decreased blood flow to oral mucosa
activation of pre-synaptic alpha2 receptors on salivary gland neurons = reduced saliva production
physical long term consequences
weight loss
skin breakdown
sores, picking → delusions
meth mouth → poor oral hygiene, tooth decay, jaw grinding tic
corrosive contaminants
excessive NE symptoms
psychological long term consequences
exaggerated psychological effects → sensitization
unprovoked aggression, homicidal/suicidal thoughts, extreme anxiety
DA depletion → movement, memory, decision-making
damage to DA, NE, 5HT terminals
as cells recover from MAO inhibition (high [AMPH]), elevated DA metabolism results in reactive species formation = cellular stress
damage to cell membrane, proteins, mitochondria
over triggering of neurons → excitotoxicity = cell death = permanent brain damage
abstinent addicts
dopamine transporter levels may recover
function will not → intact circuits?
neuron loss in the limbic system
damage = reduced brain volume + reduced number of neurons
seen in schizophrenia, Parkinson’s, dementia → pathways shut down
most significant loss in cingulate gyrus
hippocampal losses → work-recall issues
dopaminergic neurons die → meth users = 75% more likely to develop Parkisonism
nAChR antagonists
block AMPH from triggering nicotinic acetylcholine receptors = prevent Ca2+ influx that leads to reactive oxygen species production and cellular stress
prevent brain damaging effects
