Amphetamines Flashcards
What is Ma huang?
A traditional Chinese medicine herb that has been used therapeutically for 5000 years
Who is Lazar Edeleanu?
He synthesized alpha-methylphenethylamine (amphetamine) in 1887 to treat asthma
What does L-amphetamine do?
Raises BP, opens nasal passages, causes headaches
What does D-amphetamine do?
Has the same effects as L-form but also elevates mood and enhances energy
Why does meth have increased potency and brain effects in relation to L-amphetamine and D-amphetamine?
Increased lipid solubility due to the addition of a methyl group
Easier to enter the BBB
What can meth be made from?
Pseudoephedrine or ephedrine from over-the-counter decongestants
Commercial phenylacetone
What is the process to make meth from decongestants?
Nagai synthesis
What are the processes to make meth from commercial phenylacetone?
Reductive amination or Leuckart synthesis
Why are amphetamines able to bind to neurotransmitter transporters?
Because of their chemical similarity to catecholeamines
What comprises the catecholamine nucleus?
A phenolic group with 2 hydroxyl groups
How AMPHs be absorbed?
Ingested, injected, snorted, or smoked
What is ice?
HCl salt which is smokeable meth
What is the half-life of ice?
12 hours
What is the bioavailability of ice?
Effectively absorbed from the GI tract, 70-100% bioavailability
Does meth or cocaine last longer in the blood?
Meth lasts much longer than cocaine
Where are AMPHs distributed?
Brain, lungs, liver, kidney, spleen
What is the onset of AMPHs?
30-120 minutes
Where are AMPHs excreted?
Kidneys, sweat, saliva
What metabolizes meth?
Liver CYP2D6
How is meth metabolized?
Meth is broken down into 4-HA and norephedrine which are stimulants
4-HA activates trace amino associated receptor (TAAR) which stimulates NE release and inhibits monoamine oxidase
What is TAAR?
An intracellular GPCR
What does MAO do?
Degrades monoamine NTs like DA, NE, 5HT
What does CYP2D6*10 do?
It reduces the rate of metabolism, dopamine and other excitatory NTs last longer in the system
What are the acute effects of AMPHs?
Euphoria, energy, aggression, grandiosity, decreased appetite
Sympathomimetic effects (NE)
Delusional parasitosis and perceptual disturbances ( increased 5HT release)
Locomotor activity (increased DA)
What is punding?
At high doses, causes repetitive meaningless behaviours because too much DA leads to less movement selectivity in the basal ganglia
What do AMPHs do to NTs?
Elevates the ability of DA, NE, 5HT
Do AMPHs require DA-ergic neuron firing?
No, DAT transporter brings meth into nerve endings and also enter by diffusion (VMAT pumps)
What is the mechanism of AMPHs at the synapse?
AMPH binds to DAT and enters the terminal
VMAT transports AMPH into storage vesicles which displaces DA into the cytoplasm
MAO is bound by AMPH and can’t degrade DA
AMPH-TAAR complex and cytoplasmic DA build-up reverse DAT, DA leaks across synapse resulting in a DA spike
How do AMPH mechanisms differ from cocaine?
Smaller structure allows the transporter to complete transport
AMPH activates TAAR (activates phosphorylation-dependent signalling) that targets DAT which reverses transport
What are the adverse effects of the acute use of AMPHs?
Poisoning from contaminants
Combining with other drugs can enhance stimulant effects (MAO inhibitors)
How is AMPH tolerance achieved?
Depletion of DA, 5HT, NE via displacement of these NTs from terminals
Inhibition of tyrosine hydroxylase to reduce synthesis of DA and NE
Acute dosing reduces DAT function = reduced effects
What are the symptoms of AMPH withdrawal?
Physical and psychological
Cravings, depression, lethargy, muscle pain, abnormal sleep, anhedonia, emotional volatility
How long can AMPH withdrawal last?
Depends on dosing
Can last 12 months due to permanent damage
How do users become dependent on AMPH?
Chronic AMPH dosing causes reduced cell-surface expression of transporters for DA and NE
What occurs upstream of reduced transporter expression?
TAAR activation
What are TAAR1 knockout mice more sensitive to?
DA activation
What do TAAR1 agonists do?
Reduce effects of AMPHs
What are the long-term consequences of AMPH use?
Weight loss
Skin breakdown
Sores, picking
Poor oral hygiene, tooth decay, jaw grinding (meth mouth)
Contaminants may be corrosive
Reduced saliva production
What are the psychological effects of long-term AMPH use?
Psychological effects are exaggerated, sensitization
Unprovoked aggression, homicidal/suicidal thoughts, extreme anxiety
Where is DA depletion significant after long-term use of AMPH?
Areas of the brain responsible for movement, memory, and decision making
What kind of damage is done to DA, NE, 5HT terminals after long-term AMPH use?
When cells recover from MAO inhibition, elevated DA metabolism results in reactive species formation
Excitotoxicity stresses neurons and kills them, brain damage
What underlies long-term symptoms of AMPH use?
Neuron loss in the limbic system
Where is neuron loss most significant due to AMPH use?
In the cingulate gyrus
What do hippocampal neuronal loss correlate with in meth users?
Word-recall issues
What are meth users 75% more likely to develop?
Parkinson’s disease due to the death of DA-ergic neurons
