Amphetamines

Question 1

What is Ma huang?

Answer 1

A traditional Chinese medicine herb that has been used therapeutically for 5000 years

Question 2

Who is Lazar Edeleanu?

Answer 2

He synthesized alpha-methylphenethylamine (amphetamine) in 1887 to treat asthma

Question 3

What does L-amphetamine do?

Answer 3

Raises BP, opens nasal passages, causes headaches

Question 4

What does D-amphetamine do?

Answer 4

Has the same effects as L-form but also elevates mood and enhances energy

Question 5

Why does meth have increased potency and brain effects in relation to L-amphetamine and D-amphetamine?

Answer 5

Increased lipid solubility due to the addition of a methyl group
Easier to enter the BBB

Question 6

What can meth be made from?

Answer 6

Pseudoephedrine or ephedrine from over-the-counter decongestants
Commercial phenylacetone

Question 7

What is the process to make meth from decongestants?

Answer 7

Nagai synthesis

Question 8

What are the processes to make meth from commercial phenylacetone?

Answer 8

Reductive amination or Leuckart synthesis

Question 9

Why are amphetamines able to bind to neurotransmitter transporters?

Answer 9

Because of their chemical similarity to catecholeamines

Question 10

What comprises the catecholamine nucleus?

Answer 10

A phenolic group with 2 hydroxyl groups

Question 11

How AMPHs be absorbed?

Answer 11

Ingested, injected, snorted, or smoked

Question 12

What is ice?

Answer 12

HCl salt which is smokeable meth

Question 13

What is the half-life of ice?

Answer 13

12 hours

Question 14

What is the bioavailability of ice?

Answer 14

Effectively absorbed from the GI tract, 70-100% bioavailability

Question 15

Does meth or cocaine last longer in the blood?

Answer 15

Meth lasts much longer than cocaine

Question 16

Where are AMPHs distributed?

Answer 16

Brain, lungs, liver, kidney, spleen

Question 17

What is the onset of AMPHs?

Answer 17

30-120 minutes

Question 18

Where are AMPHs excreted?

Answer 18

Kidneys, sweat, saliva

Question 19

What metabolizes meth?

Answer 19

Liver CYP2D6

Question 20

How is meth metabolized?

Answer 20

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

Question 21

What is TAAR?

Answer 21

An intracellular GPCR

Question 22

What does MAO do?

Answer 22

Degrades monoamine NTs like DA, NE, 5HT

Question 23

What does CYP2D6*10 do?

Answer 23

It reduces the rate of metabolism, dopamine and other excitatory NTs last longer in the system

Question 24

What are the acute effects of AMPHs?

Answer 24

Euphoria, energy, aggression, grandiosity, decreased appetite
Sympathomimetic effects (NE)
Delusional parasitosis and perceptual disturbances ( increased 5HT release)
Locomotor activity (increased DA)

Question 25

What is punding?

Answer 25

At high doses, causes repetitive meaningless behaviours because too much DA leads to less movement selectivity in the basal ganglia

Question 26

What do AMPHs do to NTs?

Answer 26

Elevates the ability of DA, NE, 5HT

Question 27

Do AMPHs require DA-ergic neuron firing?

Answer 27

No, DAT transporter brings meth into nerve endings and also enter by diffusion (VMAT pumps)

Question 28

What is the mechanism of AMPHs at the synapse?

Answer 28

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

Question 29

How do AMPH mechanisms differ from cocaine?

Answer 29

Smaller structure allows the transporter to complete transport AMPH activates TAAR (activates phosphorylation-dependent signalling) that targets DAT which reverses transport

Question 30

What are the adverse effects of the acute use of AMPHs?

Answer 30

Poisoning from contaminants Combining with other drugs can enhance stimulant effects (MAO inhibitors)

Question 31

How is AMPH tolerance achieved?

Answer 31

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

Question 32

What are the symptoms of AMPH withdrawal?

Answer 32

Physical and psychological Cravings, depression, lethargy, muscle pain, abnormal sleep, anhedonia, emotional volatility

Question 33

How long can AMPH withdrawal last?

Answer 33

Depends on dosing Can last 12 months due to permanent damage

Question 34

How do users become dependent on AMPH?

Answer 34

Chronic AMPH dosing causes reduced cell-surface expression of transporters for DA and NE

Question 35

What occurs upstream of reduced transporter expression?

Answer 35

TAAR activation

Question 36

What are TAAR1 knockout mice more sensitive to?

Answer 36

DA activation

Question 37

What do TAAR1 agonists do?

Answer 37

Reduce effects of AMPHs

Question 38

What are the long-term consequences of AMPH use?

Answer 38

Weight loss Skin breakdown Sores, picking Poor oral hygiene, tooth decay, jaw grinding (meth mouth) Contaminants may be corrosive Reduced saliva production

Question 39

What are the psychological effects of long-term AMPH use?

Answer 39

Psychological effects are exaggerated, sensitization Unprovoked aggression, homicidal/suicidal thoughts, extreme anxiety

Question 40

Where is DA depletion significant after long-term use of AMPH?

Answer 40

Areas of the brain responsible for movement, memory, and decision making

Question 41

What kind of damage is done to DA, NE, 5HT terminals after long-term AMPH use?

Answer 41

When cells recover from MAO inhibition, elevated DA metabolism results in reactive species formation Excitotoxicity stresses neurons and kills them, brain damage

Question 42

What underlies long-term symptoms of AMPH use?

Answer 42

Neuron loss in the limbic system

Question 43

Where is neuron loss most significant due to AMPH use?

Answer 43

In the cingulate gyrus

Question 44

What do hippocampal neuronal loss correlate with in meth users?

Answer 44

Word-recall issues

Question 45

What are meth users 75% more likely to develop?

Answer 45

Parkinson's disease due to the death of DA-ergic neurons