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Pmcol 305 > Amphetamines > Flashcards

Amphetamines Flashcards

1
Q

Ma huang

A

traditional Chinese medicine herb
has been used therapeutically for 5000 years

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2
Q

Lazar Edeleanu

A

synthesized alpha-methylphenethylamine in 1887 to treat asthma
amphetamine

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3
Q

stereochemistry of amphetamines

A

1-phenyl 2-propanamine
(benzene + propyl + amine)

L-amphetamine and D-amphetamine differ by the orientation of the methyl group

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4
Q

L-amphetamine

A

raises blood pressure
opens nasal passages
causes headache

least potent

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5
Q

D-amphetamine

A

same effects as L-form: raises bp, opens nasal passages, causes headache

also elevates mood, enhances energy
more potent than L-form

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6
Q

Benzedrine

A

racemic mixture of L- and D- enantiomers
equal proportions

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7
Q

methamphetamine

A

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

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8
Q

meth synthesis

A

Nagai synthesis
Reductive amination
Leuckart synthesis

dangerous → synthesis creates by-products (reactive oxygen species)

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9
Q

Nagai synthesis

A

addition of chemicals (hydriodic acid; red phosphorus) to pseudoephedrine or ephedrine
over the counter decongestants

contains contaminants

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10
Q

Reductive amination

A

add methlamine (methyl + amine) to commercial phenylacetone

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11
Q

Leuckart synthesis

A

add N-methylformamide (CH3NHCHO) to commercial phenylacetone

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12
Q

chemical similarity to catecholamines

A

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

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13
Q

Meth = drug of choice

A

extra methyl group

slower metabolism → extended duration of action; longer half-life
CNS-intensive effects, euphoria
smokeable form = cheap

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14
Q

absorption

A

ingestion (rx - avoid euphoria, slower delivery)
injection
snorted
smoking → fastest onset

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15
Q

Ice

A

HCl salt
smokeable meth
12 hour half-life
→ Ice = crack

70-100% bioavailability

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16
Q

meth vs cocaine

A

meth high lasts much longer than cocaine
peaks ~ 20min, lasts for 90+

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17
Q

metabolism

A

liver CYP2D6
amphetamine is metabolized to 4-hydroxyamphetamine and norephedrine
meth is metabolized to amphetamine = active metabolite

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18
Q

norephedrine

A

metabolite of amphetamine
stimulant

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19
Q

4-HA

A

metabolite of amphetamine
stimulant

activates TAAR, stimulates NE release, and inhibits MAO

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20
Q

TAAR

A

trace amino associated receptor
intracellular GPCR

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21
Q

MAO

A

monoamine oxidase
degrades monoamine neurotransmitters - dopamine, norepinephrine, and serotonin

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22
Q

CYP2D6*10

A

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

23
Q

excretion

A

kidneys
sweat
saliva

24
Q

distribution

A

brain
lungs
liver
kidneys
spleen

onset 30-120 min

25
Q

acute effects of AMPHs

A

euphoria, high energy levels, aggression, grandiosity, decreased appetite

sympathomimetic effects
delusional parasitosis; perceptual disturbances
locomotor activity

26
Q

increased NE release

A

sympathomimetic effects

27
Q

increased 5-HT release

A

increased serotonin → reroute sensory information
delusional parasitosis
perceptual disturbances

28
Q

increased dopamine

A

affected locomotor activity
- punding

too much dopamine in basal ganglia (control of selection of action) = less selectivity → no inhibition of execution of behaviours

29
Q

punding

A

repetitive meaningless behaviours
common in Parkinson’s patients

30
Q

mechanism of action

A

elevates dopamine, NE, 5HT availability in synapses

  1. blocks reuptake
  2. increases release of dopamine into the synapse
  3. at high concentrations, inhibits MAO
  4. reverses transporter
31
Q

amph enters nerve terminals

A

by dopamine transporter and diffusion

32
Q

DA transporter

A

AMPH binds DAT → transported into terminal
competes with dopamine = stays in synapse

smaller structure than cocaine = not blocked, transport is completed

33
Q

VMAT

A

vesicular monoamine transporter
transports amph into storage vesicles = replaces dopamine
→ dopamine is displaced from vesicles into synapse

34
Q

MAO inhibition

A

amph binds MAO so it cannot degrade dopamine

35
Q

AMPH-TAAR complex

A

activation of TAAR → activates phosphorylation-dependent signaling → phosphorylates DAT
= reverse transport
dopamine moves back into synapse

36
Q

differences between amphetamine and cocaine

A

AMPH does not require dopaminergic neuron firing, unlike cocaine
smaller structure = does not block transporter
+ activation of TAAR

37
Q

DA spike in synapse

A

= post-synaptic cell activation

38
Q

AMPHs → dopamine surge in basal ganglia

A

microdialysis in rats shows that there is a greater increase in dopamine in the nucleus accumbens, compared to the caudate nucleus

39
Q

NE and 5-HT

A

similar effects cause increased synaptic availability

40
Q

adverse effects

A

poisoning from contaminants
polypharmacy - combining with other drugs can enhance stimulant effects
- ex. MAO inhibitors facilitate effects of meth = greater release of monoamines

41
Q

tolerance

A

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

42
Q

meth - reverse tolerance

A

similar to cocaine, behavioural sensitization

43
Q

withdrawal

A

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

44
Q

dependence

A

chronic use → reduced cell-surface expression of transporters for dopamine and NE

TAAR activation occurs upstream of reduced transporter expression

45
Q

TAAR1 knockout mice

A

more sensitive to DA activation

46
Q

TAAR1 agonists

A

reduce effects of AMPHs
compete for binding

47
Q

excessive NE symptoms

A

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

47
Q

physical long term consequences

A

weight loss
skin breakdown
sores, picking → delusions
meth mouth → poor oral hygiene, tooth decay, jaw grinding tic

corrosive contaminants
excessive NE symptoms

48
Q

psychological long term consequences

A

exaggerated psychological effects → sensitization
unprovoked aggression, homicidal/suicidal thoughts, extreme anxiety

DA depletion → movement, memory, decision-making

49
Q

damage to DA, NE, 5HT terminals

A

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

50
Q

abstinent addicts

A

dopamine transporter levels may recover
function will not → intact circuits?

51
Q

neuron loss in the limbic system

A

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

52
Q

nAChR antagonists

A

block AMPH from triggering nicotinic acetylcholine receptors = prevent Ca2+ influx that leads to reactive oxygen species production and cellular stress

prevent brain damaging effects

Pmcol 305 (18 decks)

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