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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
acute effects of AMPHs
euphoria, high energy levels, aggression, grandiosity, decreased appetite sympathomimetic effects delusional parasitosis; perceptual disturbances locomotor activity
26
increased NE release
sympathomimetic effects
27
increased 5-HT release
increased serotonin → reroute sensory information delusional parasitosis perceptual disturbances
28
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
29
punding
repetitive meaningless behaviours common in Parkinson's patients
30
mechanism of action
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
amph enters nerve terminals
by dopamine transporter and diffusion
32
DA transporter
AMPH binds DAT → transported into terminal competes with dopamine = stays in synapse smaller structure than cocaine = not blocked, transport is completed
33
VMAT
vesicular monoamine transporter transports amph into storage vesicles = replaces dopamine → dopamine is displaced from vesicles into synapse
34
MAO inhibition
amph binds MAO so it cannot degrade dopamine
35
AMPH-TAAR complex
activation of TAAR → activates phosphorylation-dependent signaling → phosphorylates DAT = reverse transport dopamine moves back into synapse
36
differences between amphetamine and cocaine
AMPH does not require dopaminergic neuron firing, unlike cocaine smaller structure = does not block transporter + activation of TAAR
37
DA spike in synapse
= post-synaptic cell activation
38
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
39
NE and 5-HT
similar effects cause increased synaptic availability
40
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
41
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
42
meth - reverse tolerance
similar to cocaine, behavioural sensitization
43
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
44
dependence
chronic use → reduced cell-surface expression of transporters for dopamine and NE TAAR activation occurs upstream of reduced transporter expression
45
TAAR1 knockout mice
more sensitive to DA activation
46
TAAR1 agonists
reduce effects of AMPHs compete for binding
47
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
47
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
48
psychological long term consequences
exaggerated psychological effects → sensitization unprovoked aggression, homicidal/suicidal thoughts, extreme anxiety DA depletion → movement, memory, decision-making
49
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
50
abstinent addicts
dopamine transporter levels may recover function will not → intact circuits?
51
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
52
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

Pmcol 305 (18 decks)

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