Exam 2: Psychostimulants Flashcards
What is a monoamine?
Catecholamines AND indoleamines
What is a catecholamine?
Dopamine, Norepinephrine, Epinephrine
Catecholamine synthesis enzymes
TH (+OH)
AADC (-COOH)
DBH (-H –> - OH)
PNTM (add -CH3)
How and why are catecholamines stored in vesicles?
VMAT2 transporter
ion trapping- proton pump acidifies vesicles ionizing catecholamines,
which are WEAK BASES. low pH in vesicle = ion trapping
how does reserpine affect vesicular storage of catecholamines
Reserpine= inhibits vesicularization of monoamines.
Frees monoamines degraded by enzyme (MAO). Depletes monoamines
Induces sedation, low bp
What are the subtypes of noradrenergic receptors?
1) alpha 1
2) alpha 2
3) Beta 1
What role do receptor subtypes (noradrenergic) play in mediating effects of catecholamines (e.i. autonomic activity)
1) alpha 1- increase phosphoinositide, muscle contraction, activating
2) alpha 2- inhibiting, low cAMP
3) beta 1- activating, increase cAMP
What is the difference between reuptake transporters and autoreceptors?
Reuptake= brings NE and DA back into the cell for degradation/reuptake into vesicles
Autoreceptor: binds to cause decrease in vesicular release
Norepinephrine/Epinephrine degradation
COMT and MAO, doesn’t matter the order, leads o Vanillylmadnelic Acid (VMA)
Norepinehprine: alpha 2 vs. beta 1
Beta 1: Gs, increase cAMP
alpha 2: Gi, low cAMP
NE and heart rate stuff
Beta 1 vs. Ach’s M2 to increase heart rate with adenyl cyclase
Autonomic control of bladder
Beta 2 (NE)- relax bladder
M3 - contracts bladder
Alpha 1- contracts sphincter
M1- relax sphincter
Autoreceptors
D2 - DOPAMINE
Alpha 2= NE
1) Bind DA/NE
2) Close Ca2+ channels
3) Reduce vesicular transmitter release
Free base vs. Hydrochloride cocaine
Free base: unionized, LS, Base, vaporizes.
Hydrochloride: Ionized, WS, Salt, purified, degraded before vape
Cocaine is an (acid/base)
Base
Cocaine HCL (stable salt)–> Free base or crack?
Free base: mix with ammonia, extra with ether, then evaporate
Crack: Mix with baking soda, heat, filter and wash
Cocaine HCL (stable salt)–> Free base or crack?
Free base: mix with ammonia, extra with ether, then evaporate
Crack: Mix with baking soda, heat, filter and wash
Kinetics of cocaine? (- admin, other card)
2) Absorption
3) Distribute
4) Metabolize
5) Excretion
2) Weak base, increase absorption by increase pH
3) Cross BBB
4) via liver, 1st order
metabolites: benzoylecgonine & cocaethylene
5) after ~4 hr. metabolites may persist up to 3-5 days.
What is the primary pharmacodynamic mechanism by which cocaine is proposed to
affect neuronal activity? (Binding/action)
Blocks REUPTAKE of DAT
Blocks UPTAKE of SERT/NET
Blocks local sodium channels
What evidence implicates dopamine in cocaine craving as experienced by heavy users?
Cocaine blocks DA reuptake in mesolimbic pathway.
Cocaine rats: want paired compartment, unless DAT KO.
Also, increased dendrite spines in NA
Mechanisms of toxic/lethal effects of cocaine admin?
increases heart rate/bp by decreasing NE reuptake
Also constricts coronary artery, reduces oxygen to heart.
What is the only approved therapeutic use of cocaine?
Local anesthetic, block Na+ channels for surgeries and reduce blood flow to site
(e.i. procaine and lidocaine)
What are the different chemical forms of amphetamine? Parent compound?
??
Desired effects associated with amphetamine/cocaine admin?
Arousal, alert, wake, energy, concentrate, no distraction, confidence, euphoria, physical performance
How does renal pH affect 1/2 life of amphetamine?
??
Amphetamines and vesicular storage: primary mechanism
Enters vesicle by VMAT2
Increases pH in vesicle
reduces ionization/ion trapping, so molecules leak out
Mechanisms behind toxic/lethal effects of amphetamine admin?
increases heart rate/bp by increasing NE release
What are approved/off label therapeutic applications of amphetamine?
FDA: narcolepsy/ADHD
Off-Label: Obesity/Depression
How are stimulant/non-stimulants proposed to manage ADHD symptoms?
Improve attention/focus, no distraction, etc.
Increase DA/NE from VTA/LC to PFC regions for inhibition of motor, basal ganglia, and cerebellum.
What are some important features/consequences of psychostimlant tolerance?
Slow tolerance in ADHD/narcolepsy
Tolerance to therapeutic effects fast for other disorders.
Reverse tolerance possible for some effects (brain seizures).
Psychostimulant dependence.
Withdrawal: fatigue, sleep, depression, hunger
Positive reinforcement: craving, anhedonia
Effect of drugs of abuse on synaptic dopamine levels: 11C-raclopride
1) baseline density
2) density after drug abuse
3) (1-2), decrease in 11C-R binding=
A) Decrease in D2/D3 receptors
B) increase in synaptic dopamine
Cocaine adminstration
Internasal: onset min, duration 60 min
Inhalation: onset sec, duration 15 min
Adminstration: Coco Leaves
Buccal
Admin: Cocaine HCL or Speed
intranasal/intravenous
Admine: Cocaine base or Ice
inhalation
What amphetamine is racemic and less potent?
dextrolevoamphetamine (Benzedrine)
What amphetamine is an active isomer?
dextroamphetamine (Dexedrine)
What amphetamine is more potent in CNS?
dextromethamphetamine (Desoxyn)
Amphetamine adminstration (uppers)
Uppers: Oral
Amphetamine onset and duration of action: Oral vs. inhalation
Oral: Onset in 30 Minutes, Variable Duration
– Inhalation: Onset in Seconds, Duration of 15 Minute
Amphetamine elimination
Half-life between 6-36 hours depending on renal pH
Metabolites persist up to 3-5 days after last
administration in urine and saliva, 90 days in hair
Detection is affected by amount and duration of
use, route of administration, metabolism, hydration,
body size, percent body fat, age
Cocaine is ___ than amphetamine
larger
Amphetamine stimulates what?
Release DA/NE 1) enter by reuptake 2) leaky vesicles (primary) 3) inhibits MAO 4) High Concentration of DA and NE in Cytoplasm Reverses the Transport of DA and NE into Synapse
sympathomimic effects
dilation airway/pupils
inhibit digestions
urinary retention
increase body temp
Toxic effects
Headache • Dizziness • Confusion • Agitation • Fatigue • Insomnia • Seizures • Cardiac Arrest • Stimulant Psychosis • Dental Disease (Amphetamine) • Neurotoxicity (Amphetamine)
stimulant psychosis
paranoia, hallucination, delusion, stereotypy
reverse tolerance for amphetamines can occur for
brain seizures
cocaine vs. amphetamine in mesolimbic pathway
cocaine- blocks DA reuptake
amphetamine- stimulates DA release
