Cocaine

Question 1

Three main consumable forms of cocaine

Answer 1

coca leaves
cocaine hydrochloride - white powder
free-base cocaine = crack

Question 2

absorption

Answer 2

insufflation
inhalation of free-base smoke
injection

Question 3

insufflation

Answer 3

absorbed through mucous membranes
~70% bioavailability
dissolves to pass membranes → creates HCl - corrosive to nasal structures
onset 3-5 min
duration 30-40 min

cocaine HCl pyrolyzes (breaks down with heat) before it vapourizes ~195 degrees

Question 4

inhalation of free-base smoke

Answer 4

onset 6-10 sec
duration 5-30 min - intense
crack vapourizes at 98 degrees

lungs → left heart → brain = lots of drug fast into brain = greater euphoria

Question 5

injection

Answer 5

onset 10-15 sec (longer than inhalation)
duration 10-20 min

Question 6

metabolism

Answer 6

cocaine is hydrolyzed into benzoylecgonine within 4 hours of use - 40% degrades with exposure to water (spontaneously)

primarily liver CYP3A4
liver/plasma esterases generate ecgonine methylester (~35%)

Question 7

methylecgonidine

Answer 7

by product of pyrolysis
metabolism of crack

Question 8

co-administration of cocaine with alcohol

Answer 8

generates cocaethylene metabolite
both cocaine and cocaethylene are potent vasoconstrictors
= synergism - effect amplified

Question 9

excretion

Answer 9

primarily kidneys
detectable in urine up to 4 days after use
2 weeks in chronic users

Question 10

distribution

Answer 10

brain
spleen
kidney

Question 11

acute effects

Answer 11

stimulant drug
= stimulating, invigorating
sympathomimetic → fight or flight
brain, heart, lungs, GI

Question 12

physiological effects

Answer 12

anasthetic
dysrhythmias
sympathomimetic

Question 13

anasthetic effect

Answer 13

blocks Na+ channels = blocks neurotransmission of afferent information → no pain

Question 14

dysrhythmia

Answer 14

blockage of Na+ channels in heart alter rhythm

Question 15

sympathomimetic effect

Answer 15

block reuptake of dopamine, serotonin, norepinephrine and epinephrine
increased heart rate, blood pressure
anorexia, insomnia, agitation, hyperthermia

Question 16

effect on basal ganglia

Answer 16

repetitive, compulsive movements
stereotyped activity

Question 17

effect on prefrontal cortex

Answer 17

influences planning, problem-solving, social behaviours

Question 18

effect on nucleus accumbens

Answer 18

extremely rewarding
dopamine

Question 19

effect on medulla

Answer 19

high dose can affect brain stem
respiratory and circulatory failure

Question 20

physiological mechanism

Answer 20

blocks transporter activity within synapses
leads to prolonged stimulation of post-synaptic nerves

aromatic ring and amine group mimic neurotransmitters

enhances VTA sensitivity to Glutamate and reward

Question 21

dopamine excess

Answer 21

in basal ganglia, prefrontal cortex, VTA,, and nucleus accumbens

Question 22

5-HT excess

Answer 22

underlies mood, sleep, appetite, and temperature dysregulation

Question 23

NE excess

Answer 23

underlies sympathomimetic effects

Question 24

acute adverse effects

Answer 24

irritability, hostility, anxiety, fear, restlessness
formication: delusion of crawling insects under skin
psychological events - depression, aggression, paranoia
increased acute infections in GI tract
nosebleeds
allergic reactions at injection sites, HIV

Question 25

potent vasoconstrictor

Answer 25

reduced blood flow causes tissue to die - can cause acute infections

Question 26

reinforcing mechanism of cocaine

Answer 26

blocks dopamine reuptake keeps dopamine in synapse longer, enhancing levels

Question 27

dopamine transporter

Answer 27

dopamine triggers conformational change of transporter to allow it to move through

Question 28

mechanism of cocaine binding to dopamine transporter

Answer 28

cocaine binds to the same site as dopamine due to chemical mimicry larger than DA - locks transporter in stable conformation = inactivation not solely responsible for cocaine effects

Question 29

not just dopamine involved in cocaine mechanism

Answer 29

exclusive DAT blockers do not mimic cocaine effects

Question 30

cardiovascular effects

Answer 30

due to block of NE and EP reuptake hypertension and heart rate

Question 31

effect on mood and appetite

Answer 31

due to 5-HT reuptake block

Question 32

cellular mechanisms of tolerance

Answer 32

exhaustion of dopamine biosynthetic pathways → depleted dopamine = reduced euphoria increase DAT efficiency to override blocking phosphorylation to facilitate transport in nucleus accumbens internalization of D1 and D2 receptors via rapid mechanisms - shut off constant stimulation by removing receptors form membrane so they aren't available to bind drug

Question 33

reverse tolerance

Answer 33

increased susceptibility to hyperthermia, convulsions, stereotyped movements sensitization down-regulated internalization after two weeks might cause D1 up-regulation more receptors left functional - facilitate activity basal ganglia and hypothalamus

Question 34

altered opioid-ergic signaling

Answer 34

tolerance striatal dynorphin expression is induced (endogenous opioid)

Question 35

withdrawal

Answer 35

symptoms include depression, anxiety, appetite changes → all psychological strong drug cue-associated cravings as long-term DAT efficiency increases faster dopamine reuptake decreased hedonic tone relatively mild, ~ 30 min after use exhausted DA circuits

Question 36

dependence

Answer 36

mild physical intense psychological → hijacked reward pathway and circuit association disincentivized addiction - anxiety, loss of motor control

Question 37

treating acute cocaine intoxication

Answer 37

drugs with opposite activity: benzos nitroglycerine ice bath butyrylcholinesterase

Question 38

benzos

Answer 38

control agitation and overstimulation decrease bp and heart rate to counteract cardiac effects by decreasing NT release

Question 39

nitroglycerine

Answer 39

evokes NO production → counteract vasoconstrictive effects

Question 40

butyrylcholinesterase

Answer 40

experimental iv treatment enzyme that degrades active chemical and causes rapid elimination of cocaine extended enzyme half life 72+ hours

Question 41

maintaining abstinence

Answer 41

reduce drug cravings topiramate - anti-seizure med that enhances GABAA receptor activity and inhibits Glu receptor activity

Question 42

long term consequences

Answer 42

cardiovascular disease arrhythmias - arrest due to inhibited Na+ channels constricts vessels psychosis in high dose users accelerated brain aging rhabdomyolysis increased stroke risk

Question 43

rhabdomyolysis

Answer 43

breakdown of muscle tissue due to hyperthermia (hypothalamus) → myoglobinuria and kidney failure

Question 44

increased stroke risk

Answer 44

increased blood coagulability decreased fibrinolysis

Question 45

long-term brain effects

Answer 45

decreased brain volume and mass reduced D2 expression in the striatum