Cocaine Flashcards
Three main consumable forms of cocaine
coca leaves
cocaine hydrochloride - white powder
free-base cocaine = crack
absorption
insufflation
inhalation of free-base smoke
injection
insufflation
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
inhalation of free-base smoke
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
injection
onset 10-15 sec (longer than inhalation)
duration 10-20 min
metabolism
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%)
methylecgonidine
by product of pyrolysis
metabolism of crack
co-administration of cocaine with alcohol
generates cocaethylene metabolite
both cocaine and cocaethylene are potent vasoconstrictors
= synergism - effect amplified
excretion
primarily kidneys
detectable in urine up to 4 days after use
2 weeks in chronic users
distribution
brain
spleen
kidney
acute effects
stimulant drug
= stimulating, invigorating
sympathomimetic → fight or flight
brain, heart, lungs, GI
physiological effects
anasthetic
dysrhythmias
sympathomimetic
anasthetic effect
blocks Na+ channels = blocks neurotransmission of afferent information → no pain
dysrhythmia
blockage of Na+ channels in heart alter rhythm
sympathomimetic effect
block reuptake of dopamine, serotonin, norepinephrine and epinephrine
increased heart rate, blood pressure
anorexia, insomnia, agitation, hyperthermia
effect on basal ganglia
repetitive, compulsive movements
stereotyped activity
effect on prefrontal cortex
influences planning, problem-solving, social behaviours
effect on nucleus accumbens
extremely rewarding
dopamine
effect on medulla
high dose can affect brain stem
respiratory and circulatory failure
physiological mechanism
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
dopamine excess
in basal ganglia, prefrontal cortex, VTA,, and nucleus accumbens
5-HT excess
underlies mood, sleep, appetite, and temperature dysregulation
NE excess
underlies sympathomimetic effects
acute adverse effects
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
potent vasoconstrictor
reduced blood flow causes tissue to die - can cause acute infections
reinforcing mechanism of cocaine
blocks dopamine reuptake
keeps dopamine in synapse longer, enhancing levels
dopamine transporter
dopamine triggers conformational change of transporter to allow it to move through
mechanism of cocaine binding to dopamine transporter
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
not just dopamine involved in cocaine mechanism
exclusive DAT blockers do not mimic cocaine effects
cardiovascular effects
due to block of NE and EP reuptake
hypertension and heart rate
effect on mood and appetite
due to 5-HT reuptake block
cellular mechanisms of tolerance
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
reverse tolerance
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
altered opioid-ergic signaling
tolerance
striatal dynorphin expression is induced (endogenous opioid)
withdrawal
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
dependence
mild physical
intense psychological → hijacked reward pathway and circuit association
disincentivized addiction - anxiety, loss of motor control
treating acute cocaine intoxication
drugs with opposite activity:
benzos
nitroglycerine
ice bath
butyrylcholinesterase
benzos
control agitation and overstimulation
decrease bp and heart rate to counteract cardiac effects by decreasing NT release
nitroglycerine
evokes NO production → counteract vasoconstrictive effects
butyrylcholinesterase
experimental iv treatment
enzyme that degrades active chemical and causes rapid elimination of cocaine
extended enzyme half life 72+ hours
maintaining abstinence
reduce drug cravings
topiramate - anti-seizure med that enhances GABAA receptor activity and inhibits Glu receptor activity
long term consequences
cardiovascular disease
arrhythmias - arrest due to inhibited Na+ channels
constricts vessels
psychosis in high dose users
accelerated brain aging
rhabdomyolysis
increased stroke risk
rhabdomyolysis
breakdown of muscle tissue due to hyperthermia (hypothalamus)
→ myoglobinuria and kidney failure
increased stroke risk
increased blood coagulability
decreased fibrinolysis
long-term brain effects
decreased brain volume and mass
reduced D2 expression in the striatum
