Cocaine Flashcards
What were some of the original uses of cocaine?
used as an anesthetic for eye surgeries
Freud and colleague were the first people to report its ability to anesthetize by using pins to touch their own corneas
Freud –> treatment of depression and addiction
used to be part of OTC remedies and drinks like coca-cola
Where are the major sources of cocaine?
many come from Columbia, Peru and Bolivia
How is cocaine smuggled?
mostly transported in bricks of powder form
drug “mules” swallow multiple baggies of cocaine
there has also been a trend of smuggling liquid cocaine in carry-on
What is the plant derivative of cocaine?
natural product of coca plant
grows in highlands of south america
locals usually chew the leaves mixed with basic substance like lime (from rock)
what is the chemical name for cocaine?
benzolymethylecgonine
How is cocaine produced?
leaves of coca plant are dumped in makeshift trench
there is 500kg of leaves for only 1kg of cocaine paste
Kerosene or gasoline is added to the leaves to extract active ingredients
after leaves dry, cocaine paste is obtained
about 75% of cocaine is produced from this but heavily contaminated with solvent
What is cocaine hydrochloride?
refinement of the cocaine paste can result in a salt
this salt is cocaine hydrochloride
it is more easily transported and is polar and soluble in water
cocaine hydrochloride is often cut (diluted) with other white powders to maximize profit and increase the weight
other white powders include: powdered milk, laxatives, other numbing anesthetics like lidocaine or benzocaine
What happens when cocaine is cut (diluted) with levamisole? what is levamisole? and what does it result in?
levamisole is an anti-helminthic drug given to cattle but shown to mildly increase dopamine release
causes inflammation in blood vessels with immune system launching to those areas (mainly distal) and depriving them from O2
leads to purpura (purple discolouration) leading to necrosis of tissue due to vasculitis (inflammation of vasculature)
70% of cocaine in the US is contaminated
How is cocaine usually administered?
insufflation (snorting) of cocaine hydrochloride
onset is in 3-5 minutes
effects last 30-40 minutes
absorption occurs through mucous membranes of your nose
what is a side effect of snorting cocaine?
chronic snorters can lose cartilage separating nostrils from mix of vasoconstriction to that area and acidic erosion from hydrochloride acid of cocaine hydrochloride
What are the effects of cocaine hydrochloride being injected IV?
onset is 15-30 seconds
effects last 10-20 minutes
severe vasoconstriction and necrosis is a danger if needle goes into an artery
vasoconstriction due to prevention of noradrenaline uptake and decreased nitric oxide production
can lead to gangrene, and amputation
Why is cocaine hydrochloride not smokeable?
cocaine hydrochloride will burn before it produces vapour to smoke so its destroyed in the process of smoking
pyrolysis (degradation by heat) and vapours from cocaine HCl occur at approx. same temp of 195 degrees Celsius
so it must convert to a different form to smoke it - the freebase form
what is free-base cocaine?
smoke-able version of cocaine
freebase cocaine vaporizes at 98 degrees Celsius (vaporizes before it burns)
how do you make high quality freebase cocaine?
- dissolve cocaine hydrochloride into water
- add a base (usually ammonia - NH3)
- extract with ether (highly explosive and flammable) to get cocaine out of the NH4Cl
- evaporate to dryness
what is crack-cocaine?
named after the crackling sound it makes when smoked
- dissolve low-purity cocaine in water
- add sodium bicarbonate (baking soda) to neutralize the hydrochloride
- heat it up (usually using candle under a spoon)
- freebase will precipitate and can be purified
- obviously end result is less pure than true freebase
has a lot of contaminants but can still cause a high
using baking soda as opposed to ammonia to neutralize the HCl is cheaper and easier to do without explosions due to ether
how is crack-cocaine/freebase cocaine administered?
smoking
onset is 6-10 seconds
- intense but short duration, only minutes
usually requires repeated doses
What is the half life of cocaine?
approx 1 hr
what enzymes metabolize cocaine and where?
metabolized by carboxyl esterase enzymes in blood and liver
what is the major metabolite of cocaine? what is the second metabolite?
benzoylecgonine is a major metabolite of cocaine and appears within 4 hours of using it and has a half life of approximately 6 hours
ecgonine methyl ester is the second metabolite found
what is the metabolite produced when cocaine is taken with alcohol?
cocaethylene –> damages heart tissue but might enhance euphoria… results in sudden death
what is the metabolite produced when cocaine is smoked?
methylecgonidine
how long can metabolites be detected in the urine for?
up to 4 days after use
what are 5 psychological effects of cocaine?
- feeling extreme euphoria and energy
- hyperactivity, hypersexuality
- confidence
- makes mundane life more pleasurable
- can develop psychosis and can be dangerous
what are two big physiological effects?
- local anesthetic actions –> blocks sodium channels, prevents nerve conduction (no pain signals)
- sympathetic system is stimulated –> due to excess NT in synapses, HR and BP increase and can cause anorexia and insomnia
What is the mechanism of action of cocaine?
blocks action of transporter proteins that normally remove NT
- results in prolonged and greater stimulation of post-synaptic receptors
- results in large dopamine accumulation at the nucleus accumbens
- aromatic and nitrogen important –> may mimic the same groups found in dopamine and other NT
- still not clear if it binds to same site as dopamine or to different part of the transporter and might help in binding to dopamine transporter
- still not clear if it binds to same site as dopamine on the transporter or to a different part of the transporter
causes blockage of presynaptic uptake and dopamine remains in the synapse and prolongs signal
what effects does cocaine have on the level of the nucleus accumbens?
cocaine inhibits transporters at the dopamine releasing nerve terminals of the VTA
cocaine therefore, increases the amount of dopamine at the nucleus accumbens because it is not cleared in the synapse when VTA releases dopamine
Is the DAT receptor the only receptor cocaine has an affect on?
most research focuses on the dopamine transporter (DAT)
but if you block DAT in animals to get same effects of cocaine, you are not able to
therefore this shows that dopamine is not entirelyy responsible for the effects and theres prob involvement from 5-HT and NORE receptors as well
what happens to level of DAT activity with chronic cocaine use? (describe experiment)
DAT activity increase with chronic use of cocaine
in an experiment where animals were exposed to cocaine for several days, the nerve endings were isolated from specific brain regions (caudate-putamen and nucleus accumbens)
then radioactive dopamine was added to the preparation and measurements were taken in how much dopamine gets transported into the nerve endings
compared the uptake to animals exposed to saline instead of cocaine for the same about of time
found increased DAT activity in the NA and caudate putamen but more in NA.
this is due to the brain compensating for the high amounts of dopamine
in the absence of cocaine, users tend to feel depressed because theres so much DAT activity responding to dopamine in normal amounts so dopamine levels are lowered when cocaine is not being taken
what are some of the damages that cocaine use can lead to? (5)
- high acute dose can lead to effects on medulla- respiratory and circulatory failure
- hyperactivity combined with vasoconstriction can lead to hyperthermia because the heat in your body can’t escape from your BV to the surface of your skin as sweat so you end up over-heating
- Rhabdomyolosis (break down of mm. tissue) bc less oxygen getting there due to vasoconstriction
- As a result of 3) can cause myoglobinuria (myoglobin in urine) which leads to kidney failure
- psychosis in chronic users of high doses
What are the cardiac affects of cocaine?
in the first hour after its use, the risk of myocardial infarction increases 24 fold
associated with approx 25% of all heart attacks in patients between 18-45 years old
cocaine causes lots of demand for oxygen but at the same causes vasoconstriction even around the heart so it icauses high o2 demand with low o2 supply which leads to ischemia, infarction and to death
What are some withdrawal symptoms of cocaine?
withdrawal symptoms are usually mild compared to sedatives and alcohol
depression is the most prominent
acutely, a “let down” occurs within 30 minutes of cocaine use
the severity of the “Let down” is related to dose and duration of use (dose dependant)
In what ways can gamma-vinyl-gaba (vigabatrin) help in treatment of cocaine addiction?
Vigabatrin inhibits GABA-transferase, the enzyme that degrades GABA
GABA has an inhibitory effect on dopamine release in the VTA.
reduces dopamine release in reward pathway
if you add a radioactive compound that binds with dopamine receptors, it competes with the dopamine released by cocaine
the more dopamine that is released, the less radioactive compound binds (so the higher the signal, the less the dopamine)
useful for heroin and alcohol addiction as well
what other types of treatment can be used for cocaine addiction?
drugs that increase GABAergic activity are efficacious in decreasing the reward of cocaine
topiramate, is an antiseizure drug that enhances GABA-A receptor activity and habits glutamate receptor activity and is reported to reduce craving
