Cocaine

Question 1

What were some of the original uses of cocaine?

Answer 1

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

Question 2

Where are the major sources of cocaine?

Answer 2

many come from Columbia, Peru and Bolivia

Question 3

How is cocaine smuggled?

Answer 3

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

Question 4

What is the plant derivative of cocaine?

Answer 4

natural product of coca plant

grows in highlands of south america

locals usually chew the leaves mixed with basic substance like lime (from rock)

Question 5

what is the chemical name for cocaine?

Answer 5

benzolymethylecgonine

Question 6

How is cocaine produced?

Answer 6

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

Question 7

What is cocaine hydrochloride?

Answer 7

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

Question 8

What happens when cocaine is cut (diluted) with levamisole? what is levamisole? and what does it result in?

Answer 8

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

Question 9

How is cocaine usually administered?

Answer 9

insufflation (snorting) of cocaine hydrochloride

onset is in 3-5 minutes

effects last 30-40 minutes

absorption occurs through mucous membranes of your nose

Question 10

what is a side effect of snorting cocaine?

Answer 10

chronic snorters can lose cartilage separating nostrils from mix of vasoconstriction to that area and acidic erosion from hydrochloride acid of cocaine hydrochloride

Question 11

What are the effects of cocaine hydrochloride being injected IV?

Answer 11

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

Question 12

Why is cocaine hydrochloride not smokeable?

Answer 12

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

Question 13

what is free-base cocaine?

Answer 13

smoke-able version of cocaine

freebase cocaine vaporizes at 98 degrees Celsius (vaporizes before it burns)

Question 14

how do you make high quality freebase cocaine?

Answer 14

• 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

Question 15

what is crack-cocaine?

Answer 15

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

Question 16

how is crack-cocaine/freebase cocaine administered?

Answer 16

smoking

onset is 6-10 seconds
- intense but short duration, only minutes
usually requires repeated doses

Question 17

What is the half life of cocaine?

Answer 17

approx 1 hr

Question 18

what enzymes metabolize cocaine and where?

Answer 18

metabolized by carboxyl esterase enzymes in blood and liver

Question 19

what is the major metabolite of cocaine? what is the second metabolite?

Answer 19

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

Question 20

what is the metabolite produced when cocaine is taken with alcohol?

Answer 20

cocaethylene –> damages heart tissue but might enhance euphoria… results in sudden death

Question 21

what is the metabolite produced when cocaine is smoked?

Answer 21

methylecgonidine

Question 22

how long can metabolites be detected in the urine for?

Answer 22

up to 4 days after use

Question 23

what are 5 psychological effects of cocaine?

Answer 23

• feeling extreme euphoria and energy
• hyperactivity, hypersexuality
• confidence
• makes mundane life more pleasurable
• can develop psychosis and can be dangerous

Question 24

what are two big physiological effects?

Answer 24

1. local anesthetic actions –> blocks sodium channels, prevents nerve conduction (no pain signals)
2. sympathetic system is stimulated –> due to excess NT in synapses, HR and BP increase and can cause anorexia and insomnia

Question 25

What is the mechanism of action of cocaine?

Answer 25

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

Question 26

what effects does cocaine have on the level of the nucleus accumbens?

Answer 26

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

Question 27

Is the DAT receptor the only receptor cocaine has an affect on?

Answer 27

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

Question 28

what happens to level of DAT activity with chronic cocaine use? (describe experiment)

Answer 28

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

Question 29

what are some of the damages that cocaine use can lead to? (5)

Answer 29

1. high acute dose can lead to effects on medulla- respiratory and circulatory failure
2. 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
3. Rhabdomyolosis (break down of mm. tissue) bc less oxygen getting there due to vasoconstriction
4. As a result of 3) can cause myoglobinuria (myoglobin in urine) which leads to kidney failure
5. psychosis in chronic users of high doses

Question 30

What are the cardiac affects of cocaine?

Answer 30

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

Question 31

What are some withdrawal symptoms of cocaine?

Answer 31

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)

Question 32

In what ways can gamma-vinyl-gaba (vigabatrin) help in treatment of cocaine addiction?

Answer 32

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

Question 33

what other types of treatment can be used for cocaine addiction?

Answer 33

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