Drugs of Abuse 2 (22.01.2020) Flashcards
What plant is cocaine derived from?
Erythroxylum coca
How much cocaine do leaves of the Erythroxylum
coca plant contain?
0.6 - 1.8 %
How are different cocaine formulations made?
Paste’ ~ 80% cocaine (organic solvent) - i.v., oral, intranasal
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Cocaine HCl’ - dissolve in acidic solution - i.v., oral, intranasal
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‘Crack’ - precipitate with alkaline solution (e.g. baking soda) - i.v., oral, intranasal
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‘Freebase’ - dissolve in non-polar solvent (e.g. ammonia + ether) - inhalation
Why is cocaine so addictive?
- very rapid onset - strong association of reward with cocaine administration (SECONDS!!)
- your system quickly gets rid of it so you want to take it again to restore the euphoria - leads to frequent administration and drug seeking behaviour
RoA of cocaine
- i.v.
- intranasal
- oral
- inhalation
Bioavailability of cocaine
- i.v. highest BA and very fast speed of onset and peak effect very quick
- inhalation: only absorbed once in the alveoli, BA is not too high. Smoke is an acidic environment and because cocaine has a high pKa (8.7) it tends to be more ionised in that environment and less likely absorbed. Only absorbed once in the alveoli because there diffusion is quite easy for almost anything.
- oral: bad absorption in the stomach because the environment is acidic. Also later onset of action then the other RoA
- nasal slightly slower onset of action than i.v. and inhalation
Metabolism of cocaine
- metabolised very rapidly
- the metabolites are not active ( ecgonine methyl ester & benzoylecgonine)
- highly metabolised by the liver
- it can be metabolised in the blood and liver (plasma and liver cholinesterases)
Half-life of cocaine
20-90 minutes
Pharmacodynamics of cocaine - local anaesthetic
- still used sometimes as a local anaesthetic but very rarely
- blocks sodium channels and stops sodium influx and stops APs
- works much better when it blocks the receptor from inside the cell so you want it to enter the cell and then block the ion channel;
- pKA of 8.7; pH inside: 7; pH outside: 7.4 (more unionized the closer you are to the pKa)
- if it is unionised it is more likely to cross the membrane and if it is charged it is more likely to interact with its targets.
- you want It more unionised outside the cell so that it can enter and more ionised inside the cell so that it can act on and block the ion channel
Pharmacodynamics of cocaine - reuptake inhibition
- Blocks monoamine reuptake which would remove NA and other NTs from the synapse
- the NTs remain in the synapse longer; cocaine enhances the effects of these NTs.
- the affinity for the receptor is unaffected.
Pharmacodynamics of cocaine - euphoria
- it acts on the dopamine transporter in the synapse between the neurone coming from the VTA and the dopaminergic neurone in the NAcc
- this leads to a buildup of dopamine in that synapse which then acts on D1Rs and has an euphoric and rewarding effect
Pharmacodynamics of cocaine - other effects
Mild-moderate effects = positive, reinforcing
- mood amplification (both euphoria and dysphoria)
- heightened energy
- sleep disturbance, insomnia
- motor excitement, restlessness
- talkativeness, pressure of speech
- increased libido
- hyperactive ideation
- mild to moderate anorexia
- inflated self-esteem
Severe effects = negative, stereotypic
- irritability, hostility, anxiety, fear, withdrawal
- total insomnia
- extreme energy or exhaustion
- compulsive motor stereotypes
- decreased sexual interest
- possible extreme violence
- total anorexia
- delusions of grandiosity
- It is dose related whether you have more positive or negative effects
- negative effects in chronic use or in high doses
- Partly due to tolerance i.e. cocaine causes massive dopamine release but by blocking reuptake, the neurone fails to replenish the dopamine. Further cocaine use results in much lower euphoria, which can lead to other effects being manifest e.g. irritability.
Pharmacodynamics of cocaine - MI
- cocaine increases catecholamines via monoamine re-uptake inhibition
- local anaesthetic - interferes with sodium transport
- can increase sympathetic output (not completely understood)
- chronically it can induce hypertension
- most of these effects are sympathetic
- > Coronary vasoconstriction
- > increased HR
- > increased contractility
- > increased BP
- > increased platelet activation
These cause:
- increased oxygen demand
- increased endothelial injury
- atherosclerosis
- decreased myocardial oxygen supply
There are bits of the heart that are not receiving enough oxygen -> myocardial ischaemia/infaarction
-> arrythmias/sudden death
Pharmacodynamics of cocaine - Hyperthermia
Cocaine overdose
- > increased locomotor activity
- > increased agitation (over activation of the brain is agitation and anxiety)
- > involuntary muscle contraction
These processes need ATP and produce heat.
In a hot environment this can be very dangerous -> hyperthermia
Heat dissipation:
- increased sweat production
- drink
- cutaneous vasodilation
- alter central threshold for thermoregulation
In summary, what are the effects of cocaine?
- local anaesthetic (blocks Na+ channels)
- Euphoria (monoamine reuptake inhibition)
- other
- MI
- hyperthermia
