Drugs of Abuse - Cocaine and Nicotine (+caffeine) Flashcards
What is the major medicinal form of cocaine, what was it useful for and how is it prepared?
- Cocaine HCl
- Formed by dissolving the leaves in acidic solution
- Used as an anaesthetic
1) How do you make crack cocaine?
2) How to purify it and what is crack cocaine purified by this method called?
1)
- Precipitate cocaine HCl with an alkaline solution (e.g. using baking soda)
2)
- Purify by dissolving in a non-polar solvent
- E.g. Ammonium or ether
- Called ‘Freebase’
Discuss the different routes of administration that are possible and their speed of absorption and how well the cocaine is absorbed by this method - or how much cocaine is bioavailable through this route
INTRAVENOUS
- Highest bioavailability (100%)
- Rapid absorption as delivered right into circulation
INHALATION (SMOKING)
- Worst bioavailability - lots is lost because not all can reach the exchange surfaces of the lungs that low down or a lot is breathed out
- Rapid absorption as the alveolar exchange surface does not provide much of a barrier and also the lungs are situated very near the heart so its not long before the heart can pump it out rapidly and circulate it
NASAL (SNORTING)
- Similar-ish bioavailability to inhalation
- Slow absorption due to the impedance by the mucous membranes in the nose
ORAL
- Low bioavailability due to first pass metabolism
- Lowest rate of absorption - as it has to pass through the whole digestive system before entering the circulation
Why might the slow rate of absorption by oral administration be desirable sometimes when it comes to drugs?
- Prolonged action
1) What is cocaine metabolised by?
2) Why are its metabolites (what is it metabolised into)?
3) Why is it metabolised so rapidly?
1)
- Plasma and liver cholinesterases
2)
- Ecgonine methyl ester
- Benzoylecgonine
3)
- Because the enzymes (the cholinesterases) are found in both the liver and the plasma
Why is cocaine so addictive?
- SPEED OF ONSET
* Rapid onset - SPEED OF BREAKDOWN
- Rapid clearance
- Therefore reinforcing effect → cocaine binging
What are the 2 physiological actions of cocaine and at what doses does it have at each of these effects?
- Local anaesthetic (high dose)
- Blocks sodium ion channels
- Reduced AP propagation
- Suppressed nociceptor firing so reduced pain sensation
- NT reuptake inhibition
- Prevents reuptake of various neurotransmitters including dopamine, noradrenaline and serotonin by inhibiting the reuptake transporter
- Thereby prolonging their time spent within the synapse
- So higher synaptic concentration of these NTs
- This is what causes the euphoria (higher synaptic [dopamine])
Explain the physiology behind how cocaine causes its euphoric effect
- Prevents reuptake of dopamine into the pre-synaptic neurone by inhibiting the reuptake transporter
- Thereby it increases [synaptic dopamine]
- Action within the nucleus accumbens
- So direct activation of the reward pathway
What are the 2 types of effects that cocaine have (I’m not talking about the mechanistic actions, just the effects), like what are the classifications and when do they occur?
Note: you don’t have to list examples
- POSITIVE (REINFORCING) EFFECTS - ACUTE USE
- NEGATIVE (STEREOTYPIC) EFFECTS - CHRONIC USE
Why can you lose some of the euphoric effects of cocaine when you cocaine binge and also get some of the negative (stereotypic) effects?
- Due to inhibition of the reuptake of dopamine into the presynaptic neurones
- You really actually want dopamine to be recycled but this prevents this
- Dopamine persists within the synapse and is therefore prone to be metabolised
- Depletion of dopamine vesicles
- You therefore develop tolerance to the cocaine
- And may also start developing the negative (stereotypic) effects
How can cocaine impact the cardiovascular system and why can this lead to death?
- Increased sympathetic output due to inhibition of reuptake of NA into presynaptic neurones
- Therefore increased heart rate and force of contraction and higher blood pressure - this increases the myocardial O2 demand
- Cocaine stimulates endothelin-1 (vasoconstrictor) and inhibits nitric oxide (a vasodilator), thereby causing vasoconstriction
- Cocaine also promotes platelet aggregation
- Both the vasoconstriction and the promotion of platelet aggregation cause lower O2 supply to the myocardium
- The mismatch of myocardial O2 demand and supply causes ischaemia and infarction and thereby death (it also causes impaired LV function which contributes to the other CVS effect leading to death)
- The local anaesthetic type effect that cocaine has at high doses where it blocks sodium ion channels causes impaired LV function directly and…
- … Causes arrythmia such as QRS and QT prolongation
- Note that impaired LV function also contributes to these arrythmias
- Ultimately these arrythmias can lead to death
How does cocaine use cause seizures?
- Vasoconstrictory effect that cocaine has (by stimulating the vasoconstrictor endothelin-1 and inhibiting the vasodilator nitric oxide) as well as hyperpyrexia that it can cause both lead to seizures
How is nicotine delivered to the lungs in cigarettes?
- Nicotine is dissolved in tar droplets
- Which enter the lung tissue and exchange occurs via this
Including cigarette smoke, give other alternative nicotine delivery methods and order them in terms of bioavailability of nicotine that it delivers
- Nicotine patches
- Nicotine gum
- Nicotine spray
- Cigarette smoke
Why does cigarette smoke give the lowest ultimate bioavailability of nicotine, and its lower than other alternatives such as nicotine spray and gum
- Because cigarette smoke is quite acidic
- Whereas the pKa of nicotine is very high at 7.9
- Therefore it will be in its ionised form so there is limitied buccal absorption as it cannot pass through the lipid membrane very well
- Whereas alveolar absorption is independent of pH so its still absorbed ok here
- But nicotine gum and spray aren’t acidic so the nicotine won’t be in its ionised form, it will be unionised so there will be more buccal absorption as well as alveolar absorption
