13. Drugs of abuse 2 Flashcards
Where is cocaine derived from?
- Plant-based compound (alkaloid)
- Erythroxylum coca plant
- Cocaine in the leaves on the plant
How is cocaine (and crack cocaine) made?
• Crush leaves to make organic solvent to form a paste (extracts around 80% cocaine)
• Dissolve the leaves in acidic solution to form cocaine HCl
- degrades when heated, so solution is crack cocaine
• Precipitate with an alkaline solution (e.g. baking soda)
• Purify by dissolving in a non-polar solvent e.g. ammonia or ether
• ‘Freebase’ formed, which can be inhaled
Describe the solubility of cocaine?
- Cocaine HCl - water soluble
* Crack cocaine - lipid soluble
Why does the regular snorting of cocaine cause septal defects?
- Powerful vasoconstriction
- Reduced blood flow
- Necrosis
Compare the speed of onset and bioavailability of cocaine for the different routes of administration
- Inhalation and IV speed of onset is virtually the same
- Inhalation - lot of drug lost due to absorption issues: lowest bioavailability
- IV bioavailability: 100%
• Snorting (intranasal) has a slower speed of onset
• Oral administration has the slowest speed of onset
- pKa = 8.7
- ionised in acidic GIT
- slower absorption (less in stomach)
How does absorption time affect time of action?
- Slower absorption = prolonged action
- This is because the liver deals with a smaller dose (over a longer time)
- Metabolised more slowly
How is cocaine metabolised?
• Metabolised by plasma and liver cholinesterases
• 75-90% of cocaine is broken down into inactive, inert metabolites
- ecgonine methyl esther
- benzoylecgonine
• Rapid due to the enzymes in the blood as well as the liver
Why is cocaine so addictive?
- High speed of onset - faster onset => more powerful behavioural stimulus
- High speed of breakdown - fast clearance leads to continuously taking it (binging) to reinforce the effect
(crack cocaine is the most addictive drug in the world)
How can cocaine be used as a local anaesthetic (high dose effect)?
- Cocaine diffuses from inside the cell membrane into the cytoplasm
- Can move into an open channel (hydrophilic pathway) or diffuse into a closed channel (hydrophobic pathway)
- Uncharged in membrane, charged in channels
- Blocks sodium channels in the nerves
- Less depolarisation - reduced propagation of APs
How does cocaine inhibit reuptake at synapses?
- Dopamine transporters reuptake dopamine back into the pre-synaptic cell (type of monamine transporter)
- Found in the nucleus accumbens
- Cocaine blocks these transporters
- This can affect dopamine, NA and serotonin
- Euphoria
How does cocaine affect dopamine affinity and efficacy for the dopamine receptor?
It doesn’t
What are positive/reinforcing effects, and give some examples of these effects of cocaine
- Acute affects of increased dopamine in synaptic cleft
* Euphoria, dysphoria, insomnia, motor excitement, increased libido, anger
What are negative/stereotypic effects, and give some examples of these effects of cocaine
- More common with chronic use
- Associated with cocaine binging leading to tolerance, due to depletion of dopamine vesicles
- Anxiety, extreme exhaustion, incoherent speech, decreased libido, anorexia
There is a strong link between cocaine and which cardiovascular condition?
Myocardial infarction
Describe the effects of cocaine on the sympathetic nervous system and the subsequent effects
• Inhibits catecholamine reuptake at sympathetic nerve terminals • Stimulated central symapthetic outflow • Increased NA: - Increased work of the heart - Increased BP - Increased oxygen demands
- platelet activation
- platelet adherence
- decreased oxygen supply
• Cocaine stimulates release of endothelin-1 (potent vasoconstrictor)
Describe the effects of using cocaine as a local anaesthetic, on the CVS
- Blocks sodium channels
- Depressed CVS parameters
- Interference with rhythm and left ventricular function
Why can cocaine cause seizures?
- Vasoconstriction in the brain
- Reduced blood flow to certain parts
- Also stimulation of hyperpyrexia (high fever)
- Combination are associated with seizure induction and epilepsy
How can cocaine lead to hyperthermia (rare)?
- Increased agitation, locomotor activity and involuntary muscle contraction all increase body temperature
- Sweat production is enhanced as it is SNS, but the threshold is elevated
- Cutaneous vasodilation is inhibited
- Causes rapid increase in body temperature before these cooling mechanisms can kick in
Which form of cocaine is used intranasally?
Cocaine HCl
What is the onset and half life time of cocaine?
- Onset - seconds
* Half life - <90 minutes
What percentage of cigarettes is volatile matter and particulate matter?
- 95% volatile (N, CO, benzene, HCN)
* 5% particulate (alkaloids, tar)
How is nicotine delivered from the cigarette to the lungs?
- When a cigarette is heated, tar droplets form, in which the nicotine dissolves
- Droplets enter the lungs and nicotine diffuses across the alveoli
How much nicotine is there per cigarette?
9-17mg
What are replacement methods of nicotine administration to wean smokers of cigarettes?
- Nicotine spray (1mg)
- Nicotine gum (2-4mg)
- Nicotine patch (15-22mg/day)
(cigarettes have a lower bioavailability than all these methods)
