Drugs of abuse 2 Flashcards
(35 cards)
Which plant does cocaine come from
Erythroxylum coca – leaves contain 0.6-1.8% cocaine.
Describe the history of the uses of cocaine
Peruvian indians – Coca leaves + lime
(6th Century)
1886 – ‘Brain Elixir’ (Cocaine + Caffeine)
Describe the different preparations of cocaine
§ Forms of cocaine – gets purer/stronger as you go down:
o Oral, IV, intranasal:
§ “Paste” – 80% cocaine (organic solvent).
§ “Cocaine HCl” – dissolved in acidic solution.
o Inhalational:
§ “Crack” – precipitated with alkaline solution (e.g. baking soda).
§ “Freebase” – dissolved in a non-polar solvent (e.g. ammonia + ether). - this gives you a purer version of cocaine
What is important to remember about cocaine paste and cocaine HCL
Can’t be inhaled- the compound breaks down upon heating
Cocaine HCl can be used therapeutically as an anaesthetic.
Explain the pKa-pH partition hypothesis
If a drug has a pKa greater than 7. It will be unionised in alkaline conditions (making it easier to access tissues), but ionised in acidic conditions (making it harder to access tissues).
Explain why crack cocaine can be smoked
Cocaine use increased dramatically when the free-base form (‘crack’) became available as a street drug. When an aqueous solution of cocaine hydrochloride is heated with sodium bicarbonate, free-base cocaine, water, CO2 and NaCl are produced. The free-base cocaine is insoluble in water, precipitates out and can then be rolled into ‘rocks’ of crack. Free-base cocaine vaporises at around 90°C, much lower than the melting point of cocaine hydrochloride (190°C), which burns rather than vaporises. Thus crack can be smoked, with the uncharged free base being rapidly absorbed across the large surface area of the alveolae, giving rise to a greater CNS effect than that obtained by snorting cocaine.
Which routes of administration of cocaine give the fastest absorption
Smoking (though IV gives a higher bioavailability)
Both as fast as each other
Both give a rapid and short-lasting high
Why does smoking and oral absorption of cocaine have a lower bio availability than snorting it or injecting it
Cocaine itself has a PKa of 8.7
Smoke and the stomach are acidic
Therefore cocaine is ionised in smoke and in the G.I.T- meaning that it is poorly absorbed.
However, cocaine still readily diffuses across the alveoli.
Slower absorption, prolonged action
Describe the metabolism of cocaine
Liver (75%-90%) – inactive metabolites: ecgonine methyl ester+ benzoylecgonine (metabolised by liver cholinesterases)
Plasma – it can be metabolised by plasma cholinesterases so it doesn’t last long in the plasma
What is the half-life of cocaine
T1/2 - 20-90min
How do you think that cocaine pharmacokinetics contribute to the addictive potential of the drug?
Very rapid onset (I.V and inhalational) - so strong association between stimulus and reward
Rapid clearance- euphoric effects lost quickly, so drug-seeking behaviour adopted to prolong euphoric effects.
Describe how high dose cocaine can be used as a local anaesthetic
pH of blood is 7.4 pH of cell is 7.0 Therefore, as the pH of the blood is closer to the pKa of cocaine- it is more likely to be unionised in the blood, but ionised inside the cell. This means that cocaine can enter the cell through the lipid bilayer and block the Na+ channel in this HYDROPHOBIC pathway.
Alternatively, it can enter the cell and then become ionised, and then block the Na+ channel this way –HYDROPHILIC pathway
Channel closed in hydrophobic- but still open in hydrophoilic- but both prevent the influx of Na+ and thus the generation of an action potential- and thus prevent the transmission of painful stimuli.
Describe the role of low dose cocaine in monamine re-uptake inhibition
o MAO-A re-uptake inhibitor (uptake 1).
o This can affect re-uptake of – NA/AD, DA, 5-HT.
o Note – this is not changing the affinity or efficacy dopamine, just increasing the DA in the synaptic cleft.
Cocaine binds to and inhibits the transporters NET, DAT and SERT (see Chs 15, 16 and 40), thereby producing a marked psychomotor stimulant effect, and enhancing the peripheral effects of sympathetic nerve activity.
Describe how cocaine can cause euphoria
o Reduces re-uptake of DA into pre-synaptic neurone so more DA in the NAcc (from the VTA).
Thus more dopamine can act on D1 receptors to produce euphoric effects.
What are the differences between the effects of cocaine in low dose/acute users and high dose/chronic users
Low dose – positive reinforcement – more energetic, need less sleep, more sociable, more talkative
High dose – negative/stereotypical effects – exhaustion, irritability, hostility, insomnia
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.
Outline how cocaine can lead to myocardial infarction
Cocaine is known to increase catecholamine activity (decreased monamine reuptake transporters) and also to act centrally to increase sympathetic output, and also increases the sensitivity of adrenergic nerve endings to norepinephrine.
As a result:
coronary vasoconstriction- which can also activate platelets as well as reducing myocardial oxygen supply
increased platelet activation- leading to atherosclerosis and thus a reduced myocardial oxygen supply- but also to endothelial injury and thrombosis
increased HR, contractility and BP- increasing myocardial oxygen demand (increased HR can also lead to endothelial injury)
Reduced Na+ transport- reduced left ventricular function – arrythmias, sudden death and endothelial injury
Inflammation- . In addition, cocaine stimulates the release of endothelin-1, a potent vasoconstrictor, from endothelial cells and inhibits nitric oxide production, the principal vasodilator produced by endothelial cells.
Ultimately, the increased myocardial oxygen demand cannot be matched by the myocardial oxygen supply- leading to myocardial infarction, ischaemia and thus arrythmias and sudden death.
What are the cardiovascular effects of reduced Na+ transport
Impaired LV function
Prolonged QRS and QT
Arrythmias.
Describe the opposing cardiovascular effects of cocaine at different doses
Cocaine stimulates the sympathetic nervous system by inhibiting catecholamine reuptake at sympathetic nerve terminals, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine. Cocaine also acts like a class I antiarrhythmic agent (local anesthetic) by blocking sodium and potassium channels, which depresses cardiovascular parameters. Of these 2 primary, opposing actions, enhanced sympathetic activity predominates at low cocaine doses, whereas the local anesthetic actions are more prominent at higher doses.
How can cocaine prompt seizures
It causes vasoconstriction in various arteries of the brain and it also causes an increase in temperature (hyper-pyrexia), which can prompt seizures
It is linked to the development of epilepsy
Describe how cocaine use is linked to hyperthermia
Cocaine overdose can lead to:
Agitation
Increased locomotor activity
Increased involuntary muscle contraction
All of these, by increasing the hydrolysis of ATP- will lead to increased heat production. In a hot environment this can lead to hyperthermia.
Normally, thus hyperthermia would be managed by increased heat dissipation- mediated by increased sweat production, cutaneous vasodilation and central threshold for thermoregulation.
However, althout cocaine enhances sweat production, it does inhibit cutaneous vasodilation (NA mediated) and elevates threshold for sweating/cutaneous vasodilation three fold
What is sweating and cutaneous vasodilation mediated by
ACh
Where does nicotine come from
Nicotana tabacum
Describe the compositions of particulate and volatile matter in cigarette smoke
Cigarettes produce:
o 95% - volatile substances – e.g. N2, CO/CO2, benzene, HCN.
o 5% - particulates – e.g. alkaloids (nicotine), tar.
§ Nicotine diffuses out of the tar droplets in the lungs when deposited.
Volatile matter contains most of the carcinogenic elements (i.e benzene).
Describe the different doses of nicotine in its various administration routes
Nicotine spray – 1mg (20-50%)
Nicotine Gum – 2-4mg Nicotine (50-70%) - not oral- instead liquid contains nicotine and diffuses across lipid membranes in the buccal cavity.
Cigarettes – 9-17mg nicotine (variable as most is exhaled and it depends on how you smoke it) (20%)
Nicotine Patch – 15-22mg/day (70%)
