Drugs of Abuse 2: Cocaine/Nicotine Flashcards
cocaine:
pharmacokinetics dosing
paste - approx. cocaine
cocaine HCl- dissolve in acidic solution
crack- precipitate with alkaline solution
freebase- dissolve in a non-polar solvent
cocaine:
pharmacokinetics administration
-why does it have a low conc in the body after administration?
pKa = 8.7 oral cocaine ionised in GIT
slower absorption, prolonged action
in smoke- mouth-ionised, area is acidic, but cocaine is alkaline
how do you think that cocaine pharmacokinetics contribute to the addictive potential of the drug?
cocaine
there’s plasma and liver cholinesterases which can break cocaine down.
metabolites not active
inactivated v quickly and so effect is lost
T1/2 - 20-90min
- rapid onset
- quickly cleared from the system, addictive to restore the euphoric effects leading to drug seeking behaviour
how does cocaine work in local anaesthetic
blocks the sodium channels- this disrupts action potentials
-cocaine works by accessing the sodium ion channel from the inside (cytoplasm)
the pH outside is 7.4, but inside 7.0, so it’s more ionised on the inside so it’s better at interacting with target
how does cocaine reuptake inhibition work?
cocaine blocks the noradrenaline reuptake transporter, so more neurotransmitters in the synapse enhancing the NA like effects
Does cocaine influence dopamine affinity/efficacy for the dopamine receptor?
no
how does cocaine cause its euphoric effects?
blocks dopamine transporter in the nucleus accumbens
leads to increased dopamine released
effects of low and high doses of cocaine levels
low dose: positive effects energy
high dose: negative effects irritability/exhaustion
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.
cardiovascular effects of cocaine
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. 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. Cocaine promotes thrombosis by activating platelets, increasing platelet aggregation
CNS effects due to cocaine
leads to hyperthermia
How would you expect cocaine to influence sweat production and
cutaneous vasodilation?
normal reaction due to the heat production of cocaine due to: heat dissipation increased sweat production cutaneous vasodilation central threshold for thermoregulation
cocaine inhibits with cutaneous vasodilation and enhances sweat production
pharmacokinetics dosing
nicotine
nicotine spray
nicotine gum
cigarettes
nicotine patch
why is there no buccal absorption with nicotine?
Nicotine spray – 1mg 20-50%
Nicotine Gum – 2-4mg Nicotine 50-70%
Cigarettes – 9-17mg nicotine 20%
Nicotine Patch – 15-22mg/day 70%
pKa 7.9. Cigarette smoke is acidic ie
no buccal absorption.
Absorption in alveoli independent of pH
pharmacokinetics-metabolism of nicotine
Hepatic CYP2A6
-> cotinine
T1/2 - 1 to 4 h
pharmacodynamics of nicotine
upregulates the nicotinic receptor,
hence activating the dopinameric neurones
- more dopamine
