Drugs of Abuse 2 – Cocaine and Nicotine Flashcards
What are the four different forms of cocaine and how are theymade?
Cocaine paste –this is simply the plant (erythroxylum coca) mushed up in a solvent
Cocaine HCl – therapeutic form of cocaine: you take the cocaine paste and dissolve it in an acidic solution
Crack – cocaine is precipitated with an alkaline solution (e.g. baking soda)
Freebase – slightly purer form of crack: you take crack and dissolve it in a non-polar solvent (e.g. ammonia and ether)
Which route of administration of cocaine gives the fastest absorption?
Smoking (though IV gives a higher bioavailability)
Why is cocaine very slowly absorbed in the GI tract?
Cocaine has a pKa of 8.7 so it is mainly ionised in the stomach meaning that it isn’t very lipid soluble and it isn’t very easily absorbed
This does, however, mean that the cocaine has a prolonged action
What is the half-life of cocaine?
20-90 mins
Where is cocaine metabolised and what is it metabolised into?
broken down into inactive metabolites: ecgonine methyl ester+ benzoylecgonine
Liver- liver cholinesterases
Plasma – it can be metabolised by plasma CHOLINESTERASES so it doesn’t last long in the plasma
Which factors affect the addictive potential of a drug?
The speed at which you associate the euphoria with taking the drug and the speed with which the effects are lost
Explain how cocaine can act as a local anaesthetic.
Cocaine blocks sodium channels and hence inhibits nerve transmission (only at high doses)
By what mechanism does cocaine exert its most profound effects?
Inhibition of monoamine transporters – leads to an accumulation of monoamines (e.g. dopamine) at the synapse
Happens at all doses
How does cocaine cause euphoria?
Cocaine blocks the monoamine transporters at the end of the dopaminergic neurones projecting to the nucleus accumbens – this leads to an accumulation of dopamine in the synapse at the nucleus accumbens –> EUPHORIA
What are the differences between the effects of low dose cocaine and high dose/chronic cocaine use?
Low dose – positive reinforcement – more energetic, need less sleep, more sociable, more talkative
High dose – negative/stereotypical effects – exhaustion, irritability, hostility, insomnia
Describe how cocaine is associated with a significantly increased cardiovascular risk.
see slide 15
Increased sympathetic outflow leads to a mismatch between myocardial supply and demand. (hence leading to myocardial ischaemia/infarction)
At high doses, Na+ channel block affects conduction
Together, they lead to arrhythmias and sudden death
How can cocaine prompt seizures?
It causes vasoconstriction in various arteries of the brain and it also causes an increase in temperature, which can prompt seizures
It is linked to the development of epilepsy
What percentage of a cigarette is particulate and what percentage is volatile?
5% particulate
95% volatile
Why is the nicotine delivery via a cigarette so effective?
Heating the cigarette melts the tar so that it forms lipid droplets
The alkaloids dissolve in the lipid droplets, which are then widely distributed across the lungs and can be easily absorbed
Which matter contains most carcinogenic elements?
Volatile
Why is the cigarette not particularly efficient in delivering nicotine to the body? If it is smoked through the mouth, why is it not absorbed via buccal absorption?
Some is swallowed and some is exhaled back out.
pKa is 7.9. Cigarette smoke is acidic so nicotine is ionised in the smoke ie
little buccal absorption during inhalation
However, absorption in alveoli is independent of pH as it is so thin that it doesn’t matter if it is ionised or not
Describe the metabolism of nicotine. What is the product?
Nicotine is metabolised by CYP2A6 in the liver
This produces COTININE, which is then excreted in the urine
What is the half-life of nicotine?
1-4 hours
Describe how nicotine causes euphoria.
Nicotine binds to nicotinic acetylcholine receptors on the cell bodies of dopaminergic neurones in the ventral tegmental area and stimulates sodium influx
This leads to an increase in the firing rate of the dopaminergic neurones, hence, more dopamine secretion
How does nicotine increase cardiovascular disease risk?
slide 28
Similar to cocaine but nicotine’s effects are slower in progression instead of acute. The effects are similar because both cocaine and nicotine eventually lead to more dopamine secretion/dopamine stimulation in the nucleus accumbens
What is different to cocaine is that nicotine also increases FFA and cholesterol (VLDL and LDL) which will further contribute to atherosclerosis in the coronary arteries and hence mismatch in demand/supply
Nicotine does not have the sodium channel blocking effects of cocaine
What effect does nicotine have on metabolism?
It increases metabolism
So chronic smokers often find that they gain weight after quitting
Explain how nicotine reduces the risk of Parkinson’s disease.
Nicotine increases the activity of the CYP450 enzymes in the brain, so it is better able at removing neurotoxins that have the potential to contribute to the onset of Parkinson’s disease
Explain how nicotine reduces the risk of Alzheimer’s disease.
Chronic nicotine diminishes some of the proteins that contribute to
Alzheimer’s disease (decrease in beta-amyloid toxicity, decrease in amyloid precursor protein)
Explain how caffeine can cause mild euphoria.
Adenosine acts via adenosine receptors to decrease dopamine release and decrease D1 receptor function
Caffeine is an adenosine receptor antagonist so it will remove the inhibitory effect of adenosine
However, the inhibitory effect of adenosine is very minimal so caffeine will not cause a significant rise in dopamine release
How does cocaine cause hyperthermia?
increased body temperature as a result of increased locomotion, agitation and involuntary muscle contractions
This is accompanied by body’s reduced ability in heat dissipation.
If drug is taken in hot environment then the person will get hyperthermia
How is the body’s ability of heat dissipation reduced?
Cocaine inhibits cutaneous vasodilation (because it promotes vasoconstriction)
It also increases central threshold for sweating and cutaneous vasodilation
NB it INCREASES sweating
