Drugs of Abuse 2 – Cocaine and Nicotine Flashcards
What are the four different forms of cocaine and how are they made?
Paste: plant mushed up in a solvent
HCl: therapeutic form: cocaine paste dissolved in acidic solution
Crack: cocaine precipitate with an alkaline solution (e.g. baking soda)
Freebase: slightly purer form of crack: crack dissolved in a non-polar solvent (e.g. ammonia + 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 is mainly ionised in the stomach meaning it isn’t very lipid soluble + isn’t easily absorbed
Thus 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?
Liver: inactive metabolites
Plasma: by plasma cholinesterases so doesn’t last long in plasma
Which factors affect the addictive potential of a drug?
Speed at which you associate euphoria with taking the drug
Speed of clearance (metabolised)
Explain how cocaine can act as a local anaesthetic.
Blocks Na+ channels + hence inhibits nerve transmission
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
How does cocaine cause euphoria?
Blocks monoamine uptake transporters at the end of the dopaminergic neurones projecting to the nucleus accumbens: 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.
Causes an increase in sympathetic output (NA is also a monoamine)
Leads to vasoconstriction, increased HR, BP + contractility, causing an increase in cardiac work, increasing O2 demand
Also activates platelets + promotes atherosclerosis, leading to narrowing of vessels + decreased O2 supply to the heart
Could lead to myocardial infarction
How can cocaine prompt seizures?
Causes vasoconstriction in various arteries of the brain + an increase in temperature, which can prompt seizures
Linked to 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 it forms lipid droplets
Alkaloids dissolve in the lipid droplets, which are then widely distributed across the lungs + can be easily absorbed
Which matter contains most carcinogenic elements?
Volatile
Why is the cigarette not particularly efficient in delivering nicotine to the body?
Cigarette smoke is acidic whereas the pKa of nicotine prefers a more alkaline environment
This means nicotine in cigarette smoke becomes ionised + hence, is less easily absorbed
What is involved in the metabolism of nicotine? What is the product?
CYP2A6 in the liver
Produces COTININE, which is then excreted in urine
What is the half-life of nicotine? Why is nicotine so addictive?
1-4 hours
Its metabolised very fast to an inactive metabolite
Describe how nicotine causes euphoria.
Binds to nicotinic ACh receptors on cell bodies of dopaminergic neurones in the ventral tegmental area + stimulates Na+ influx
This leads to an increase in firing rate of dopaminergic neurones, hence, more dopamine secretion
How does nicotine increase cardiovascular disease risk?
Causes an increase in sympathetic drive: increased HR + SV, so more cardiac work
Vasoconstriction of coronary arterioles reduces O2 delivery to the myocardium
Also increases platelet activity + promotes atherosclerosis
All these factors increase O2 demand + decrease O2 supply
What effect does nicotine have on metabolism?
Increases metabolism
So chronic smokers often find that they gain weight after quitting
Explain how nicotine reduces the risk of Parkinson’s disease.
Increases activity of CYP450 enzymes in the brain, so it’s better able at removing neurotoxins that have the potential to contribute to the onset of PD
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 + amyloid precursor protein)
Explain how caffeine can cause mild euphoria.
Adenosine acts via adenosine receptors to decrease dopamine release + decrease D1 receptor function
Caffeine is an adenosine receptor antagonist so will remove the inhibitory effect of adenosine
However, the inhibitory effect of adenosine is very minimal so caffeine won’t cause a significant rise in dopamine release
Which forms of cocaine can be inhaled?
Crack
Freebase
Describe why a drug e.g. cocaine is more effective once inside a cell
Outside cell, pH is closer to cocaines pKa, so cocaine is more unionised, diffuses easily across plasma membrane
Inside cell, pH is further from pKa, so cocaine becomes more ionised
When charged, much better at interacting with its receptor
How does cocaine increase body temperature? What may this lead to?
Increased locomotor activity
Increased agitation (ovaeractivation of brain)
Increased muscle contraction
Hyperthermia
How is increase in body temperature exacerbated by cocaine?
Cocaine enhances sweat production but inhibits cutaneous vasodilation
Also elevates threshold for sweating + cutaneous vasodilation
What effect does nicotine have on lipid profile?
Negative effect.
Increases free fatty acids, leading to increased VLDL + LDL
