Drugs of Abuse 2 – Cocaine and Nicotine

Question 1

What are the four different forms of cocaine and how are they made?

Answer 1

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)

Question 2

Which route of administration of cocaine gives the fastest absorption?

Answer 2

Smoking (though IV gives a higher bioavailability)

Question 3

Why is cocaine very slowly absorbed in the GI tract?

Answer 3

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

Question 4

What is the half-life of cocaine?

Answer 4

20-90 mins

Question 5

Where is cocaine metabolised and what is it metabolised into?

Answer 5

Liver: inactive metabolites
Plasma: by plasma cholinesterases so doesn’t last long in plasma

Question 6

Which factors affect the addictive potential of a drug?

Answer 6

Speed at which you associate euphoria with taking the drug

Speed of clearance (metabolised)

Question 7

Explain how cocaine can act as a local anaesthetic.

Answer 7

Blocks Na+ channels + hence inhibits nerve transmission

Question 8

By what mechanism does cocaine exert its most profound effects?

Answer 8

Inhibition of monoamine transporters: leads to an accumulation of monoamines (e.g. dopamine) at the synapse

Question 9

How does cocaine cause euphoria?

Answer 9

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

Question 10

What are the differences between the effects of low dose cocaine and high dose/chronic cocaine use?

Answer 10

Low dose: positive reinforcement; more energetic, need less sleep, more sociable, more talkative
High dose: negative/stereotypical effects; exhaustion, irritability, hostility, insomnia

Question 11

Describe how cocaine is associated with a significantly increased cardiovascular risk.

Answer 11

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

Question 12

How can cocaine prompt seizures?

Answer 12

Causes vasoconstriction in various arteries of the brain + an increase in temperature, which can prompt seizures
Linked to development of epilepsy

Question 13

What percentage of a cigarette is particulate and what percentage is volatile?

Answer 13

5% particulate

95% volatile

Question 14

Why is the nicotine delivery via a cigarette so effective?

Answer 14

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

Question 15

Which matter contains most carcinogenic elements?

Answer 15

Volatile

Question 16

Why is the cigarette not particularly efficient in delivering nicotine to the body?

Answer 16

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

Question 17

What is involved in the metabolism of nicotine? What is the product?

Answer 17

CYP2A6 in the liver

Produces COTININE, which is then excreted in urine

Question 18

What is the half-life of nicotine? Why is nicotine so addictive?

Answer 18

1-4 hours

Its metabolised very fast to an inactive metabolite

Question 19

Describe how nicotine causes euphoria.

Answer 19

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

Question 20

How does nicotine increase cardiovascular disease risk?

Answer 20

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

Question 21

What effect does nicotine have on metabolism?

Answer 21

Increases metabolism

So chronic smokers often find that they gain weight after quitting

Question 22

Explain how nicotine reduces the risk of Parkinson’s disease.

Answer 22

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

Question 23

Explain how nicotine reduces the risk of Alzheimer’s disease.

Answer 23

Chronic nicotine diminishes some of the proteins that contribute to Alzheimer’s disease (decrease in beta-amyloid toxicity + amyloid precursor protein)

Question 24

Explain how caffeine can cause mild euphoria.

Answer 24

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

Question 25

Which forms of cocaine can be inhaled?

Answer 25

Crack

Freebase

Question 26

Describe why a drug e.g. cocaine is more effective once inside a cell

Answer 26

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

Question 27

How does cocaine increase body temperature? What may this lead to?

Answer 27

Increased locomotor activity
Increased agitation (ovaeractivation of brain)
Increased muscle contraction
Hyperthermia

Question 28

How is increase in body temperature exacerbated by cocaine?

Answer 28

Cocaine enhances sweat production but inhibits cutaneous vasodilation
Also elevates threshold for sweating + cutaneous vasodilation

Question 29

What effect does nicotine have on lipid profile?

Answer 29

Negative effect.

Increases free fatty acids, leading to increased VLDL + LDL