Drugs of Abuse 2 – Cocaine and Nicotine

Question 1

What are the four different forms of cocaine and how are theymade?

Answer 1

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)

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 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

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 – it can be metabolised by plasma cholinesterases so it doesn’t last long in the plasma

Question 6

Which factors affect the addictive potential of a drug?

Answer 6

The speed at which you associate the euphoria with taking the drug and the speed with which the effects are lost

Question 7

Explain how cocaine can act as a local anaesthetic.

Answer 7

Cocaine blocks sodium channels and 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

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

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

Cocaine causes an increase in sympathetic output (NOTE: noradrenaline is also a monoamine)
This leads to vasoconstriction, thus causing an increase in cardiac work
It will also activate platelets and promote atherosclerosis, leading to thenarrowing of vessels and decreased oxygen supply to the heart
This could lead to myocardial infarction

Question 12

How can cocaine prompt seizures?

Answer 12

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

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 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

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 that the nicotine in cigarette smoke becomes ionised and, hence, it is less easily absorbed

Question 17

Describe the metabolism of nicotine. What is the product?

Answer 17

Nicotine is metabolised by CYP2A6 in the liver

This produces COTININE, which is then excreted in the urine

Question 18

What is the half-life of nicotine?

Answer 18

1-4 hours

Question 19

Describe how nicotine causes euphoria.

Answer 19

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

Question 20

How does nicotine increase cardiovascular disease risk?

Answer 20

Nicotine causes an increase in sympathetic drive – increased heart rate and stroke volume, so more cardiac work
Vasoconstriction of coronary arterioles – reduces oxygen delivery to the myocardium
In addition it also promotes atherosclerosis and increases thromboxane A2 (hence increases platelet activity)
All of these factors increase oxygen demand and decrease oxygen supply

Question 21

What effect does nicotine have on metabolism?

Answer 21

It 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

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

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, decrease in amyloid precursor protein)

Question 24

Explain how caffeine can cause mild euphoria.

Answer 24

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

Question 25

When is cocaine most effective at blocking Na channels in nerves

Answer 25

If it has diffused into the cell and then blocks the channel

Question 26

What makes cocaine so good at entering nerve cell and then blocking Na channel

Answer 26

Outside the cell ph is 7.4 and with cocaines pKa of 8.7 it exists more in unionised state so can enter the cell. Inside the cell the pH is 7 so the cocaine becomes more ionised- in its ionised state it has more of a blocking effect

Question 27

How can cocaine lead to hyperthermia

Answer 27

Only occurs in overdose

Increased locomotive activity, agitation and involuntary muscle contraction can lead to an increase in body temperature

Question 28

Effects of cocaine on bodies mechanism for thermoregulation

Answer 28

Inhibits sweat production and cutaneous vasodilation

Question 29

Problem with cocaine usage and environment used

Answer 29

Associated with clubs where very hot so not helping the hyperthermic effects of cocaine