Drugs of abuse 2 - Cocaine & Nicotine

Question 1

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

Answer 1

For iv/oral/intranasal;

1. Cocaine paste – plant (erythroxylum coca) mushed up in an orgainic solvent
2. Cocaine HCl – cocaine paste dissolved in an acidic solution (therapeutic form of cocaine)

For inhalation;

3. Crack – precipitate the above with an alkaline solution (e.g. baking soda)
4. Freebase – dissolve crack in a non-polar solvent (e.g. ammonia and ether) to obtain a slightly purer form

Question 2

Which route of administration of cocaine gives the fastest absorption/quickest onset of effects?

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 => mainly ionised in the stomach => isn’t very lipid soluble/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

Metabolized by cholinesterase enzymes (primarily in the liver and plasma) into ecgonine methyl ester and benzoylecgonine (inactive metabolites)

Question 6

Why is cocaine such an addictive drug?

Answer 6

Rapid onset of euphoria with the effects also rapidly lost

Question 7

Explain how cocaine can act as a local anaesthetic.

Answer 7

Cocaine blocks sodium channels and hence inhibits nerve transmission
Extracellular pH is closer to the pKa of cocaine and so the cocaine is mainly unionised here (meaning it can passively diffuse into the cell), once inside it largely becomes ionised => charged cocaine can block the sodium channels from within

Question 8

By what mechanism does cocaine exert its most profound effects?

Answer 8

Inhibition of monoamine transporters (reuptake inhibition) => accumulation of monoamine neurotransmitters (e.g. dopamine, serotonin and NA/A) at the synapse

Question 9

How does cocaine cause euphoria?

Answer 9

Cocaine blocks the monoamine transporters at the dopaminergic nerve terminals in the nucleus accumbens. 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/reinforcing effects – more energetic, need less sleep, more sociable, more talkative
*High dose => negative/stereotypical effects – exhaustion, irritability, hostility, insomnia

• Partly due to tolerance i.e. cocaine causes massive dopamine release but by blocking re-uptake, the neurone fails to replenish the dopamine; further cocaine use results in much lower euphoria

Question 11

Explain why cocaine is associated with significantly increased cardiovascular risk, specifically myocardial infarction

Answer 11

1. Especially at lower doses, cocaine stimulates the SNS by inhibiting catecholamine re-uptake at sympathetic nerve terminals and directly stimulate central sympathetic outflow => increased HR, contractility, BP
2. Cocaine stimulates the release of endothelin-1, (vasoconstrictor), and inhibits nitric oxide production (vasodilator) from endothelial cells => coronary vasoconstriction
3. Cocaine promotes thrombosis by activating platelets

1 and 3 (via endothelial injury) contribute to promote atherosclerosis, which together with 2 lead to decreased myocardial supply. 3 also leads to increased myocardial demand therefore => myocardial ischaemia/infarction

Question 12

At higher doses of cocaine, what effect is more dominant?

Answer 12

Cocaine acts like a class I antiarrhythmic agent (local anesthetic) by blocking sodium and potassium channels, which depresses cardiovascular parameters

Question 13

Explain how cocaine overdose causes hyperthermia

Answer 13

Cocaine overdose => increased agitation, locomotor activity and involuntary muscle contraction => increased body temperature (which leads to hyperthermia if in a hot environment)

Question 14

How does cocaine affect the thermoregulatory mechanism namely for heat dissipation?

Answer 14

• Inhibits cutaneous vasodilation
• Somewhat enhances sweat production
• Elevates threshold for sweating/cutaneous vasodilation three fold (via central effects)

Question 15

What percentage of a cigarette is particulate and what percentage is volatile? State the components in each case

Answer 15

5% particulate - alkaloids, tar

95% volatile - Nitrogen, Carbon Monoxide/Dioxide, Benzene, Hydrogen Cyanide

Question 16

Why is the nicotine delivery via a cigarette so effective?

Answer 16

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 17

Why is there no buccal absorption of nicotine?

Answer 17

pKa of nicotine = 7.9

Cigarette smoke is acidic and so is mainly ionised
Note that absorption in alveoli independent of pH

Question 18

Which route of administration of nicotine has the highest bioavailability? Which is fastest acting?

Answer 18

Nicotine patch (>gum>spray/cigarette)

Cigarette

Question 19

Describe the metabolism of nicotine. What is the product?

Answer 19

Nicotine is metabolised by CYP2A6 in the liver

This produces COTININE, which is then excreted in the urine

Question 20

What is the half-life of nicotine?

Answer 20

1-4 hours

Question 21

Describe how nicotine causes euphoria.

Answer 21

Nicotine binds to nicotinic acetylcholine receptors on the cell bodies of dopaminergic neurones in the VTA and stimulates sodium influx.
This leads to an increase in the firing rate of the dopaminergic neurones, hence, more dopamine secretion.

Question 22

How does nicotine increase cardiovascular disease risk?

Answer 22

Increases sympathetic output so therefore works in the same way as cocaine (see other card)
ALSO, nicotine increases FFAs, VLDLs and LDLs which further accelerates atherosclerosis

Question 23

What effect does nicotine have on metabolism? What happens therefore following smoking cessation?

Answer 23

It increases metabolism

So chronic smokers often find that they gain weight after quitting

Question 24

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

Answer 24

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 25

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

Answer 25

Decrease in beta-amyloid toxicity

Decrease in amyloid precursor protein

Question 26

Explain how caffeine can cause mild euphoria.

Answer 26

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