Drugs of abuse - cocaine and nicotine

Question 1

Where does cocaine come from?

Answer 1

• Cocaine is s plant-based compound (erythroxylum coca plant)
• The leaves of the plant contain cocaine

Question 2

How is cocaine paste formed? What % is extracted?

Answer 2

• Crushing up the leaves with an organic solvent to form a paste -> extract around 80% of cocaine

Question 3

How is cocaine HCl made and what is its use?

Answer 3

• Cocaine HCl (major medicinal form of cocaine) is formed by dissolving the leaves in acidic solution
• Cocaine HCl was used as an anaesthetic, but was also the major form that was abused initially

Question 4

What is the problem with cocaine HCl?

Solution?

Answer 4

• It degrades when heated

- Solution: CRACK COCAINE

Question 5

What is crack cocaine?

Answer 5

• Precipitate cocaine HCl with an alkaline solution (e.g. baking soda)
• Once this solution dries and hardens, you end up with little cocaine rocks (you can inhale the vapour)

Question 6

What is the most prevalent drug in terms of usage on the planet?

Answer 6

crack cocaine

Question 7

How can crack be purified?

Answer 7

• By dissolving it in a non-polar solvent (e.g. ammonia or ether)
• This is called freebase and can be inhaled

Question 8

How do the speeds of onset from inhaling and injecting cocaine differ?
What about intranasal and oral?

Answer 8

• nearly the same

- intranasal (snorting) is still fast but oral is the slowest

Question 9

Why form of cocaine administration giver larger bioavailability and why out of injecting and inhaling

Answer 9

• Intravenous administration is much better for getting a larger amount of the drug into the blood (100% bioavailability)
• In inhalation, a lot of the drug is lost due to absorption issues

Question 10

Why does cocaine taken via the oral route have prolonged absorption?

Answer 10

pKa = 8.7, so if taken via the oral route, cocaine will be ionized in the GIT (acidic environment). Because it is ionised, it is slower absorbed -> prolonged action.

Question 11

Which method of administering is poorest in terms of bioavailabilty?

Answer 11

inhaling

Question 12

How fast is cocaine metabolised? Why?
What is its half life?
Which enzymes?

Answer 12

• Cocaine is rapidly metabolised (half life of 20-90 minutes)
• By plasma and liver cholinesterases
• The speed is related to the fact that there are enzymes in the blood (plasma) as well as the liver

Question 13

What are the metabolites of cocaine?

What % of cocaine is metabolised into these metabolites?

Answer 13

There are two major metabolites produced: ecgonine methyl esther and benzoylecgonine

Around 75-90% of cocaine is broken down into these inactive, inert, metabolites

Question 14

Why is cocaine so addictive?

Answer 14

SPEED OF ONSET Addiction is very closely correlated with how fast the effect comes on. The faster the onset of the effect, the more powerfully addictive it is (associated with stimulus)

o SPEED OF BREAKDOWN There is a powerful euphoric high very quickly, and it is then lost very quickly too (due to fast clearance). This is a reason for continuously taking it (cocaine ‘binging’) -> reinforcing effect

Question 15

What are the 2 major effects of cocaine?
How does it do these things?
What doses is this at?
Which effect is seen more commonly and why?

Answer 15

1. LOCAL ANAESTHETIC (HIGH DOSE) The major clinical use of the drug is that it is a local anaesthetic. It does this by blocking sodium channels within nerves -> reduced propagation of APs -> suppressed pain sensation
2. REUPTAKE INHIBITION (LOW DOSE) Dopamine is released into the synapse; it binds to the receptor and produces an effect. It eventually needs to be removed from the synapse so the effect can be ceased, via the dopamine transporter. The dopamine transporter takes molecules of dopamine from the synapse, and flips it back into the pre-synaptic cell.
   Cocaine blocks these dopamine transporters. This can affect dopamine, NA and serotonin. This is a lower dose effect, so it is seen more commonly than the local anaesthetic effect.

Question 16

How does cocaine produce a euphoric effect?

Answer 16

Cocaine goes straight to the nucleus accumbens and blocks the dopamine transporter. This results in many more dopamine molecules in the synapse, binding to dopamine receptors and stimulating euphoria.

Question 17

What are some of the effects of cocaine in the brain?

Answer 17

• mood amplification
• sleep disturbance, insomnia
• talkativeness
• anorexia
• inflated self-esteem
• irritability, anxiety, fear
• extreme energy or exhaustion
• incoherent speech
• delusions of grandeur
• extreme violence

Question 18

How can the effects of cocaine in the brain be classified?

Answer 18

POSITIVE/REINFORCING: Acute effects (as a general rule)

NEGATIVE/STEREOTYPIC: More common with chronic use in cocaine. They are commonly associated with cocaine binging (leads to increased tolerance to cocaine due to depletion of dopamine vesicles)

Question 19

What happens in cocaine bingers and why?

Answer 19

• After chronic use of cocaine, some of the euphoric effect is lost (due to increased tolerance)
• Reuptake is being blocked -> dopamine is not being reabsorbed back into the presynaptic neurone
• You will not get any dopamine back into the neurone -> dopamine vesicles become fewer in number
• This results in a loss in the positive/reinforcing euphoria, and more negative/stereotypic effects

Question 20

What are the cardiovascular effects of cocaine?

Answer 20

• Cocaine stimulates the sympathetic NS by inhibiting catecholamine reuptake at sympathetic nerve terminals, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine
• Cocaine also acts like a class I antiarrhythmic agent (local anaesthetic) by blocking sodium and potassium channels, which depresses CVS parameters.

Question 21

What are the 2 major CVS problems of cocaine?

Describe why

Answer 21

Effects on the sympathetic NS
- Due to increased catecholamines (predominantly NA). Increased NA -> increased work of the heart -> increased BP -> increased oxygen demand. Increased NA also -> vasoconstriction -> decreased blood flow. The sympathetic NS activates platelets -> platelet adherence. This will lead to decreased oxygen supply despite increased demand -> ischemia and infarction

2. Decreased sodium transport creating a local anaesthetic effect This is a high dose effect. These can be quite negative to the heart (interfere with rhythm and left ventricular function)

Question 22

Why are seizures common in cocaine overdoses?

Answer 22

• This is due to a vasoconstricting effect in the brain (reduced blood flow to certain parts of the brain)
• Cocaine stimulates hyperpyrexia (high fever)
• The combination of vasoconstriction and hyperpyrexia are associated with seizure induction and epilepsy

Question 23

Where does nictoine come from?

Answer 23

plant

Question 24

Are nicotine and cocaine stimulants?

Answer 24

yes

Question 25

Do cigarettes contain a lot of nicotine?

How is nicotine delivered into the lungs?

Answer 25

• In nicotine cigarettes, there is only a small amount (nicotine is an alkaloid)
• A cigarette is 95% volatile material (N, CO/CO2, benzene, HCN) and 5% particulate matter (alkaloids, tar)
• When the cigarette is heated, tar droplets form, in which nicotine dissolves
• Tar droplets are the delivery mechanism – droplets enter the lungs and nicotine diffuses across alveoli
• The large proportion of cigarette smoke is the volatile matter (contains lots of nasty compounds)

Question 26

How can nicotine be administered and what are the different doses they contain?

Answer 26

• Cigarettes are the most prevalent method of administration of nicotine (9-17 mg per cigarette)
• Nicotine spray (1mg)
• Nicotine gum (2-4mg)
• Nicotine patch (15-22mg/day)

Question 27

How does the bioavailability of nicotine, spray, gum, patches and cigarettes differ?

Answer 27

Nicotine spray 1mg (20-50%)

Nicotine gum 2-4mg (50-70%)

Cigarettes 9-17mg (20%) – cigarettes are the least effective in terms of bioavailability

Nicotine patch 15-22mg/day (70%)

Question 28

Why does nitotine from smoke have poor bioavailability?

Answer 28

Cigarette smoke is quite acidic, and nicotine has a high pKA of 7.9. This means that nicotine is very poorly absorbed if it is within the smoke (it is heavily ionised). Cigarette smoke is therefore an ineffective method of administering nicotine (no buccal absorption). Absorption in alveoli is independent of pH.

Question 29

What is the idea behind methods used to wean off smoking?

Why does this not work that well?

Answer 29

• The idea of replacement methods is to maintain a low level of nicotine in the blood
• This is meant to interfere with the craving to smoke
• The problem with cigarettes is that you get a spike – this is the feeling that people want to replace
• This is why people binge on cigarettes. They are constantly trying to maintain the peak level of nicotine, to restore the high.
• Replacement methods don’t produce this high spike in nicotine because it is dangerous

Question 30

How is nictoine metabolised?
How fast and where?
What is the major metabolite?
How long is its half life?

Answer 30

• The vast majority (70-80%) of nicotine is broken down in the liver very quickly by hepatic CYP2A6
• The major metabolite is cotinine – it is an inactive and inert metabolism
• Metabolism is slightly slower than cocaine (half life of 1-4 hours)
• Therefore, like cocaine, nicotine is pretty powerfully reinforcing because the effect is lost quickly

Question 31

Which receptor does nicotine bind to?

What does this mean?

Answer 31

• Nicotine can bind the nicotinic ACh receptor. Therefore, all the effects of nicotine are predominantly driven by an interaction with the nACh receptor
• They are found through the whole autonomic NS – so as a result, nicotine can interfere with quite a lot of autonomic function

Question 32

How does nicotine cause euphoria?

Answer 32

• Because nicotine is a stimulant, it will act directly on the neurone itself to stimulate it. There are lots of nACh receptors on the cell body of reward dopaminergic neurones
• When the neurone is heavily stimulated, you get dopamine release in the nucleus accumbens -> feeling of reward

Question 33

What are the effects of long term nicotine use?

Answer 33

• Lung cancers and emphysema are predominantly associated with the volatile matter
• Nicotine -> consistent autonomic stimulation (in the CNS and adrenal glands). This leads to increased HR and SV (sympathetic). This occurs alongside reduced blood flow (vasoconstriction of coronary and skin arterioles). Vasodilation in the skeletal muscle arterioles
• Nicotine is pro-atherogenic – it has a negative effect on the lipid profile
• Nicotine increases thromboxane (promotes platelet aggregation) and decreases NO

Question 34

What happens when people stop smoking?

Answer 34

• Nicotine is a stimulant
• It increases metabolic rate
• Hence stopping is associated with weight gain

Question 35

What is the effect of nicotine in neurodegenerative disorders: parkinsons, alzheimers?

Answer 35

PARKINSON’S DISEASE In Parkinson’s, long-term nicotine use increases the number of brain cytochromes (CYPs). These cytochromes metabolise toxins (neurotoxins). This suggests that chronic nicotine has a positive impact on Parkinson’s disease (decreases neurotoxins that are present and contribute to disease development).

ALZHEIMER’S DISEASE Chronic nicotine use is associated with decreased beta-amyloid toxicity, and decreased amyloid precursor protein (APP). Therefore, nicotine has a positive effect on the progression of Alzheimer’s

Question 36

Caffeine, how does it work ad cause euphoria?

Why is the euphoria from caffeine small?

Answer 36

• Caffeine is a stimulant and should cause euphoric effects
• Adenosine activates adenosine receptors, which tend to decrease the euphoric effect
• Adenosine therefore downregulates D1 function and decreases dopamine secretion
• Caffeine is an adenosine receptor antagonist
• Therefore, caffeine increases dopamine release and enhances tissue response to dopamine
• Caffeine is generally orally administered – so the euphoria effect is less obvious

Question 37

Chocolate

Answer 37

Some of the compounds in chocolate have stimulant properties. However, there is no evidence that any compounds in chocolate directly interact with the reward pathway. Chocolate acts like a lot of natural stimuli for the reward pathway (no direct effect, just a behavioural effect)