Drugs of Abuse - Cocaine and Nicotine

Question 1

What is cocaine?

Answer 1

plant-based compond (erythroxylum coca plant)

stimulant

Question 2

What is crack cocaine?

Answer 2

precipitate cocaine HCl with an alkaline solution (e.g. baking soda)

Once this solution dries and hardens, you end up with little cocaine rocks

• Crack can be purified by dissolving it in a non-polar solvent (e.g. ammonia or ether)
• freebase (can be inhaled)

Question 3

What is cocaine HCl?

Answer 3

major medicinal form of cocaine formed by dissolving the leaves in acidic solution

• was used as an anaesthetic, but was also the major form that was abused initially
• big problem with cocaine HCl is that it degrades when heated -> solution: CRACK COCAINE

Question 4

Compare the speed of onset and biavailabilty of different routes of administration of cocaine

Answer 4

the speed on onset is virtually the same for inhalation and intravenous however, 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

Snorting (intranasal) has a slower speed of onset, but still is pretty fast

Oral administration is the slowest. 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 5

How is cocaine metabolised?

Answer 5

Cocaine is rapidly metabolised (half life of 20-90 minutes) by plasma and liver cholinesterases

TWO MAJOR METABOLITES PRODUCED:

• ecgonine methyl esther
• benzoylecgonine
• Around 75-90% of cocaine is broken down into these INACTIVE, INERT METABOLITES
• The speed is related to the fact that there are enzymes in the blood (plasma) as well as the liver

Question 6

Why is cocaine so addictive?

Answer 6

Addiction is very closely correlated with how fast the effect comes on - faster the onset of the effect, the more powerfully addictive it is (powerful behavioural stimulus)

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 7

What are the major effects of cocaine?

Answer 7

1. LOCAL ANAESTHETIC (HIGH DOSE)
   - major clinical use is that it is a local anaesthetic - blocks 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
   - Cocaine blocks these dopamine transporters. - can affect dopamine, NA and serotonin

*Cocaine DOES NOT influence dopamine affinity or efficacy for the dopamine receptor

Question 8

How does cocaine cause euphoria?

Answer 8

goes straight to the nucleus accumbens and blocks the dopamine transporter -> more dopamine in synapse

Question 9

What are the other effects of cocaine in the brain?

Answer 9

Other effects of cocaine in the brain can be split into positive/reinforcing effects and negative/stereotypic effects

POSITIVE/REINFORCING: Acute effects (as a general rule) e.g mood amplification ( euphoria and dysphoria), heightened energy, insomnia, restlessness, anger, talkativeness

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) e.g irritability, anxiety, exhaustion, total insomnia, rambling, total anorexia, delusions

Question 10

What are the effects of cocaine binging on dopamine levels in the brain?

Answer 10

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 (dopamine is not being recycled back into the neurone frequently enough) -> dopamine will eventually be metabolised to a degree

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 11

What are the cardiovascular effects associated with cocaine?

Answer 11

1. Increased NA by inhibiting catecholamine reuptake-> 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 -> ISCHAEMIA AND INFARCTION.

• cocaine stimulates the release of endothelin-1, a potent vasoconstrictor, from endothelial cells and inhibits nitric oxide production, the principal vasodilator produced by endothelial cells. Cocaine promotes thrombosis by activating platelets, increasing platelet aggregation

2. at high dose -decreased sodium transport creating a local anaesthetic effect
   - interfere with rhythm and left ventricular function)
   - class I antiarrhythmic agent (local anaesthetic) by blocking sodium and potassium channels, which depresses CVS parameters

Question 12

How can cocaine cause seizures?

Answer 12

vasoconstricting effect in the brain (reduced blood flow to certain parts of the brain)

Cocaine stimulates hyperpyrexia. The combination of vasoconstriction and hyperpyrexia are associated with seizure induction and epilepsy

Question 13

How is nicotine administered?

Answer 13

usually cigarettes:

• 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
• 9-17 mg nicotine per cigarette
• Nicotine spray 1mg
• Nicotine gum 2-4mg
• Nicotine patch 15-22mg/day

Question 14

What is the bioavailability of different routes of administration of nicotine?

Answer 14

Bioavailability:

• Nicotine spray 1mg (20-50%)
• Nicotine gum 2-4mg (50-70%)
• Cigarettes 9-17mg (20%)
• Nicotine patch 15-22mg/day (70%)

*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 15

How do cigarette replacement methods work?

Answer 15

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 16

Describe the metabolism of nicotine

Answer 16

• 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) and is pretty powerfully reinforcing because the effect is lost quickly

Question 17

What does nicotine bind to?

Answer 17

nicotinic ACh receptors

• therefore can interfere with a lot of autonomic function

Question 18

How does nicotine cause euphoria?

Answer 18

acts 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 19

What are the cardiovascular effects associated with long term nicotine use?

Answer 19

Lung cancers and emphysema are predominantly associated with the VOLATILE MATTER

Nicotine -> consistent autonomic stimulation (in the CNS and adrenal glands) -> 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 20

What is the impact of nicotine in Parkinson’s disease?

Answer 20

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

Question 21

What is the impact of nicotine in Alzheimer’s disease?

Answer 21

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 22

What is the effect of caffeine?

Answer 22

Theoretically, 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.