Cocaine and nicotine

Question 1

What is cocaine?

Answer 1

Plant-based alkaloid from leaves of Erythroxlyum coca

Question 2

What are the different forms of cocaine?

Answer 2

Cocaine HCl - heat labile
Crack
Freebase

Question 3

Summarise the administration and absorption of cocaine

Answer 3

Oral < intranasal < IV < inhalation

IV and inhalation - seconds

• Inhalation - extremely rapid absorption – plasma conc = 500–1000 ng/mL (freebase)
• Cocaine HCl is heat labile
• Rapid absorption also achieved if cocaine HCl is injected i.v.
• Snorting (cocaine HCl) – absorbed through mucous membranes lining sinuses; results in slower absorption – 100–500 ng/mL

Question 4

Why does oral administration of cocaine give a very slow rate of onset?

Answer 4

• Cocaine has a high pKa (8.7)
• In stomach, cocaine is mostly ionised
• Slows down absorption as it doesn’t cross membrane easily
• But has a prolonged action

Question 5

How is cocaine metabolised?

Answer 5

• Mostly in liver into inactive metabolites (mainly ecgonine methyl ester and benzoylecgonine on first passage)
• Cleared from urine quickly
• Half-life = 90 mins
• Both metabolites, account for 75–90% of cocaine metabolism
• Also broken down by cholinesterases
• Some in plasma so can be metabolised in blood straight away

Question 6

Why is cocaine so addictive?

Answer 6

The quicker you associate the euphoric effect with taking the drug, the more addictive it is

1. Powerful euphoric effects
2. That come on quickly (fast onset)
3. And leave quickly (active cocaine doesn’t last long in blood)

Question 7

How can cocaine act as a local anaesthetic?

Answer 7

High dose
Blocks Na channels
Blocks nerve conduction

Question 8

How does cocaine cause euphoria?

Answer 8

• NAcc presynaptic monoamine transporter blocker
• Inhibits reuptake of dopamine in NAcc
• Dopamine remains in synapse for longer
  Prolonged effects of dopamine
  Euphoria

Question 9

How does cocaine affect dopamine’s affinity and efficacy for the dopamine receptor?

Answer 9

• It doesn’t

- Just increases number of dopamine molecules in synapse at 1 given time

Question 10

What are the mild/moderate effects of cocaine?

Answer 10

• Mood amplification: euphoria, dysphoria
• Heightened energy
• Sleep disturbance, insomina
• Motor excitement, restlessness
• Talkativeness
• Hyperactive ideation
• Increased libido
• Anger, verbal aggression
• Mild-moderate anorexia
• Inflated self-esteem

Question 11

What are the severe effects of cocaine?

Answer 11

• Irritability, hostility, anxiety, fear, withdrawal
• Extreme energy or exhaustion
• Total insomnia
• Compulsive motor stereotypies
• Rambling, incoherent speech
• Disjointed flight of ideas
• Decreased libido
• Possible extreme violence
• Total anorexia
• Delusions of grandiosity

Question 12

How does cocaine affect the CVS?

Answer 12

Strong link between cocaine use and MI:

1. Increased symp output
2. Vasoconstriction and platelet activation
3. Atherosclerosis and vessel narrowing
4. Heart must do MORE WORK
5. DECREASED O2 SUPPLY

If severe enough:
Tissue ischaemia –> MI –> death

Also:
Prompt seizures
Vasoconstriction –> reduced blood flow to brain –> heat build-up in areas –> hyperpyrexia –> seizures, can –> epilepsy

Question 13

What is nicotine?

Answer 13

Plant-based alkaloid from Nicotiana tabacum

Question 14

How can nicotine be administered? Compare bioavailability and rate of onset

Answer 14

Spray 20-50%
Gum 50-70%
Cigarette 20% - NOT PARTICULARLY EFFICIENT
Patch 70%

Inhalation has rapid onset but effects are lost quickly

Onset = seconds

Question 15

Why is there no buccal absorption of nicotine?

Answer 15

pKa 7.9
Cigarette smoke is acidic
Nicotine is ionised tf cannot be absorbed

Question 16

How is nicotine metabolised?

Answer 16

Liver
Nicotine --> cotinine
Rapid clearance in urine
Hepatic CYP2A6 - 70-80%
Half life = 1-4 hours
Tissue half life = 2-3 hours

Question 17

Why is nicotine so addictive?

Answer 17

Rapidly broken down tf keep smoking to keep blood [nicotine] high

Question 18

How does nicotine cause euphoria?

Answer 18

Binds to and activates nicotinic AChR on cell body of dopaminergic VTA neurone
Na influx activates dopaminergic neurone
Increased firing rate
Increased dopamine secretion from NAcc

Question 19

How does nicotine affect the CVS?

Answer 19

↑ blood coagulation.
↑ myocardial work
↓ oxygen carrying capacity of blood (due to CO)
Coronary and peripheral vasoconstriction
↑ LDL and VLDL, FFA and ↓ HDL
↑ risk for atherosclerosis, myocardial infarction, cardiovascular disease

Question 20

Why do chronic smokers tend to put on weight once they stop?

Answer 20

Nicotine increases metabolic rate

Decreases appetite

Question 21

How does nicotine affect neurological systems?

Answer 21

Seems to provide some protection

1. Parkinson’s Disease
   Increases brain CYPs
   Increases ability to metabolise neurotoxins
2. Alzheimer’s Disease
   Decreases B-amyloid toxicity
   Decreases amyloid precursor protein

Question 22

Summarise the pharmacokinetics of nicotine

Answer 22

• Particulate droplets reach the small airways and alveoli
• Rapid absorption from the lung (faster than i.v.)
• Distributes rapidly to different tissues, incl the brain (within 10-20s)
• Chronic smokers – Plasma nicotine levels between 20-40ng/ml
• Elimination half life – 2-3h
• Extensive metabolism in liver (lung and brain) to cotinine (70-80%) + other metabolites

Question 23

Summarise the pharmacodynamics of nicotine

Answer 23

Low dose – sympathetic activation via peripheral chemoreceptors (or direct effect on brain) → ↑ HR and BP

Higher doses – binds to nicotinic cholinergic receptors; ganglionic stimulation and catecholamine release from the adrenals

Very high dose – ganglionic blockade and possibly vagal stimulation

Question 24

What effect does nicotine have on the reward pathway?

Answer 24

Nicotinic receptors located somatodendritically on dopaminergic VTA neurones – directly ↑ firing rate

Question 25

What are the endocrine effects of nicotine

Answer 25

↑ACTH/cortisol