Drugs of Abuse: Cocaine and Nicotine

Question 1

Describe the methods of cocaine administration

Answer 1

Paste (80%) and cocaine HCL (dissolved in acidic solution) - IV, oral, intranasal

Crack (precipitate with alkaline solution) and freebase (dissolved in non-polar solvent) - inhalation

Question 2

Why is the bioavailability after admin via smoking, nasal and orally so low compared to when given via IV

Answer 2

pKa = 8.7
Oral cocaine ionized in GIT - unlikely to diffuse across plasma membranes
Inhaled cocaine unable to cross the membrane of the lungs
Slower absorption, prolonged action

Question 3

What is the half life of cocaine

Answer 3

20-90 minutes

Question 4

Describe the metabolic pharmacokinetics of cocaine

Answer 4

75-90% - liver cholinesterases produces prodecgonine methyl, ester benzoylecgonine (inactive)

Plasma cholinesterases mean cocaine can be metabolised in the blood

Question 5

How does cocaine pharmacokinetics contribute to the addictive potential of the drug?

Answer 5

Rapid onset of action gives a reward of massive euphoria

Quick clearance from the system due to metabolism in the liver and blood, driving drug-seeking behaviour

Question 6

Describe the pharmacodynamic effects of cocaine

Answer 6

Local anaesthetic
Reuptake inhibition 
Euphoria
Myocardial infarction (CVS)
Hyperthermia (CNS)

Question 7

Explain why cocaine has a local anaesthetic effect

Answer 7

Blocks the sodium channel and stops sodium influx
Disrupts action potentials, especially in nerves
Cocaine’s effect as a local anaesthetic are more effective when cocaine enters the sodium channel from the inside of the cell

Question 8

Explain why cocaine causes reuptake inhibition

Answer 8

Cocaine blocks noradrenaline reuptake transporters
More neurotransmitter remains in the synapse
Enhances NA, dopaminergic effects etc.

Question 9

Does cocaine influence dopamine affinity/efficacy for the dopamine receptor?

Answer 9

No

Question 10

Explain why cocaine causes euphoria

Answer 10

Ventral tegmental area -> nucleus accumbens for dopamine release
Cocaine inhibits the dopamine transporter, causing dopamine to accumulate in the synapse resulting in longer activation of the D1R receptor

Question 11

What are the other effects of cocaine

Answer 11

Mild dose - positive reinforcing effects e.g. confidence, talkative, high energy

Chronic usage/high dose - negative/stereotypic e.g. irritability, hostility, extreme exhaustion

Question 12

Explain how cocaine can lead to a myocardial infarction

Answer 12

Cocaine stimulates the sympathetic nervous system by inhibiting catecholamine reuptake
Sensitivity of adrenergic nerve endings to norepinephrine increases
Increased myocardial demand and atherosclerosis, decreased myocardial supply

Question 13

Describe the opposing cardiovascular effects of cocaine

Answer 13

Acts as a class I anti-arrhythmitic by blocking sodium and potassium channels BUT this is dominated by the stimulation of the sympathetic nervous system

Question 14

What are the effects of sympathetic stimulation due to cocaine

Answer 14

Release of endothelium-1 + Inhibition of NO production -> vasoconstriction

Activation of platelets -> platelet aggregation -> thrombosis

Increase in HR, Contractility and BP

Question 15

Draw a diagram that summarises the CVS pharmacodynamics of cocaine

Answer 15

-

Question 16

Explain how cocaine causes hyperthermia

Answer 16

Increase in agitation, locomotor activity and involuntary muscle contraction
Leads to an increased body temperature

Question 17

How does cocaine influence sweat production and cutaneous vasodilation?

Answer 17

Elevates threshold for sweating/cutaneous vasodilation three fold

Question 18

What proportion of cigarettes are volatile and what substances does this include

Answer 18

95%
Nitrogen
Carbon monoxide/dioxide 
Benzene
Hydrogen cyanide

Question 19

What proportion of cigarettes are particulates and what substances does this include

Answer 19

5%
Alkaloids (nicotine)
Tar

Question 20

Describe the dosing for nicotine spray, gum, patches and cigarettes

Answer 20

Nicotine spray - 1mg
Nicotine gum - 2-4mg
Cigarettes - 9-17mg
Nicotine patch - 15-22mg

Question 21

What is the pKa of nicotine and how does it affect pharmacokinetics

Answer 21

pKa = 7.9
Cigarette smoke is acidic - no buccal absorption
Absorption in alveoli is independent of pH

Question 22

Describe the time taken for absorption of nicotine via cigarettes, sprays, gums and patches

Answer 22

Cigarette - very quick to peak in 10 minutes
Spray - same peak time as cigarettes but much lpwer
Gum - slower increase, peak at 30 mins
Patch - very slow increase, remains at similar levels throughout use

Question 23

Describe the metabolic pharmacokinetics of nicotine

Answer 23

Hepatic CYP2A6 converts to inactive metabolite conitine

70-80%

Question 24

What is the half life of nicotine

Answer 24

1-4 hours

Question 25

What is the effect of nicotine on the sympathetic nervous system

Answer 25

Binds to cholinergic receptors | Drives both sympathetic and parasympathetic function - involved in autonomic function

Question 26

Explain how nicotine causes euphoria

Answer 26

Nicotine directly stimulates the dopaminergic neurone at the ventral tegmental area to cause increased dopamine release at the nucleus accumbens

Question 27

What are the cardiovascular effects of nicotine

Answer 27

Myocardial ischaemia, infarction -> arrhythmias and sudden death

Question 28

Explain how cocaine causes myocardial infarction

Answer 28

Causes increase in free fatty acids and LDL -> atherosclerosis Increase SNS activity leads to platelet activation, coronary vasoconstriction and increase in heart rate, contractility and BP Reduction in myocardial supply but increase in demand

Question 29

What effect does nicotine have on metabolism and appetite

Answer 29

Increases metabolic rate and prevents weight gain Reduces appetite

Question 30

What effect does nicotine have on Parkinson's and Alzheimers

Answer 30

Parkinson’s Disease; increase brain CYPs → neurotoxins Alzheimer’s Disease: decrease beta-amyloid toxicity decrease amyloid precursor protein (APP)

Question 31

Describe the effect of caffeine on nerves

Answer 31

Binds to A1 receptors on both the pre- and post-ganglionic bulbs

Question 32

Explain why cocaine's local anaesthetic effect is more effective intracellularly

Answer 32

1. Cocaine diffuses across the nerve to the inside of the cell and access the channel from beneath 2. Due to its pKa it is more unionised extracellularly which can diffuse across the plasma membrane 3. Once in the nerve cell, it becomes more ionised and can access the inside of the sodium channel 4. When cocaine is charged it is a lot better at interacting with its target (sodium channel)

Question 33

What is the bioavailability for nicotine spray, gum, cigarettes and patches

Answer 33

Nicotine spray - 20-50% Nicotine gum - 50-70% Cigarettes - 20% Nicotine patch - 70%