Drugs of Abuse: Cocaine and Nicotine Flashcards
Describe the methods of cocaine administration
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
Why is the bioavailability after admin via smoking, nasal and orally so low compared to when given via IV
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
What is the half life of cocaine
20-90 minutes
Describe the metabolic pharmacokinetics of cocaine
75-90% - liver cholinesterases produces prodecgonine methyl, ester benzoylecgonine (inactive)
Plasma cholinesterases mean cocaine can be metabolised in the blood
How does cocaine pharmacokinetics contribute to the addictive potential of the drug?
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
Describe the pharmacodynamic effects of cocaine
Local anaesthetic Reuptake inhibition Euphoria Myocardial infarction (CVS) Hyperthermia (CNS)
Explain why cocaine has a local anaesthetic effect
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
Explain why cocaine causes reuptake inhibition
Cocaine blocks noradrenaline reuptake transporters
More neurotransmitter remains in the synapse
Enhances NA, dopaminergic effects etc.
Does cocaine influence dopamine affinity/efficacy for the dopamine receptor?
No
Explain why cocaine causes euphoria
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
What are the other effects of cocaine
Mild dose - positive reinforcing effects e.g. confidence, talkative, high energy
Chronic usage/high dose - negative/stereotypic e.g. irritability, hostility, extreme exhaustion
Explain how cocaine can lead to a myocardial infarction
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
Describe the opposing cardiovascular effects of cocaine
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
What are the effects of sympathetic stimulation due to cocaine
Release of endothelium-1 + Inhibition of NO production -> vasoconstriction
Activation of platelets -> platelet aggregation -> thrombosis
Increase in HR, Contractility and BP
Draw a diagram that summarises the CVS pharmacodynamics of cocaine
-
Explain how cocaine causes hyperthermia
Increase in agitation, locomotor activity and involuntary muscle contraction
Leads to an increased body temperature
How does cocaine influence sweat production and cutaneous vasodilation?
Elevates threshold for sweating/cutaneous vasodilation three fold
What proportion of cigarettes are volatile and what substances does this include
95% Nitrogen Carbon monoxide/dioxide Benzene Hydrogen cyanide
What proportion of cigarettes are particulates and what substances does this include
5%
Alkaloids (nicotine)
Tar
Describe the dosing for nicotine spray, gum, patches and cigarettes
Nicotine spray - 1mg
Nicotine gum - 2-4mg
Cigarettes - 9-17mg
Nicotine patch - 15-22mg
What is the pKa of nicotine and how does it affect pharmacokinetics
pKa = 7.9
Cigarette smoke is acidic - no buccal absorption
Absorption in alveoli is independent of pH
Describe the time taken for absorption of nicotine via cigarettes, sprays, gums and patches
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
Describe the metabolic pharmacokinetics of nicotine
Hepatic CYP2A6 converts to inactive metabolite conitine
70-80%
What is the half life of nicotine
1-4 hours
What is the effect of nicotine on the sympathetic nervous system
Binds to cholinergic receptors
Drives both sympathetic and parasympathetic function - involved in autonomic function
Explain how nicotine causes euphoria
Nicotine directly stimulates the dopaminergic neurone at the ventral tegmental area to cause increased dopamine release at the nucleus accumbens
What are the cardiovascular effects of nicotine
Myocardial ischaemia, infarction -> arrhythmias and sudden death
Explain how cocaine causes myocardial infarction
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
What effect does nicotine have on metabolism and appetite
Increases metabolic rate and prevents weight gain
Reduces appetite
What effect does nicotine have on Parkinson’s and Alzheimers
Parkinson’s Disease; increase brain CYPs → neurotoxins
Alzheimer’s Disease: decrease beta-amyloid toxicity
decrease amyloid precursor protein (APP)
Describe the effect of caffeine on nerves
Binds to A1 receptors on both the pre- and post-ganglionic bulbs
Explain why cocaine’s local anaesthetic effect is more effective intracellularly
- Cocaine diffuses across the nerve to the inside of the cell and access the channel from beneath
- Due to its pKa it is more unionised extracellularly which can diffuse across the plasma membrane
- Once in the nerve cell, it becomes more ionised and can access the inside of the sodium channel
- When cocaine is charged it is a lot better at interacting with its target (sodium channel)
What is the bioavailability for nicotine spray, gum, cigarettes and patches
Nicotine spray - 20-50%
Nicotine gum - 50-70%
Cigarettes - 20%
Nicotine patch - 70%
