DOA 2 - Cocaine/Nicotine Flashcards
History of cocaine?
Cocaine/Erythroxylum coca
• leaves contain 0.6-1.8% cocaine
Explain the forms of cocaine
Gets PURER/STRONGER as you go down:
- ‘Paste’ - 80% cocaine (ORGANIC SOLVENT)
- ‘Cocaine HCl’ - dissolved in ACIDIC SOLUTION
- ‘Crack’ - precipitated with ALKALINE SOLUTION (e.g. baking soda)
- ‘Freebase’ - dissolved in a NON-POLAR SOLVENT (e.g. ammonia + ether)
How are the different forms of cocaine taken?
Oral, IV, Intranasal
• Paste
• Cocaine HCl
Inhalation
• Crack
• Freebase
Explain the adminisatrion of cocaine in terms of pharmacokinetics
IV
• a FAST ONSET of action
• SHORT-LASTING high
Oral, nasal & smoking
• SLOWER ONSET/ absorption
• pKa = 8.7 SO oral cocaine is ionised in GIT
- less can be absorbed as cannot cross membrane
- i.e. if high pKa, unionised in alkaline, ionised in acidic
• PROLONGED action
Explain the metabolism of cocaine
75-90% is metabolised very FAST into:
• Ecogonine methyl ester
• Benzoylecgonine
(NOT active)
T1/2 = 20-90mins
Can be metabolised in the blood via
• plasma & liver cholinesterases
How do you think that cocaine pharmacokinetics contribute to the addictive potential of the drug?
FAST onset & SHORT half-life
Lots of methods to take the drug
Main pharmacodynamics effects of cocaine?
Local anaesthetic
Re-uptake inhibition
Euphoria
Explain the pharmacodynamics of cocaine as a LA
High-dose cocaine
• can BLOCK the Na+-channels to cause a LA effect
• inhibits conduction of AP
Needs to be taken into the neurone and work on the channel from the inside
• pKa of cocaine is 8.74, whilst the pH outisde = 7.4 & inside = 7.0
• outside the neurone, cocaine is unionised (as pH closer to pKa) so can move into the neruone
• once inside the neurone, it is ionised (+ve charge) so can work of the channel
• CHARGED COCAINE interacts with the target BETTER
Explain the pharmacodynamics of cocaine as a re-uptake inhibitor
Low-dose cocaine
• MOA-A re-uptake inhibitor (uptake 1)
Can affect the re-uptake of NA, DA, 5-HT
• with NA, particularly the NA reuptake transporter
Does cocaine influence dopamine affinity/efficacy for the dopamine receptor?
NO
As only increasing the no. of DA in the synaptic cleft
• will still bind to receptors (affinity) & cause a reaction (efficacy) so simply just increasing the receptor interactions
Explain the pharmacodynamics of cocaine and its euphoric effect
REDUCES re-uptake of DA into the pre-synaptic neurone
• BLOCKS the dopamine transporter
• SO more DA in the NAcc (from the VTA)
What are other pharmacodynamic effects of cocaine?
Harder to distinguish due to its generalised effect on MONOAMINES (DA, NA, serotonin etc)
Acute-use - mild/moderate effects
• Initially positively reinforcing effects such as mood amplification & heightened energy
BUT FLIPS TO
Chronic use - severe effects
• Tend to then start to exhibit severe effects such as total insomnia & decreased libido
Two main -ve effects of cocaine use?
Cardiovascular (MI)
CNS - Hyperthermia
Explain the pharmacodynamics behind the cardiovascular effects of cocaine?
Increased SNS output
Increased catecholamines (via effect on monoamine uptake)
• increases O2 demand on heart (as can lead to coronary vasoconstriction, endothelial injury, atherosclerosis)
• results in ischaemia of the heart muscle
Also leads to inflammation & reduced Na+ transport
• reduces L-ventricle function which can lead to arrhythmias & sudden death
Explain the pharmacodynamics behind the CNS effects of cocaine
HYPERthermia
• increased agitiation, locomotor activity & involuntary muscle contraction INCREASES body temperature
• coupled w. HOT ENVIRON. can lead to hyperthermia
Mechanisms used to stop it can include
• sweat production
• cutaneous vasodilation
• central threshold for thermoregulation
How would you expect cocaine to influence sweat production and cutaneous vasodilation?
Both are related to ACh as moderates its effects so cocaines effects may not be as useful (as effects NA)
• tends to INHIBIT cutaneous vasodilation
• tends to ENHANCE sweat production
Cocaine also elevates threshold for sweating/cutaneous vasodilation X3
What do cigarettes produce?
95% volatile substances • Nitrogen • CO/CO2 • Benzene • HCN
5% PARTICULATES
• Alkaloids e.g. NICTOINE
• Tar
- Nicotine diffuses OUT of the tar droplets in the lungs when deposited
Explain the dosing of nicotine in terms of the different forms it can be administered in
• Nicotine spray - 1mg
- 20-50% effective
• Nicotine gum - 2-4mg
- 50-70% effective
• Cigarettes - 9-17mg
- 20% effective
- pKa = 7.9 SO cigarette smoke is ACIDIC so NO buccal/mouth absorption
- absorption in the ALVEOLI is INDEPENDENT of pH however
• Nicotine patch - 15-22mg
- 70% effective
How does nicotine lead to addiction?
Again similar to cocaine
• SHORT-LASTING action
&
• FAST REDUCTION in [plasma]
Explain the metabolism of nicotine in terms of pharmacokinetics
T1/2 = 1-4hours
Hepatic CYP-2A6 metabolises 70-80%
• into COTININE
• NOT active & RAPIDLY cleared
Difference in metabolism between cocaine & nicotine?
Cocaine CAN BE metabolised in the BLOOD
• Nicotine can NOT
HENCE why cocaine is metabolised FASTER
Explain the pharmacodynamics behind nicotine
Nicotine binds to NICOTINIC receptors
• found on ACh receptors (onenote!!)
• stimulates Na+ transport
Using pharmacodynamics, explain how nicotine can cause euphoria
nAChRs are found on the soma of the DA nuclei in VTA
• stimulation of these receptors stimulates DA release in the NAcc
This is DIFFERENT to cocaine which works on DA reuptake whilst nicotine is DIRECTLY affecting the nerve
Using pharmacodynamics, explain the cardiovascular effects of nicotine
Stimulation of the nAChRs leads to SNS activation & increased catecholamines (as stimulating ACh receptor)
• affects CNS & adrenals
• increases HR & SV
• vasoCONSTRICTION of skin arterioles
• vasoDILATION of coronary arterioles, skeletal muscle arterioles
(similar effects to cocaine then = MI)
Also INCREASES lipolysis, FFAs, VLDLs DECREASES HDL INCREASES TXA2 DECREASES NO • long-term use = CVD
Using pharmacodynamics, explain the metabolic effects of nicotine
Nicotine leads to
• INCREASE in metabolic rate
&
• DECREASED appetite
SO after STOPPING smoking, can lead to WEIGHT GAIN (no longer have faster metabolism)
Using pharmacodynamics, explain the neurodegenerative disorders associated with nicotine and if it is a good/bad thing
Parkinson’s disease
• INCREASE in brain CYPs (neurotoxin enxymes)
• INCREASES BREAKDOWN of these neurotoxins (which normally cause Parkinson’s)
Alzheimer’s disease
• DECREASE beta-amyloid toxicity
&
• DECREASES APP (amyloid precursor protein)
SO nicotine seems to be PROTECTIVE against both diseases
How does caffeine cause euphoria?
By BLOCKING A1 receptors
ADENOSINE acts of its A1 receptors
• found ON the NAcc & the D1R
• INHIBITING the reward pathways
Caffeine hence BLOCKS these A1 receptors
• STIMULATING the rewards pathway
ONENOTE!!
