Drugs of abuse 1 - General/Cannabis Flashcards
Generally speaking, how do the drugs of abuse cause the feeling of euphoria?
The hijack the mesolimbic dopaminergic pathway – the central reward pathway
Describe the central reward pathway.
The dopaminergic neurones project from the ventral tegmental area to the nucleus accumbens
Dopamine release into the nucleus accumbens will stimulate the feeling of euphoria
Put the routes of administration of drugs in ascending order of speed of absorption/onset of euphoria
Oral < Intranasal (snorting) < Intravenous < Inhalation (smoking)
Why is the speed of absorption/onset of euphoria for smoking/inhalation slightly quicker than IV injections?
Smoking brings the drug to the alveoli where it easily crosses the alveoli and enters the pulmonary circulation
There is a shorter distance from the pulmonary circulation to the heart and then to the brain than from the site of IV injection to the heart and then to the brain
What is an alkaloid?
Any class of nitrogenous organic compound of plant origin that has profound physiological actions on humans
What are the active components of the Cannabis sativa plant?
Cannabinoids (there are over 60 of them in the plant)
1) What is the most potent cannabinoid in the plant?
2) What is another important cannabinoid that appears to counteract some of the negative effects of this potent cannabinoid?
Delta-9-tetrahydrocannabinol (Delta-9-THC)
Cannabidiol
How has cannabis production changed over the last 10-15 years? Why is this relevant?
There has been an increase in the amount of 9-THC in the cigarette meaning that there is less cannabidiol
This suggests that cannabis production is heading towards being more pro-psychotic
Describe the bioavailability of cannabis for the oral and and inhaled routes of administration?
Oral = 5-15% Inhalation = 25-35%
Describe the accumulation of cannabis in the brain following administration.
Cannabis levels in the brain rise very quickly after administration but, because the brain is highly perfused, the cannabis levels in the brain fall rapidly as well
Describe the accumulation of cannabis in fat following administration.
Cannabis (as well as its metabolites) is very lipid soluble so it slowly accumulates in the fat - ratio of concentration in fat to plasma = 10^4 : 1
This means that cannabis will leak from the store in the fat for a long time after administration
Note: intensive accumulation occurs in less vascularised tissues and finally body fat
What is an important metabolite of cannabis?
11-hydroxy THC (this is more potent than Delta-9-THC)
What happens to this metabolite once it has been produced?
It is excreted in the bile into the GI tract but then it undergoes enterohepatic recycling and re-enters the blood stream where it can exert its physiological effects
Because of this, plasma Delta-9-THC levels are a poor measure of intoxication
Urine excretion (25%) Gut excretion (65%)
Where are the different cannabinoid receptors found?
CB1 – brain (Hippocampus/cerebellum/
cerebral cortex/basal ganglia)
CB2 – peripheral immune cells
What type of receptor is the cannabinoid receptor?
Inhibitory G protein coupled receptor (i.e. negatively coupled with adenylate cyclase) => depressive effects
Name an endogenous cannabinoid.
Anandamide
Summarise the mechanism by which cannabis causes euphoria
Cannabis binds to CB1 receptors expressed by GABA interneurons => removal of the inhibitory influence of GABA interneurons on the dopaminergic neurones of the reward pathway => increased firing
(i.e. inhibiting the inhibition)
What area of the brain does cannabis interact with that is linked to its psychotic effects?
What is this part of the brain responsible for?
Anterior Cingulate Cortex
- Involved with performance monitoring with behavioural adjustment in order to avoid losses
- There is hypoactivity in the anterior cingulate cortex in chronic cannabis users
What effect does cannabis have on appetite/food intake, and why?
Positive effect on orexigenic neurones in lateral hypothalamus;
1. Presynaptic inhibition of GABA increases MCH neuronal activity
2. Increased orexin
production
What effect does cannabis have on the immune system?
Cannabis is a powerful immunosuppressant
How does cannabis cause memory loss?
It decreases the production of BDNF (brain derived neurotrophic factor), which is important in the hippocampus in forming memories
In general, cannabis has a depressant effect on the hippocampus
How does cannabis cause impaired psychomotor performance?
Depressives effect on the cerebral cortex
State and explain another peripheral effect of cannabis
Causes tachycardia, and vasodilation (especially in the conjunctivae - blood shot eyes)
- Cannabis acts via the TRPV1 receptor to cause calcium influx
Why is it not possible to overdose on cannabis?
There is very low expression of CB1 in the medulla (which is where you find the cardio-respiratory centres)
Up-regulation of endogenous cannabinoids and CB1 receptors is involved in what in terms health and disease?
Multiple sclerosis/pain/stroke (regulatory)
Fertility/obesity (pathology)
State 4 drugs that are either cannabinoid agonists or antagonists.
Dronabinol - Delta-9-THC
Nabilone - Delta-9-THC
Sativex - Delta-9-THC + cannabidiol
Rimonabant – CB1 antagonist
What can cannabinoid receptor agonists be used for?
Treatment of nausea due to chemotherapy
What is Sativex used for?
Symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis
What can Rimonabant be used for?
Anti-obesity medication (removed because it was shown to cause depression and suicidal thoughts)
Half-life of cannabis?
7 days
