Pharmacology 13 - Drugs of Abuse 1 Flashcards
Compare the speed of absorption between the administration methods of drugs of abuse
- Snort is slow absorption across the mucous membranes of nasal sinuses (veins through the heart then to the brain)
- Eating is GI, very slow absorption
- Smoking via small airways and alveoli, rapid absorption (fastest route)
- Injection is rapid
How are drugs of abuse classified?
- Narcotics/painkillers - opiate like drugs eg. heroin
- Depressants (downers) eg. alcohol, benzodiasepines, barbituates
- Stimulants (uppers) eg. cocaine, ampheramine, caffiene, metamphetamine
- Miscellaneous eg. cannabis, ecstasy
List the constituents of cannabis
- Cannabinoids - mostly trichomes (extracted with solvent to form hash oil)
- Delta 9-tetrahydrocannabinol most powerful, cannabidiol also very abundent
Describe the pharmacodynamics of cannabis
- CB1 (cannabinoid 1) receptors in the hippocampus, cerebellum, cerebral cortex and basal ganglia.
- CB2 receptors on immune cells - peripherally
- CB receptors are negatively coupled to adenylate cyclase via G1 proteins
- Anandamide is the endogenous molecule that binds to these receptors
How does cannabis cause schitzophrenia/ psychosis?
- Anterior cingulate cortex is involved in error detection, performance monitoring and behavioural adjustment in order to avoid losses (ensure the best outcomes by redirecting cognitive processes)
- Hypoactivity in cannabis users, therefore the ability to monitor and change behaviour decreases
How does cannabis affect food intake?
- Positive effect on orexigenic neurones in the lateral hypothalamus
- Presynaptic inhibition of GABA increases MCH neuronal activity and increases orexin production
- Increased orexin increases food intake and hunger
How does cannabis act as an immunosuppressant?
- CB2 receptors found on immune cells
- Cannabis can influence NK cells, T and B lymphocytes, mast cells and macrophages
- Depresses activity in these cells
How are CB1 receptors altered in disease?
- Increased regulation of CB receptors occurs in disease
- MS, pain and stroke can be regulatory (elevation of CB1 receptors, which has protective effect in the body)
- Fertility and obesity CB1 receptors increase, which seems to lead to an increase in that pathology (decrease testosterone, inhibit pituitary gland, interfere with sperm production)
List the effects of cannabis
- Euphoria
- Tachycardia/ vasodilation (via TRPV1)
- Immune suppression
- Psychosis/ schitzophrenia
- Memory loss
- Psychomotor performance
- Increased food intake
Why are drugs abused?
- Euphoria
- Neuron from ventral tegmental area in the substantia nigra to the nucleus accumbens in the thalamus
- Release of dopamine results in euphoria (mesolimbic dopamine system)
Describe dosing and bioavailability of cannabis
- In the 60s and 70s there would be 10mg THC, now 150mg to 300mg THC
- When taken orally, delayed onset, slow absorption and first pass metabalism (5-15% bioavailability)
- Inhalation faster (25-35% bioavailability, as when you inhale a drug most the time you breathe out 50% of the drug, and the drug needs to get deeply into the lungs)
How does increased THC effect outcomes?
- As THC conc increases, there is an increase in negative effect rather than positive effect
- Thought that cannabidiol moderates some negative effects of THC
Describe distribution of cannabis
- Inhaled, passes round the blood and can diffuse into any tissue
- Cannabis is very lipid soluble, so will diffuse into the tissues with higher blood supply (therefore brain receives cannabis quickly, and cannabis builds up here too as the brain is fatty)
- Adipose tissue is poorly perfused, however as cannabis is very lipid soluble it will slowly accumulate in fatty tissues in chronic users. It will then slowly leak back into the blood
- 100000:1 fatty tissue to plasma
Describe metabolism of cannabis
- Liver 11-hydroxy-THC is the phase 1 metabolite
- This is more potent than the THC in cannabis itself.
Describe excretion of cannabis
- Enterohepatic recycling in GIT (65% - excreted into bile, absorbed in the gut, and then recycled through the blood to the liver)
- Therefore, there is poor correlation between plasma cannabinoid concentration and degree of intoxication
- Urine (25%)
How long after smoking a cannabis cigarette will the effects persist in the body?
30 days
How does cannabis cause euphoria?
- Cannabis binds to CB1 receptors on GABA interneurones, which are depressant and slow activity of GABA neurones (disinhibition)
- Therefore, this removes inhibition on the VTA neurons and increases dopamine release from the nucleus accumbens
How does cannabis cause memory loss?
- By effects on the limbic regions
- Amnestic effects by decreasing brain derived neurotrophic factor (BDNF increases memory formation)
Why is it important that there is low CB1 receptor expression in the medulla?
- Medulla is where cardiovascular and respiratory control occurs
- Therefore, cannabis does not cause cardiorespiratory failure and overdose does not cause death
Give examples of drugs that act on CB1 receptors
- Delta9-THC (dronabinol and nabilone)
- Delta9-THC and CBD (sativex)
- Antagonists (rimonabant)
What are dronabinol and nabilone used for?
- Used to stimulate appetite (in AIDS patients or those who have undergone chemotherapy)
- Prevent feelings of nausea (anti-emetic)
What is sativex used for?
- Analgesic
- Neuropathic pain
- Multiple sclerosis
What is rimonbanant used for?
- Blocks the effects of CB1 receptors (antagonist - inverse agonist)
- Anti-obesity agent (decreases weight)
- However, it was associated with suicide use and therefore is not used anymore
What is fatty acid amide hydrolase?
The enzyme that metabolises anandimide, which could be blocked to increase anandimide and treat pain
