13: Drugs of Abuse 1 (Cannabis) Flashcards
Why are “drugs of abuse” abused?
Because they make addictive
–> by stimmulating the reward system in the brain and inducing euphoria
How does the reward system in the brain work?
Which locations does it include?
Neurons originate in the ventral tegmenta area and release dopamine in the nucleus accumbens (in the ventrals striatum)
–> induce good feeling
What are the most common ROA for drugs of abuse?
- Snorting –> intra-nasal (via mucus membranes)
- PO
- Inhalation
- IV
What is the fastes ROA for drugs of abuse (or drugs in general)?
Normally: From fast to slow:
- Inhalation
- IV
- Intra-nasal
- Oral
How could you classify drugs of abuse?
Name examples for each class
- Narcotics/Painkillers
- opiate like drugs e.g. heroin
- Depressants – ‘downers’
- e.g. alcohol, benzodiazepines (valium), barbiturates
- Stimulants – ‘uppers’
- e.g. cocaine, amphetamine (‘speed’), caffeine, metamphetamine (‘crystal meth’)
- Miscellaneous – e.g. Cannabis, Ecstasy (MDMA)
- have partial characteristics of one class but also additional properties
What is the main potent canabidoid in cannabis?
∆9-Tetrahydrocannabinol (THC)
What are the two main cannabidoid in cannabis ?
How is their dose in relation to each other important?
Main active compounent: ∆9-Tetrahydrocannabiol and Canabidiol
- Canabidiol (CBD) is thought to balance the negative effects of THC
Explain the main ROA of Cannabis
What is their respective bioavailibility?
- Oral – 5-15%
- delayed onset/slow absorption
- first pass metabolism
- Inhalation – 25-35%
What are the pharmaockinetic properties of Cannabis?
What does this lead to?
It is very lipid soluble
–> leads to accumulation in the body fat and brain (expecially with choronic use)
–> up to 104:1 body fat to plasma ratio!
Explain the time course of the effects of Cannabis after use and name and explain its t1/2
It is very lipid soluble and accumulates into tissues and slowly gets released over days (up to 30 day) with a t 1/2 of 7 days
- normally after 5 days release from fat is highest
- a substantial proportion of accumulation in fat is thought to be 11-OH-THC
Explain the metabolism of Cannabis
- Phase 1 metabolism in liver –> conversion into
- 11-hydroxy-THC – >more potent than ∆9THC
How is cannabis excreted?
How does this influence its long t1/2?
- 25% is excreted via the urine
- 65% via bile –> but because of high lipid-solubility high rates of enterohepatic recycling
Explain the correlation between plasma Cannabis concentration and level of intoxication
Poor correlation between plasma
cannabinoid concentration and degree
of intoxication (because of accumulation in tissues)
What is the endogenous compound that binds to the Cannabinoid receptors?
Anandamide
What are the different kinds of Cannabinoid receptors?
Where are they located?
- CB1 receptor in brain
- Hippocampus/cerebellum/cerebral cortex/basal ganglia
- CB2 receptors on immune cells
Explain the intracellular response that is set of with cannabis binding to a Cannabinoid receptor
It has an inhibitory effect
- sets of an inhibitory G-protein
- Reduced Adenyly cyclase activity
- reduced cAMP
How does cannabis induce euphoria?
By disinhibition of the GABA-supressed reward system
- Cannabis switsches of GABA inhibition of domamine release in the reward system
What is disinhibition?
The process of activating a system by supressing its inhibition
What is the physiological role of the Anterior cingulate cortex (ACC)?
Normally involved in Error Detection and
Behavioral monitoring and adjustment in order to avoid losses
Explain the function of the Anterior cingulate system in cannabis users
What does it lead to?
It is hypoactive in cannabis users leading to
- decreased ability to regulate and monitor (appropriate) behaviour
Explain the Effects of Cannabis on Food intake
It enhances food intake via
- Disinhibition of GABA increases MCH neuronal activity in lateral hypothalamus –> stimmulates food intake (MCH neurons stimmulatory)
- Increased orexin production
Explain the effects of Cannabis on the Immune system
Mediated by the CB2 receptors
–> Immunusupressant
What are the central effects of cannabis?
- Euphoria
- increased food intake
- psychosis/schizophrenia
- Memory loss
- supressed hippocampus+ limbic regions
- Amnestic effects/↓ BDNF Brain-derived neurotrophic factor
- Impaired Psychomotor performance (cerebral cortex)
What are the peripheral effects of cannabis?
- Immunosuppressant
- Tachycardia/vasodilation (Vanilloid receptor via conjugate)
- Medulla – Low CB1 receptor expression –> does not supress Breathing/CVS !
Why does an overdose with cannabis not cause death?
Medulla – Low CB1 receptor expression
–> no slow down of CVS and breathing
What are the clinical uses of Cannabis?
- Multiple sclerosis/pain/stroke – regulatory increase in CB1 receptors it seen to be helpful physiologically
- Fertility/obesity - pathology
What are Dronabinol or Nabilone?
What is their use and MOA?
∆9-Tetrahydrocannabiod derivate
- CB1 agonists
- used to
- increase appetite (e.g. in chemotherapy patients)
- anti-emetics
What is Sativex?
What is its clinical use?
∆9THC+ CBD agonist
- used as
- analgesic in
- neuropathic pain
- MS-related pain
What is Rimonabant?
What is its clinical use?
It is a CB1 antagonist –> not clinically used anymore
- used to be an anti-obestiy drug
- but associated with depression and increasing suicides
Name drugs that modulate the CB receptors
- ∆9THC
- Dronabinol
- Nabilone
- ∆9THC+CBD
- Sativex
- CB antagonist
- Rimonabant
Which is IV administration of a drug slower thatn inhalation?
It depends on the drug but genereally if its gets into the blood stream right away:
- venous blood has to go to heart first and be pumped around to reach circulation
- Inhalation goes directly to left heart and body (less way to overcome)
