12. Drugs of abuse 1 Flashcards
Why do people abuse drugs?
• Centred on reward pathway - mesolimbic dopamine system
• Collection of dopaminergic neurones:
- originate in the ventral tegmental area (cell bodies)
- project down to the ventral striatum (nucleus accumbens)
• Dopamine release
• Feeling of reward
- Lots of stimuli e.g. food, induce reward
- Drugs of abuse hack this - excessive dopamine release
Describe 4 different routes of administration for drugs?
Snort (intranasal)
• drug enters nasal sinus
• mucous membrane slows absorption
• venous drainage => lung => heart => brain
Eat or drink (oral)
• stomach
• small intestine => portal system => liver => heart => brain
Smoke (inhalation)
• lungs => heart => brain
• rapid absorption
Inject (IV)
• vein => heart => brain
• rapid absorption
Which route of administration leads to the fastest drug effect in the brain and why?
- Inhalation
- Close to IV time
- Lungs are right next to the heart
- Alveoli are not much of a barrier to diffusion
What are 4 of the classifications of drugs of abuse?
- Narcotics/painkillers - opiate like drugs
- Depressants - alcohol, benzodiazepines
- Stimulants - cocaine, amphetamine
- Miscellaneous - cannabis, ecstasy (MDMA)
What is an alkaloid?
- Class of nitrogenous organic compound of plant origin
- Has pronounced physiological actions on humans
- Includes drugs (morphine, cannabis) and poisons (atropine)
What are the compounds that produce the high effect when smoking cannabis?
Cannabinoids
What is the most potent cannabinoid?
Δ9-tetrahydrocannabinol (Δ9 -THC)
Which part of the cannabis sativa plant are cannabinoids most concentrated in?
- Glandular hairs of the plant (trichomes)
* Hashish/resins
How has the potency of cannabis changed over the last few decades?
- Has become greater
- Cannabis cigarettes in 60s contained 10mg THC
- Farming methods have concentrated THC in last 10/20 years
- More recent version have 150mg/300mg THC + hashish oil
How do positive and negative effects of THC change with increased dose?
- Both positive and negative effects increase
* However, effect is much greater with negative effects
What are the routes of administration of cannabis and how are they different?
Inhalation
• 25-35% enters blood
• 50% lost automatically, as only this amount gets far enough into the lungs to diffuse into the blood
• Lots breathed out
Oral
• 5-15% enters blood
• delayed onset/slow absorption (first pass metabolism)
Describe the solubility of cannabis in lipids and the effect this has
• Very lipid soluble
• Most cannabis goes to very well perfused tissues e.g. brain
• However, it can still accumulate in poorly perfused fatty tissues:
- unaltered THC and its hydroxy metabolites
- substantial portion consists of fatty acid conjugates of 11-OH-THC - very potent
• Therefore there is a poor correlation between plasma conc. and degree of intoxication
• Can accumulate in the brain after chronic use as it’s a fatty tissue
Describe 11-OH-THC and its clearance
- Major metabolite of THC
- More potent than Δ9 -THC
- Metabolism can’t deactivate it
- End up going down bile duct => small intestine => potential reabsorption
- 65% secreted into gut
- 25% lost in urine
- All of the drug eventually cleared
What is the half life of cannabis and how long will the effect persist after smoking?
- Half life - 7 days
* Effects persist for around 30 days
What is the most prevalent cannabis-like substance that the body produces?
Endogenous anandamide
What are the targets for anandamide?
- CB1 receptors - predominantly brain (hippocampus, cerebellum, cerebral cortex, basal ganglia)
- CB2 receptors - predominantly immune cells in the periphery
How does anandamide affect the CB receptors?
- G-protein negatively coupled to adenylate cyclase
* Down-regulates adenylated cyclase => depressant
How does cannabis cause euphoria?
- GABA exerts a negative influence on the dopaminergic neurones of the central reward pathway
- Cannabis binds to CB1 on GABA neurones and switches off its function
- Loss of inhibitory influence over dopaminergic pathway
- Dopaminergic neurones start firing
- Euphoric effect
Describe how cannabis affects appetite
- Positive effect on neurones in the lateral hypothalamus
- There are orexinergic and melanin concentrating hormone (MCH), both involved in stimulating appetite
- Cannabis inhibits GABA neurones, which regulate (inhibit) MCH neurones
- Therefore MCH neurones are less inhibited
- Cannabinoids also directly stimulate orexin production - stimulating appetite
Describe how chronic cannabis use affects the immune system?
- CB2 receptors found in the periphery, on immune cells
- Down-regulation of immune response
- Anti-inflammatory effects
- Causes immunsuppression
List all the effects of cannabis use
- Euphoria
- Food intake
- Memory loss
- Psychosis
- Schizophrenia
- Psychomotor performance
Peripheral
• Immunosuppression
• Tachycardia
• Vasodilation (particularly in the conjunctivae)
Which part of the brain does cannabis affect to cause memory loss?
- Limbic regions
- Especially the hippocampus
- Decreased BDNF (brain derived neurotrophic factor) effects - allows formation of memories
Why is it very difficult to die from cannabis, but easier to die from alcohol and heroin (with reference to the brain)?
- Very low CB1 receptor expression in the medulla
- Medulla contains the cardio-respiratory centre
- Alcohol and heroin have profound effects in the medulla
- Can lead to coma and death if cardio-respiratory centre is depressed
Explain the up-regulation of CB receptors and endocannabinoids in certain disease processes?
Positive
• e.g. MS, pain, stroke
• compensate for disease by down-regulating pain and spasticity
- reduces inflammation in post-stroke ischaemia
Negative
• can directly contribute to the pathology in some cases e.g. fertility and obesity
