Why are drugs of abuse used?
For euphoria -> cell bodies in the ventral tegmental area which project into nucleus accumbens, releasing DA to induce a euphoric high
What are the methods of admin of drugs of abuse?
Intra-nasal (Mucous membranes of nasal sinuses, slow absorption), oral (GIT, v. slow), inhalation (Small airways and alveoli = rapid), IV (veins, rapid)
What are the classes of drugs of abuse?
Narcotics (opiates - heroin), depressant (alcohol, benzodiazepines, barbiturates), stimulants (cocaine, amphetamine, caffeine, methamphetamine), misc. (cannabis, ecstasy)
What is cannabis?
- From the cannabis sativa plant;
- cannabinoids being the main compound (delta-9 THC is the main compound)
- main part of plant are the trichomes on the plant.
- Main aim of new versions of cannabis are to increase levels of delta-9 THC (seem to increase -ve consequences)
What are the methods of admin of cannabis?
Oral - 5-15% (delayed onset/slow absorption with 1st pass metabolism); inhalation - 25-35% to be absorbed in blood stream
Once in the blood stream, what occurs to cannabis?
- VERY lipid soluble
- Diffuses to highly perfused tissues first and slow accumulation in not well perfused tissues
- slowly accumulated in poorly perfused fatty tissues, with ratio 10^4 fatty tissue : 1 plasma, which will slowly release back into the plasma.
- Distributes also to the brain and sits in the brain tissues for a long time, with prolonged effect as it isn't clearing from the tissues
What occurs to cannabis when broken down?
In the liver - a more potent cannabinoid is formed (11-OH-THC) from the cannabinoid; In the GIT (65%), most of it goes into the bile (to be excreted) so it is recycled in the enterohepatic circulation; excreted 25% via urine. Poor correlation between plasma cannabinoid concentration and degree of intoxication
How long after smoking a cannabis cigarette will the effects persist in the body? 5 hours 12 hours 7 days 30 days 10 years
What are the receptors that cannabis acts on?
- cerebral cortex
- basal ganglia.
- CB2 - on immune cells.
- Acts on adenylate cyclase to inhibit it (hence depressant).
- Body's cannabinoid = endogenous anandamide
- cerebral cortex
- basal ganglia.
What is the pharmacodynamics of euphoria?
- GABA maintains the pathway inhibited to prevent constant euphoria.
- Cannabis depresses the GABA inhibition, inhibiting the inhibition, to increase firing of VTA so NAcc releases more DA
What are the functions of cannabis?
- memory loss (limbic regions with amnestic effects with decreased BDNF),
- psychomotor performance (cerebral cortex),
- tachy/vasodilation (red eyes via vanilloid receptor),
- medulla (low CB1 receptor expression so it is very difficult to OD on cannabis so no decrease to cardioresp centre in medulla)
What does the Anterior cingulate cortex do and what occurs to it with cannabis?
- Involved with performance monitoring with behavioural adjustment in order to avoid losses
- hypoactivity in cannabis users;
- can increase psychosis and schizophrenia
What is the effect of cannabis on food intake?
- Positive effect on orexigenic neurones in lateral hypothalamus
- presynaptic inhibition of GABA increases MCH activity;
- inceased orexin production
How does cannabis cause immunosuppression?
What are the medical uses of cannabis?
- Increased regulation of CB receptors;
- MS/pain/stroke = regulatory;
- fertility = in males with upregulation of CB1 receptors interferes with sperm production;
- and in obesity there is an upregulation of CB1
What are the functions of the drugs that affect the CB receptors?
- Dronabinol/nabilone used as anti-emetic for cancer patients;
- sativex as analgesic for MS;
- rimonobant used for obesity as downregulates hunger but now withdrawn as instances of suicide associated
What is the t1/2 of cannabis and the elimination method?
t1/2= 7d; elimination = synth into 11OH THC - 65% in gut, urine 25%
What is cocaine and the different forms?
Plant derived (erythroxylum coca).
How do you admin cocaine?
Oral isn't a good admin method
How do you metabolise cocaine?
How do cocaine pharmacokinetics contribute to the addictive potential of the drug?
Short elimination time means that it's effects are short lived so want constant admin; also quick method of admin makes it more likely to be admin
What are the functions of cocaine?
- Local anaesthetic,
- reuptake inhibition,
- euphoria -> mild-moderate effects are positive/reinforcing effects and severe effects are negative/stereotypical effects;
- cardiovascular, MI
How does cocaine act as a local anaesthetic?
High dose -> blocks Na channels
How does cocaine act as a reuptake inhibitor?
- Blocks uptake systems so more DA in the synapse
- doesn't affect affinity/efficacy,
- but increase DA in synapse,
- so more present to try to bind to the receptor to outcompete
How does cocaine cause euphoria?
Blocks DA transporter in the NAcc to increase DA in synapse which is released
How does cocaine cause MI/cardiovascular problems?
- With dose increasing as you go down;
- Releases endothelin-1 which increases vasoconstriction;
- CNS effects -> vasoconstriction and hyperpyrexia (caused by increase ANS activation) which can affect epilepsy
What is nicotine?
- From plant;
- present in cigarettes;
- tar droplets deposited in lung and nicotine diffuses through that into the alveoli.
- Nicotine in particulate side
How is nicotine admin?
Cigarettes are acidic and nicotine is alkaline, so is ionised in cig smoke, but then diffuses across the alveoli as the membrane is so thin.
How is nicotine metabolised?
Met by cytochrome P450 in liver (70-80%) into cotinine. T1/2= 1-4h Eliminated via urine
Where does nicotine act?
Acts on ANS nAChR