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Pharmacology > Drugs of abuse - cannabis > Flashcards

Drugs of abuse - cannabis Flashcards

1
Q

What is the pathway responsible for why people abuse drugs?

A

The reward pathway - mesolimbic dopamine pathway

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2
Q

Describe the mesolimbic dopamine pathway

A

The reward pathway is a collection of dopaminergic neurones that originate in the ventral tegmental area (this is where the cell bodies are), and project down to the ventral striatum (in particular, an area called the nucleus accumbens). Dopamine is released and causes a feeling of reward.

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3
Q

What causes euphoria?

A

Excessive dopamine release within the nucleus accumbens

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4
Q

What are the routes of admission of cannabis?

A
  • snorting (intranasal)
  • eating/drinking (oral)
  • smoke (inhalation)
  • inject (intravenous)
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5
Q

Describe the route that cannabis takes when snorted (inhaled)

How fast is absorption?

A

Drug enters nasal sinus -> venous drainage -> lung -> heart -> brain

  • Mucous membranes of the nasal sinuses will slow absorption
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6
Q

Describe the route that cannabis takes when taken orally

How fast is absorption?

A

Stomach -> small intestine -> portal system -> liver -> heart -> brain

  • There is very slow absorption due to the GI tract
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7
Q

Describe the route that cannabis takes when inhaled

How fast is absorption?

A

Lungs (right next to the heart) -> heart -> brain

  • Rapid absorption (seconds)
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8
Q

Describe the route that cannabis takes when injected

How fast is absorption?

A

Vein -> heart -> brain

  • Rapid absorption (seconds)
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9
Q

Via which route will cannabis enter the brain the fastest?

A

INHALATION - inhaling is slightly faster than intravenous as the lungs drain into the left side of the heart so it doesn’t have to travel through both sides unlike intravenous. Also alveoli aren’t a barrier to diffusion.

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10
Q

What are the the different classifications of drugs of abuse?
Give examples of each

A

Narcotics/Painkillers – opiate like drugs e.g. heroin

Depressants – e.g. alcohol, benzodiazepines (valium), barbiturates

Stimulants – e.g. cocaine, amphetamine (‘speed’), caffeine, metamphetamine (‘crystal meth’)

Miscellaneous – e.g. Cannabis, Ecstasy (MDMA

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11
Q

What is the compound in cannabis that causes the effect?

What is the most powerful cannabinoid?

A

cannabinoids

tetrahydrocannibol (delta 9- THC)

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12
Q

Where in the plant are cannabinoids most concentrated?

A

glandular hairs of the plant

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13
Q

What happens as the dose of THC is increased?

A

As you increase the dose of THC, a greater effect is seen (in terms of both positive symptoms and negative symptoms), however the effect is much greater in terms of negative symptoms.

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14
Q

What are the most common routes of cannabis administration?

A

oral or inhaling

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15
Q

What % of cannabis enters the blood from inhaling and oral consumption and why?

A

oral - 5-15% (slow absorption and first pass metabolism)
inhaling - 25-35% (anything inhaled suffers 50% loss automatically as only that much gets far enough into lungs to be absorbed and lots breathed back out)

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16
Q

Describe the pharmacokinetics of cannabis, where can it accumulate and why?

A
  • Cannabis is very lipid soluble, which can cause a few problems
  • It accumulates in poorly perfused fatty tissues

Lungs -> bloodstream -> most of the cannabis goes to well perfused tissues

  • However, adipose tissue receives a bit of CO so very lipid soluble drugs can diffuse into fat
17
Q

What does adipose store from the cannabis? Is it long or short term storage and what does this mean?

A
  • As cannabis traverses the blood, it diffuses out over time and into high perfusion tissue
  • Low perfusion tissue (fat) begins to accumulate cannabis slowly
  • Fat tissue acts as a store
  • Intensive accumulation occurs in less vascularised tissues and finally in body fat (major long-term storage site), resulting in concentration ratios between fat and plasma of up to 10^4:1 - The products stored include: THC, its hydroxy metabolites, fatty acid conjugates of 11-OH-THC
18
Q

What is one of the metabolites of THC? Is it more or less potent that delta 9 THC?

A

11-hydroxy-THC

MORE POTENT

19
Q

Why does the cannabis take a long time to be cleared from the body (besides it being stored in adipose)?

A
  • A large amount of cannabis is secreted by the bile (enterohepatic recycling)
  • Therefore, it ends up going down the bile duct -> small intestine -> potential reabsorption
  • 65% of 11-hydroxy-THC is secreted into the gut, which is then heavily reabsorbed back into the system
  • Eventually, you will clear the cannabis (urine loss accounts for 25%)
20
Q

How long will cannabis remain after smoking a cigarette?

A

30 days

21
Q

Is plasma cannabinoid concentration a good indicator of intoxication level?
Why?

A
  • There is a very poor correlation between plasma cannabinoid concentration and degree of intoxication
  • In post-mortems of chronic cannabis users there is a small amount of THC and its metabolites in the blood
  • When we look at the brain tissue however, this amount increases dramatically. The brain is a very fatty tissue, so if you chronically use cannabis, it will accumulate in the brain
22
Q

What do cannbinoids act on?

A
  • We have an endogenous cannabinoid system – the body produces cannabis-like substances
  • They are Gi coupled receptors
  1. CB1 RECEPTORS: predominantly brain (hippocampus, cerebellum, cerebral cortex, basal ganglia
  2. CB2 RECEPTORS: predominantly on immune cells in the periphery

Cannabis is a depressant at cellular level -> downregulates adenylate cyclases

23
Q

What is the endogenous substance acting on cannabinoid receptors?

A

Anandamide – behaves like cannabis

Anandamide binds to receptors -> G-protein is negatively coupled to adenylate cyclase

24
Q

What happens when CB1/2 are activated?
What happens when CB1 is stimulated?

HINT: GABA and dopamine

A
  • Induction of euphoria
  • Stimulation of the CB1 receptor will switch off and blocks GABA transmission
  • Normally GABA suppresses the reward pathway – when the reward pathway needs to be activated, GABA is inhibited
  • Cannabis hijacks this system
  • There are lots of CB1 receptors on GABA neurones
  • Cannabis binds -> reduces firing rate of GABAergic neurones (depressant) -> dopaminergic neurone firing increases -> euphoria
25
Q

What are some serious effects of cannabis?

A

psychosis, schizophrenia

26
Q

What does the anterior cingulate cortex normally do?

A
  • It is a part of the brain that has various functions. It is important in error detection and it is very important in terms of monitoring behaviour. The ACC is heavily involved with performance monitoring with behavioural adjustment in order to avoid losses (to ensure that good things happen).
27
Q

What happens to the ACC in cannabis users?

A

Hypoactivity - they cannot adjust their behaviour appropriately (element of psychosis)

28
Q

How does cannabis affect appetite?

A
  • Cannabis has a positive effect on orexigenic (increases appetite) neurones in lateral hypothalamus
  • The arcuate nucleus has two populations of neurone: one that stimulates appetite (AgRP) and one that inhibits appetite (POMC). They send signals to either the lateral hypothalamus (stimulates eating) or ventromedial hypothalamus (inhibits eating)
  • Cannabis therefore leads to:
  1. Presynaptic inhibition of GABA -> increases MCH neuronal activity (in lateral hypothalamus)
  2. Increased orexin production (in lateral hypothalamus)

Cannabis switches off GABA -> more firing of MCH. Cannabis also has a direct stimulatory effect on appetite increasing neurones

29
Q

What are the 3 main parts of the appetite regulation system in the brain?

A

Arcuate nucleus -> gets signals from periphery and determines what happens
It then sends signals to either:

  • lateral hypothalamus (stimulates eating)
  • ventromedial hypothalamus (inhibits eating)
30
Q

What happens to the immune system of cannabis users?

A
  • CB2 receptors are found in the periphery on immune cells -> down regulation of immune response
  • Cannabis affects the activity of NK cells, macrophages, mast cells, T lymphocytes and B lymphocytes
  • Chronic cannabis users have an impaired immune system
31
Q

What are the effects of cannabis use?

A

Psychosis, Schizophrenia, food intake affected (Hypothalamus), memory loss (limbic system), psychomotor performance affected (cerebral cortex)

Peripheral effects: Immunosuppressant, tachycardia/vasodilation (conjunctivae – bloodshot eyes)

32
Q

What is the importance of there being low CB1 receptor expression in the medulla?

A

The medulla contains the cardio-respiratory centre. Whereas substances such as alcohol and heroin have profound effects in the medulla (-> death), cannabis doesn’t have this effect. It’s therefore very difficult to die from cannabis.

33
Q

When may CB receptor numbers change in the body? Is this good or bad?

A
  • There is upregulation of CB receptors in many disease processes
  • This can be positive (e.g. multiple sclerosis/ pain/stroke – regulatory effect – CB receptors are trying to compensate for the disease process)
  • In some cases, the upregulation of CB receptors is directly contributing to the pathology (fertility/obesity)
34
Q

Give examples of cannabis agonist/antagonist used in medicine

A

AGONISTS OF CANNABIS:

  • Dronabinol and nabilone have a primary use to either prevent nausea in chemotherapy patients or to stimulate appetite in AIDS patients or cachectic patients
  • Sativex is an analgesic used in multiple sclerosis for example

ANTAGONIST:
- Rimonabant was one of the first anti-obesity agents to target the cannabinoid receptor. It was decent, but the problem was its propensity to cause depression, and suicide (so it was pulled).

35
Q

What are fatty acid amide hydrolases?

A

Enzymes that break down endogenous cannabinoids

36
Q

What is cannabidiol?

A

A cannabicnoid that is believed to have a protective effect from the negative effects by THC - regulates the effects

37
Q

Where does cannabis come from?

A

cannabis sativa plant

38
Q

How has the concentration of cannabis in cigarettes for example changed?

A
  • Over the last few decades, the potency of cannabis has become a lot greater
  • Cannabis cigarettes in the 60s will probably have contained 10mg of total THC
  • In the last 10/20 years, the farming methods have changed to try and concentrate THC
  • More recent versions of cannabis are far more concentrated in Δ9-THC (150mg/300mg + hashish oil)

Pharmacology (26 decks)

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