Drugs of abuse 1: General drugs & Cannabis Flashcards

1
Q

Why are certain drugs abused?

A

They induce euphoria (feeling of intense happiness)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

How do drugs induce euphoria?

A

The reward system

  • Dopaminergic neurones from the ventral tegmental area (VTA) project to the nucleus accumbens (NAcc)
  • Dopamine release at the nucleus accumbens stimulates feelings of reward and happiness
  • Essentially this pathway is activated by any stimuli which make you feel happy and rewarded
    • Examples:
      • Food
      • Money
      • Social interaction

Drugs can also stimulate the reward system in the brain → euphoria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the different routes of administration for drugs of abuse?

A
  • Intranasal (snort)
  • Oral (eat)
  • Inhalational (smoke)
  • Intravenous (inject)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Describe how fast the drug would have an effect on the brain with each route of administration.

A

REMEMBER:

  • To have an effect on the brain, the drug needs to enter the systemic circulation
    • Arterial part of the circulation as it has to supply the brain
  • So the drug which is first absorbed into the bloodstream will reach and have its effect on the brain the fastest

Routes of administration

  • Intranasal (snort)
    • The drug has to be absorbed through the mucous membranes of the nasal sinuses
      • This absorption is slow
  • Oral (eat)
    • The drug has to be absorbed through the walls GI tract
      • This absorption is very slow
  • Inhalational (smoke)
    • The drug has to be absorbed through the alveoli
      • This absorption is rapid
  • Intravenous (inject)
    • The drug is injected straight into the veins so doesn’t even need to be absorbed
      • Rapid

Pathway to the brain

Oral, intranasal, IV:

  • Once absorbed, the drug enters the venous system
    • Or in the case with IV, the drug is directly injected into the venous sytem
  • Venous system → RA → RV → lungs → LA → LV → arterial system → brain
  • Therefore, the quicker the drug is absorbed into the venous system, the faster the drug will have its effect on the brain
  • So out of these 3 routes of administration, fastest → slowest:
    • IV → intranasal → oral

Inhalational:

  • This is the fastest to have an effect on the brain
  • Alveoli → LA → LV → arterial system → brain
    • You are skipping the whole venous system → RA → RV part which means that it gets to the lungs faster
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

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

A
  • Narcotics/painkillers - opiate-like drugs
    • EXAMPLE:
      • Heroin
  • Depressants (‘downers’)
    • EXAMPLES:
      • Alchohol
      • Benzodiazepines (valium)
      • Barbiturates
  • Stimulants (‘uppers’)
    • EXAMPLES:
      • Cocaine
      • Amphetamine (‘speed’)
      • Caffeine
      • Metamphetamine (‘crystal meth’)
  • Miscellaneous
    • EXAMPLES:
      • Cannabis
      • Ecstasy (MDMA)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Describe where the drug cannabis comes from.

A

Cannabis = marijuana

The whole Cannabis sativa plant contains:

  • Over 400 compounds - within which there are…
  • Over 60 cannabinoids
    • Cannabinoids = the active component which acts on cannabinoid receptors in the body
    • Highest concentration of cannabinoids in the trichomes (glandular hairs) of the plant

Drug extraction:

  • Trichomes are secretory in function
  • Substances secreted by plants is known in general as resin
    • Hashish is a cannabis concentrate made from the resin of the cannabis plant
  • Hash oil is also a cannabis concentrate, where extraction from the plant involves a solvent
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

State two major cannabinoids.

A

Δ9-Tetrahydrocannabinol (Δ9-THC)

  • This is the most potent cannbinoid

Cannabidiol

  • This moderates some of the negative effects of Δ9-THC
    • Protective in function
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe how the dose of cannabinoids extracted from a Cannabis sativa plant has changed over time. Describe the effect this has on the drug user

A

Before (60s and 70s):

  • From a plant you would be able to extract 10mg of Δ9-THC

Nowadays:

  • Various forms of the Cannabis sativa plant have been farmed so that a higher dose of Δ9-THC can be exracted from them - 150-300mg

Increase in Δ9-THC dose = more powerful drug effect

  • However, these farmed forms of the plants also have a lower proportion of cannabidiol
    • Increased the amount of Δ9-THC at the expense of cannabidiol
  • This means that you have essentially lost the protective effect of cannabidiol

Increase in Δ9-THC dose leads to increase in negative effects

  • Δ9-THC has negative effects so it makes sense that increase in dose leads to increase in negative effects
  • However, the decrease in the proportion of cannabidiol with an increased dose of Δ9-THC means you have reduced protection against the negative effects → increased negative effects

NOTE: Long term cannabis use is associated with decreased performance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the main routes of administration of cannabis?

A

Oral

  • Bioavailability: 5-15%
    • This is due to first pass metabolism (in GI tract, liver)
  • ​Slow absorption through GI tract → delayed onset

Inhalation

  • Bioavailability: 25-30%
    • When you inhale a drug, you lose 50% of it through exhalation (i.e. when you exhale)
    • Of that 50% which isn’t lost, you need to inhale deep enough for the drug to reach the alveoli and be absorbed into the bloodstream
      • ​The deeper you inhale, the more drug will reach the alveoli before you have to exhlae again

NOTE: Bioavailability = proportion of unchanged drug that reaches the systemic circulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Describe the pharmacokinetics of cannabis.

A
  • Cannabis is very lipid soluble
  • Fat (adipose tissue) is poorly perfused - receives 2% of CO
  • Therefore, cannabis slowly accumulates in fatty tissues as fatty acid conjugates
    • Slow accumulation due to poor perfusion
      • Takes time for blood to reach fatty tissue
    • Accumulation due to poor perfusion
      • Drug does not get as much opportunity to diffuse back into the bloodstream via fatty tissue**​
  • Ratio of cannabis concentration - fat : plasma
    • 104 : 1
  • REMEMBER:
    • Cannabis does slowly leak back into the bloodstream
    • This allows drug clearance
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How long do the effects of cannabis last in the body?

A

30 days

  • This is because cannabis accumulates in fatty tissues and leaks slowly back into the bloodstream, allowing clearance
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the correlation like between plasma cannabinoid concentration and degree of intoxication?

A

Poor correlation

  • This is due to the accumulation of cannabis in fatty tissue
  • 60% of brain content is lipid
    • This lipid has a structural function
    • It is not available to be metabolised for energy so this proportion stays the same
  • Cannabis can accumulate in the fatty tissue in the brain and leak out to affect the brain → intoxication
    • Cannabis is much more concentrated in the brain than in the plasma - therefore poor correlation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

How is cannabis excreted?

A

NOTE: THC (Δ9-THC) is the major component (cannabinoid) in the cannabis taken nowadays

  • Liver converts THC → 11-hydroxy-THC (more potent)
  • 11-hydroxy-THC can be conjugated with bile and be excreted
    • So 65% excreted via GI tract
    • BUT:
      • Intestinal bacteria hydrolyses the bile conjugate, releasing the free drug (THC)
      • Since THC is very lipid soluble, it can diffuse back into the blood → enterohepatic recycling
  • ​25% excreted in the urine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Where does cannabis act in the body?

A

Cannabis acts on cannabinoid (CB) receptors

  • CB1
    • Found centrally
      • ​Hippocampus
      • Cerebellum
      • Cerebral cortex
      • Basal ganglia
  • CB2
    • Found peripherally
      • Immune cells - major location but found elsewhere

NOTE: These receptors are found as part of the endocannabinoid system in the body, which is involved in a wide variety of physiological processes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What endogenous substance act on the CB receptors?

A

Anandamide - an endocannabinoid

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What types of receptors are CB receptors?

A

G-protein coupled receptors

  • Gi → inhibits adenylate cyclase → decreases cAMP → decreases cellular activity
  • Therefore cannabis functions as a depressant
17
Q

How does cannabis cause euphoria?

A
  • Cannabis stimulates the reward pathway by disinhibition
  • Cannabis binds to the CB1 receptor on GABA interneurones
    • This inhibits GABA release
    • Makes sense as CB receptors are depressant
    • So when activated, they would slow down the activity of the GABA interneurones, preventing GABA release
  • GABA has an inhibitory effect on the reward pathway
    • So if you inhibit the inhibition → increased activity/firing of the reward pathway neurones → increased dopamine release → euphoria
18
Q

What does the anterior cingulate cortex (ACC) do?

A
  • Involved with performance monitoring and behavioural adjustment in order to avoid losses
    • Essentially, the ACC is continously motinoring the changing environment/situation and how this would influence performance
    • This allows it to adjust behaviour accordingly
  • At a very basic level, it is involved with error detection
    • Error detection is part of performance monitoring
    • e.g. ‘GREEN’ written in red
      • ACC detects this as a condition under which errors are likely to occur so you can essentially be more careful to avoid the error
  • EXAMPLE:
    • You can drive a car and talk to the passenger at the same time
    • But then you enter a narrow mountain road and a heavy storm breaks out (darker and raining)
    • The ACC detects this and how this would influence your performance - i.e. it would be harder to drive
    • Therefore, you discontinue your conversation in order to better focus your cognitive resources on safe driving - i.e. behavioural adjustment
19
Q

What is the link between cannabis and the anterior cingulate cortex?

A

In cannabis users there appears to be hypoactivity in the anterior cingulate cortex → impaired behavioural adjustment

This could explain the link between taking cannabis and psychosis and schizophrenia

  • Psychosis = you interpret reality very differently from those around you
    • You might see, hear, or believe things that aren’t real
  • ​Schizophrenia - type of psychosis
20
Q

What effect does cannabis have on food intake?

A

Cannabis stimulates food intake - due to positive effect on orexigenic neurones in lateral hypothalamus

Does this by:

  • Pre-synaptic inhibition of GABA → increases MCH neuronal activity
  • Increasing orexin production

EXPLANATION:

  • MCH neurones are present in the lateral hypothalamus so are orexigenic (stimuates appetite)
    • ​Lateral hypothalamus - feeding centre in the brain
    • MCH = melanin concentrating hormone - neuropeptide
  • GABA neurones synapse with MCH neurones and inhibit MCH neuronal activity
  • Cannabis inhibits GABA release (CB1 mediated) → loss of MCH neurone inhibition → increased MCH neuronal activity → increased appetite
    • Presynaptic inhibition - because you are inhibiting the presynaptic neurone in the GABA-MCH neurone synapse
  • There is also another group of orexinergic neurones in the lateral hypothalamus
    • These produce orexin - stimulate appetite
    • CB1 receptors interact with these neurones
      • ​Stimulation of these receptors by cannabis increases activity of these neurones → increased appetite
      • Remember CB1 is a depressant so when stimulated, it is depressing something (don’t know what) which leads to increased orexin production
21
Q

What effect does cannabis have on the immune system?

A

Cannabis is an immunosuppressant

  • It binds to the CB2 receptor on these immune cells:
    • Macrophage
    • Mast cell
    • B-cell
    • T-cell
    • Natural killer cell
  • Cannabis acts as a depressant to decrease cellular activity → decreases activity of these immune cells
22
Q

List the central effects of cannabis.

A
  • Psychosis, schizophrenia
  • Food intake
    • Affects lateral hypothalamus
  • Memory loss
    • Affects (i.e. depresses activity of) limbic regions
      • Hippocampus - involved in memory formation
    • Amnestic effects due to decreased BDNF (Brain Derived Neurotrophic Factor)
      • ​BDNF is generally important in the nervous to support the neuronal survival, neuronal growth and synapse formation
      • ​This is important in the hippocampus - synaptic plasticity (change) is required for memory formation
      • So reduced BDNF acting on the hippocampus → deterioration of hippocampal function → memory loss
  • Psychomotor performance (i.e. conscious movement)
    • Affects cerebral cortex - depresses activity
23
Q

List the peripheral effects of cannabis.

A
  • Immunosuppression
  • Tachycardia and vasodilation
    • This is via interaction with a different receptor - TRPV1
    • Cannabis activates the TRPV1 receptor which leads to tachycardia and vasodilation
      • Tachycardia probably by stimulation of calcium influx through the ionotropic receptro (ion channel)
      • Vasodilation - activation of the receptor stimulates release of a vasodilator
    • Vasodilation is particularly seen in the conjunctivae (lines inside of eyelids and covers the sclera)
      • ​This leads to bloodshot eyes
24
Q

Describe CB1 receptor expression in the medulla. Explain why this is important.

A

The medulla has a low CB1 receptor expression

  • The medulla contains the respiratory and cardiovascular control centre
    • So if you had high CB1 expression, cannabis would depress the activity of these centres → death
  • BUT due to low receptor expression in the medulla, cannabis cannot depress the activity of these centres - not capable of supressing cardiorespiratory control
    • Therefore, you cannot overdose on cannabis to the point where you can kill yourself
25
Q

In what disease states are CB receptors upregulated.

A

This can either be:

  • Regulatory
  • Pathological

Regulatory

  • This has a protective effect against the diesease
  • Seen in these conditions:
    • Multiple sclerosis
      • Demylinating disease - due to autoimmunity
      • Therefore, immunosuppressive effects by CB receptor upregulation would be useful
    • Pain
      • CB1 receptors present within the nervous system - within structures involved in the processing and perception of pain
      • CB receptors - depressant affect → can lead to pain depression
    • Stroke
      • ​Ischaemia in the brain can trigger inflammation
      • So immunosuppressive effects by CB receptor upregulation would be neuroprotective

Pathological

  • This contributes to the disease
  • Seen in these conditions:
    • Fertility (i.e. pathology = infertility)
      • Particularly male infertility
      • CB receptor upregulation:
        • Decreases testosterone
        • Inhibits pituitary gland (i.e. HPG axis)
        • Interferes with sperm production
    • Obesity
      • CB1 receptors upregulated in adipose tissue (on adipocytes) and the liver (on hepatocytes)
      • This seems to directly contribute to the development of obesity

NOTE: Explanations of each condition are extra

26
Q

State some drugs which affect the CB receptor and their uses.

A

CB receptor agonists:

  • ∆9-THC (synthetic)
    • Dronabinol
      • Anti-emetic (treats nausea and vomiting) in patients undergoing chemotherapy
      • Used to treat loss of appetite and weight loss in people who have acquired immunodeficiency syndrome (AIDS)
    • Nabilone
  • ∆9-THC and cannabidiol (synthetic)
    • Sativex
      • Symptom improvement in adult patients with moderate to severe spasticity
      • Pain control (spasticity causes pain)

These are used to treat the diseases in which CB receptor upregulation has a regulatory (protective) effect

CB receptor antagonists:

  • Rimonabant
    • ​Anti-obesity agent - no longer available as it was associated with suicide

These are used to treat the diseases in which CB receptor upregulation has a pathological (negative) effect

27
Q

In terms of CB receptor activity, what other drug is relevant?

A

Fatty acid amide hydrolase inhibitor

  • Fatty acid amide hydrolase breaks down anandamide
  • So by inhibiting this, you have more anandamide (an endogenous cannabinoid) to act on and stimulate the CB receptor
  • So it would essentially have the same effect as a CB receptor agonist
  • Possible use - treatment of chronic pain