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Pharmacology (Winter) > Cannabinoids & Medical Marijuana > Flashcards

Cannabinoids & Medical Marijuana Flashcards

1
Q

What is Cannabis?

A
  • Cannabis sativa
  • Hemp
  • originates from Asia
  • grown around the world
  • hemp plant
  • contains 100’s of chemical substances!!!
  • many are termed “cannabinoids”
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2
Q

What are Cannabinoids?

A
  • stored in trichomes
  • effect cell receptors in brain/body
  • effects cell communication and behaviour
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3
Q

What are the types of Cannabinoids?

A
  1. Phytocannabinoids
  2. Endocannabinoids
  3. Synthetic Cannabinoids
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4
Q

What is apart of Phytocannabinoids?

A

a. THC
b. CBD
c. Terpenes

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5
Q

What is THC?

A
  • most commonly researched
  • “high”
  • harmful effects increase with concentration
  • beneficial effects seen at lower doses
  • dose - % of weight
  • (1980s=3%, 2019=15%) – much higher percentage in modern cannabis
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6
Q

What is CBD?

A
  • no “high”
  • may decrease effects of THC in brain
  • possible therapeutic effects
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7
Q

What is Terpenes?

A
  • trichromes
  • distinctive smell
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8
Q

What are the short term health effects?

A
  • “high” feeling
  • well-being
  • relaxation
  • heightened senses
  • confusion
  • tiredness
  • impaired ability to concentrate/remember
  • anxiety/fear/panic
  • low blood pressure
  • increased heart rate
  • smoke inhalation – damaged blood vessels
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9
Q

What are the long term health effects?

A

(near daily use over weeks/months/years)
* increase risk of addiction
* decreased cognitive functions (memory, intelligence, decision- making)
* worsen when used in adolescence
* effects may not be reversible once stopped
* effects similar to tobacco use:
* bronchitis, lung infections, cough, mucus build-up

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10
Q

What is the health effects with pregnancy?

A
  • lower birth weight
  • developmental effects in child: hyperactivity, memory impairment
  • substances are carried in breast milk and fetal blood supply
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11
Q

What is apart of Endocannabinoids? What are they?

A

ex: 2-arachidonyl-glycerol (2-AG) and anandamide (AEA)
* endogenously produced by the body
* synthesized “on demand”
* derivatives of long chain polyunsaturated fatty acids

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12
Q

What is apart of Synthetic Cannabinoids? What are they?

A
  • ex: CB13, JWH133, spice
  • analogs of natural products, or endocannabinoids
  • pharmacological probes to target specific endocannabinoid receptors
  • synthetic variants are abundant
  • changing chemical structure, alters:
  • affinity
  • potency
  • selectivity
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13
Q

What is the ECS?

A

…CB receptor agonists and the proteins, that bind, transport and metabolize these lipids

  • lipid signaling system
  • implicated in a number of physiological processes
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14
Q

What can dysfunction of the ECS can lead to?

A
  • pain
  • inflammation
  • psychiatric disorders
  • neurodegenerative diseases
  • may contribute to other human diseases
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15
Q

What does the ECS consist of?

A
  1. cannabinoidreceptors
    - CB1R
    - CB2R
  2. endocannabinoids
    - endogenous
    - e.g. 2-AG, AEA
  3. enzymes
    - synthesis
    - degradation
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16
Q

What are the Cannabinoid receptors?

A

G-coupled protein receptors
* cannabinoid type 1 (CB1R)
* cannabinoid type 2 (CB2R)

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17
Q

Compare & contrast ECS cannabinoid receptors (CB1R & CB2R)

A
  • cannabinoid receptor expression
  • CB1R and CB2R have somewhat distinct tissue distribution
  • both are GPCRs
  • influence the release of neurotransmitters
  • CB1R - is linked to the “high” and psychoactive properties of cannabis
  • central nervous system activity
  • CB2R – is not associated with “high”
  • found in peripheral tissue
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18
Q

CB1R:

A

central and peripheral nervous system
* one of the most abundant GPCRs
- cerebral cortex, hippocampus, cerebellum, etc.

also found in:
* adipocytes, leukocytes, spleen, heart, lungs, GI tract, liver, kidney, bladder, reproductive organs, bones, joints, skin

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19
Q

CB2R:

A
  • tissues and cells of the immune system, leukocytes, spleen
  • bone, liver, heart, nerve cells (astrocytes, microglia)
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20
Q

Other receptors:

A
  1. GPR55: g-protein coupled receptor 55
  2. TPRV1: transient receptor potential vanilloid 1
  3. PPARs: peroxisome proliferator-activated receptor
    * create even more complexity for modulation of the ECS
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21
Q

Cannabinoid receptors ligands:

A

a. endogenous ligands:
* endocannabinoids
* ex: 2-arachidonyl-glycerol (2-AG), and anandamide
* amides, esters, ethers
* long chain polyunsaturated fatty acids

b. exogenous ligands:
* ex: THC, CBD, synthetics, etc.

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22
Q

Endogenous cannabinoid receptor ligands:

A
  • synthesized “on-demand”
  • neuron – action potential
  • biological stimulus
  • controlled system
  • synthesized from phospholipid pre-cursors
  • both derived from arachidonic acid
    – endocannabinoids and eicosanoids
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23
Q

Enzymes:

A

for synthesis and degradation

  • a. synthesizing enzymes
    1. phospholipase C
  • affinity for 2-AG
    2. N-acyltransferase
  • affinity for anandamide

b. degradation/hydrolytic enzymes:
* terminate cannabinoid signal transduction
1. FAAH-fattyacidamidehydrolase
* post-synaptic
* affinity for anandamide
2. MAGL-monoacylglycerol
* pre-synaptic
* catabolism of 2-AG

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24
Q

What are the parts of the CB1R?

A
  • THC
  • Dronabinol
  • Nabilone
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25
Q

What is the overview of the process of the ECS?

A
  • Endocannabinoids produced on demand on POST-SYNAPTIC terminal
  • Diffuse RETROGRADE TO PRE-SYNAPTIC terminal
  • Both endogenous and exogenous cannabinoids
    (dronabinol, nabilone, etc.) will bind to CB1R
  • Will (through series of ion channel openings) arrest of excitatory and inhibitory neurotransmitters
  • Both endocannabinoids will BREAK DOWN TO ARACHIDONIC ACID
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26
Q

Dysregulation of ECS:

A
  • can result pathological conditions
  • modulation can be harmful or beneficial
  • targeting specific metabolic pathways
  • antagonism or agonism of receptors
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27
Q

What are the therapeutic challenges:

A
  • selectivity in targeting disease/symptoms
  • cannabis use (THC dominant strains)
  • effect mood and cognition
  • clinical studies: non-cancer pain (mainly neurologically)
  • low does THC (smoke/vaporize) may have benefits with little psychoactive effect
    – (<3mg/dose)
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28
Q

What are the PD of THC?

A
  • partial agonist of CB1 and CB2 receptors
  • activity found at other targets, as well
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29
Q

What are the PD of CBD?

A
  • non-competitive, allosteric modulator of CB1 receptors
  • not a partial agonist to CB1 or CB2 receptors
  • interacts with ion channels, other receptors and may modulate enzymes
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30
Q

What is the PK?

A
  • limited information on interactions
  • discrepancies and opposing results
  • Research study discrepancies:
  • dosing
  • ratios (THC:CBD)
  • routes of administration
  • pre-treatment, co-administration (THC and CBD)
  • acute vs. chronic use
  • in vivo animal models
  • endpoints
  • most studies investigating attenuation of the psychoactive effects of THC via CBD dosing
  • pre-treatment
  • co-administration
  • ratio alteration
  • i.e. CBD:THC, 8:1 vs. 2:1
  • CBD may effect THC effects
  • via altering metabolism of THC in liver
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31
Q

What are the ROA for Cannabis?

A
  1. inhalation
    * smoked, vaporized
    * absorbed via lung
  2. oral preparations
    * edibles, capsules, sprays
    * absorbed via intestine
  3. rectally
    * suppositories
    * absorbed via colon
  4. dermally
    * topicals
    * absorbed via skin
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32
Q

What is the absorption of SMOKED admin?

A
  • rapid onset of action
  • higher concentration of cannabinoids in blood
  • acute pharmacodynamic response
  • THC concentration is variable
  • bioavailability variable
  • 2-56% absorption
  • 25% of total THC content from cannabis is absorbed/delivered
33
Q

What is the absorption of VAPORIZED admin?

A
  • bioequivalence compared to smoking not well established
34
Q

What is the absorption of ORAL admin?

A
  • acute effects occur over hours
  • slower onset
  • lower blood levels
  • longer duration of pharmacodynamic effects
  • preferred by medical users
  • systemic availability 4-11%, slow and unreliable
  • dissolve better in fats > oils > lipid free
35
Q

What is the absorption of TOPICAL admin?

A

cannabinoids are highly hydrophobic
* transport across layers of the skin are the rate-limiting step in diffusion

pre-clinical dermal patch
* CBD permeation 10x higher than THC

pre-clinical transdermal CBD gel
* dose-response seen with permeation into skin

36
Q

What is the metabolism of Cannabis?

A
  • occurs mainly in liver
  • dependent on route of administration
37
Q

What is the metabolism of THC?

A

oxidation - epoxidation – decarboxylation – conjugation

38
Q

What is the metabolism of CBD?

A
  • 30 different metabolites found in urine
  • hydroxylated metabolites
  • phase 1 metabolism - sulfation
39
Q

What is the excretion of the smoked admin?

A

THC and CBD levels in plasma decrease rapidly after smoking

40
Q

What is the excretion of the oral admin for THC & CBD?

A
  • THC:
  • 10-15% in urine, mainly biliary excretion
  • phase II metabolite – glucuronidated
  • CBD:
  • half-life = 2 - 5days
41
Q

PK tolerance?

A
  • changes in absorption, metabolism, excretion
  • occurs with repeated use
  • occurs less than PD tolerance
42
Q

PD tolerance?

A
  • linked to changes in the availability of the cannabinoid
    receptors
  • mainly CB1 receptors
    – desensitization and downregulation in THC users
  • Clinical studies:
  • CB1R downregulation reversible
  • 2 days saw improvement
  • 28 days not significantly different than control group
43
Q

What is THC & CBD avail for & its storage?

A
  • available for medical and recreational use
  • humidity, temperature, oxidation, light
  • effect stability
  • storage at 18oC over 5 years
  • lost 1/3rd of THC concentration
  • licensed commercial retailers in Canada
  • should supply storage and expiration
44
Q

What is THC?

A

delta-9-tetrahydrocannabinol (THC)
* predominant phytocannabinoid
* well-studied
* psychoactive and physical effects

45
Q

What does THC exist as?

A

exists in active and inactive form in Cannabis sativa
* inactive: monocarboxylic acid
* active: decarboxylated compound
- promoted by heating (98-200oC)
– pyrolysis (i.e. smoking)
— promotes conversion of 100’s of cannabinoids

46
Q

What is THC properties?

A

lipophilic and lipid soluble
* taken up primarily by fatty tissues
* highly perfused in organs
* brain, heart, lung, and liver
* highest THC content found in the heart
* 1000x higher that of plasma
* blood-brain barrier limits accumulation in the brain
* despite high perfusion in brain

47
Q

What is THC stored in?

A

stored in fatty adipose tissue
* slow release in bloodstream
* THC in blood detected 30 days after smoking

48
Q

What is CBD?

A

CBD - cannabidiol
* non-psychoactive phytocannabinoid
* interacts indirectly with endocannabinoid system

  • interacts with multiple receptors:
  • GPR55 - antagonist
  • TPRV1 – agonist (weak)
  • PPAR – agonist
  • pleiotropic effects reported
  • anti-inflammatory, anti-epileptic
49
Q

What is Amandamide (endocannabinoids)?

A
  • partial agonist of CB1 receptor, stimulates TPRV1 receptor
  • 1st endocannabinoid to be discover
  • plays role in:
  • thought processes, control of movement, forming short-term connections between nerve cells
  • immune system function, pain management
50
Q

What is 2-AG (endocannabinoids)?

A
  • partial agonist of CB1/CB2 receptor
  • binds with higher affinity to CB2 than anandamide
  • plays role in:
  • appetite, immune system function and pain management
51
Q

What is CB13 (synthetic cannabinoids)?

A
  • dual cannabinoid receptor agonist
  • peripherally restricted
  • synthetically created to not cross blood-brain barrier
  • lack of psychoactive effects from CB1 receptors present in brain
  • peripheral effects at low doses
52
Q

What is JWH 133 (synthetic cannabinoids)?

A
  • potent CB2 receptor agonist
  • 200x more selective for CB2 vs. CB1
53
Q

What is K2/Spice (synthetic cannabinoids)?

A
  • extremely potent
  • mimics effects of CBD
  • dangerous - can have bad SE’s
54
Q

What is Cannabidiol rx?

A
  • US only - right now
  • 98% CBD - oil-based extract
  • Dose: 5 - 20 mg/kg/d
  • treatment for:
  • seizures
  • Lennox-Gastaut or Dravet syndromes
  • for patients older than 2 years of age
  • give before meal
  • food/fat increases absorption
55
Q

What is Dronabinol rx (THC synthetic)?

A
  • THC synthetic
  • US only – no longer available in Canada
  • treatment of:
  • severe nausea from cancer chemotherapy
  • AIDS related anorexia
  • appetite enhancer
  • Dose: 2.5–20mg of THC per day
56
Q

What is Nabilone rx (THC synthetic)?

A
  • synthetic THC analogue
  • available in Canada
  • treatment of:
  • severe nausea from cancer chemotherapy
  • off-label
  • AIDS related anorexia
  • palliative pain
  • neuropathic pain
  • Dose: 0.2-6 mg per day
57
Q

What is Nabiximols (THC:CBD)?

A
  • not available in USA
  • a botanical cannabis extract containing approximately equal concentrations of THC:CBD
  • plus terpenoids and flavonoids
  • ora-mucosal administration
  • 4 sprays: 10 mg CBD and 10.8 mg THC
  • Dose: 1-16 sprays per day
  • THC blood levels similar to oral administration
58
Q

What is Nabiximols (THC:CBD) tx for?

A
  • advanced cancer pain
  • multiple sclerosis neuropathic pain or spasticity
  • spasticity may require lower dose than pain
  • 4-5 sprays vs. >8 sprays
59
Q

What is the MOA of Nabiximols (THC:CBD)?

A
  • works through CB receptors
  • central nervous system and in immune cells
  • contains extracts from chemically and genetically characterised Cannabis Sativa plants
60
Q

What are the pt candidates for Cannabinoids?

A

cannabinoids not considered 1st line or 2nd line treatments
* reserve for patients who have tried other medications

61
Q

What are the contraindications of Cannabinoids?

A
  • pregnancy/breastfeeding
  • <25 years old
  • history of schizophrenia
  • history of substance abuse
  • respiratory disease
62
Q

What are the negative effects of Cannabinoids?

A
  • substance abuse of cannabinoids
  • abuse of other substances
  • addiction
  • cognitive function impairment
  • behavioural modification (specifically in youth)
63
Q

What are the therapeutic targets of ECS?

A
  • Challenging and possibly rewarding
  • ECS implicated in numerous physiological and pathophysiology processes
  • 1950’s
  • first chemical constituents of ECS were discovered
  • THC and CBD, then endocannabinoids
  • ECS activated “on demand”
  • cell and time-specific function during pathological state
  • activation of inhibition of ECS (i.e. through CB1R)
  • interference with normal CB1 function in non-target cells
  • Pathological implications from altering ECS signaling
  • altered expression/function of:
  • CB receptors
  • endocannabinoid metabolic enzymes
  • CB1 is one of the most abundant and widespread GPCR in the mammalian brain
  • Therapies that exploit pathological changes
  • agonist/antagonists of CB receptors
  • inhibitors of metabolic enzymes
64
Q

What is Dravet syndrome (epilepsy)?

A
  • childhood epilepsy disorder
  • drug resistant and high mortality rates
  • loss-of-function gene mutation
  • cognitive impairment in patients
65
Q

What is Lennox-Gastaut syndrome?

A
  • childhood onset epilepsy
  • cognitive impairment/dysfunction
  • more common in males than females
  • occur with no history of disorder in family – sporadic
  • randomly occurs de novo during cell formation in-utero
66
Q

What is the overview of epilepsy?

A

1/3rd of patients with epilepsy have seizures that are resistant to antiepileptic medications

67
Q

What are the defects of the ECS in epilepsy?

A
  • low levels of anandamide
  • low CB1 mRNA
  • low DAGL – (2-AG synthesis enzyme)
68
Q

ECS activated by seizures:

A
  • upregulation of CB1 receptors
  • reduction of endocannabinoid metabolic degradation prevented induced seizures
  • CB1 antagonists induced seizure-like discharges
  • CB1 agonists prevented
69
Q

Cannabidiol in epilepsy:

A
  • cannabidiol shown to be effective in small pre-clinical trials
  • inconsistencies between studies
  • may act through GPR55
  • decrease pre-synaptic glutamate
  • may exert antioxidant and anti-inflammatory effects
70
Q

THC in epilepsy:

A
  • activation of CB1 receptors
  • CB1 agonists – pre-clinical research is contradictory
  • reduced seizures
  • had no effect
  • increased convulsant activity
71
Q

Dravet syndrome clinical studies:

A
  • drug-resistant seizures
  • cannabidiol shown effective in clinical trials
  • 2-18yo, 120 patients
  • 20 mg/kg CBD
  • CBD: 12.4 to 5.9 seizures per month
  • placebo: 14.9 to 14.1 seizures per month
72
Q

Lennox-Gavaut syndrome clinical studies:

A

CBD treatment
* 52% reduction in seizures
* improvement in function and quality of life

73
Q

Parkinson’s Disease:

A
  • broad media interest and incredible case reports
  • internet platforms showing tremendous improvement of symptoms after marijuana use
  • specifically dyskinesia/tremor
  • began with unusual approval in EU
  • ECS and Parkinson’s:
  • high level of CB receptors in basal ganglia of PD patients
  • basal ganglia – controls voluntary motor movement
74
Q

Parkinson’s Disease Pre-clinical studies:

A
  • CB1 receptor agonists
  • reduce akinesia, motor impairment, tremor
  • receptor-independent mechanism
  • THC
  • increase bradykinesia
  • Cannabis may influence dopaminergic system
  • synthesis and release of dopamine
  • fine tuning of movement
  • substantia nigra communicates with basal ganglia releasing dopemine
  • in PD: neurons of substantia nigra degenerate, dopamine lowered
75
Q

Parkinson’s Disease Clinical Studies:

A
  • numerous single cases show promise
  • clinical trials for PD motor function are more rare and less promising
  • randomized placebo controlled

4 randomized control trials, 3 showed no effect
* CBD, THC:CBD, nabilone as an add-on therapy
* 1 RCT showed increased motor function vs. baseline
* 1 RCT showed severity but not duration of dyskinesia improved

76
Q

What is Parkinson’s Disease MOA?

A

Specific mechanism of action is unknown
* might induce neuroprotective effects related to direct receptor-independent mechanisms
* activation of anti-inflammatory cascades in glial cells via CB2 receptor
* CB1 receptors may increase acetylcholine release
* may reduce cholinergic deficit in PD

77
Q

What are the facts vs. myths?

A
  • lots of anecdotal single case stories in media
  • pre-clinical, clinical and epidemiological studies emerging
  • ECS is complicated
  • cannabis does have side-effects
  • THC:CBD ratios
  • medication comes first
78
Q

What are the challenges w/ Cannabis research?

A
  1. limited and small-in-size randomized control trials
    * short duration, studying differing routes, forms & types of cannabinoids
  2. difficult to assess benefits
    * trials with longer duration tend to show less benefit
    * implying that if an effect exists, it may wear off over time.
  3. cannabinoid trials are not adequately blinded due to the psychoactive effects of cannabinoids
    * ~90% of patients can guess their allocation
    * bias results towards benefit

Pharmacology (Winter) (23 decks)

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