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PHAR324 > Cannabis 2 > Flashcards

Cannabis 2 Flashcards

1
Q

Which cannabinoid is most of the data for?

A

THC (some for CBD)

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2
Q

Are cannabinoids lipophilic or hydrophilic?

A

lipophilic
-they partition into fatty tissues a lot
-high Vd

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3
Q

Describe the PK of smoked and vaporized cannabis.

A

rapidly partitions into the blood from the lungs ( < 30 min)
bioavailability of ~35% (2-56%)
transformed in the liver to 11-OH-THC (primary) and THC-COOH (secondary) - both are psychoactive
-11-OH-THC > THC-COOH
threshold for intoxication vary based on genetics, past use, etc

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4
Q

Describe the PK of sublingual and nasopharyngeal cannabis.

A

sublingual and oromucosal administration bypasses the liver to enter the systemic circulation
bioavailability of 13%
duration of action is much longer

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5
Q

Describe the PK of oral cannabis.

A

similar to oromucosal but bioavailability is lower (~6%) due to 1st pass metabolism
delayed onset of action and lower Cmax but longer duration of action

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6
Q

Describe the PK of transcutaneous & topical cannabis.

A

very few clinical studies have been conducted, but generally those that do exist show:
-good local bioavailability

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7
Q

What is transcutaneous & topical cannabis being explored for?

A

nausea
hyperemesis
addiction
glaucoma
pain control

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8
Q

What is the concern with transcutaneous & topical cannabis?

A

concern that individuals may extract drug from patches (similar to fentanyl)

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9
Q

True or false: THC is used recreationally IV

A

false

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10
Q

What is the most common route of cannabis consumption?

A

smoking

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11
Q

Describe absorption of smoked cannabis.

A

THC is rapidly absorbed into the blood stream but with a high degree of intra-individual variability
oral absorption across the gut epithelium is ~100% but 1st pass makes bioavailability ~6%
onset is 0.5-1h, tmax 2-4h, Cmax 1.32 ng/ml

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12
Q

Describe t1/2 of smoked cannabis.

A

t1/2 varies widely based on genetics, body fat content, and frequency of use
-THC: 18h-4.1d
-11-Oh-THC & THC-COOH: 3d-12.6d

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13
Q

Describe cannabinoid distribution.

A

as a lipophilic drug, THC concentrates in fatty tissue (and in lungs if smoked)
ratio of ~ 21:1 adipose : brain in multiple species, including humans
Vd ~ 3.4-10 L/kg (very high)
~95% plasma protein bound; otherwise rapidly cleared from plasma and liver
THC partitions into the placenta and breast milk

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14
Q

Describe cannabinoid metabolism.

A

THC (and other cannabinoids) are metabolized in liver by CYP 2C9 > CYP 3A4 + CYP 2D6 to become 11-Oh-THC and/or THC-COOH
extra-hepatic B-glucuronidases in the gut, cerebellum, and brain stem also transform THC
cannabinoids may interfere with each others metabolism
metabolite levels peak 0.5-4h after administration and are detectable for several days

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15
Q

Describe cannabinoid elimination.

A

80-90% of THC is eliminated in 5d and detectable by current techniques for up to 5 weeks
65% feces vs 20% urine
clearance average from human studies is 0.2 L/kg/h with a range which is hugely variable

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16
Q

Which drugs do cannabinoid metabolism overlap with?

A

opioids
NSAIDs
3A4 and 2D6
2C9 for NSAIDs and cannabinoids

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17
Q

Which CB receptor polymorphisms affect drug efficacy?

A

no known CB receptor polymorphisms

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18
Q

Differentiate poor metabolizer, normal metabolizer, and ultra metabolizer.

A

poor metabolizer: at least 2 loss of function alleles
normal metabolizer: extensive metabolizer
ultra metabolizer: at least 3 copies of functional alleles

19
Q

Describe the major themes of gene polymorphisms.

A

if drugs are pro-drugs or metabolism produces an active compound, then polymorphisms that increase metabolism will increase drug efficacy & ADRs = reduced safety
polymorphisms that reduce metabolism may lead to high [drug] = reduced safety
polymorphisms that enhance drug metabolism will reduce drug efficacy and may be misconstrued as drug-seeking behavior

20
Q

What can be said about cannabinoids & opioids PD?

A

their PD effects likely synergize

21
Q

What are the disease targets for cannabis?

A

agonism:
-cachexia
-glaucoma
-multiple sclerosis
-pain
-epilepsy
-IBS
antagonism:
-obesity
-addiction?

22
Q

What are the issue with existing clinical data?

A

cannabis and cannabinoids were prohibited and controlled substances which made clinical research challenging, the studies that do exist typically suffer from:
-low power
-lack of blinding
-heterogeneity of disease
-heterogeneity of drug (whats in this cannabis)
-heterogeneity of exposure route
-poor dosing criteria
-no PK assessment
the evidence base of cannabis-based medicines is a work in progress

23
Q

What is cachexia?

A

wasting syndrome characterized by loss of weight, muscle weakness, fatigue, atrophy, and loss of appetite
-seen in late-stage cancers, patients receiving chemotherapy, AIDS, COPD, late-stage MS, CHF

24
Q

How is cachexia currently managed?

A

thalidomide
NSAIDs
ghrelin receptor agonists
omega-3 fatty acids
cannabinoid therapy

25
Q

How does cannabis work for cachexia?

A

inhibit orexin and enhance ghrelin signaling
reduces nausea through CB1

26
Q

What is the evidence for cannabis in cachexia?

A

no rigorous phase I or II clinical trials or validated PK demonstration of reliable benefit
-dronabinol is approved

27
Q

How does topical application of CB1R agonists reduce IOP?

A

reduced production of aqueous humor
increase outflow through the trabecular meshwork
localized decreased in blood pressure

28
Q

What is the American Glaucoma Society’s statement on cannabis and glaucoma?

A

cannabis is not a legitimate treatment for elevated IOP, for reasons including short duration of action and side effects that limit many activities of daily living

29
Q

What is MS?

A

autoimmune demyelinating disease
-characterized by lesions, inflammation, permeation of BBB
-blurred vision, spasm and spasticity, problems with speech, chronic pain, unstable mood

30
Q

What is the evidence for cannabis and spasticity in MS?

A

16 published trials:
-nabiximol: no improvement
-THC: inconsistent results
-smoked cannabis: worsened balance
patients reported benefit, but no improvements were seen in objective measures

31
Q

What is the evidence for cannabis and central pain & spasm in MS?

A

nabiximol: no improvement or reduced pain intensity
THC or THC/CBD: 28-31% of pts reduction in pain and spasm
smoked cannabis: reduced pain and spasms
nabiximol, THC, THC/CBD, smoked cannabis are effective for pain and painful spasms

32
Q

What is the evidence for cannabis and bladder dysfunction in MS?

A

nabiximols are effective whereas THC is not

33
Q

What is the evidence for cannabis and tremor in MS?

A

6 published trials
-THC and oral cannabis extracts are ineffective for tremor
»50 clinical trials ongoing or completed (without results) for Sativex, dronabinol, or other GW Pharmaceutical Products

34
Q

What is the FDA-approved cannabis-based drug available in the US for epilepsy?

A

Epidiolex
-cannabidiol

35
Q

What is the evidence for cannabis in epilepsy?

A

of the 6 placebo-controlled trials of CBD conducted to date:
-39-50% reduction in seizure frequency (incl. Dravet and Lennox-Gastaut Syndromes)
-side effects are mild & infrequent

36
Q

How does cannabis work for epilepsy?

A

no clue

37
Q

How does cannabis work for pain?

A

CB receptors inhibit nociceptive transmission centrally
inflammation and nociceptive peripherally

38
Q

What is the evidence for cannabis in pain?

A

chronic pain: moderate-quality evidence to support the use of cannabis-based medicines for the tx of chronic pain but not as 1st line therapy
rheumatic disease & fibromyalgia: insufficient evidence to recommend any cannabis-based medicine for sx management
uncertainty about whether cannabinoids improve pain but if they do it is neuropathic pain and the benefit is likely small

39
Q

What is BIA 10-2474?

A

FAAH inhibitor under development for the treatment of anxiety, chronic pain, and several other potential diseases
-5/10 days in at 50 mg 1 man died, another 4 were hospitalized for hemorrhagic and necrotic brain legions

40
Q

How does cannabis work for IBD?

A

decreased intestinal motility and gut secretion
inhibition of inflammation
decreased LES relaxation, gastric emptying, gastric acid secretion
decreased NV, improved appetite and pain control

41
Q

What is the MOA of rimonabant?

A

CB1R inverse agonist

42
Q

What was rimonabant used for?

A

weight loss complimentary to diet and exercise in BMI > 30, T2DM or CV disease

43
Q

What was the issue with rimonabant?

A

16x more likely to experience depression and 8x more likely to express suicidal ideation

44
Q
A

PHAR324 (9 decks)

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