Cannabis 2 Flashcards
Which cannabinoid is most of the data for?
THC (some for CBD)
Are cannabinoids lipophilic or hydrophilic?
lipophilic
-they partition into fatty tissues a lot
-high Vd
Describe the PK of smoked and vaporized cannabis.
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
Describe the PK of sublingual and nasopharyngeal cannabis.
sublingual and oromucosal administration bypasses the liver to enter the systemic circulation
bioavailability of 13%
duration of action is much longer
Describe the PK of oral cannabis.
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
Describe the PK of transcutaneous & topical cannabis.
very few clinical studies have been conducted, but generally those that do exist show:
-good local bioavailability
What is transcutaneous & topical cannabis being explored for?
nausea
hyperemesis
addiction
glaucoma
pain control
What is the concern with transcutaneous & topical cannabis?
concern that individuals may extract drug from patches (similar to fentanyl)
True or false: THC is used recreationally IV
false
What is the most common route of cannabis consumption?
smoking
Describe absorption of smoked cannabis.
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
Describe t1/2 of smoked cannabis.
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
Describe cannabinoid distribution.
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
Describe cannabinoid metabolism.
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
Describe cannabinoid elimination.
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
Which drugs do cannabinoid metabolism overlap with?
opioids
NSAIDs
3A4 and 2D6
2C9 for NSAIDs and cannabinoids
Which CB receptor polymorphisms affect drug efficacy?
no known CB receptor polymorphisms
Differentiate poor metabolizer, normal metabolizer, and ultra metabolizer.
poor metabolizer: at least 2 loss of function alleles
normal metabolizer: extensive metabolizer
ultra metabolizer: at least 3 copies of functional alleles
Describe the major themes of gene polymorphisms.
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
What can be said about cannabinoids & opioids PD?
their PD effects likely synergize
What are the disease targets for cannabis?
agonism:
-cachexia
-glaucoma
-multiple sclerosis
-pain
-epilepsy
-IBS
antagonism:
-obesity
-addiction?
What are the issue with existing clinical data?
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
What is cachexia?
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
How is cachexia currently managed?
thalidomide
NSAIDs
ghrelin receptor agonists
omega-3 fatty acids
cannabinoid therapy
How does cannabis work for cachexia?
inhibit orexin and enhance ghrelin signaling
reduces nausea through CB1
What is the evidence for cannabis in cachexia?
no rigorous phase I or II clinical trials or validated PK demonstration of reliable benefit
-dronabinol is approved
How does topical application of CB1R agonists reduce IOP?
reduced production of aqueous humor
increase outflow through the trabecular meshwork
localized decreased in blood pressure
What is the American Glaucoma Society’s statement on cannabis and glaucoma?
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
What is MS?
autoimmune demyelinating disease
-characterized by lesions, inflammation, permeation of BBB
-blurred vision, spasm and spasticity, problems with speech, chronic pain, unstable mood
What is the evidence for cannabis and spasticity in MS?
16 published trials:
-nabiximol: no improvement
-THC: inconsistent results
-smoked cannabis: worsened balance
patients reported benefit, but no improvements were seen in objective measures
What is the evidence for cannabis and central pain & spasm in MS?
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
What is the evidence for cannabis and bladder dysfunction in MS?
nabiximols are effective whereas THC is not
What is the evidence for cannabis and tremor in MS?
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
What is the FDA-approved cannabis-based drug available in the US for epilepsy?
Epidiolex
-cannabidiol
What is the evidence for cannabis in epilepsy?
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
How does cannabis work for epilepsy?
no clue
How does cannabis work for pain?
CB receptors inhibit nociceptive transmission centrally
inflammation and nociceptive peripherally
What is the evidence for cannabis in pain?
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
What is BIA 10-2474?
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
How does cannabis work for IBD?
decreased intestinal motility and gut secretion
inhibition of inflammation
decreased LES relaxation, gastric emptying, gastric acid secretion
decreased NV, improved appetite and pain control
What is the MOA of rimonabant?
CB1R inverse agonist
What was rimonabant used for?
weight loss complimentary to diet and exercise in BMI > 30, T2DM or CV disease
What was the issue with rimonabant?
16x more likely to experience depression and 8x more likely to express suicidal ideation
