chemical structures of the main representative endo phyto...
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Cannabinoids: Concerns for Pharmacy Practice
Pongsatorn Meesawatsom, BPharm, PhDDepartment of Pharmacology
Faculty of PharmacyMahidol University
Chemical structures of the main representative endo‐, phyto‐and synthetic cannabinoids
Botanical and phytochemical background Cannabis genus
Cannabis sativa L. Cannabis indica Cannabis ruderalis
Phytocannabinoid are mostly present in the resin secreted from the trichomes of female plants
Phytocannabinoids contents influenced by particular extreme environmental conditions of humidity, temperature, radiation, soil nutrients, and parasites
Bioaccumulator
J Ethnopharmacol. 2018 Dec 5;227:300‐315.
More than 750 natural chemical constituents identified in Cannabis Sativa
Chemical class Identified compounds
Terpenes 140
Cannabinoids 86
Hydrocarbons 50
Sugars and related compounds 34
Nitrogenous compounds 27
Noncannabinoid phenols 25
Fatty acids 23
Flavonoids 23
Simple acids 20
Chemical class Identified compounds
Simple ketones 13
Simple esters and lactones 13
Simple aldehydes 12
Proteins, enzymes, and glycoproteins 11
Steroids 11
Elements 9
Simple alcohols 7
Vitamins 3
Pigments 2
Nutraceuticals, 2016, pp. 735‐754
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Structures of phytocannabinoids in Cannabis sativa L.
Prog Chem Org Nat Prod. 2017; 103: 103–131.
Most abundant Less abundant
Δ9‐tetrahydrocannabinol (Δ9‐THC), Δ8‐tetrahydrocannabinol (Δ8‐THC), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), and cannabichromene (CBC), Δ9‐tetrahydrocannabivarin (THCV), cannabivarin (CBV),cannabidivarin (CBDV), cannabinodiol (CBND), cannabielsion(CBE), cannabicyclol (CBL) and cannabitriol (CBT)
Cannabinoid productsMarijuanna/cannabisPlant concentrated extract (oil)
High THCHigh CBDPure plant extract CBD (Epidiolex)THC:CBD 1:1 or nabiximol (Sativex)Uncharacterized oil
Pure chemicalsTHC, nabilone (Cesamet), dronabinol (Marinol)
ขอตกลงเบองตน แนวทางนไมแนะนาใหใชผลตภณฑกญชาในการรกษา และ/ หรอควบคมอาการของผปวยเปนการ รกษาลาดบแรก (first-line
therapy) ในทกกรณ โดยเฉพาะผลตภณฑกญชาทางการแพทยทยงไม ผานการรบรองตารบ (unapproved products)(ยกเวนในกรณทไดรบขอมลทางการแพทย และ เปนความประสงคของผปวยและครอบครวตามสทธขนพนฐาน unapproved products ตองปลอดภยจากสารปนเปอนตาง ๆอาท สารโลหะหนก ยาฆาแมลง ยา ฆาเชอรา และสารอนตรายอน ๆในกรณทไมทราบอตราสวนของ THC และ CBD ในแตละผลตภณฑ
การใชอาจทาไดโดยใชปรมาณทนอยทสด และเพมขนาดทละนอยโดยสงเกตการตอบสนองและผลขางเคยงทไมพงประสงคทอาจเกดขน
การใช unapproved products ตองคานงถงความปลอดภยและประสทธผลกอนนามาใชรวมถง ใหการดแล ตดตามผปวยอยางใกลชด
การใชผลตภณฑกญชาทางการแพทยควรจากดเฉพาะกรณทการรกษาดวยวธมาตรฐานตาง ๆไม ไดผล/ หรออาจเกดผลขางเคยงทผปวยไมสามารถทนได
การใชผลตภณฑกญชาควรใชเพอเปนสวนเสรมหรอควบรวมกบการรกษาตามมาตรฐาน
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ขอตกลงเบองตน
ผสงใชผลตภณฑกญชาทางการแพทยควรเปนแพทยผเชยวชาญดานอายรกรรม และ/ หรอเฉพาะโรค, ทนตแพทยผเชยวชาญทใหการรกษานน ๆหากไมใชผเชยวชาญเฉพาะทาง ผสงใชควรอยภายใตการ กากบ ดแล หรอไดรบคาแนะนาในการรกษาผปวยจากบคคลดงกลาวขางตน
ผสงใช/ ผจายผลตภณฑกญชาตองผานการอบรมหลกสตรการใชกญชาทางการแพทยทกระทรวง สาธารณสขรบรอง และไดรบอนญาตการเปนผสงใช/ ผจายผลตภณฑกญชา
ผลตภณฑกญชาทางการแพทยไดประโยชนเนองจากมหลกฐานทางวชาการทมคณภาพสนบสนนชดเจน
ภาวะคลนไสอาเจยนจากเคมบาบด (chemotherapy induced nausea and vomiting)
โรคลมชกท ร กษายาก และโรคลมชกท ด อ ตอยารกษา (intractable epilepsy)
ภาวะกลามเนอหดเกรง (spasticity) ในผ ปวยโรคปลอกประสาทเสอมแข ง (multiple sclerosis)
ภาวะปวดประสาท (neuropathic pain)
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Features of endocannabinoid system
Lipid derived On‐demand biosynthesis Act locally
Retrograde neurotransmitterCB1 locates mostly on presynaptic terminals, therefore is essential for controlling neurotransmitter release
Quickly degradedTransient activation of EC is enable the body to handle with stress
Basic pharmacology of cannabinoids
Each cannabinoid has unique mechanisms of action
Most cannabinoids are promiscuous molecules
Cannabinoid receptor dependent effectsCB1CB2
Cannabinoid receptor independent effects Other GPCRs, ion channels, nuclear receptor, transporters Direct antioxidant effects
Lancet Neurol 2019; 18: 504–12
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Basic pharmacology of THC and CBD
THC is an agonist of CB1 and CB2 receptor and more potent than endocannabinoidsCNS depressant (CB1>>>>CB2)Psychoactive effect (CB1)Appetite stimulating (CB1)Antiemetic (CB1 + 5‐HT3 antagonist) Immunomodulation (CB2)
CBD may act as a negative modulator of CB1 but very affinity (Ki >10,000 nM)Non‐psychoactive
THC and CBD target multiple receptors
Possible sites of action of THC on CB1 receptorAreas Effects
Cortical and subcortical areas Sedative, anti‐seizureChemoreceptor trigger zone (CTZ) in the medulla oblongata, nucleus tractus solitarius and visceral cortex
Antiemetic effect
Ventromedial hypothalamus Increased appetiteAmygdala, corticolimbic system AnxiolysisAnterior cingulate cortex Anxiolysis, reduced pain aversive effectSpinal cord dorsal horn lamina I‐II AnalgesiaSpinal cord ventral horn, corticospinal tract SpasmolyticNucleus accumbens Euphoria, dysphoria, psychosisPrefrontal cortices Impaired judgement and cognitionHippocampus Impaired memory, depression in chronic use
Basal ganglia, cerebellum Impaired motor performance
Neuropsychiatric effects from CB1 receptor activation
CNS depressant effects Drowsiness, decrease alertness, impair short term memory, impaired motor coordination
Low dose: Elation, euphoria, decrease anxiety, increased appetite, heightened perception, impulsivity
High dose: Dysphoria, increase anxiety, irritability, impaired short term memory, hallucination, panic reaction, paranoia, sensory distortions
Headache. 2015 Jun;55(6):885‐916.
Other adverse effects from THC
CVSTachycardia ( 20‐100% following smoking)
Vasodilation and hypotension in intermittent use
Platelet activationProartherogenic
Xerostomia
Long term useAltered brain development, lower IQ
Increased risk of schizophreniaTolerance, addiction (9%)Cannabinoid hyperemesis syndrome (CHS)
Vasospasm Reversible cerebral vasoconstriction syndrome (RCVS) due to cerebral artery dysregulation
Coronary vasospasm Peripheral arterial disease
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Cardiometabolic effects from CB1 receptor activation
European Heart Journal. 2008;10 (Supplement B):B34–B41.
Adverse effects Precautions with cannabis use
Sedation, drowsiness, dizziness
• Increases the risk of motor vehicle accidents. All patients should be advised not to drive for a minimum of 3 to 4 h after smoking, 6 h after oral consumption, and 8 h if euphoria occurs.
• Avoid in patients with heavy alcohol consumption or receiving high‐dose opioids, benzodiazepines, or sedatives due to potential for additive effects on cognitive impairment.
Impaired cognition
Avoid in patients aged 25 years or younger due to increase risk of long‐term neuropsychological impairment and psychiatric illness in those with genetic vulnerabilities.
Cannabis use disorder
Avoid in patients with active substance abuse.
Anxiety and panic attacks
Avoid in patients with mood or anxiety disorder.
Psychosis, hallucinations
Avoid in patients with a history or strong family history of psychosis.
Can J Kidney Health Dis. 2019 Feb 22;6:2054358119828391.
Adverse effects Precautions with cannabis use
Increased mortality postmyocardialinfarction
Avoid smoked cannabis in patients with cardiovascular disease
Orthostatic hypotension
Consider initiating at a low dose with gradual titration. Tolerance may develop with repeated administration in 1 to 2 days
Chronic bronchitis, COPD, lung cancer
Avoid smoked cannabis in patients with respiratory disease.
Can J Kidney Health Dis. 2019 Feb 22;6:2054358119828391.
Exposure to cannabinoids is associated with a range of adverse effects. These effects can vary by patient group and by prevalence
Nat Rev Rheumatol. 2018 Aug;14(8):488‐498.
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Functional activities on non‐CB receptors of 9‐THC and CBD and potential therapeutic implications
Target Potential therapeutic implication
9‐THC CBD
5‐HT1A agonist Anxiolysis, analgesia ‐
Blocker of N‐type calcium channel,voltage‐gated sodium channels
Anti‐seizure, antineuropathic pain
?
Glycine receptor positive allosteric modulator
Analgesia, anti‐seizure, spasmolytic
Anandamide uptake Inhibitor Increase anadamidelevel
‐
TRP channels Analgesia? TRPV2, 3, 4 agonist TRPV1, V2, V3 , A1 agonist, TRPM8
antagonistGPR18 agonist Anti‐inflammation,
anticancer
GPR55 antagonist Antagonist; anti‐osteoporosis, anticancer
Agonist
PPAR‐γ agonist Insulin sensitizing
Prog Chem Org Nat Prod. 2017;103:103‐131., Sci Rep. 2019 Jan 15;9(1):121. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=2424http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=41500
Key pharmacological effects of CBD
Anti‐epileptic
Anxiolytic
Analgesia
Spasmolytic
Immuno‐modulation
Inhibit anadamideuptake
Antiemetic
Appetite stimulating
Psychoactive
CBD
Cannabinoid pharmacokinetics
Most cannabinoids are highly lipophilicAbsorption
Low GI absorption (F<6%) but higher for inflation, intranasal and oromucosaladmin.
DistributionCBD and THC are high Vd ~32 l/kg (generally 10 l/kg)
MetabolismHigh first pass metabolismMultiple CYP450 isozymes (primarily by 2C19, 3A4 and also 2C9 2D6)Genetic polymorphism influences the levels
EliminationT1/2 at least 22 h, increased in repeated dosing Metabolites can detected several days (>100 h post dose)
Br J Clin Pharmacol 2018;84:2477–2482.
Potential drug interactions
Pharmacodynamics – changes in drug effectsCNS depressant effect
THC+high dose opioids, benzodiazepines, sedating antipsychotics/antidepressantsOrthostatic hypotension
THC+CCBs/alpha blockers/drugs for PDHepatotoxicity
CBD+valproate
Pharmacokinetics – changes in drug levelsTHC and CBD are substrates of CYP450 isozymes and also act as competitive inhibitors of the enzymes
P‐glycoprotein induction/inhibition Life Sci. 2007;80:1415‐1419.Clin Pharmacol Ther. 2009;85:273‐276.
Drug Metab Rev. 2014;46:86‐95.Life Sci. 2011;89:165‐170.
https://www.sps.nhs.uk/articles/cannabis‐based‐medicinal‐products‐potential‐drug‐interactions/
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Potent CYP450 inhibitors/inhibitors can alter THC and CBD levels
CYP isozyme Inhibitors Results
CYP2C9 inhibitors amiodarone, cimetidine, cotrimoxazole, metronidazole, fluoxetine, fluvoxamine, fluconazole, and voriconazole
Expected to THC based on pharmacogenetic data of 3‐fold increase in THC level in poor metabolizer
CYP3A4 inhibitors Ketoconazole, clarithromycin, erythromycin, cyclosporine, verapamil, itraconazole, voriconazole, and boceprevir
Peak and AUC of THC by 1.2‐ and 1.8‐fold
plasma concentration of CBD 2‐fold
CYP3A4 inducer Rifampin THC level 20‐40%No data for CBD
THC and CBD can alter other drug levels
THC is a competitive inhibitor CYP3A4, CYP2D6 and 2C9CBD is a potent inhibitors of CYPsMost potent than other cannabinoids in inhibiting CYP3A4, CYP2D6 and 2C9
CYP1A1, 1A2, 1B1, 2B6, 2C19, and 2C8 were strongly inhibitedUGT1A9, and 2B7 are inhibited by CBD
Polyaromatic hydrocarbons from cannabis smoking can induce CYP1A2 similar to tobacco smoking theophylline, clozapine, levels
CYP2C19
THC CYP2C9 Various metabolites
S‐Warfarin CYP2C9 Inactive metabolites
CYP1A2R‐Warfarin
CYP3A4Dihydropyridines
Inactive metabolites
Inactive metabolites
CYP3A4Fentanyl Inactive metabolites
Potential clinical effectsAmiodarone
Sustained tachycardia
CYP3A4
THC, CBD
Hypotension
THC, CBD Sedation,respiratory depression
THC, CBD
INR, increase risk of bleeding
N‐desmethyclobazam
Inactive metabolitesCBD
Sedation
Interactions of cannabinoids and other drugs reported in the literature
Nat Rev Rheumatol. 2018 Aug;14(8):488‐498.
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ผลตภณฑกญชาทางการแพทยไดประโยชนเนองจากมหลกฐานทางวชาการทมคณภาพสนบสนนชดเจน
ภาวะคลนไสอาเจยนจากเคมบาบด (chemotherapy induced nausea and vomiting)
โรคลมชกท ร กษายาก และโรคลมชกท ด อ ตอยารกษา (intractable epilepsy)
ภาวะกลามเนอหดเกรง (spasticity) ในผ ปวยโรคปลอกประสาทเสอมแข ง (multiple sclerosis)
ภาวะปวดประสาท (neuropathic pain)
THC
CBD
THC CBD1:1
Nabilone
THC CBD1:20
Marijuanna
THC CBD1:1???
NabiloneDronabinol
CBD
ผลตภณฑกญชาทางการแพทยนาจะไดประโยชน (ในการควบคมอาการ)
Use of cannabis products for medical purposes
NEED to know the products, what they are and how they actNEED to use the right product for each indicationNEED to justify the indication of the use
Medically needed?Evidence‐based supported?Optimal standard treatment offered?
NEED to balance between benefit and risk and communicate to patients
NEED titrationNEED reevaluationNEED extensive pharmacovigilance
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