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Kannabinoidlerin Farmakolojisi

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Kannabinoidlerin Farmakolojisi KANNABİNOİDLERİN FARMAKOLOJİSİ Prof. Dr. Ahmet ULUGÖL Trakya Üniversitesi Tıp Fakültesi Tıbbi Farmakoloji Anabilim Dalı Kannabis (kenevir) esrar, marijuana, haşiş Kannabinoidler Fitokannabinoidler (doğal kannabinoidler) Sentetik kannabinoidler ve analogları Endokannabinoidler Araşidonil etanolamin (anandamid, AEA) 2-araşidonilgliserol (2-AG), vb. Fitokannabinoidler Δ9-tetrahidrokannabinol (THC) (psikoaktif) Kannabidiol (CB reseptörlere afinite, psikoaktif değil) Kannabinol Δ9-tetrahidrokannabivarin Δ9-tetrahidrokannabiorkol Kannabigerol Kannabikromen, vb. Sentetik kannabinoidler ve analogları Dronabinol (sentetik THC, Marinol) Nabilon (dronabinol analogu, Cesamet) THC + kannabidiol (Nabiximols, Sativex) Levonantradol, metanandamid WIN 55,212-2, HU-210, CP 55,940 CT-3 (ajulemik asit) rimonabant (SR141716A, Acomplia), vb. Endokannabinoidler Endokannabinoi CB1 CB2 TRPV1 d Anandamid +++ + + 2-AG +++ ++ 0 Virodhamin Agonist/parsiyel + 0 agonist N-araşidonil-dopamin +++ 0 +++ Noladin ether +++ + 0 CB1 & CB2 reseptörlerinin dağılımı CB1 CB2 immun sistem: dalak, tonsiller, timus - microglia, makrofaj, mast hücresi, vb. Kannabinoid reseptörlerinin sinyal ileti mekanizmaları Mekanizma Reseptör Gi/O protein aktivasyonu CB1/CB2 Adenilil siklaz inhibisyonu CB1/CB2 Kalsiyum kanallarının blokajı CB1 Potasyum kanallarının aktivasyonu CB1 MAPK aktivasyonu CB1/CB2 Kannabinoid tetradı Lokomotor aktivitede Hipotermi Katalepsi Analjezi Fizyolojik sistemlere etkiler Santral sinir sistemi Öfori-kannabinoid sarhoşluğu İntellektüel ve psikomotor performansta bozulma Analjezi, termoregülasyon bozuklukları Psikotik epizodlar, bellek bozuklukları Antiemetik etkinlik, iştah artırıcı etkinlik Anksiyete ve stres giderici etkinlik Nöroprotektif etkiler, antikonvulsif özellikler, tolerans gelişimi Kardiyovasküler sistem Taşikardi, vazodilatasyon, kan basıncında Fizyolojik sistemlere etkiler Solunum sistemi Bronkodilatasyon, öksürük kesici etki Gastrointestinal sistem İntestinal transit inhibisyonu, kolonda antiinflamatuvar etki Lokomotor sistem Hipomobilite, antispastik özellikler Oküler sistem İntraoküler basınçta Diğer: tümör büyümesinin inhibisyonu, immun fonksiyonlara etki İlaç Onay Ülke Onaylı endikasyon Nabilone 1985 U.S.A., Kanada Diğer antiemetiklere yeterli yanıt (Cesamet) vermeyen kanser kemoterapisine bağlı kusma Canasol 1987 U.S.A., Kanada, vd. İntraoküler basıncın eşlik ettiği geç-dönem glokom Dronabinol 1985 U.S.A., Kanada Konvansiyonel tedavilere yeterli (Marinol) yanıt vermeyen kanser kemoterapisine bağlı bulantı ve kusma 1992 U.S.A. AİDS hastalığına bağlı kilo kaybının eşlik ettiği anoreksi Nabiximols 1995 Kanada Erişkilerde multipl skleroza bağlı (Sativex) nöropatik ağrı, spastisite 1997 Kanada Kanser ağrısı İstenmeyen etkiler 31 randomize kontrollü çalışma + 8 gözlemsel çalışma % 96.6 ciddi değil baş dönmesi % 15.5 % 3.4 ciddi multipl skleroz relapsı % 12.8 kusma % 9.8 üriner sistem infeksiyonları % 9.1 (Wang ve ark. CMAJ, 2008) Wang GS JAMA Pediatrics, 2013 Yakın Dönem Hedefleri: I. Selektif periferik CB1 agonistleri II. Selektif CB2 agonistleri III.Endokannabinoid sistemin modülasyonu IV.Kombinasyon 1- Selektif periferik CB1 agonistleri CT3 (ajulemic acid) – Indevus (Karst et al., 2003) AZD1940 - AstraZeneca 2- Selektif CB2 agonistleri PRS-211,375 – Cannabinor, Pharmos Corp. (Faz II) GW842166 – GlaxoSmithKline (Faz II) 3- Endokannabinoid sistemin modülasyonu FAAH (yağ asidi amid hidrolaz) AEA araşidonik asit + etanolamin MAGL (monoaçilgliserol lipaz) 2-AG araşidonik asit + gliserol Re-uptake inhibisyonu (öz. AEA) 3- Endokannabinoid sistemin modülasyonu FAAH inhibitörleri: URB597, OL135, PF-04457845 MAGL inhibitörleri: OMDM169, JZL184 (klinik araştırma henüz yok) Re-uptake inhibitörleri: AM404, VDM11 (klinik araştırma henüz yok) 4- Kombinasyon Opioidler (Smith ve ark., 2007; Desroches ve Beaulieu, 2008; vb.) Periferik analjezikler (parasetamol, dipiron) FAAH/TRPV1 dual inhibitörleri: N-araşidonil- serotonin, OMDM198 (Costa ve ark. 2010) FAAH/MAGL dual inhibitörleri: SA-57, JZL195 (Niphakis ve ark. 2012, Wise ve ark. 2012) Paracetamol – kannabinoid sistem FAAH Parasetamol p-aminofenol AM404 (karaciğer) (beyin) Re-uptake FAAH inhibisyon inhibisyon u u Dipiron (metamizol) – kannabinoid sistem FAAH Dipiron araşidonil amidler COX-1, -2 CB1, 2 inhibisyon reseptörlere afinite u Daha Fazla Bilgi Edinilebilecek Kaynaklar: Dogrul A, Seyrek M, Yalcin B, Ulugol A. Involvement of descending serotonergic and noradrenergic pathways in cannabinoid CB1 receptor-mediated antinociception. Prog Neuropsychopharmacol Biol Psychiatry 38: 97-105, 2012 Dogrul A, Seyrek M, Yalcin B, Ulugol A. Involvement of serotonergic system in cannabinoid analgesia. In: Endocannabinoid Regulation of Monoamines in Psychiatric and Neurological Disorders (Ed. Van Bockstaele EJ). Springer, New York, 277-295, 2013 Escobar W, Ramirez K, Avila C, Limongi R, Vanegas H, Vazquez E. Metamizol, a non-opioid analgesic, acts via endocannabinoids in the PAG-RVM axis during inflammation in rats. Eur J Pain 16: 676-689, 2012 Guindon J, Beaulieu P, Hohmann AG. Pharmacology of the cannabinoid system. In: Pharmacology of Pain (Eds. Beaulieu D, Lussier D, Porreca F, Dickenson AH) pp. 111-138, 2006 Staroeicz K, Di Marzo V. Non-psychotropic analgesic drugs from the endocannabinoid system: ‘’Magic bullet’’ or ‘’multiple-target’’ strategies. Eur J Pharmacol 716: 41-53, 2013 Kinsey SG, Long JZ, O’Neal ST, Abdullah RA, Poklis JL, Boger DL, Cravatt BF, Lichtman AH. Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain. JPET 330: 902-910, 2009 Mallet C, Daulhac L, Bonnefont J, Ledent C, Etienne M, Chapuy E, Libert F, Eschalier A. Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain 139: 190-200, 2008 Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A. The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors. Eur J Pharmacol 531: 280-281, 2006 Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics 6: 713-737, 2009 Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo V, Nüsing R, Imming P. Novel bioactive metabolites of dipyrone (metamizol). Bioorgan Med Chem 20: 101-107, 2012 Ulugöl A. Kannabinoidler ve nöropatik ağrı. Kannabinoidlerin Tıpta Kullanımı Sempozyumu. Ankara, 23 Mayıs 2012 Wang T et al. Adverse effects of medical cannabinoids: a systematic review. CMAJ 178: 1669-1678, 2008 TEŞEKKÜRLER .
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