ZDRAVILA, KI VPLIVAJO NA METABOLIZEM LIPIDOV
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1 ZDRAVILA, KI VPLIVAJO NA METABOLIZEM LIPIDOV Prof. Lovro Stanovnik Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
2 Kratek povzetek zgodbe
3 Pregled Nastanek aterosklerotičnega plaka Metabolizem lipidov v plazmi (lipoproteinov) Zdravila, s katerimi lahko vplivamo na te procese
4 Nastanek aterosklerotičnega plaka vdor lipidov skozi endotel oksidacija lipidov fagocitoza (makrofagi) penaste celice (foam cells) adhezija trombocitov
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6 Leukocyte Endothelial Adhesion Molecules Mono T B PMN
7 Macrophage Functions in Atherogenesis Attachment
8 Macrophage Functions in Atherogenesis Penetration
9 Macrophage Functions in Atherogenesis Activation
10 Macrophage Functions in Atherogenesis Division
11 Faktorji, ki sodelujejo v vnetnih dogajanjih v ateromu Vascular Cell Adhesion Molecule 1 (VCAM-1) Monocyte Chemoattractant Protein 1 (MCP-1) Scavenger receptors Macrophage Colony-Stimulating Factor (M-CSF) Tumor necrosis factor receptor (TNFR = CD40)
12 Molecular Mediators of Atherogenesis VCAM-1 MCP-1 M-CSF
13 Cell Types in the Human Atheroma Monocyte/ Macrophage Intima Tunica Media T-lymphocytes Endothelium Smooth muscle cells
14 Schematic Time Course of Human Atherogenesis Ischemic Heart Disease Cerebrovascular Disease Lesion initiation No symptoms + Symptoms Peripheral Vascular Disease Symptoms Time (y)
15 M-CSF Expression in Atheroma Intimal M-CSF in Atheroma
16 Anatomy of the Atherosclerotic Plaque Fibrous cap Lumen Intima Lipid Core Shoulder Media Elastic laminæ Internal External
17 Matrix Metabolism and Integrity of the Plaque s s Fibrous Cap Synthesis Breakdown IFN- Collagen-degrading Proteinases Fibrous cap Lipid core CD-40L IL-1 TNF- MCP-1 M-CSF Tissue Factor Procoagulant Libby P. Circulation 1995;91:
18 Inflammation Can Promote Thrombosis Tissue Factor CD40L Fibrinogen Fibrin Via gp llb/llla Platelet Platelet- Fibrin Thrombus Platelet Fibrinopeptides
19 CRP and CV Risk CRP is an excellent marker of inflammation Elevated CRP correlates with increased risk of cardiac events and mortality Proven therapies (ASA, clopidogrel, statins) Greater benefit among patients with elevated CRP In some cases also reduce CRP levels (statins) PROVE IT TIMI TIMI 22 and REVERSAL provide evidence that targeting inflammation (CRP) may lead to decreased atherosclerosis and optimized outcomes? Need randomized trial of CRP-based intervention vs. standard cardiac rehab/risk factor modification
20 Pregled Nastanek aterosklerotičnega plaka Metabolizem lipidov v plazmi (lipoproteinov) Zdravila, s katerimi lahko vplivamo na te procese
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22 Metabolizem lipidov Transport lipidov po telesu Lipoproteini CE (estri holesterola) TG (trigliceridi) proteini (apolipoproteini( apolipoproteini) ligandi za receptorje, kofaktorji encimov
23 Lipoproteini (LP) Več vrst glede na sestavo in gostoto (centrifugiranje na osmotskem gradientu): hilomikroni VLDL LP zelo majhne gostote IDL LP srednje gostote LDL LP majhne gostote HDL LP velike gostote Razlike v vsebnosti in vrsti lipidov in v vrstah apolipoproteinov (ApoA, ApoB, ApoC, ApoE, Apo(a)
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25 Gelna elektroforeza različnih LP
26 Transport in metabolizem lipidov Pot za endogene lipide Pot za eksogene lipide
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30 VLOGA HDL Transport CE in TG med različnimi lipoproteini in jetri Prenos apolipoproteinov CII, CIII, apo E Povratni transport holesterola Antiaterogeno delovanje
31 Structure of HDL Particle A-I CE TG A-I A-II A-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglycerides
32 Production of HDL by Liver and Intestine Liver Intestine A-I A-I A-II HDL HDL A-I, A-II = apolipoprotein A-I, A-II
33 HDL Metabolism and Reverse Cholesterol Transport Bile FC Liver CE SR-BI A-I CE Mature HDL LCAT A-I FC Nascent HDL FC ABC1 CE Macrophage ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin:cholesterol acyltransferase; SR-BI = scavenger receptor class BI
34 Role of CETP in HDL Metabolism F C Liver Bile CE LDLR SR-BI Mature HDL Macrophage A-I Nascent HDL A-I LCAT ABC1 CE FC CE FC SRA CETP CE B Oxidation VLDL/LDL CETP = cholesteryl ester transfer protein LDL = low-density lipoprotein LDLR = low-density lipoprotein receptor VLDL = very-low-density lipoprotein
35 Role of Hepatic Lipase and Lipoprotein Endothelium CMR/IDL Lipase in HDL Metabolism HL B PL LPL A-I CE TG HDL 2 PL Kidney CM = chylomicron; CMR = chylomicron remnant; HDL = high-density lipoprotein; HL = hepatic lipase; IDL = intermediate-density lipoprotein; LPL = lipoprotein lipase; PL = phospholipase; TG = triglyceride B TG CM/VLDL A-I CE HDL 3 C-II Phospholipids and apolipoproteins
36 Pregled lipoproteinov (LP) VRSTA LP GLAVNE SESTAVINE APOPROT. MESTO SINTEZE POTI KATABOLIZMA Hilomikroni (CH) in ostanki CH) Trigliceridi (TG) in holesterol (C) v hrani,, 10:1 B-48, E, A-I, A A-IV, C-I, C C-C II, C-IIIC Črevo Hidroliza TG z LPL. Privzem ostankov CH v jetrih preko ApoE VLDL Endogeni ali jetrni TG, 5:1 B-100, E, C-I, C C-II, C-IIIC Jetra Hidroliza TG z LPL IDL Holesterilni estri (CE) in endogeni TG B-100, E, C-C II, C-IIIC Katabolni produkt VLDL 50% v LDL, posredovana z jetrno lipazo (HL), 50% privzem v jetra z ApoE
37 Pregled LP VRSTA LP GLAVNE SESTAVINE APOPROTEINI MESTO SINTEZE POTI KATABOLIZMA LDL CE B-100 Katabolni produkt VLDL Privzem z LDL-R (~75% v jetrih), posredovan z ApoB-100 HDL Fosfolipidi, CE A-I, A-II, A E, C-C I, C-II, C C-IIIC Črevo, jetra, plazma Prenos CE v VLDL in LDL. Privzem HDL C v hepatocite Lp(a) CE B-100, apo(a) Jetra Neznano
38 LASTNOSTI APOLIPOPROTEINOV I APOLIPOPROTEIN ApoA-I ApoA-II MESTO SINT. Jetra, črevo Jetra ApoB-100 Jetra ApoB-48 Črevo VLOGA Sestavina HDL, kofaktor LCAT, ligand za HDL-R, reverzni transport C Tvori -S-S- kompleks z apoe-2 2 in E-3, E kar prepreči vezavo apoe-2 in apoe-3 na LP-R Strukturni protein VLDL, IDL, LDL, ligand LDL-R Strukturni protein hilomikronov (CM)
39 LASTNOSTI APOLIPOPROTEINOV II APOLIPOPROTEIN ApoC-I ApoC-II ApoC-III ApoE Apo(a) MESTO SINT. Jetra Jetra Jetra Jetra, možgani gani, koža, gonade, vranica Jetra VLOGA Aktivator LCAT. Modulira vezavo ostankov CM na R Kofaktor LPL Modulira vezavo ostankov CM na R Ligand za LDL-R R in za ostanke CM, reverzni transport C (HDL z apoe) Modulator fibrinolize
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41 Pregled Nastanek aterosklerotičnega plaka Metabolizem lipidov v plazmi (lipoproteinov) Zdravila, s katerimi lahko vplivamo na te procese
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44 Pregled zdravil za zdravljenje hiperlipidemij Inhibitorji HMG-CoA reduktaze Smole, ki vežejo ejo žolčne kisline Ezetimib Derivati fibrične kisline (fibrati( fibrati) Nikotinska kislina (niacin( niacin) Probukol Kombinacije zdravil Druga zdravila
45 HMG-CoA reduktazni inhibitorji Hidroksi-metil metil-glutaril-coa reduktaza ključni (rate limiting) encim pri sintezi holesterola HMG-CoA mevalonska kislina Posledica: koncentracija holesterola Povečana ekspresija gena za HMG-CoA reduktazo Povečana ekspresija gena za LDL-R Povečano odstranjevanje LDL koncentracija LDL
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47 *
48 Farmako kokinetikakinetika Dobra obsorpcija iz prebavil Ekstrakcija v jetrih delovanja) (mesto Izločanje preko jeter (metabolizem) Vezava na plaz. belj.. ( > 90% )
49 Klinična na uporabnost Zmanjšajo ajo morbiditeto in mortaliteto pri izbranih bolnikih Indicirani pri bolnikih z manifestno aterosklerozo in tistih z večjim tveganjem za koronarno bolezen Neučinkoviti (razen atorvastatina) ) pri homozigotni družinski hiperholesterolemiji
50 Stranski učinki Relativno skromni jetrne transaminaze previdnost pri jetrnih boleznih Miopatija ( rabdomioliza ) kontrola kreatin fosfokinaze ( CPK ) 0,1% pacientov z blažjim miozitisom itisom verjetnost večja pri sočasni uporabi fibratov in nikotinske inske kisline
51 Smole, ki vežejo ejo žolčne kisline Delovanje v črevesu ni sistemskih učinkovu Preprečevanjeevanje enterohepatične ne cirkulacije žolčnih kislin ( 97 % ) izločanje iz telesa Holesterol žolčne kisline konc. Holesterola koncentracija HMG-CoA reduktaze sinteza LDL-R sinteza cholesterola in TG
52 Predstavnika Holestiramin Kolestipol
53 Klinična na uporabnost Uporabne v kombinaciji s statini (ob nezadostnem učinku) u Kot monoterapija pri bolnikih s povečanim holesterolom in normalnimi trigliceridi, če e so statini kontraindicirani
54 Stranski učinki Napihnjenost v trebuhu Zaprtje alkalne fosfataze (jetra) - zmerno Hipertrigliceridemijaigliceridemija Interakcije s številnimi zdravili na nivoju absorpcije: tiroksin kardiotonični glikozidi antikoagulansi nekateri tiazidi nekatera antilipemična na zdravila: nekateri statini gemfibrozil
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56 EZETIMIB Relativno novo zdravilo (ZDA 2002, SLO 2005) Selektivna inhibicija absorpcije holesterola in fitosterol tosterolovov v črevesu. Ezetimib se veže e v luminalni membrani epitelnih celic (brush border) v črevesu. Molekularna tarča ezetimiba je prenašalec alec za sterole (sterol transporter).
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58 Ezetimib - učinki Znižanje LDL mehanizem podoben kot pri smolah Povečan nivo HDL Farmakokinetika Biološka uporabnost variabilna Razpolovni čas okrog 22 ur Metabolizem: ezetimib-glukuronid
59 Ezetimib stranski učinkiu Relativno skromni Bolečine v trebuhu Mialgija (pogostejša a ob kombinaciji s statini)
60 Derivati fibrične kisline (fibrati) Delovanje preko PPARs (peroxisome proliferator activated receptors) (jedrni receptorji regulacija transkripcije različnih genov LPL, ApoA, ) VLDL HDL aktivnost LPL VLDL IDL sintezo ApoC-III (ki( je inhibitor LPL) sintezo VLDL v jetrih aktivnost in agregacijo trombocitov CRP Fenofibrat urikozurično delovanje
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62 Predstavniki: Klofibrat Gemfibrozil Fenofibrat Bezafibrat
63 Farmakoinetika inetika: Hitra in skoraj popolna absorpcija t 1/2 različen pri različnih predstavnikih: gemfibrozil fenofibrat 1 h 20 h Izločajo se kot glukuronidi
64 Od strani GIT Redko: Stranski učinki: alergični pojavi spremenjeni jetrni encimi Miozitis Nagnjenost k holelitiazi Interakcije: antikoagulansi ( učinek ) inhibitorji itorji HMG-CoA reduktaze (miozitis)
65 Nikotinska kislina (niacin) Vitamin produkcija VLDL sinteza TG dotok FFA do jeter HDL (? mehanizem)
66 Farmakokinetika in stranskis učinki Dobra absorpcija Kratek t 1/2 ( 1 ura ) Naval krvi v zgornji del telesa (flushing) udeleženost enost PG (NSAID( zmanjšajo ajo ta učineku ) Pruritus (povezan s prejšnjim njim) Motena funkcija jeter transaminaze toleranca glukoze Palpitacije (pogosto spremljajo navale krvi)
67 Antioksidant Zelo lipofilna snov Probukol
68 Učinki probukola LDL ( spremenjena sestava ) Učinkovit tudi pri homozigotni družinski hiperholesterolemiji HDL (mehanizem( ni jasen) CETP Apo A-IA Inhibicija transporta holesterola skozi črevesno steno Motenje sinteze holesterola v zelo začetni stopnji
69 Farmakokinetika Slaba in nepredvidljiva absorpcija (boljša ob jemanju s hrano) Kopičenje v maščevju vrh koncentracije v plazmi dosežen en po 4 mesecih Dokazljiv v plazmi še 6 mesecev po prenehanju jemanja
70 Stranski učinki GIT (diareja(, navzea) Glavobol, omotičnost Podaljšanjeanje Q-T intervala kontraindiciraniciran pri uporabi antiaritmikov, TCA, fenotiazinov Kontraindiciran pri bolnikih, ki niso na dieti z malo maščobe
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73 Effects of Lipid-Modifying Drugs on HDL-C C Levels Niacin 15 35% Fibrates 10 15% 15% Estrogens 10 15% 15% Statins 5 10% Belalcazar LM et al. Progr Cardiovasc Dis 1998;41:
74 Drug Effects on HDL: Niacin NIACIN B TG C-II LPL CM/VLDL Intestine B Liver LDLR NIACIN * A-I CE Mature HDL LCAT HL A-I FC Nascent HDL ABC1 CMR/IDL CE FC Macrophage *Inhibits uptake of apoa-i but not CE
75 Drug Effects on HDL: Fibrates B TG C-II LPL + FIBRATES CM/VLDL Intestine B LDLR + CMR/IDL Liver A-I CE Mature HDL FIBRATES LCAT HL A-I FC Nascent HDL ABC1 FC CE Macrophage
76 Drug Effects on HDL: Statins B TG C-II LPL Intestine CM/VLDL + B LDLR + STATINS CMR/IDL Liver A-I CE Mature HDL STATINS LCAT HL? A-I FC Nascent HDL STATINS ABC1 FC CE Macrophage
77 Combination Therapy Adding Niacin or a Fibrate to a Statin Pros Better TG and HDL-C May LDL-C C more (niacin or fenofibrate) Lp(a) ) (niacin) LDL particle size Fibrinogen (fibrates( fibrates) Angiographic data Cons Increased cost and complexity Increased myositis risk Increased hepatitis risk (niacin) Potential for other drug interactions Lack of outcome data
78 Drugi faktorji z vplivom na lipide oz. na tveganje za CVI Ribje olje Homocistein Antioksidanti Vitamin E Vitamin C Koencim Q10 Česen (alicin( alicin) Karotenoidi Beta karoten Licopen
79 Ribje olje Vsebuje -3 trigliceride TG holesterol (LDL) Mehanizem ni znan Zmanjša a obolevnost za koronarno boleznijo Vpliv na hemostazo: eikozipentaenoična na kislina zamenja arahidonsko kislino manj učinkoviti eikozanoidi (TXA 2 )
80 Essential Fatty Acid Families H 3 C H 3 C C20:4 ω-6 ω-6 family C18:2 ω-6 Linoleic Corn Oil Safflower Oil Sunflower Oil COOH COOH Arachidonic More thrombotic and inflammatory metabolites H 3 C H 3 C C18:3 ω-3 ω-3 family -Linolenic Flaxseed Oil Canola Oil Soybean Oil COOH C20:5 ω-3 Eicosapentaenoic (EPA) H 3 C COOH C22:6 ω-3 Docosahexaenoic (DHA) Less thrombotic and inflammatory metabolites COOH Oily Fish Fish Oil Capsules
81 Zdravila v fazi preizkušanja Inhibitorji acil-koencim A holesterol aciltransferaze (ACAT) paktimib Preprečevanje evanje kopičenja holesterola v makrofagih Inhibicija nastajanja penastih celic Živalski modeli in vivo zmanjšanje anje volumna of intravaskular ularnega ateroma Klinične ne študije ni bilo pričakovanega učinka
82 Dodatni viri
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