Lægemidler med virkning på respirationsvejene Astma Farmakologisk behandling 1 P Jeffery, in: Asthma, Academic Press 1998 Before 10 minutes after challenge P Howarth 2 Astma Sygdom karakteriseret af bronkokonstriktion og inflammation To grupper af medikamentel behandling 1) Bronkodilaterende midler 2) Antiinflammatoriske midler Medikamentel behandling af astma Bronkodilaterende midler - sympatomimetika - methylxanthiner - antikolinergika Antiinflammatoriske midler - corticosteroider - leukotrienantagonister - (kromoner) 3 Sympatikomimetika Adrenalin/noradenalin Isoprenalin Beta-2 receptor agonister korttidsvirkende langtidsvirkende - salbutamol,terbutalin,fenoterol o.a. - salmeterol,formoterol, (bambuterol) (UABA’s - indacaterol) Sympatikomimetika Adrenalin Salbutamol Salmeterol 4 Beta-2 receptor agonister - virkningsmekanisme ATP AC Gs Beta-2 agonist + Ca2+ cAMP MLCK beta-2 receptor + membran interaktioner (lipophilicitet) ? Beta-2 receptor agonists - time/response FORM 24µg SALM 50µg SALB 200µg FEV1 (% change) 40 30 20 10 0 0 1 2 3 4 5 6 7 Hours 8 9 10 11 12 Van Noord et al 1995 5 Beta-2 receptor agonister - bivirkninger Tremor Palpitationer / tachycardi Hyperglycæmi (DM) Hypokaliæmi Tachyphylaxi ? Tolerance for beta-2 agonister - klinisk relevans ? Placebo (n=77) Salbutamol 200x4 (n=72) FEV1 (% pred.) 100 90 80 70 60 0 6 12 Hours Pearlman ,NEJM 1992 6 Methylxanthiner Theofyllin, teofylamin Theofyllin 7 Theofyllin - virkningsmekanisme ATP PDE AC Gi A1 - receptor cAMP (÷) AMP ÷ Theofyllin (PDE4-hæmmere, ex. roflumilast) Methylxanthiner Theofyllin, teofylamin Lavt terapeutisk index! Bivirkninger - gastrointestinale gener, rastløshed, hovedpine kramper, arrytmier Stor biologisk variation TDM cimetidin, ciprofloxacin, disulfiram, erytromycin rygning 8 Antikolinergika Atropin Ipratropium muskarin antagonist ≠ beta-2 agonister - ikke protektiv, mindre effektiv supplerende - astma (og KOL) bivirkninger - smag, (glaucom) - dosering Atropin Ipratropium Antikolinergika Tiotropium 9 Corticosteroider Parenteralt - methylprednisolon, hydrocortison Peroralt - prednison, prednisolon Inhalation - beclomethason, budesonid, fluticason, mometason (flunisolid, triamcinolon, ciclesonid) Corticosteroider Cortisol Budesonid 10 Corticosteroider - virkningsmekanisme GCS Hsp90 GCS receptor GCS receptor guarded by Hsp90 Transcription factor (eg. AP-1, NF-kB) GCS receptorcomplex DNA Decoiling Transrepression Transactivation Decrease inflammatory proteins Increase antiinflammatory proteins Side-effects (eg. metabolic) Inhalationssteroider- bivirkninger Systemiske - suppression af HPA-aksen - væksthæmning - hudforandringer - (osteoporose, glaukom, katarakt) 11 Inhalationssteroider- bivirkninger Systemiske - suppression af HPA-aksen - væksthæmning - hudforandringer - (osteoporose, glaukom, katarakt) Lokale - hæshed - svamp i mundhule og svælg Leukotrienantagonister Montelukast - cysLT1 receptor antagonist Montelukast 12 Leukotriene biosynthesis Arachidonic acid ÷ 5-LO inhibitors (eg Zileuton) 5-HPETE BLTR - chemotaxis (neutrophil) "respiratory burst" LTB4 LTA4 CysLT1-receptor - eosinophil chemotaxis ÷ bronchoconstriction LTC4 LTD4 CysLT1-receptor antagonists (eg Zafir-, Pran-, Montelukast) LTE4 CysLT2-receptor Leukotrienantagonister Montelukast - cysLT1 receptor antagonist Supplerende til corticosteroid Aspirinintolerans x1 p.o., virker indenfor ~ 1 døgn Få bivirkninger (dyspepsi) 13 Comparative efficacy - corticosteroid/LTA BDP 200µg bd Montelukast 10mg od Placebo Change in FEV1 (%) 18 15 12 * 9 6 3 0 0 3 6 9 Weeks in active treatment * p = 0.01 12 15 Malmstrom et al Ann Int Med 1998 Kromoner Kromoglikat, nedocromil, (ketotifen) Tachykininantagonist ? Mastcellestabiliserende ?? Inhiberende effekt på sensoriske nerver ? Atoksiske Kun inhalation 14 Kromoner - effekt ? am pm 440 Nedocromil 16mg/d FP 500µg/d PEF (L/min) 420 400 * 380 360 340 320 0 0 1 2 3 4 Weeks 5 6 * p < 0.0001 7 8 Pauli et al EJCR 1995 Klassifikation af astma Symptomer Lungefunktion Dag Nat Trin 4 Svær persisterende Konstante Nedsat fysisk aktivitet Hyppige exacerbationer Hyppige FEV1/ PEF < 60% forventet PEF variabilitet > 30% Trin 3 Moderat persisterende Daglige Dagligt behovsmedicin Forværringer < 2/uge > 1/uge FEV1/ PEF 60–80% forv. PEF variabilitet > 30% Trin 2 Mild persisterende > 1 gang/uge, ikke dagligt > 2/måned FEV1/ PEF ≥ 80% forv. PEF variabilitet 20–30% ≤ 2/måned FEV1/ PEF ≥ 80% forv. PEF variabilitet < 20% Trin 1 < 1 gang/uge Mild intermitterende NIH publication no. 97-405, 1997 15 Farmakoterapeutisk strategi - astma Trin 1 Inhaleret korttidsvirkende beta-2 agonist p.n. Farmakoterapeutisk strategi - astma Trin 1 Inhaleret korttidsvirkende beta-2 agonist p.n. Trin 2 + inhaleret corticosteroid (lav-medium dosis) 16 Farmakoterapeutisk strategi - astma Trin 1 Inhaleret korttidsvirkende beta-2 agonist p.n. Trin 2 + inhaleret corticosteroid (lav-medium dosis) Trin 3 + inhaleret langtidsvirkende beta-2 agonist eller leukotrienantagonist (eller theofyllin) Farmakoterapeutisk strategi - astma Trin 1 Inhaleret korttidsvirkende beta-2 agonist p.n. Trin 2 + inhaleret corticosteroid (lav-medium dosis) Trin 3 + inhaleret langtidsvirkende beta-2 agonist eller leukotrienantagonist (eller theofyllin) Trin 4 Maksimer inhalationssteroid Overvej peroral steroidbehandling (Antikolinergika ved akut astma) 17 Astma Kontrol Characteristic Controlled (All of the following) Partly Controlled (Any measure present in any week) Daytime symptoms None (twice or less/week) More than twice/week Limitations of activities None Any Nocturnal symptoms/awakening None Any Need for reliever/ rescue treatment None (twice or less/week) More than twice/week Lung function (PEF or FEV1) Normal < 80% predicted or personal best (if known) Exacerbations None One or more/year* Uncontrolled Three or more features of partly controlled asthma present in any week One in any week† * Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate. † By definition, an exacerbation in any week makes that an uncontrolled asthma week. 18 AIRE (Asthma insights and reality in Europe) Undersøgelse af astma management i Europa Telefon-screening af 73.880 husstande ligeligt fordelt på 7 lande (Frankrig, Tyskland, Italien, Holland, Sverige, Spanien og Storbritannien) Identificerede ialt 2803 astma patienter(2050 voksne/ 753 børn) Rabe, Eur Respir J 2000;16:802-7 19 Patients estimate of asthma control Well controlled Completely controlled Patients (%) 100 80 60 40 20 0 Severe Moderate Mild Intermittent Actual level of asthma control in the past 4 weeks Rabe, Eur Respir J 2000;16:802-7 Use of asthma medications Patients (%) Anti-inflammatory 90 80 70 60 50 Quick relief 40 30 20 10 0 Severe Moderate Mild Intermittent (Asthma severity based on symptoms) Rabe, Eur Respir J 2000;16:802-7 20 Formulering af astmamedicin Lokal behandling - spray - spacer - pulverinhalator - nebulisator Systemisk behandling - tabletter - injektion 21 Fejlanvendelse af astma-sprays Handling Patient fejl (%) Fjerne låg/hætte på spray Ryste spray Ånde ud før anvendelse Anbringe spray korrekt Aktivere spray Inhalere langsomt Fortsætte inhalation Holde vejret Ånde langsomt ud 7 43 29 29 64 57 46 43 5 Ganderton, 1997 Nye behandlinger for astma IFNγ IL-12 Immunomodulators -PDE inhibitors, TH2 -Glucocorticoids, -Cyclosporine Anti-IL-5 MAb Anti-IL-4, Anti-IL-13 IL-4R TH1 B Cell Eosinophil Apoptosis -GCs -p38 MAP Inhibitors Airway Inflammation & BHR Anti-IgE IgE 22 Omalizumab (Xolair) Monoklonalt humant antistof mod IgE Kun til behandling af svær allergisk astma Gives subkutant /2 uge Effekt? Pris!!! Number of Exacerbations (Stable-Steroid Phase/16 weeks) 1.0 Exacerbations 0.8 per Patient (mean) 0.6 0.4 Placebo *p≤0.006 * 0.54 Omalizumab * 0.66 0.28 0.28 0.2 0.0 Busse Solér Busse W, et al. J Allergy Clin Immunol. 2001;108:184-190; Soler M, et al. Eur Respir J. 2001;18(2):254-261. 23
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