Lægemidler med virkning på respirationsvejene Astma Farmakologisk behandling
P Jeffery, in: Asthma, Academic Press 1998 Before 10 minutes after challenge P Howarth
Astma Sygdom karakteriseret af bronkokonstriktion og inflammation To grupper af medikamentel behandling 1) Bronkodilaterende midler 2) Antiinflammatoriske midler Medikamentel behandling af astma Bronkodilaterende midler Antiinflammatoriske midler - sympatomimetika - methylxanthiner - antikolinergika - corticosteroider - leukotrienantagonister - (kromoner)
Sympatikomimetika Adrenalin/noradenalin Isoprenalin Beta-2 receptor agonister korttidsvirkende langtidsvirkende (UABA s - salbutamol,terbutalin,fenoterol o.a. - salmeterol,formoterol, (bambuterol) - indacaterol) Sympatikomimetika Adrenalin Salbutamol Salmeterol
Beta-2 receptor agonister - virkningsmekanisme AC Beta-2 agonist + G s ATP camp beta-2 receptor Ca 2+ MLCK + membran interaktioner (lipophilicitet)? Beta-2 receptor agonists - time/response 40 FORM 24µg SALM 50µg SALB 200µg FEV1 (% change) 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Hours Van Noord et al 1995
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) 100 FEV1 (% pred.) 90 80 70 60 0 6 12 Hours Pearlman,NEJM 1992
Methylxanthiner Theofyllin, teofylamin Theofyllin
Theofyllin - virkningsmekanisme AC G i ATP camp PDE ( ) AMP A 1 - receptor Theofyllin (PDE 4 -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
Antikolinergika Atropin Ipratropium muskarin antagonist beta-2 agonister - ikke protektiv, mindre effektiv supplerende - astma (og KOL) bivirkninger - smag, (glaucom) - dosering Atropin Ipratropium Antikolinergika Tiotropium
Corticosteroider Parenteralt Peroralt Inhalation - methylprednisolon, hydrocortison - prednison, prednisolon - beclomethason, budesonid, fluticason, mometason (flunisolid, triamcinolon, ciclesonid) Corticosteroider Cortisol Budesonid
Corticosteroider - virkningsmekanisme Hsp90 GCS GCS receptor guarded by Hsp90 DNA GCS receptor GCS receptorcomplex Transcription factor (eg. AP-1, NF-kB) Decoiling Transactivation Increase antiinflammatory proteins Side-effects (eg. metabolic) Transrepression Decrease inflammatory proteins Inhalationssteroider- bivirkninger Systemiske - suppression af HPA-aksen - væksthæmning - hudforandringer - (osteoporose, glaukom, katarakt)
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
Leukotriene biosynthesis Arachidonic acid 5-LO inhibitors (eg Zileuton) 5-HPETE LTB 4 LTA 4 LTC 4 LTD 4 LTE 4 BLTR - chemotaxis (neutrophil) "respiratory burst" CysLT 1 -receptor - eosinophil chemotaxis bronchoconstriction CysLT 1 -receptor antagonists (eg Zafir-, Pran-, Montelukast) CysLT 2 -receptor Leukotrienantagonister Montelukast - cyslt1 receptor antagonist Supplerende til corticosteroid Aspirinintolerans x1 p.o., virker indenfor ~ 1 døgn Få bivirkninger (dyspepsi)
Comparative efficacy - corticosteroid/lta Change in FEV 1 (%) 18 15 12 9 6 3 0 BDP 200µg bd Montelukast 10mg od Placebo * 0 3 6 9 12 Weeks in active treatment 15 * p = 0.01 Malmstrom et al Ann Int Med 1998 Kromoner Kromoglikat, nedocromil, (ketotifen) Tachykininantagonist? Mastcellestabiliserende?? Inhiberende effekt på sensoriske nerver? Atoksiske Kun inhalation
Kromoner - effekt? 440 am pm Nedocromil 16mg/d FP 500µg/d 420 PEF (L/min) 400 380 360 340 * 320 0 0 1 2 3 4 Weeks 5 6 7 8 * p < 0.0001 Pauli et al EJCR 1995 Klassifikation af astma Symptomer Lungefunktion Dag Nat Trin 4 Konstante Hyppige FEV1/ PEF < 60% forventet Svær Nedsat fysisk aktivitet PEF variabilitet > 30% persisterende Hyppige exacerbationer Trin 3 Daglige > 1/uge FEV1/ PEF 60 80% forv. Moderat Dagligt behovsmedicin PEF variabilitet > 30% persisterende Forværringer < 2/uge Trin 2 > 1 gang/uge, ikke dagligt > 2/måned FEV1/ PEF 80% forv. Mild PEF variabilitet 20 30% persisterende Trin 1 < 1 gang/uge 2/måned FEV1/ PEF 80% forv. Mild PEF variabilitet < 20% intermitterende NIH publication no. 97-405, 1997
Farmakoterapeutisk strategi - astma Trin 1 Inhaleret korttidsvirkende beta-2 agonist p.n. Farmakoterapeutisk strategi - astma Trin 1 Trin 2 Inhaleret korttidsvirkende beta-2 agonist p.n. + inhaleret corticosteroid (lav-medium dosis)
Farmakoterapeutisk strategi - astma Trin 1 Trin 2 Trin 3 Inhaleret korttidsvirkende beta-2 agonist p.n. + inhaleret corticosteroid (lav-medium dosis) + inhaleret langtidsvirkende beta-2 agonist eller leukotrienantagonist (eller theofyllin) Farmakoterapeutisk strategi - astma Trin 1 Trin 2 Trin 3 Trin 4 Inhaleret korttidsvirkende beta-2 agonist p.n. + inhaleret corticosteroid (lav-medium dosis) + inhaleret langtidsvirkende beta-2 agonist eller leukotrienantagonist (eller theofyllin) Maksimer inhalationssteroid Overvej peroral steroidbehandling (Antikolinergika ved akut astma)
Astma Kontrol Characteristic Controlled (All of the following) Partly Controlled (Any measure present in any week) Uncontrolled Daytime symptoms None (twice or less/week) More than twice/week Limitations of activities Nocturnal symptoms/awakening Need for reliever/ rescue treatment None None None (twice or less/week) Any Any More than twice/week Three or more features of partly controlled asthma present in any week Lung function (PEF or FEV 1 ) Normal < 80% predicted or personal best (if known) Exacerbations None One or more/year* 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.
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
Patients estimate of asthma control Patients (%) 100 Well controlled Completely controlled 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 (%) 90 80 70 60 50 40 30 20 10 0 Severe Moderate Mild Intermittent (Asthma severity based on symptoms) Anti-inflammatory Quick relief Rabe, Eur Respir J 2000;16:802-7
Formulering af astmamedicin Lokal behandling Systemisk behandling - spray - spacer - pulverinhalator - nebulisator - tabletter -injektion
Fejlanvendelse af astma-sprays Handling 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 Patient fejl (%) 7 43 29 29 64 57 46 43 5 Ganderton, 1997 Nye behandlinger for astma TH 1 IFNγ IL-12 TH2 Immunomodulators -PDE inhibitors, -Glucocorticoids, -Cyclosporine Anti-IL-5 MAb Anti-IL-4, Anti-IL-13 IL-4R Eosinophil B Cell Apoptosis -GCs -p38 MAP Inhibitors Airway Inflammation & BHR IgE Anti-IgE
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) Exacerbations per Patient (mean) 1.0 0.8 *p 0.006 0.6 * 0.54 * 0.66 Placebo Omalizumab 0.4 0.2 0.28 0.28 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.