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