Lægemidler med virkning på respirationsvejene Astma
Lægemidler med virkning på respirationsvejene Astma
Lægemidler med virkning på respirationsvejene Astma
You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
<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.