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