Pharmacology
of b2-agonists
Classes of b2-agonists
Speed of
onset
RELIEVER MEDICATION
fast onset, short duration
fast
inhaled terbutaline
inhaled salbutamol
slow onset, short duration
slow
oral terbutaline
oral salbutamol
oral formoterol
short
fast onset, long duration
inhaled formoterol
slow onset, long duration
inhaled salmeterol
oral bambuterol
long
M
A
I
N
T
E
N
A
N
C
E
Duration
of action
Onset of action –
relief of acute bronchoconstriction
Comparisons 3 min after inhalation of bronchodilator
Formoterol Turbuhaler
9 g
**
Salbutamol Turbuhaler
50 g
Salmeterol Diskhaler
50 g
Placebo
0
Politiek et al, Eur Respir J 1999
5
10
15
20
25
FEV (%)
N=17, adult asthmatics
Methacholine-induced bronchoconstriction
** p<0.0001 for formoterol vs salmeterol and placebo;
no significant difference between formoterol and salbutamol
Duration of action of
inhaled formoterol
Bronchodilating capacity (%)
First pivotal experiment in humans
Oral route
Inhaled route
100
80
100
Formoterol 6 µg
80
60
40
20
Salbutamol 4 mg
60
Salbutamol
100 µg
40
20
0
0
-20
-20
0 60 120 180 240 300 360 420 480
Time (min)
Formoterol
80 µg
0 60 120 180 240 300 360 420 480
Time (min)
At 8 hours terbutaline 1.25 mg was inhaled
Löfdahl and Svedmyr Allergy 1989
Differences between b2-agonists
• Chemical structure
• Pharmacological properties:

Mode of action in the b2-receptor region

Potency

Efficacy (i.e. full/partial agonism)

Selectivity

Anti-inflammatory effects
Chemical structures of b2-agonists
HO
CH2
HO
CH3
CHCH2NH
CH3
CH3
Salbutamol: short side chain
HO
CH2
HO
H
O
OH
N
H
HO
OH
CH3
CHCH2NHCHCH 2
CH3
O
Formoterol: medium side chain
OH
CHCH2NHCH2 CH2 CH2 CH2 CH2
CH2
O CH2 CH2 CH2 CH2
Salmeterol: long side chain
History of formoterol
OH
HO
HC
CH
CH3
CH2
NH
CH
CH2
OCH3
NH
O
• Basic pharmacology described by Ida (1976)
• Tablets marketed by Yamanouchi with the name
Atock in Japan and South Korea (1984)
• The inhaled mode of administration tested by
Löfdahl and Svedmyr (1986); licensed to Ciba.
• Formoterol available as dry powder inhaler in the
mid nineties as Oxis Turbuhaler
Microkinetic diffusion theory
Aqueous biophase
Cell membrane
with ß2-receptor
Salbutamol
Hydrophilic
Short duration
Fast onset
Anderson et al., Life Sci 1993
Formoterol
Intermediate
Long duration
Fast onset
Salmeterol
Lipophilic
Long duration
Slow onset
The plasmalemma microkinetic
diffusion theory
• The lipophilicity of any molecule is determined by
its chemical structure
• The lipophilicity of a b2-agonist determines how
the molecule partitions between the aqueous
phase and the cell membrane
• This process contributes to how a b2-agonist
approaches the receptor, its speed of onset and
duration of action
Anderson et al., Life Sci 1993
Potencies of b2-agonists
Maximal possible
relaxation (100%)
 Potency
50% relaxation
for formoterol
50% relaxation
for salmeterol
0
-10
Formoterol
Källström et al., Br J Pharmacol 1994
-9
-7
-8
Log (mol l-1)
Salmeterol
-6
-5
Terbutaline
Efficacy of b2-agonists
Relaxation (%)
100
max. relaxation
for formoterol
 Efficacy
50
max. relaxation
for salmeterol
0
-10
-9
-8
-7
-6
-5
Log (mol l-1)
Formoterol
Källström et al., Br J Pharmacol 1994
Salmeterol
Terbutaline
b2-agonist affinities and selectivities
pKI (affinity)
Competing
agonist
ß1 receptor
ß2 receptor
†
Selectivity
ß2 / ß1
Isoprenaline
6.1
6.3
1
Salmeterol
5.7
8.0
190
Formoterol
6.3
8.1
60
Fenoterol
5.7
6.3
5
Salbutamol
4.7
5.8
13
† Selectivity is the ratio of the inhibition constants 10
Roux et al., AJRCCM 1996
(pKIß2 - pKIß1)
Anti-inflammatory effects
of b2 -agonists
Asthma
• Post-capillary venule: Plasma exudation 
• Mast cell:
Mediator release

• Eosinophil:
Mediator release

• Neutrophil:
Mediator release

• T-lymphocyte:
Cytokine release

Barnes, JACI 1999
Effect of b2 -agonists on
leukotriene-induced respiratory burst
in guinea-pig eosinophils
0
salmeterol
20
Inhibition of H2O2
generation (%)
40
salbutamol
60
formoterol
9
7
5
- log [ß-adrenoceptor agonist (M)]
Rabe et al., Eur J Pharmacol 1993
Bronchoprotection by formoterol AMP and histamine challenge
 PC (doubling dilutions)
20
7.5
p<0.05
Mast cell
stabilising effect
NS
5
Formoterol and salbutamol
gave similar prechallenge
bronchodilator response
2.5
0
AMP
Hist
Formoterol
9g
Nightingale et al. AJRCCM 1999
AMP
Hist
Salbutamol
200 g
Effect of formoterol on histamineinduced plasma exudation
in induced sputum
50
**
Formoterol
Placebo
40
2macroglobulin
(µg/mL)
30
20
10
0
30min
Greiff et al., Thorax 1998
8 hours
Formoterol pharmacological
properties - summary
• Inhaled formoterol has a fast onset of
bronchodilation plus a long duration of action
• Formoterol is highly potent and is an almost
full agonist
• Formoterol is highly selective for the b2-receptor
• Formoterol has inhibitory effects on
inflammatory cells