Formoterol Slide Kit

1
Pharmacology
of b2-agonists
2
Classes of b2-agonists
Speed of Onset
RESCUE MEDICATION
fast onset, short duration
fast onset, long duration
M AINTENANCE
fast
inhaled formoterol
inhaled terbutaline inhaled salbutamol
slow onset, short duration
slow onset, long duration
oral terbutaline oral salbutamol oral formoterol
slow
inhaled salmeterol oral bambuterol
Duration of Action
long
short
3
Duration of action - inhaled vs. oral formoterol
FIRST PIVOTAL EXPERIMENT IN HUMANS
Inhaled route
Oral route
100
100
salbutamol 4 mg
80
80
formoterol 6 µg
60
60
capacity ()
salbutamol 100 µg
40
40
20
20
formoterol 80 µg
0
0
-20
-20
4
0
2
3
5
6
8
1
7
Time (hrs)
Time (hrs)
4
Differences between b2-agonists

• Chemical structure
• Pharmacological properties
• Mode of action in the b2-receptor region
• Potency
• Efficacy (i.e. full/partial agonism)
• Selectivity

5
Chemical structures of b2-agonists
O
H
O
H
C
H
2
N
O
H
C
H
3
C
H
O
H
C
H
C
H
N
H
H
C
H
3
2
3
O
O
H
C
H
C
H
N
H
C
H
C
H
2
2
Formoterol medium side chain
Salbutamol short side chain
Salmeterol long side chain
6
The Exosite Binding Hypothesis
Johnson, Med Res Rev, 1995
7
Microkinetic diffusion theory
Aqueous biophase
Cell membrane with ß2-receptor
Salbutamol Hydrophilic Short duration Fast onset
Formoterol Intermediate Long duration Fast onset
Salmeterol Lipophilic Long duration Slow onset
Anderson et al., Life Sci 1993
8
Potencies of b2-agonists
Maximal possible relaxation (100)
? Potency
50 relaxation for formoterol
50 relaxation for salmeterol
0
-10
-9
-8
-7
-6
-5
Log (mol l-1)
Formoterol
Salmeterol
Terbutaline
Källström et al., Br J Pharmacol 1992
9
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
Salmeterol
Terbutaline
Källström et al., Br J Pharmacol 1992
10
b2-agonist affinities and selectivities
pK
(affinity)
I

Competing
Selectivity
receptor
receptor
ß1
ß2
ß2
ß1
/
Agonist
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 (pKIß2 - pKIß1)
Roux et al., AJRCCM 1996
11
Formoterol pharmacological properties - summary

• Formoterol displays a long duration of action
  after inhalation, while systemic formoterol
  displays a short duration of action
• Inhaled formoterol has a fast onset plus a long
  duration
• Formoterol is highly potent
• Formoterol is an almost full agonist
• Formoterol is highly selective