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 9g 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