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What is asthma?
What is COPD?
COPD

Chronic obstructive pulmonary disease (COPD), also known as chronic
obstructive airway disease (COAD), is a group of diseases characterised by
limitation of airflow in the airway that is not fully reversible. COPD is the umbrella
term for chronic bronchitis and/or emphysema. It is most often due to tobacco
smoking [1] but can be due to other airborne irritants such as coal dust or solvents.
Chronic Bronchitis
Chronic bronchitis is defined in clinical terms as a cough with sputum production on most days for 3 months of a
year, for 2 consecutive years.[6]
Chronic bronchitis is hallmarked by the increased number (hyperplasia) and increased size (hypertrophy) of the
mucus-secreting (goblet) cells of the airway. This, along with enlargement of the mucous gland, results in an
increase in production of mucus which contributes to the airway obstruction. Microscopically there is infiltration of
the airway walls with inflammatory cells, particularly neutrophils. Inflammation is followed by scarring and
remodelling that thickens the walls resulting in narrowing of the small airway. Further progression leads to an
abnormal change (metaplasia) in the nature of the tissue along with further thickening and scarring (fibrosis) of the
lower airway. The consequence of these changes is a limitation of airflow. [7]
Emphysema
Main article: Emphysema
Emphysema is defined histologically as the enlargement of the air spaces distal to the terminal bronchioles, with
destruction of their walls.[6]
The enlarged air sacs (alveoli) of the lungs reduces the surface area available for the movement of gases during
respiration. This can cause breathlessness in severe cases. The exact mechanism for the development of
emphysema is not understood, although it it known to be linked with smoking and age.
Historically, what therapeutic agents
have been used?
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Ephedrine, as part of the Chinese medicine Ma
Huang, has been used in the treatment of
respiratory diseases for over 5000 years
Ephedrine is now known to act indirectly, by
releasing endogenous catecholamines, resulting in
bronchodilation
In 1900, Solis-Cohen showed that orally
administered adrenal extract was beneficial in
asthma.
Historic
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Initially, subcutaneous injections of epinephrine
were used, followed by a nebulized epinephrine
solution.
Epinephrine is one of the most potent
vasopressor (i.e. causes constriction of the blood
vessels and corresponding rise in blood
pressure) drugs known.
Epinephrine affects respiration primarily by
relaxing the bronchial muscle.
Epinephrine is rapidly metabolized by COMT,
primarily in the liver.
Can we make an asthma drug with less side effects, and
longer lasting?
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Clues:
It is known that the 2 receptor is the target for
relaxation of bronchial smooth muscle.
Epinephrine has approx. equal affinity for both 
and  receptors
However norepinephrine has greater affinity for
the  receptors
This indicates that placing an alkyl group on the
nitrogen leads to an increase in selectivity for the
-receptors.
OH
OH
HO
NHMe
HO
NH2
HO
HO
Epinephrine
(Adrenaline)
Equal selectivity for
Both and -receptors
Norepinephrine
(Noradrenaline)
Greater selectivity for
receptors
Perhaps, still greater selectivity for -receptors could be
Generated by appending larger alkyl substituent on nitrogen
An improvement!
OH
HO
H
N
HO
Isoprenaline
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Isoprenaline was synthesized by German
chemists in the 1940’s
It had less cardiovacular side effects than
adrenaline
Became the most widely used inhaled treatment
for asthma for the next 20 years.
Further improvements needed
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Needed an agent which was longer
lasting, more resistant to COMT
Needed an agent which was more
selective for the 2 receptors in the lung
and less selective for the 1 receptors of
heart.
Arrives Salbutamol
OH
HOCH2
H
N
HO
Salbutamol
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Tert-butyl group renders salbutamol more
selective for 2
Hydroxymethyl group (in place of OH) renders
salbutamol resistant to COMT
Remains the most widely used anti-asthma drug
in the world
Salbutamol

Salbutamol (INN) or albuterol (USAN) is a short-acting β2-adrenergic
receptor agonist used for the relief of bronchospasm in conditions such
as asthma and COPD.Salbutamol sulphate is usually given by the
inhaled route for direct effect on bronchial smooth muscle. This is
usually achieved through a metered dose inhaler (MDI), nebuliser or
other proprietary delivery devices (e.g. Rotahaler or Autohaler). In these
forms of delivery, the effect of Salbutamol can take place within 5 to 20
minutes of dosing. Salbutamol can also be given orally or intravenously.
However, some asthmatics may not respond to these medications as
they will not have the required DNA base sequence in a specific
gene.Salbutamol became available in the United Kingdom in 1969 and
in the United States in 1980 under the trade name Ventolin.
OH
HOCH2
H
N
O
HO
Salmeterol
Salmeterol is a long-acting beta2-adrenergic receptor agonist drug that is currently
prescribed for the treatment of asthma and chronic obstructive pulmonary disease
COPD. It is currently available in both dry-powder inhalers (DPIs) and pressurised
metered dose inhalers (pMDIs).
It is a long acting beta-adrenoceptor agonist (LABA), usually only prescribed for
severe persistent asthma following previous treatment with a short-acting beta
agonist such as salbutamol and is prescribed concurrently with a corticosteroid,
such as beclometasone. The primary noticeable difference of salmeterol to
salbutamol is that the duration of action lasts approximately 12 hours in
comparison with 4ﾐ6 hours of salbutamol.
BRONCHODILATORS,
ADRENERGIC (Inhalation)*
In the U.S.Adrenalin Chloride 3
Airet 1
Alupent 8
Arm-a-Med Isoetharine 6
Arm-a-Med Metaproterenol 8
Asthmahaler Mist 3
AsthmaNefrin 3
Beta-2 6
Brethaire 12
Bronkaid Mist 3
Bronkaid Suspension Mist 3
Bronkometer 6
Bronkosol 6
Dey-Lute Isoetharine 6
Dey-Lute Metaproterenol 8
Foradil 5
Isuprel 7
Isuprel Mistometer 7
Maxair 9
Maxair Autohaler 9
Medihaler-Iso 7
microNefrin 3
Nephron 3
Primatene Mist 3
Proventil 1
Proventil HFA 1
S-2 3
Serevent Diskus 11
Vaponefrin 3
Ventolin 1
Ventolin HFA 1
Ventolin Nebules 1
Ventolin Rotacaps 1tolin Rotacaps 1
In CanadaAlupent 8
Apo-Salvent 1
Berotec 4
Bricanyl Turbuhaler 12
Bronkaid Mistometer 3
Foradil 5
Gen-Salbutamol Sterinebs P.F. 1
Isuprel 7
Isuprel Mistometer 7
Maxair 9
Novo-Salmol 1
Oxeze Turbuhaler 5
Pro-Air 10
Serevent 11
Serevent Diskhaler 11
Serevent Diskus 11
Vaponefrin 3
Ventodisk 1
Ventolin 1
Ventolin Nebules P.F. 1
Ventolin Rotacaps 1tolin Rotacaps 1
This information applies to the following medicines:
1.Albuterol (al-BYOO-ter-ole)‡§
2.Bitolterol (bye-TOLE-ter-ole)*†
3.Epinephrine (ep-i-NEF-rin)‡
4.Fenoterol (fen-OH-ter-ole)*
5.Formoterol (for-MOH-ter-ol))‡§
6.Isoetharine (eye-soe-ETH-a-reen)†‡
7.Isoproterenol (eye-soe-proe-TER-e-nole)‡
8.Metaproterenol (met-a-proe-TER-e-nole)‡
9.Pirbuterol (peer-BYOO-ter-ole)
10.Procaterol (proe-KAY-ter-ole)*
11.Salmeterol# (sal-ME-te-role)*
12.Terbutaline (ter-BYOO-ta-leen)