Comparison of Formoterol and Salmeterol: Structures, Effects, and Mechanisms | Study Guides, Projects, Research Acting

Eur Aesplr J

1991' 4,

218-226

REVIEW

Long-acting

~

2

-adrenoceptor

agonists: a new perspective

in

the treatment of asthma

C.G.

L6fdahl,

K.

F.

Chung*

Long-acting

{3

2-adrenoceptor agonists: a new perspective

in

the treatment

of

asthma.

C.G.

Liifdahl, K.F. Chung.

Dept

of

Pulmonary

Medicine,

Gotbenburg

University,

Renstr!lmska

Hospital,

S-402

64

G!lteborg, Sweden.

ABSTRACT:

New

long-acting

~

1

-adrenoceptor

agonlsts, formoterol and

salmeterol, may soon appear

In

several European countries for treatment

of

asthma. This review examines currently available Information and

compares the basic pharmacology and describes the clinical effects of

these new drugs. The long duration of bronchodilatlon seen in clinical

studies seems to be similar, whereas

In

isolated tissues there might be a

difference

In

the binding characteristics to the

~

2

-adrenoceptor.

Long-

acting

~

2

-agonlsts

could have an inhibitory effect on Inflammatory events

related to asthma,

but

the clinical relevance of these effects

Is

not clear

at

present. Long-term studies up to one year with both new drugs have

not

shown

any

unexpected

side-effects,

and

no tachyphylaxis to

~-adrenoceptor

stimulation has been reported. Patients appear to strongly

prefer the new drugs compared to the short-acting

~

2

-agonists.

The

potential place for these drugs in the treatment of asthma

is

discussed

and

some pitfalls pointed out.

It

is

likely that the long-acting

~

-agonists

will be beneficial

to

many asthmatic patients. 2

• Dept

of

Thoracic Medicine, National Heart and

Lung

Institute,

Royal

Brompton

Hospital,

Dovehouse Street, London, UK.

Correspondence: K.F. Chung, Dept

of

Thoracic

Medicine, National Heart and Lung Institute, Royal

Brompton Hospital, Dovehouse Street, London,

SW3

6LY

UK.

Keywords:

Asthma;

~

2

-adrenoceptor

agonist;

formoterol; salmeterol.

Received: August 1990; accepted September

8,

1990.

Supported by the Swedish Heart-Lung Foundation.

Eur Respir

J.,

1991,

4,

218-226.

~

2

-adrenoceptor

agonists used

as

bronchodilators have

played an important part in the treatment

of

asthma

during the last 20 yrs. These selective drugs have the

advantage over nonspecific

~-adrenoceptor

agonists such

as isoprenaline, being devoid particularly

of

cardiac side-

effects

[1

].

Selective

~

2

-agonists

such as salbutamol,

terbutaline and fenoterol are currently the most potent

and effective bronchodilators available for the treatment

of

asthma, particularly when administered by inhalation

[1]. They induce prompt symptomatic relief

of

wheezing

and breathlessness with a duration

of

action

of

3-5

h.

Repeated use

of

~

2

-adrenoceptor

agonists does not

appear

to

lead to tachyphylaxis on the bronchodilatory

effect in asthmatics [1].

~

2

-adrenoceptor

agonists are also potent in inhibiting

mast cell degranulation [2]. However, their effect on

various manifestations

of

the inflammatory events in

asthma has been controversial [3]. Studies

of

airway

microvascular leakage has provided conflicting results,

and there is evidence to suggest that

~

-agonists do not

inhibit activation

of

human eosinoph2

ils and alveolar

macrophages [

4,

5].

It

have also been difficult to show

any effect

of

the

~

2

-adrenoceptor

agonists on the late

phase reaction after allergen provocation [6]. Therefore,

currently available

~

2

-agonists

may not modify the

inflammatory

process

of

asthmatic

airways,

and

concomitant treatment with an inhaled glucocorticoid is

recommended, particularly

if

regular use

of

inhaled

~

-

adrenoceptor agonist is needed to control symptoms.

2

A new group

of

~

2

-adrenoceptor

agonists, formoterol

and salmeterol, characterized by their prolonged bron-

chodilator effect, has been under development during

the last few years. In clinical studies, formoterol was

found to have a long duration

of

bronchodilation when

given by inhalation but when given by oral route its

duration

of

action was similar to that

of

salbutamol [7].

Salmeterol

was

the

result

of

a

specific

research

programme to design long-acting bronchodilators by

molecular modification

of

the

~

2

-adrenoceptor

agonist

salbutamol [8-11]. Apart from their improved duration

of

action, these new drugs, salmeterol and formoterol,

may possess other properties

of

particular relevance to

asthma.

Salmeterol and formoterol may become available for

prescription in several European countries within the

next few years. In this article we will review the basic

and clinical pharmacological profiles

of

these new

~

-

agonists, and in the light

of

the information available s2

o

far we will speculate on how these drugs may be used

in the treatment

of

asthma and pinpoint some

of

the

possible problems that may arise with these drugs.

Basic pharmacology

The chemical structure

of

the two new compounds

are shown together with salbutamol, terbutaline and

fenoterol in figure 1 [11-13]. Both formoterol and

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REVIEW

Long-acting ~ 2 -adrenoceptor agonists: a new perspective

in the treatment of asthma

C.G. L6fdahl, K. F. Chung*

~ 2 -adrenoceptor agonists used as bronchodilators have

effects [1 ]. Selective ~ 2 -agonists such as salbutamol,

and breathlessness with a duration of action of 3-5 h.

Repeated use of ~ 2 -adrenoceptor agonists does not

~ 2 -adrenoceptor agonists are also potent in inhibiting

any effect of the ~ 2 -adrenoceptor agonists on the late

currently available ~ 2 -agonists may not modify the

A new group of ~ 2 -adrenoceptor agonists, formoterol

molecular modification of the ~ 2 -adrenoceptor agonist

LONG·ACfiNG ~ 2 -AGONISTS 219

HO -o ~H·CH 2 ·NH·CH 2 ·CH 2 .CH 2 ·C~.CH 2 .CH 2 ·0.CH 2 ·CH 2 .CH 2 .CH 2 • -@

HO ::(g. ~H.c~·NH1H.CH2-o OCH

Both co m po un ds are hig hl y sel ec ti ve f or ~ 2 -

the atrial ra te in isolated guinea-pig atria. By compa ri -

salmeterol was highly lipophilic. Other ~ 2 -adrenoceptor

be the only explanation, as some ~ 2 -agonist drugs have

~ 2 -antagonist but reasserts itself after wash-out [11]. In

LONG-ACTING {3 2 -AGONISTS 221

Selectivity for the ~ 2 -adrenoceptor has in clinical

~ 2 -selectivity as salbutamol (35].

222 C.G. L6FDAHL, K.F. CHUNG

Other studies have evaluated the effect of the new ~ 2 -

acting ~ 2 -agonists such as terbutaline transiently increase

Place of long-acting ~ 2 -agonists in the

place of the long-acting ~ 2 -agonists in the treatment of

the bronchodilating effect of long-acting ~ 2 -agonists, as

The most obvious place for the new ~ 2 -adrenoceptor

acting ~ 2 -agonists. Several clinical cross-over studies in

acting ~ 2 -agonists have shown a very strong preference

intake of short-acting ~ 2 -agonists with or without noc-

effect. Furthermore, long-acting ~ 2 -agonists will be

how frequently long-acting ~ 2 -agonists can be safely used

~ 2 -agonist for rescue medication would be more

and long-acting ~ 2 -agonists.

induced skin response in normals by formoterol, a new ~ 2 -

LONG-ACTING (3 2 -AGONISTS 225