1

3.6.2 Mucolytics
1.
mucolytics

bromhexine
acetylcysteine
(

)
2. 1


Bromhexine:

(ciliated epithelium)

Acetylcysteine:

3.

( acetylcysteine injection
Antidotes)
..
2542 2

( bromhexine tablet
)
( acetylcysteine granules
bromhexine tablet )
( bromhexine syrup
)
( bromhexine tablet
syrup)

2
1

.. 2546
.. 2542 33-48

2

3

.. 2542
acetylcysteine granules bromhexine
tablet 2 15



25454
8.3

mucolytics
bromhexine,
acetylcysteine granule acetylcysteine
600 mg tablet 85, 70
6 /
.. 2546 208,990,080 (47,585,690
), 19,872,562 (50,066,706 )
2,797,680 (20,548,959 )

118,201,355

AND Review[ptyp]

.. 2000
Cochrane
Library, BMJ Clinical Evidence, GINA guidelines
for asthma GOLD guidelines for COPD
4.2
. BMJ Clinical Evidence
mucolytics
acute respiratory disorder5
acute bronchitis, common cold,
community acquired pneumonia, sore
throat, upper respiratory tract
infection otitis media with
effusion
otitis media with effusion6
unlikely to be beneficial
Three small RCTs (155
children and 195 ears) comparing
bromhexine with placebo found
inconclusive results.
mucolytics

4.
4.1 Evidence search

PubMed Keyword: mucolytic[All Fields]

chronic respiratory disorder7

asthma bronchiectasis
COPD

2543; 3(3): 20-40

2 8
.. 2542

.. 2546
.. 2542 xii

www.clinicalevidence.com/ceweb/conditions/rda/rda.jsp
www.clinicalevidence.com/ceweb/conditions/ent/0502/0502.jsp
www.clinicalevidence.com/ceweb/conditions/rdc/rdc.jsp

3
bronchiectasis 8
unknown effectiveness

chronic bronchitis long term

One systematic review found insufficient

evidence from three RCTs to compare
the effects of bromhexine versus placebo
in people with non-cystic fibrosis
bronchiectasis.

.treatment with mucolytics was

associated with a small reduction in
acute exacerbations and a somewhat
greater reduction in total number of days
of disability

management COPD13

COPD9 likely to be
beneficial

bronchiectasis14

There is not enough evidence to

evaluate the routine use of mucolytics
for bronchiectasis. High doses of
bromhexine coupled with antibiotics may
help with sputum production and
clearance.

Two systematic reviews found limited

evidence that mucolytics for 324
months reduced the frequency and
duration of exacerbations compared
with placebo.

acute cough 15

The results of one trial favoured

mucolytic (letosteine) over placebo from
day four until day 10. The evidence for
effectiveness of cough medicines is
weak.

. Cochrane Review DARE

systematic review
4
BMJ Clinical Evidence

letosteine

DARE10 1

review

11

acute maxillary sinusitis

16

There was not enough evidence from

trials on the other medications (e.g.
mucolytics) to determine if they gave
additional benefit.

acute exacerbation COPD12

.mucolytics and physical therapy

lacked evidence of efficacy.

8
9

www.clinicalevidence.com/ceweb/conditions/rdc/1507/1507.jsp
www.clinicalevidence.com/ceweb/conditions/rdc/1502/1502_I8.jsp

10
11

Database of Abstracts of Reviews of Effects 2004 Issue 4

Williams JW, Aguilar C, Cornell J, Chiquette E Dolor RJ, Makela

M, Holleman DR, Simel DL. Antibiotics for acute maxillary sinusitis.

The Cochrane Database of Systematic Reviews 2002, Issue 3. Art.
No.: CD000243. DOI: 10.1002/14651858.CD000243.

12

McCrory D C, Brown C, Gray R N, Goslin R E, Kolimaga J T,

MacIntyre N R, Oddone E Z, Matchar D B. Management of acute

exacerbations of chronic obstructive pulmonary disease. 2001:
256. DARE abstracts.

Even if statistically significant, effect

sizes were small and of doubtful clinical
relevance

13

Poole PJ, Black PN. Mucolytic agents for chronic bronchitis or

chronic obstructive pulmonary disease. The Cochrane Database of

Systematic Reviews 2003, Issue 1. Art. No.: CD001287. DOI:
10.1002/14651858.CD001287.

14

Crockett AJ, Cranston JM, Latimer KM, Alpers JH. Mucolytics

for bronchiectasis. The Cochrane Database of Systematic Reviews

2001, Issue 1. Art. No.: CD001289. DOI: 10.1002/14651858.
CD001289.

15

Over-the-counter medications for acute cough in children and

adults in ambulatory settings. The Cochrane Database of

Systematic Reviews 2004, Issue 4. Art. No.: CD001831. DOI:
10.1002/14651858.CD001831.pub2.

16

Schroeder K, Fahey T. Should we advise parents to administer

over the counter cough medicines for acute cough? Systematic

review of randomised controlled trials. Arch Dis Child. 2002
Mar;86(3):170-5.

4
bromhexine chronic

. PubMed Search

original articles
review BMJ Clinical Evidence Cochrane
Review

bronchitis18 16 . 3
oxytetracycline

overall clinical
state
(p < 0.05)
clinical
endpoints

peak expiratory flow rate FEV1

surrogate endpoints (

)
( clinical
endpoints)

bromhexine


erythromycin
22
bromhexine

bromhexine bronchiectasis17
30 mg
capsule 3 ceftazidime
1 i.m. clinical
exacerbation bronchiectasis (
20 .)
88
bromhexine
16
(WMD 21.5%, 95% CI
38.9% to 4.1%) symptom score
(WMD -0.53, 95% confidence
interval -0.81 to -0.25 at 16 days)
bromhexine
8 .

4 3 16

20 4
. baseline 20 . clinical
practice

19
18

17

Lal S, Bhalla KK. A controlled trial of bromhexine ('Bisolvon') in

out-patients with chronic bronchitis.Curr Med Res Opin.

1975;3(2):63-7.
Olivieri D, Ciaccia A, Marangio E, Marsico S, Todisco T, Del Vita

M. Role of bromhexine in exacerbations of bronchiectasis. Doubleblind randomized multicenter study versus placebo. Respiration.
1991;58(3-4):117-21.

19

Bergogne-Berezin E, Pierre J, Dournovo P. [Effect of a

secretolytic agent (bromhexine) on the penetration of erythromycin

into bronchial secretions] Fortschr Med. 1982 Jun 24;100(24):116971. [Article in German]

2. 74 acute bronchitis

20

surrogate endpoints

( ) clinical
endpoints
bromhexine acute
bronchitis (n = 291) pneumonia

22
3. 1 2


bromhexine

bromhexine

4. ( 80

(n=101)21
amoxicillin 250 mg bromhexine
8 mg 4

clinical response (94%
vs 93%) bromhexine
cure rate symptom scores

1.

18% (72/392)

20

Maesen FP, Davies BI, Brouwers J, Rubingh G. Erythromycin

and bromhexine in acute exacerbations of chronic bronchitis. A

study on sputum penetration and clinical effectiveness. Eur J
Respir Dis. 1982 Jul;63(4):325-9.

21

Roa CC Jr, Dantes RB. Clinical effectiveness of a combination

of bromhexine and amoxicillin in lower respiratory tract infection. A

randomized controlled trial. Arzneimittelforschung. 1995
Mar;45(3):267-72.

)23
acute bronchitis


(
1 )
academic
detailing
3523

22

Robert J. Flaherty, MD. Evidence-Based Medicine for Student

Health Services. www.montana.edu/wwwebm/Bronchitis.htm and

Hueston WJ. Mainous III AG. Acute Bronchitis. American Family
Physician. March 1998 www.aafp.org/afp/980315ap/hueston.html

23

Gonzales R, Steiner JF, Lum A, Barrett PH Jr. Decreasing

antibiotic use in ambulatory practice: impact of a multi-dimensional

intervention on the treatment of uncomplicated acute bronchitis in
adults. JAMA. 1999 Apr 28;281(16):1512-9.

6
acetylcysteine long term
management chronic bronchitis
COPD24
1. Mucolytic treatment was associated
with a significant reduction of 0.79
exacerbations per patient per year
compared with placebo. (
3 )
2. with six patients needing regular
treatment with mucolytic agents for 3
to 6 months to achieve one less
exacerbation over that time (NNT=6).
3. Cost-effectiveness analysis suggests
that the point at which the costs of
treatment and non-treatment were
equal was 1.2 less exacerbations per
year, suggesting that treating everyone
with COPD with mucolytic agents
would not be cost effective.
acetylcysteine
(pool
data)
600 1200 .

acute exacerbation

COPD

guidelines

acetylcysteine 25
95
1
2

1,327
In infants, mucolytics agents efficacy
has never been demonstrated and some
elements suggest poor safety (paradoxical
bronchial congestion).

acetylcysteine

COPD





bromhexine acetylcysteine



. Guidelines
GINA Guidelines 200426
mucolytics
25

24

Poole PJ, Black PN. Preventing exacerbations of chronic

bronchitis and COPD: therapeutic potential of mucolytic agents.

Am J Respir Med. 2003;2(5):367-70.

Chalumeau M, Cheron G, Assathiany R, Moulin F, Bavoux F,

Breart G, Pons G. [Mucolytic agents for acute respiratory tract
infections in infants: a pharmacoepidemiologic problem?] Arch
Pediatr. 2002 Nov;9(11):1128-36.

26

Global Initiative for Asthma Guidelines 2004.

7
asthma
( 1)
1 Therapies not recommended for
treating attacks (of asthma)
o Sedatives (strictly avoid)
o Mucolytic drugs (may worsen cough)
o Chest physical therapy/physiotherapy (may
increase patient discomfort)
o Hydration with large volumes of fluid for adults
and older children (may be necessary for
younger children and infants)
o Antibiotics (do not treat attacks but are
indicated for patients who also have pneumonia
or bacterial infection such as sinusitis).
GOLD Guidelines 2004
mucolytics N-acetylcysteine
routine
COPD

27

4.3

mucolytics
bronchospasm asthma 28
anaphylactoid reactions
3% urticarial rash,
angioedema, bronchospasm hypotension

asthma 1
acetylecysteine case
report29 drug
monograph30
Intravenous acetylcysteine should be used with
caution in those with asthma because
intravenous administration may result in acute
bronchospasm or anaphylaxis.

acetylcysteine
esophageal varices peptic ulcer
GI bleeding.

.. 2547 acetylcysteine
Antidotes
paracetamol poisoning


5.
mucolytics

upper lower
respiratory tract disease acute
bronchitis, acute cough , acute
exacerbation of COPD, acute maxillary

29
The Global Initiative for Chronic Obstructive Lung Disease
(GOLD) Guidelines 2004.

A V Appelboam, P I Dargan and J Knighton. Fatal

anaphylactoid reaction to N-acetylcysteine: caution in patients with
asthma. Emerg Med J 2002; 19:594-595

Dano G. Bronchospasm caused by acetylcysteine in children

Clinical Pharmacology 2004 CD-ROM Version 2.12, Gold

27
28

with bronchial asthma. Acta Allergol. 1971 Jun;26(3):181-90.

30

Standard Multimedia.

8
sinusitis, asthma, common cold,
community acquired pneumonia, otitis
media with effusion, sore throat, upper
respiratory tract infections
acetylcysteine
COPD
acetylcysteine COPD


Standard International guidelines
GINA GOLD
mucolytics asthma COPD
6. mucolytics




acetylcysteine
paracetamol poisoning




routine





dose response relationship

BNF
bromhexine acetylcysteine



acetylcysteine


200 mg PO 2-3 times daily; 300 mg twice
daily; or 600 mg PO once daily, twice daily
or three times per week

acetylcysteine
exacerbation COPD
exacerbation

3 6
31
bromhexine
acute bronchitis

acute bronchitis

( 1 )
bromhexine

bromhexine

outcome 2
4 ( 12
31

Poole PJ, Black PN. Oral mucolytic drugs for exacerbations of

chronic obstructive pulmonary disease: systematic review. BMJ.

2001 May 26; 322(7297): 1271.

9
acetylcysteine

Expectorant & Demulcent Cough

Preparations)
.. 2547
(expectorant)

3.6.2 glyceryl
guaiacolate guaifenesin


( 12
Expectorant & Demulcent Cough
Preparations)
mucolytics

33 anaphylactoid,
reactions, hemoptysis, angioedema,
maculopapular, rash, bronchospasm,
nausea/vomiting, drowsiness, pruritus,
dysgeusia ( ),
stomatitis, rash, dyspnea, rhinorrhea,
fever, flushing wheezing

32
acetylcysteine
(
paracetamol poisoning)

acetylcysteine
anaphylactoid reaction
3
case report asthma 1

32

there is little evidence that inhaled N-acetylcysteine (NAC) is

more effective than adequate hydration for clearing bronchial

secretions. Clinical Pharmacoogy 2004 CD ROM. Gold Standard
Multimedia

33

Clinical Pharmacology 2004 CD-ROM Version 2.12, Gold

Standard Multimedia.

10

1

acute bronchitis34

34

Gonzales R, Steiner JF, Lum A, Barrett PH Jr. Decreasing antibiotic use in ambulatory practice: impact of a multi-dimensional intervention on
the treatment of uncomplicated acute bronchitis in adults. JAMA. 1999 Apr 28;281(16):1512-9.

11