Definition

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role.

The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the morning.
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma, updated 2009

Changes in Airway Morphology in Asthma

Mucous gland hypertrophy Epithelial damage Airway smooth muscle

Edema

Inflammatory cell infiltration

Mucus Vascular dilation

Thickening of basement membrane

Adapted from National Asthma Education and Prevention Program. Expert Panel Report. Guidelines for the Diagnosis and Management of Asthma. August 1991.

These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment. Clinical manifestations of asthma can be controlled with appropriate treatment.
When asthma is controlled, there should be no more than occasional flare-ups and severe exacerbations should be rare.
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma, updated 2009

Asthma Prevalence, 2004

Global burden of Asthma, 2004

Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma, updated 2009

Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma, updated 2009

Treatment Cycle, GINA, updated 2009

Assessing asthma control

Treating to achieve control

Monitoring to maintain control

Asthma Medication
reliever
Rapid acting B2agonist inhaled and oral
Systemic steroid Anticholinergics

controller

Inhaled and systemic glucocorticosteroid Leukotriene modifiers

Inhaled LABA
Theophylline Cromones

Xanthines

Oral LABA

Medication Routes
1.

Inhalation Orally Injection

Benefits: Delivered directly into the airways Producing higher local concentrations Significantly less systemic side effects

2.

3.

Inhalation Medications

Quick Relief Medicines (Rapid Acting 2-Agonist)

Act fast, generally within 15-20 minutes Relaxes the smooth muscles around the bronchial tubes Must have available at all times Is only medicine that helps breathe quickly

BRONCHODILATATION

DECREASED PLASMA EXUDATION

DECREASED CHOLINERGIC NEURO TRANSMISSION

BETA2 AGONIST ACTION IN ASTHMA

INCREASED MUCOCILIARY CLEARANCE DECREASED NEUTROPHIL FUNCTION DECREASED BACTERIAL ADHERENCE

CHARACTERISTICS OF 2 AGONIST

Onset of Action
Rapid or Slow

Duration of Action
Short or Long

Efficacy at Receptor Site

Partial or Full Agonist

Choosing Beta-2 agonist

Full-agonist

Fast-onset

Long-duration

Salbutamol Terbutaline Fenoterol Salmeterol Formoterol Procaterol

+ +

+ + + + +

+ + +

Fast onset and full-agonis for reliever Long duration for add on controller

PROCATEROL

Was found by Yoshizaki et al. at Japan in 1976 Procaterol is a potent bronchodilator even on a low dose Has the effect of ten times stronger than salbutamol and terbutalline

TABLET (ORAL)

PROCATEROL

METERED DOSE INHALER (MDI)

SOLUTIO (NEBULIZED)

PROCATEROL has fast bronchodillating effect

Mean % FEV1 - Change from baseline (Initial Dosage)
20 g Meptin air tid,n=71 10 g Meptin air tid,n=68 Placebo, n=67 :p< 0.05

35%

15%

0
M5 M30 H1.0 H2.0 H3.0 H4.0 H5.0 H6.0 H7.0 H8.0

Double-blind, randomized, 2 weeks study in 40-80% from predicted FEV-1 patients

M = minute

H= hour
Ref: Storm; W,at.al.1985.Annals of Allergy, 55: 476-478

Fast onset of action and longer duration than salbutamol

Comparative study of Meptinair vs salbutamol inhaler
Meptin air 20 g tid,n=171

Initial dose
50 40 30 20 10

Salbutamol 200 g tid,n=162 50

Week 12

40
30 20 10

Duration of Action (Hours)

2 3 4 5 6 Duration of Action (Hours)

The horizontal (dashed) line represent 15% clinical improvement in FEV1 from baseline.

Ref: Mazza J.A,et.al. 1992. Annals of Alergy, 68: 267-273

Faster and longer duration of action than fenoterol

Fenoterol (F), n=35 Meptinair (P), n=35
1800

2000

Salmeterol (S), n=35 = P< 0.05 P vs F = P< 0.05 P vs S = P< 0.05 S vs F

1600

1400

1200

15

30

300

540 (minute)

Change of FEV1 value

Ref: Yunus F.,et.al. 2001. Indonesia Allergologist Association. 4
th

National Congress Medan

The Utility of a Long-Acting Sympathomimetic Agent, Procaterol, for Nocturnal Asthma

R. P. Baughman and R. G. Loudon. Chest February 1988

Ten patients with nocturnal asthma

Procaterol 0.1mg at night

Measured FEV1 every 2 hours from 10PM to 8AM

The use of long-acting -adrenergic sympathomimetic agent reversed the obstruction of the airway seen in nocturnal asthma

Twenty (20) asthmatic patients

Two puffs of procaterol (20g) or two puffs of salbutamol (200g) MDI PEF, FVC and FEV1 were measured after 5, 15, 30, 60, 120 and 180 min

Changes in mean PEFR, FEV1 and FVC were greater after procaterol than salbutamol The difference in bronchodilatation was not significant

Pengaruh pemberian prokaterol dibandingkan dengan salbutamol secara inhalasi dosis terukur terhadap gejala klinis dan faal paru pada penderita asma
Maimunah, T. Syafiuddin. Jurnal Respirologi Indonesia, 1999

Thirty (30) asthmatic patients

Procaterol 20g TID and Salbutamol 200g TID

PEFR, FEV1, FVC, bronchodilator test every 2 weeks for 8 weeks

Within the first two weeks, both drugs showed equal efficacy dan clinical improvements
After 2 weeks, the salbutamol group showed deterioration while the procaterol group still showed some improvements

The decline in spirometry was greater in salbutamol group than in procaterol

A long-term trial of procaterol in steroid-dependent patients

D.P. Tashkin. Journal of Respirology 1997

Seventy five (75) cocticosteroiddependent with moderate to severe asthmatic patients Oral or inhaled corticosteroid and procaterol for 28 weeks in five centers

Procaterol has corticosteroid-sparing effect of procaterol without a compensatory increase in bronchodilator use

PURPOSE

The present study aimed to compare the efficacy of nebulized procaterol with nebulized salbutamol in the treatment of moderate acute asthma

METHODS

This was a randomized, double-blind, parallel group study in 140 patients with moderate acute asthma according to modified GINA 1998 Patients visiting the Emergency Room of Persahabatan Hospital - Jakarta, male or female, aged 15 to 60 years, were eligible for entry into this study Excluded from the study were pregnant or lactating women, smokers, patients with chronic obstructive pulmonary disease (COPD), heart disease, hyperthyroidism, diabetes mellitus, severe infections, or other chronic diseases

METHODS

Patients were randomly assigned to receive three doses of either nebulized procaterol or salbutamol The primary efficacy variable was the improvement in predicted PEFR, while the secondary efficacy variable was the improvement in asthma score and the incidence and severity of adverse events

RESULT

A total of 156 patients were screened and there were 140 patients eligible for safety evaluation, 137 patients eligible for ITT evaluation and 133 patients eligible for PP analysis (Figure 1)

Procaterol (n=68) VITAL SIGNS Temperature (0C) mean (SD) Heart rate (beats/min) mean (SD) Blood pressure (mm Hg) mean (SD) Systolic Diastolic Respiratory rate (resp/min) mean (SD) PHYSICAL EXAMINATIONS n (%) Normal Abnormal (hyperemic pharynx) ASTHMA SCORE mean (SD) PEFR median (range) PEFR value (L/min) % predicted < 25% - n(%) ARTERIAL BLOOD GAS ANALYSES mean (SD) PaO2 (mm Hg) PaCO2 (mm Hg) SaO2 (%) HCO3- (mEq/L) pH LABORATORY ABNORMALITIES n (%) ECG ABNORMALITIES n (%) 36.9 (0.36) 104.2 (11.7) 121.5 (10.8) 77.9 (8.9) 27.3 (2.6) 64 (94.1) 5 (5.9) 8.8 (1.5) 125 (70 - 300) 30.5 (12 - 57) 19 (27.9)

Salbutamol (n=69) 36.8 (0.48) 102.9 (12.7) 120.0 (9.7) 75.2 (7.0) 27.4 (2.2) 66 (95.7) 3 (4.3) 8.4 (1.6) 120 (80 - 320) 26.0 (15 - 64) 32 (46.4)

75.8 (16.28) 33.9 (6.67) 94.4 (4.37) 22.4 (3.84) 7.4 (0.06) 23 (33.8) 18 (26.5)

79.8 (22.18) 32.8 (5.46) 95.3 (2.66) 21.8 (2.64) 7.4 (0.06) 23 (33.3) 14 (20.3)

PEFR (% predicted) improvements in each group

Mean PEFR (% predicted) was markedly improved compared with baseline value at every timepoint (20, 40, 60 and 120 minutes) in both groups (Figure 2). Procaterol was statistically better in improving PEFR value at 120 minutes compared with salbutamol but not clinically significant. The minimum clinically significant difference in PEFR improvements between procaterol and salbutamol groups according to the investigators judgment as defined in the protocol was 5%. At other timepoints, PEFR improvements by procaterol was similar to salbutamol

PEFR (% predi cted)

Procaterol (n=68)

Timepoints (minutes)

Salbutamol (n=69)

Figure 2. PEFR (% predicted) values at different timepoints in procaterol and salbutamol groups, ITT population. The improvements from baseline were significant at all timepoints (**p<0.001)

Asthma score improvements from baseline in procaterol and salbutamol groups

The asthma scores in procaterol and salbutamol groups were markedly improved at every timepoint (20, 40, 60 and 120 minutes) (Figure 3). At 120 minutes, mean asthma score in procaterol group was 2.0 and in salbutamol group was 2.1. Asthma score improvements in procaterol group were compared with those in salbutamol group. It was shown that procaterol gave greater improvements in asthma scores at the first 40 minutes (20 and 40 minutes, p<0.001 and p<0.002, respectively). At 60 and 120 minutes, the asthma scores were consistently lower in procaterol group but not significantly different.

Time (minutes)

Procaterol (n=68)

Salbutamol (n=69)

Figure 3. Asthma scores at several timepoints in procaterol and salbutamol groups, ITT population. The improvements from baseline were significant at all timepoints (** p<0.001 )

Arterial blood gas analyses

Arterial blood gas analyses at 120 minutes are summarized in Table 2. Number of patients analyzed for blood gas was 62 patients in procaterol group and 65 patients in salbutamol group. Six patients in procaterol group and 3 patients in salbutamol group could not be included in the blood gas analysis due to the missing data on either at baseline or at 120 minutes. Overall, PaO2 in procaterol group was slightly increased, while it was slightly decreased in salbutamol group. SaO2 was unchanged in procaterol group and slightly decreased in salbutamol group, while PaCO2 slightly decreased in both procaterol and salbutamol groups

Table 2. Mean PaO2, PaCO2 and O2 saturation (SaO2) before and after treatment (120 minutes) in procaterol and salbutamol groups, PP analysis
PP analysis Blood Gas Analysis PaO2 (mmHg) SaO2 PaCO2 (mmHg) 0 minutes 120 minutes 0 minutes 120 minutes 0 minutes 120 minutes Procaterol (n=62) 76.8 81.4 95.0 95.0 33.4 31.6 Salbutamol (n=65) 80.0 76.2 95.3 94.3 32.8 31.7

Adverse events

Incidences of adverse events were very low in the present study. Adverse events recorded were sinus tachycardia and palpitation, which were common after 2 agonist administration. Palpitation was recorded as a subjective symptom. There were 2 subjects in salbutamol group experienced palpitation, and no one in procaterol group. The palpitation was considered as mild. Sinus tachycardia was found during electrocardiography at 120 minutes, which was recorded and analyzed for any changes from baseline. There were 2 (2.9%) cases of changes in ECG recordings in procaterol group and 6 (8.6%) cases in salbutamol group. No serious adverse event was found in the present study

CONCLUSIONS

Beta 2 agonists have been used as reliever in asthma management In moderate acute asthma, nebulized procaterol and nebulized salbutamol were both effective in improving PEFR and decreasing asthma score. Both treatments were well tolerated, and adverse reactions were rare, lower incidence with procaterol than with salbutamol