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1.1 OAT

1. Pharmacokinetics

 isoniazid
Isoniazid is absorbed from the gastrointestinal tract after oral administration.
The highest plasma concentrations are achieved 1-2 hours after ingestion. If
taken with food, the bioavailability will be reduced. Most of it circulates in
fluids, including cerebrospinal fluid, skin, sputum, lungs, saliva, and muscles.
Its main metabolism is to undergo acetylation in the liver, go through several
processes and be converted into the active substance by hepatic microsomal
enzymes. These active metabolites can cause hepatotoxicity.
Isoniazid is excreted in its intact form and metabolites via the kidneys, as well
as through breast milk. In addition, a small portion is excreted through saliva,
sputum, and feces. The half-life of isoniazid varies from 1-4 hours in normal
individuals, and is prolonged in renal or hepatic failure.

 Rifampicin
The bioavailability of rifampin is estimated at 90-95% because of its readily
absorbed form through the gastrointestinal tract. The highest plasma levels of
rifampin are reached 2-4 hours after oral administration. Consumption with
food will slow but not reduce drug absorption. The half-life of rifampin is 1.5-
5 hours and is prolonged in liver damage.
About 60-90% of the drug binds to plasma proteins and is distributed to
organs and body fluids such as the lungs, liver, bile, and urine. And as much
as 60-80% of this drug is metabolized in the liver. A small proportion of this
drug is metabolized to formylrifampin which has a bactericidal effect of 10%.
About 15-30% of the drug is excreted through the kidneys and only 7% of this
drug is excreted in the urine in its original form. About 60-65% of this drug is
excreted in the bile and feces.

 Pyrazinamide
Pyrazinamide is well absorbed from the gastrointestinal tract. The average
time required to reach maximum blood levels is 1.6 hours. The half-life is
about 10-20 hours. Pyrazinamide is widely distributed to tissues and fluids,
including hepatobiliary, pulmonary, and renal. Pyrazinamide can also enter
completely into the cerebrospinal fluid. The total volume of distribution in the
body of this drug reaches 1.57-1.84l/kg. The plasma level of the drug is low.
This pyrazinamide is hydrolyzed by the microsomal deamidase enzyme to
pyrazinoic acid, an active metabolite, and then hydroxylated by the enzyme
xanthine oxidase to 5-hydropyrazinoic acid. Most of the excretion of
pyrazinamide is in the form of metabolites. Within 72 hours, about 3% is in
the fixed form of pyrazinamide, 33% of pyrazinoic acid,

 ethambutol
 Ethambutol is well absorbed orally. The highest plasma levels can reach 4mg/l
and are reached within 2-4 hours after ingestion of 15mg/kgBW. The volume
of distribution can reach 39% and bind to plasma proteins as much as 25%.
Wide distribution throughout the body except the central nervous system.
Concomitant use with food will affect its absorption from the gastrointestinal
tract. Blood levels in children are lower than in adults. Metabolism of this
drug occurs in the liver, where it is converted to the inactive metabolite forms
of aldehydes and carboxylic acids. The excretion of ethambutol is as much as
50-70% via the kidneys, so the excretion of this drug will be slower in people
with renal impairment.

 Streptomycin
Streptomycin is not well absorbed from the gastrointestinal tract, but via the
intramuscular route, this antibiotic can diffuse well into the extracellular
components of body tissues and reach concentrations for its bactericidal effect,
especially in the tuberculous cavity. A small portion normally passes into the
cerebrospinal fluid, and usually this penetration into the cerebrospinal fluid
will increase if there is inflammation of the lining of the brain. The half-life of
this antibiotic is 2-3 hours, which is usually prolonged in newborns, the
elderly, and patients with renal failure. Excretion of streptomycin is intact and
excreted in the urine.

A. Pharmacodynamics

 isoniazid
The main mechanism of action of isoniazid is to focus on the formation of
various reactive compounds, namely reactive oxygen species (ROS).
After isoniazid circulating in the bloodstream, isoniazid will diffuse passively
into the body of bacteria, where the inactive form of isoniazid will be activated
by MnCl220 and the enzyme catalase-peroxidase. This enzyme also functions
to fight low pH levels when there is an oxidative process that converts oxygen
free radicals into H2O2 in the phagosome. This process also converts isoniazid
into its active form, where this active form will bind to NADH on the active
site of the InhA protein. This complex will inhibit the elongation of the last
chain of fatty acids and therefore the formation of mycolic acid and cell walls
are inhibited, thereby also causing deoxyribonucleotide acid (DNA) of
bacteria to be damaged, and then the bacteria will die.
The action of isoniazid is very important in the first week of treatment,
especially in rapidly dividing bacteria. In slow-growing bacteria, this drug acts
as a bactericidal

 Rifampicin
Rifampicin can easily diffuse across cell membranes because of its lipophilic
characteristics. The bactericidal activity of these drugs depends on their ability
to inhibit ribonucleotide acid (RNA) transcription.
The mechanism of action of this drug is by binding to the beta subunit of
DNA-dependent RNA Polymerase (RNAP), thereby inhibiting RNA
transcription. This enzyme-drug binding complex inhibits the initiation of
RNA chain formation as well as its elongation
  Pyrazinamide
Pyrazinamide acts bacteriostatically. Pyrazinamide in the form of a prodrug
will be converted to pyrazinoic acid by the bacterial pyramidase enzyme.
Pyrazinoic acid and its analogue 5-chloro-pyrazinamide can inhibit fatty acid
synthesis from bacteria.
Pyrazinamide interferes with energy traffic and transport across bacterial
membranes. Accumulation of pyrazinoic acid under acidic conditions will
acidify the cytoplasm and damage bacterial cells

 ethambutol
Ethambutol acts as a bacteriostatic against tuberculosis bacteria and bacteria
that are resistant to other antimycobacterial agents.
The mechanism of action of ethambutol is to inhibit the synthesis of important
metabolites of cell metabolism and bacterial multiplication by inhibiting the
formation of mycolic acid and cell walls. Inhibition of cell wall synthesis is
done by inhibiting arabinosyl transferases involved in cell wall synthesis. This
then causes the permeability of the bacterial cell wall to increase.

 Streptomycin
Streptomycin is an aminoglycoside that is active against active growing
bacteria. The way these antibiotics work is by inhibiting the initiation of
translation for protein synthesis. More specifically, streptomycin acts by
binding to the 30S subunit of the ribosome on the ribosomal protein S12 and
the rRNA 16 chain encoded by the rpsL and rrs genes. These two genes code
for the frequently occurring resistance. This streptomycin bond then inhibits
the formation of polypeptides so that the translation process is inhibited.

B. Drug Dosage
The flow of treatment for pediatric TB patients can be seen in the scheme
below.

In most cases of pediatric TB, 6 months of treatment is adequate. After 6

months of drug administration, do a good clinical evaluation and
investigations. Clinical evaluation of pediatric TB is the best parameter to
assess the success of treatment. If there is a marked clinical improvement even
though the radiological picture does not show significant changes, OAT is still
discontinued.
 TB drug guide for children
TB treatment is divided into 2 stages, namely the initial/intensive stage (the
first 2 months) and the rest as an advanced stage. The basic principle of TB
treatment is at least 3 types of drugs in the initial/intensive phase (first 2
months) and followed by 2 types of drugs in the continuation phase (4 months,
except for severe TB). OAT in children is given every day, both at the
intensive and advanced stages.

To ensure the availability of OAT for each patient, OAT is provided in the
form of packages. One package is made for one patient for one treatment
period. The pediatric OAT package contains drugs for the intensive stage,
namely Rifampicin (R), Isoniazid (H), Pyrazinamide (Z); while for the
advanced stage, namely Rifampicin (R) and Isoniazid (H).

DRUG DOSAGE:

 INH: 5-15 mg/kg/day, maximum dose 300 mg/day

 Rifampicin: 10-20 mg/kg/day, maximum dose 600 mg/day
 Pyrazinamide: 15-30 mg/kg/day, maximum dose 2 000 mg/day
 Ethambutol: 15-20 mg/kg/day, maximum dose 1 250 mg/day
 Streptomycin: 15–40 mg/kg/day, maximum dose 1 000 mg/day

To improve patient compliance in undergoing relatively long treatment with a

large number of drugs, OAT combinations are provided in the form of Fixed
Dose Combination = FDC (Fixed Dose Combination = FDC). KDT tablets for
children are available in 2 types of tablets, namely:

 RHZ tablet which is a combination tablet of R (Rifampicin), H

(Isoniazid) and Z (Pyrazinamide) which is used in the intensive phase.
 RH tablets which are combination tablets of R (Rifampicin) and H
(Isoniazid) which are used in the advanced stage.

The number of KDT tablets given must be adjusted to the child's weight and
the composition of the KDT tablets.
The following table is an example of a dose of KDT in which the composition
of the RHZ tablet is R = 75 mg, H = 50 mg, Z = 150 mg and the composition
of the RH tablet is R = 75 mg and H = 50 mg,

Table 14. Dosage of KDT (R75/H50/Z150 and R75/H50) in children

WEIGHT (KG) 2 MONTHS 4 MONTHS
EVERY DAY EVERY DAY
RHZ (75/50/150) RH (75/50)

5-9 1 tablet 1 tablet

10-14 2 tablets 2 tablets

15-19 3 tablets 3 tablets

20-32 4 tablets 4 tablets

Information:

 Infants weighing less than 5 kg are referred to the hospital

 Children weighing 33 kg, adjusted to the adult dose
 The drug must be given as a whole, not split
 OAT KDT can be given by: swallowed whole or crushed just
before drinking.

If the KDT package is not yet available, the Kombipak Anak OAT package
can be used. The dosage is as in the following table.
Table 15a. Dosage of Kombipak-early-phase/intensive OAT in children

TYPE OF BB<10K BB 10-20 BB 20-32

MEDICINE G KG(KOMBIP KG
AK)

isoniazid 50 mg 100 mg 200 mg

Rifampicin 75 mg 150 mg 300 mg

Pyrazinamide 150 mg 300 mg 600 mg

Table 15b. Dosage of Kombipak-advanced-phase OAT in children

TYPE OF BB<10K BB 10-20 BB 20-32

MEDICINE G KG(KOMBIP KG
 AK)

isoniazid 50 mg 100 mg 200 mg

Rifampicin 75 mg 150 mg 300 mg

In cases of severe TB, both pulmonary and extrapulmonary, such as miliary

TB, TB meningitis, joint and bone TB, and others:

 In the intensive phase, at least 4 drugs are given (INH, Rifampicin,

Pyrazinamide, Ethambutol or Streptomycin).
 In the advanced stage, INH and Rifampicin were given for 10 months.
 For certain TB cases, namely miliary TB, TB pleural effusion, TB
pericarditis, endobronchial TB, TB meningitis and TB peritonitis,
corticosteroids (prednisone) are given at a dose of 1-2 mg/kg BW/day,
divided into 3 doses. The duration of administration of corticosteroids
is 2-4 weeks with the full dose followed by tapering off in a period of
2-6 weeks. The purpose of this steroid is to reduce the inflammatory
process and prevent tissue adhesion.

Attention:Avoid the use of streptomycin in children whenever possible,

because the injection is painful, permanent damage to the auditory nerve can
occur, and there is a risk of HIV transmission due to improper treatment of the
injection device.
1.2 Asthma medicine

A. Methylxanthines

 MWork mechanism
In PDPI, 2013 Explains thatAt high concentrations, drugs of this class
have been shown to inhibit several members of the phosphodiesterase
(PDE) enzyme family in vitro. Because phosphodiesterase hydrolyzes
cyclic nucleotides, this inhibition causes an increase in intracellular
concentrations of cAMP and, in some tissues, cGMP. Cyclic AMP has
effects on a variety of cell functions including, but not limited to,
stimulation of cardiac function, relaxation of smooth muscle, and
suppression of the immune and inflammatory activities of certain cells.

Of the various known isoforms of phosphodiesterase, PDE4 appears to be the

most directly involved in the action of methylxanthines on airway smooth
muscle and on inflammatory cells. Inhibition of PDE4 in inflammatory cells
reduces the release of cytokines and chemokines, which in turn leads to
decreased migration and activation of immune cells. In an effort to reduce
toxicity while maintaining efficacy, selective inhibitors for various PDE4
isoforms have been developed. Much was overlooked after clinical trials
showed that side effects of nausea, headache, and diarrhea limited the dose to
subtherapeutic levels, but one, roflumilas, was recently approved by the Food
and Drug Administration (FDA) as a drug.

 Pharmacodynamics

Methylxanthines have effects on the central nervous system, kidneys, and

cardiac and skeletal muscles and smooth muscles. Of the three drugs,
theophylline was the most selective in its effect on smooth muscle, while
caffeine had the most striking effect on the central nervous system.
A. Effects on the Central Nervous System
B. Cardiovascular Effect
C. Effects on the Gastrointestinal Tract
D. Effects on the Kidneys
E. Effects on Smooth Muscles
F. Effects on Skeletal Muscles
B. SYMPATOMYMETIC DRUGS
Adrenoceptor agonists have several important pharmacological effects in the
treatment of asthma. These drugs relax airway smooth muscle and inhibit the release
of various bronchoconstrictive mediators from mast cells. They can also inhibit
microvascular leakage and increase mucociliary transport by increasing ciliary
activity. As in other tissues, -agonists stimulate adenylyl cyclase and increase
intracellular cAMP formation.

The most well-known effect of adrenoceptor agonists on the airways is relaxation of

airway smooth muscles. Although there is no evidence of direct sympathetic
innervation of human airway smooth muscle, ample evidence suggests that
adrenoceptors are abundant in airway smooth muscle. In general, 2 receptor
stimulation relaxes airway smooth muscle, inhibits mediator release, and causes
tachycardia and skeletal muscle tremor as side effects.

Sympathomimetic drugs that have been widely used in the treatment of asthma are
epinephrine, ephedrine, isoproterenol, and albuterol as well as other 2-selective drugs.
Because epinephrine and isoproterenol increase the rate and strength of cardiac
contraction (mediated primarily by 1 receptors), they are reserved for special
situations.

In general, adrenoceptor agonists are best administered by inhalation because they

produce the greatest local effect on airway smooth muscle with the least systemic
toxicity. The deposition of aerosols depends on the particle size, breathing pattern,
and airway geometry. Even with particles in the optimal size range of 2-5 mm, 80-
90% of the total aerosol dose settles in the mouth or pharynx. Particles measuring less
than 1-2 m remain suspended and may be expelled again. The deposition of aerosols
in the bronchi is increased by slow inhalation with almost full breathing and by
holding the breath for 5 seconds at the end of inspiration.

Epinephrineis a fast-acting bronchodilator that is effective when injected

subcutaneously (0.4 mL of a 1:10,000 solution) or inhaled as a microaerosol from a
pressure vessel (320 mcg per spray). Maximum bronchodilation is achieved 15
minutes after inhalation and persists 60-90 minutes. Because epinephrine stimulates
and 1 and 2 receptors, side effects of this therapy are tachycardia, arrhythmias, and
worsening of angina pectoris. The cardiovascular effects of epinephrine are useful for
treating acute vasodilation and shock and bronchospasm in anaphylaxis, but its use in
asthma has been displaced by other 2-selective drugs.

Ephedrinebeen used in China for more than 2000 years before being introduced to
Western medicine in 1924. Compared to epinephrine, ephedrine has a longer duration
of action, can be given orally, has a more pronounced central effect, and is potent.
which is much lower. Due to the development of more effective selective 2-agonists,
ephedrine is now rarely used for asthma.

Isoproterenolis a powerful bronchodilator; when inhaled in microaerosol form from a

pressure vessel, isoproterenol 80-120 mcg causes maximal bronchodilation in 5
minutes. Isoproterenol has a working life of 60 to 90 minutes. The increase in asthma
mortality that occurred in England in the mid-1960s is thought to be due to cardiac
arrhythmias arising from the use of high-dose isoproterene inhalants. This drug is now
rarely used for asthma. (GINA, 2016)

C. ANTI_MUSCARINIC MEDICINE

 Work mechanism:

Muscarinic antagonist. competitively inhibits the effects of acetylcholine at

muscarinic receptors. In the airways, acetylcholine is secreted from the
efferent endings of the vagus nerve, and muscarinic antagonists inhibit airway
smooth muscle contraction and the increase in mucus secretion that occurs in
response to vagal activity. Very high concentrations are required—well above
levels achieved even with maximal therapy—to inhibit the response of airway
smooth muscle to non-mucarinic stimulation. The selectivity of these
muscarinic antagonists makes them a research tool in examining the role of the
parasympathetic system in bronchomotor responses but limits their use in
preventing bronchospasm. At a given dose, antimuscarinic drugs inhibit only
the part of the response mediated by muscarinic receptors,

 Clinical Use:

Antimuscarinic drugs are effective bronchodilators. When given

intravenously, atropine, the prototype muscarinic antagonist, causes
bronchodilation at doses lower than those required to increase heart rate. The
selectivity of the effects of atropine can be further enhanced by administering
the drug by inhalation or using atropine's more selective quaternary
ammonium derivative, ipratropium bromide.

Ipratropium can be given in high doses by this route because it is poorly

absorbed into the circulation and does not readily enter the central nervous
system. Studies with this drug show that the degree of involvement of the
parasympathetic pathways in the bronchomotor response varies from person to
person. In some cases, bronchoconstriction is effectively inhibited; in others,
only moderate. The failure of high-dose muscarinic antagonists to further
inhibit the response in these individuals suggests that there must be other
mechanisms at play outside of the parasympathetic reflexes.

Even in people who are least protected by these antimuscarinic drugs,

bronchodilation and partial inhibition of bronchoconstriction remain of
potential clinical value, and antimuscarinic drugs are useful in patients who
are intolerant of -inhalant agonists. Although antimuscarinic drugs appear to
be slightly less effective than -agonist drugs in relieving asthmatic
bronchospasm, in severe acute asthma the addition of ipratropium increases
the bronchodilation produced by nebulized albuterol.

Ipratropium appears to be at least as effective in patients with COPD that

includes a partially reversible component. The longer-acting selective
antimuscarinic drug, tiotropium, has been approved to treat COPD. The drug
binds to M1, M2, and M3 receptors with equal affinity, but releases more
rapidly than M2 receptors, which are expressed on efferent nerve endings.
This means that ipratropium does not inhibit M2-mediated auto-down
regulation of acetylcholine release, and therefore has some degree of receptor
selectivity.

Tiotropium is also given by inhalation, and a single dose of 18 mcg has a

duration of action of 24 hours. Daily inhalation of tiotropium has been shown
to not only improve the functional capacity of patients with COPD, but also
reduce the frequency of exacerbations of their disease, and tiotropium has
been approved by the FDA as a treatment for COPD. It is not yet approved as
a treatment for asthma, but the addition of tiotropium has recently been shown
to be as effective as the addition of a long-acting -agonist in patients poorly
 controlled by inhalant corticosteroid therapy alone.

 Examples of drugs and dosages:

-Ipratropium Bromide = adults and the elderly: 1 dose of UDV 3-4 times a
day. Patients with chronic pulmonary obstruction who have a smoking habit,
are advised to consult a doctor to determine the dose and smoking habits
should be stopped if there is no improvement in chronic pulmonary
obstruction.

-Tiotropium Bromide = adults (including the elderly), 1 time a day one

capsule for inhalation (22.5 mcg of tiotropium bromide is equivalent to 18
mcg of tiotropium), should not be swallowed, should not be used more than 1
time a day.

-Glycoprionium Bromide = 50 micrograms once a day

.(Bruton LL,2017)

Picture:

D. Corticosteroids
  Work mechanism:

In Bruton LL's Book, 2017 it is known that:

Corticosteroids have been used to treat asthma since the 1950s and are thought
to act through their broad anti-inflammatory effect, which is mediated in part
by inhibition of the formation of inflammatory cytokines. Drugs of this class
do not relax airway smooth muscle directly but reduce bronchial reactivity and
reduce the frequency of asthma recurrence if used regularly. Their effect on
airway obstruction may be due in part to the contraction of swollen blood
vessels in the bronchial mucosa and amplification of the effect of -receptor
agonists, but their most important effect is to inhibit airway infiltration by
lymphocytes, eosinophils, and mast cells.

 Clinical Use:

Because of the severe side effects when given long-term, oral and parenteral
corticosteroids are reserved for patients requiring immediate therapy, ie those
who do not improve adequately after bronchodilators or experience worsening
of symptoms despite maintenance therapy. Regular or "controller" therapy is
maintained with aerosolized corticosteroids.

Immediate therapy is often initiated with an oral dose of 30-60 mg of

prednisone per day or an intravenous dose of 1 mg/kg of methylprednisolone
every 6-12 hours; The daily dose is decreased after the airway obstruction
improves.

In most patients, systemic corticosteroid therapy can be discontinued within 7-

10 days, but in other patients symptoms may worsen when the dose is
lowered. Because adrenal suppression by corticosteroids is dose related and
because endogenous corticosteroid secretion has diurnal variations,
corticosteroids are usually given in the morning after endogenous
adrenocorticotropic hormone secretion peaks. However, to prevent nocturnal
asthma, oral or inhaled corticosteroids are most effective when given in the
afternoon.

Aerosol therapy is the best way to avoid the systemic side effects of
corticosteroid therapy. The introduction of various corticosteroids such as
beclomethasone, budesonide, cyclesonide, flunisolid, fluticasone,
mometasone, and triamcinolone allows us to deliver corticosteroids into the
airways with minimal systemic absorption. The average daily dose of four
twice-daily sprays of beclomethasone (400 mcg/day) is equivalent to about 10-
15 mg/day of oral prednisone for asthma control with far fewer systemic side
effects.

Indeed, one of the things that needs to be considered in changing a patient

from oral to inhalant corticosteroid therapy is to gradually decrease oral
therapy to avoid adrenal insufficiency. In patients requiring continued
administration of prednisone despite standard-dose inhaled corticosteroids,
higher doses appear to be more effective; Inhaled fluticasone and higher doses
of cyclesonide, for example, have been shown to be effective in weaning
patients off chronic prednisone. Although high doses of these inhaled steroids
can cause adrenal suppression, the risk of systemic toxicity from chronic use
appears to be negligible compared to the risks of the oral corticosteroid
therapy they substitute.

A particular problem with inhaled corticosteroids is the development of

oropharyngeal candidiasis. The risk of this complication can be reduced by
asking the patient to rinse his mouth with water and spit it out after each
inhalant therapy. Hoarseness may also occur due to the direct local effect of
inhaled corticosteroids on the vocal cords. These drugs are relatively free of
other short-term complications in adults, but may increase the risk of
osteoporosis and cataracts on long-term administration. In children, inhalant
corticosteroids have been shown to slow growth rates by about 1 cm in the
first year of treatment, but not growth rates thereafter. the effect on adult
height is minimal.

 Examples of drugs and dosages:

 -Beclomethasone Dipropionate= inhalation aerosol: 200 mcg 2 times a day or
100 mcg 3-9 times a day (in more severe conditions the initial dose is 600-800
mcg per day). Children: 50-100 mcg 2-4 times daily or 100-200 mcg 2 times
daily.

-Budesonide= Inhaled glucocorticoid therapy has been started, severe asthma,

dose reduction or discontinuation of oral glucocorticoids: adults, 200-1200
mcg per day, divided into 2-4 doses. Maintenance dose 200-400 mcg twice
daily morning and evening, may be increased to 1200 mcg in severe asthma.

Picture:

E. Xhantin

The xanthine group has a lower bronchodilator effect, besides being a bronchodilator
this drug also increases the strength of the diaphragm muscle. The metabolism of
xanthine drugs is influenced by age, smoking, heart failure and bacterial infections.
These drugs provide therapeutic effects in the form of relaxation of bronchial
muscles, reduce pulmonary hypertension, improve diaphragmatic contractility,
increase cardiac output and inhibit mediator release.
Its broncho-relaxation effect is estimated based on adenosine receptor blockade.
These receptors modulate the activity of adenylyl cyclase and adenosine, which have
caused airway smooth muscle contraction and led to the release of histamine from
airway mast cells. Theophylline counteracts this effect by blocking cell surface
adenosine receptors. In addition, theophylline prevents hyperactivity and works
prophylactically.

Dosage: orally 2-4 dd 175-350 mg. in severe attacks (exacerbations) iv 240 mg, rectal
2-3 dd 360 mg. maximum dose of 1.5 g per day. (Rang HP, 2015)
REFERENCES

Brunton LL, Knollman BC, Dandan RH. Goodman and Gilman's The Pharmacological Basis of
Therapeutics. 13th ed. San Diego: McGraw-Hill; 2017

Rang HP et al. Rang & Dale's Pharmacology. 8th ed. Philadelphia: Elsevier; 2015

GINA (Global Initiative for Asthma)., 2006. Pocket Guide for Asthma

Management and Prevention. Based on the Global Strategy for Asthma

Management and Prevention

PDPI (Indonesian Lung Doctors Association)., 2003. Asthma. Diagnostic Guidelines

and Management of Asthma in Indonesia.

1.3 OAT Recipe
1.4 Asthma Medication Recipes