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ASHMA BRONKIAL DRUGS

BY
WAHYU SEFTIANI HARTA
1111012057
CLASS C
Defenition
Asthma is associated with mast cells,
eosinophils, and T lymphocytes. Mast
cells are the allergy-causing cells that
release chemicals like histamine.
Histamine is the substance that causes
nasal stuffiness and dripping in a cold or
hay fever, constriction of airways in
asthma, and itchy areas in a skin allergy.
Eosinophils are a type of white blood cell
associated with allergic disease. T
lymphocytes are also white blood cells
associated with allergy and inflammation.

Signs and Symptoms of
Bronchial Asthma
With bronchial asthma, you may have
one or more of the following signs and
symptoms:
Shortness of breath
Tightness of chest
Wheezing
Excessive coughing or a cough that
keeps you awake at night

Drugs to Treat Bronchial
Asthma
1. Drugs Used to relieve the Symptoms of
Asthma
Drugs which open up the airways are called
bronchodilators because they act by dilating
(opening up) the bronchial tubes. They are used
to reverse or decrease obstruction to the flow of
air to the lungs caused by narrowing of these
tubes. This occurs in bronchial asthma which is a
chronic inflammation, causing spasm of the
muscles in the bronchial tubes (bronchospasm),
swelling of the lining surfaces and an increased
production of secretions. Narrowing of the
airways may also occur in chronic chest
disorders such as emphysema and bronchitis. In
these disorders the small bronchial tubes are
scarred, distorted and narrowed by repeated
infections (e.g. bronchitis)
2. Drugs Used to Prevent Asthma
Non-steroidal Anti-inflammatory Drugs
Sodium cromoglycate (in Aerocrom, Cromogen,
Intal) and nedocromil sodium (Tilade) act on the
surface of special cells (mast cells) to prevent the
release of chemicals (in response, for example, to an
allergen) which cause bronchospasm (wheezing) and
inflammation of the lining of the bronchial tubes. They
are used to prevent attacks of asthma but are not
effective if taken after the reaction has started. They
should be tried on adults who need to use a
bronchodilator more than once a day and who get night
symptoms and/or who should not take corticosteroids.
Sodium cromoglycate should be tried for at least six
weeks in children before using corticosteroids. They are
also effective for preventing wheezing triggered by
exercise, aspirin, industrial dusts, chemicals and cold
air. Nedocromil should not be used in children.

Steroidal Anti-Inflammatory Drugs
Corticosteroids
Corticosteroids by inhalation are the treatment of
choice to prevent asthma attacks in children and
adults who need to use an adrenoreceptor
stimulant bronchodilator more than once a day or
who get night symptoms. They are of doubtful
value in chronic bronchitis and emphysema. They
take 37 days to produce maximum benefit and
they are best used with a spacer device to prevent
deposits in the mouth and throat causing thrush.
Preparations of corticosteroids for inhalation
include beclometasone (Aerobec, Asmabec,
Beclazone, Becloforte, Becodisks, Becotide,
Filair, Qvar, in Ventide), budesonide (Pulmicort)
and fluticasone (Flixotide, in Seretide).
Types of Bronchodilators for
Asthma
Short-acting bronchodilators
Short-acting bronchodilators are called
"quick-acting," "reliever," or "rescue"
medications. These bronchodilators relieve
acute asthma symptoms or attacks very
quickly by opening the airways. The rescue
medications are best for treating sudden
asthma symptoms. The action of inhaled
bronchodilators starts within minutes after
inhalation and lasts for two to four hours.
Short-acting bronchodilators are also used
before exercise to prevent exercise-induced
asthma.

Short-Acting Bronchodilator Inhalers
Available in the United States Include:
Albuterol (AccuNeb, Proventil HFA,
Ventolin HFA, also available as a generic
solution for nebulizers)
Alupent (Metaproterenol, available as a
generic solution for nebulizers, see
below)
Levalbuterol (Xopenex)
Pirbuterol (Maxair)

The long-acting bronchodilators
The long-acting bronchodilators are used to
provide control -- not quick relief -- of asthma.
They should only be used in conjunction with
inhaled steroids for long-term control of
asthma symptoms. The long-acting
bronchodilators are used twice a day.
Long-Acting Bronchodilator Asthma
Inhalers Available in the United States
Include:
Advair and Symbicort (a combination of a long-
acting beta-agonist bronchodilator and an inhaled
steroid)
Serevent (salmeterol)
Foradil (formoterol)
Perforomist (formoterol solution for nebulizers)

DRUGS PHARMACOKINETICS
1. Albuterol
The pharmacokinetics of inhaled (R,S)-albuterol following
pulmonary absorption were studied in healthy human
subjects. Ten subjects (5 females and 5 males) inhaled two
puffs (180 microg) of albuterol via a metered-dose inhaler and
spacer device. All subjects were nonsmoking and had normal
pulmonary function. Charcoal slurries were ingested to block
gastrointestinal absorption of drug. Venous samples were
obtained from each subject at thirteen time points from 0
through 12 h post dose. (R,S)-Albuterol concentration in
plasma was measured using a gas chromatography-mass
spectrometry (GC-MS) assay. The plasma concentration-time
profiles conformed to a two-compartment extravascular model
with first-order absorption kinetics. The drug levels reached
maximum in 12.6 +/- 2.2 (SD) minutes, which is in contrast
with previous reports that maximum plasma concentrations
occur within 2 to 4 h. The mean peak plasma level was 1469
+/- 410 pg/mL. The mean half-life of distribution was 17.9 +/-
8.2 min. The mean half-life of elimination was 4.4 +/- 1.5 h.
Female subjects achieved peak concentration more rapidly
than male subjects (10.4 vs 14.8 min, p = 0.01) and had a
higher mean peak concentration (1778 vs 1159 pg/mL, p =
0.04).

2. Ipratropium Bromide
The bronchodilation following inhalation of ipratropium
is primarily a local, site-specific effect, not a systemic
one. Much of an inhaled dose is swallowed as shown
by fecal excretion studies. Following nebulization of a
1-mg dose to healthy volunteers, a mean of 4% of the
dose was excreted unchanged in the urine.
Ipratropium bromide is minimally (0% to 9% in vitro)
bound to plasma albumin and 1-acid glycoproteins. It
is partially metabolized to inactive ester hydrolysis
products. Following intravenous administration,
approximately one-half is excreted unchanged in the
urine. The half-life of elimination is about 1.6 hours
after intravenous administration. Ipratropium bromide
that reaches the systemic circulation is reportedly
removed by the kidneys rapidly at a rate that exceeds
the glomerular filtration rate. The pharmacokinetics of
ipratropium bromide and albuterol sulfate inhalation
solution or ipratropium bromide have not been studied
in the elderly and in patients with hepatic or renal
insufficiency
3. Albuterol Sulfate

Albuterol sulfate is longer acting than
isoproterenol in most patients by any
route of administration, because it is not
a substrate for the cellular uptake
processes for catecholamine nor for the
metabolism of catechol-O-methyl
transferase. Instead the drug is
conjugatively metabolized to albuterol 4'-
O-sulfate.

4. Metaproterenol Sulfate
Absorption
Less than 10% is absorbed intact.
Metabolism
Metabolized through sulfate conjugation in the GI tract. The
major metabolite is metaproterenol-o-sulfate.
Dosage and Administration
Tablets
Adults and Children (9 yr of age and older or at least 60
lbs)
PO 20 mg 3 to 4 times daily.
Children (6 to 9 yr of age or weight less than 60 lbs)
PO 10 mg 3 to 4 times daily.
Syrup
Adults and Children (9 yr of age and older or at least 60
lbs)
PO 10 mL 3 to 4 times daily.
Children (6 to 9 yr of age or weight less than 60 lbs)
PO 5 mL 3 to 4 times daily.

5. Levalbuterol
Metabolism and Elimination
Information available in the published literature suggests that
the primary enzyme responsible for the metabolism of
albuterol enantiomers in humans is SULT1A3
(sulfotransferase). When racemic albuterol was administered
either intravenously or via inhalation after oral charcoal
administration, there was a 3- to 4-fold difference in the area
under the concentration-time curves between the (R)- and
(S)-albuterol enantiomers, with (S)-albuterol concentrations
being consistently higher. However, without charcoal
pretreatment, after either oral or inhalation administration the
differences were 8- to 24-fold, suggesting that (R)-albuterol is
preferentially metabolized in the gastrointestinal tract,
presumably by SULT1A3.

The primary route of elimination of albuterol enantiomers is
through renal excretion (80% to 100%) of either the parent
compound or the primary metabolite. Less than 20% of the
drug is detected in the feces. Following intravenous
administration of racemic albuterol, between 25% and 46% of
the (R)-albuterol fraction of the dose was excreted as
unchanged (R)-albuterol in the urine.

Special Populations
Hepatic Impairment: The effect of hepatic
impairment on the pharmacokinetics
of Levalbuterol HCl Inhalation Solution has
not been evaluated.
Renal Impairment: The effect of renal
impairment on the pharmacokinetics of
racemic albuterol was evaluated in 5 subjects
with creatinine clearance of 7 to 53 mL/min,
and the results were compared with those
from healthy volunteers. Renal disease had
no effect on the half-life, but there was a 67%
decline in racemic albuterol clearance.
Caution should be used when administering
high doses of Levalbuterol HCl Inhalation
Solution to patients with renal impairment

6. Salmeterol
Absorption
Salmeterol acts locally in the lung. Plasma levels
do not predict therapeutic effect. Depending on
dose, T
max
is 20 min and mean C
max
is 167
pg/mL.
Distribution
Protein binding is 96%; xinafoate moiety is greater
than 99%.
Metabolism
Extensively metabolized by hydroxylation.
Elimination
Eliminated in feces (60%) and urine (25%); half
life is 5.5 days. Xinafoate moiety half-life is 11
days.

Special Populations
Renal Function Impairment
Has not been studied in patients with
renal impairment.
Hepatic Function Impairment
May lead to accumulation of
salmeterol in plasma.
Elderly
Has not been studied in elderly
patients.

7. formoterol
Absorption
Inhalation powder
C
max
is 92 pg/mL and T
max
is 5 min.
Inhalation solution
C
max
is 72 pg/mL and T
max
is 12 min.
Distribution
Protein binding is 61% to 64%.
Metabolism
Formoterol is primarily metabolized by direct glucuronidation and O-
demethylation by CYP-450 2D6, 2C19, 2C9, and 2A6 isozymes.
Elimination
Inhalation powder
Eliminated in the urine (59% to 62%) and feces (32% to 34%).
About 10% is excreted unchanged in the urine, and
about 15% to 18% is excreted in the urine as conjugates. Mean
half-life is 10 h.
Inhalation solution
1.1% to 1.7% excreted unchanged in the urine. The half-life is 7
h.

Special Populations
Children
The pharmacokinetics of formoterol inhalation
solution have not been studied in children.
Gender
Pharmacokinetics did not differ between men
and women.
Elderly/Hepatic and renal function
impairment
Pharmacokinetic studies have not been done
in elderly patients or in subjects with hepatic
or renal function impairment.

8. Theofilline
Absorption:
Theophylline administered in the fed state is completely absorbed after oral
administration.
Distribution:
Once Theophylline enters the systemic circulation, about 40% is bound to
plasma protein, primarily albumin. Unbound Theophylline distributes
throughout body water, but distributes poorly into body fat. The apparent
volume of distribution of Theophylline is approximately 0.45 L/kg (range 0.3-
0.7 L/kg) based on ideal body weight. Theophylline passes freely across the
placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva
Theophylline concentrations approximate unbound serum concentrations, but
are not reliable for routine or therapeutic monitoring unless special
techniques are used. An increase in the volume of distribution of
Theophylline, primarily due to reduction in plasma protein binding, occurs in
premature neonates, patients with hepatic cirrhosis, uncorrected acidemia,
the elderly and in women during the third trimester of pregnancy. In such
cases, the patient may show signs of toxicity at total (bound+unbound) serum
concentrations of Theophylline in the therapeutic range (10-20 mcg/mL) due
to elevated concentrations of the pharmacologically active unbound drug.
Similarly, a patient with decreased Theophylline binding may have a sub-
therapeutic total drug concentration while the pharmacologically active
unbound concentration is in the therapeutic range. If only total serum
Theophylline concentration is measured, this may lead to an unnecessary
and potentially dangerous dose increase. In patients with reduced protein
binding, measurement of unbound serum Theophylline concentration
provides a more reliable means of dosage adjustment than measurement of
total serum Theophylline concentration. Generally, concentrations of unbound
Theophylline should be maintained in the range of 6-12 mcg/mL.


Metabolism:
Following oral dosing, Theophylline does not undergo
any measurable first-pass elimination. In adults and
children beyond one year of age, approximately 90%
of the dose is metabolized in the liver.
Biotransformation takes place through demethylation
to 1 methylxanthine and 3-methylxanthine and
hydroxylation to 1,3- dimethyluric acid. 1-
methylxanthine is further hydroxylated, by xanthine
oxidase, to 1-methyluric acid. About 6% of a
Theophylline dose is N-methylated to caffeine.
Theophylline demethylation to 3-methylxanthine is
catalyzed by cytochrome P-450 1A2, while
cytochromes P-450 2E1 and P-450 3A3 catalyze the
hydroxylation to 1,3-dimethyluric acid. Demethylation
to 1-methylxanthine appears to be catalyzed either by
cytochrome P-450 1A2 or a closely related
cytochrome. In neonates, the Ndemethylation pathway
is absent while the function of the hydroxylation
pathway is markedly deficient. The activity of these
pathways slowly increases to maximal levels by one
year of age.

Excretion:
In neonates, approximately 50% of the Theophylline
dose is excreted unchanged in the urine. Beyond the
first three months of life, approximately 10% of the
Theophylline dose is excreted unchanged in the urine.
The remainder is excreted in the urine mainly as 1,3-
dimethyluric acid (35-40%), 1-methyluric acid (20-
25%) and 3-methylxanthine (15-20%). Since little
Theophylline is excreted unchanged in the urine and
since active metabolites of Theophylline (i.e., caffeine,
3-methylxanthine) do not accumulate to clinically
significant levels even in the face of end-stage renal
disease, no dosage adjustment for renal insufficiency
is necessary in adults and children >3 months of age.
In contrast, the large fraction of the Theophylline dose
excreted in the urine as unchanged Theophylline and
caffeine in neonates requires careful attention to dose
reduction and frequent monitoring of serum
Theophylline concentrations in neonates with reduced
renal function
9. Aminofilin
Absorption
(Note: Information for the pharmacokinetics/dynamics section was
taken from theophylline because aminophylline is a mixture of
theophylline and base.) Rapidly and completely absorbed in solution
or immediate-release. C
max
is 10 mcg/mL (5 to 15 mcg/mL). T
max
is
1 to 2 h. Food and antacid does not cause any clinically important
changes; therapeutic range is 10 to 20 mcg/mL.
Distribution
40% protein bound (primarily albumin). Unbound theophylline
distributes throughout the body water, but distributes poorly into
body fat. Vd is 0.45 L/kg (0.3 to 0.7 L/kg) based on ideal body
weight. Freely passes across the placenta into breast milk and into
CSF.
Metabolism
Does not undergo any measurable first-pass elimination. About 90%
of dose is metabolized in the liver in adults and children older than 1
yr of age. Caffeine and 3-methylxanthine are the only theophylline
metabolites with pharmacological activity.
Elimination
In neonates, about 50% of theophylline dose is excreted unchanged
in the urine (ie, excretion is by the kidneys). 10% of theophylline
dose is excreted unchanged in the urine in infants 0 to 3 mo of age.

10. Beclometason kortikosteroid
Absorption
Rapidly absorbed.
Nasal inhalation
Primarily deposited in the nasal passage; majority of the drug is
eventually swallowed. Bioavailability following administration is 44%
( Beconase AQ ).
Oral inhalation
Systemic bioavailability from lungs is about 20%.
Distribution
87% protein bound (94% to 96% for beclomethasone 17-
monoprionate).
Metabolism
Metabolized to beclomethasone 17-monopropionate (active) and
free beclomethasone (very weak activity).
Elimination
Primarily excreted in feces. Less than 10% excreted in urine. The
half-life is 2.8 h for beclomethasone 17-monopropionate.

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