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Contents

. Defining Asthma. 1
. Signs and Symptoms. 2
.Cause. 3

. Drugs of Treatment.7
Short-acting, selective beta2 7.1
. adrenoceptor agonists
.Sablutmol (albuterol) 7.1.1

.Pathophysiolo.4
.Emergency treatment. 8
. Diagnosis.5
.Prevention.9
.Treatment.6
.prevention drugs.10
.Medical 6.1

Drugs on inhaled 10.1

.Pharmaceutical 6.2

.Fluticasone 10.1.1

.Long-acting 2-agonist 6.3

. Trigger avoidance. 11

.Defining Asthma. 1

Asthma Is a chronic
condition involving the
respiratory system in which
the airways occasionally
constricts and are extra
sensitive, becomes
inflamed and swollen, and
is lined with excessive
amounts of mucus .this
swelling and mucus make
.the airways narrower

Signs and Smptoms. 2


Symptoms 2.1
:Some or all of the following symptoms may be present in those with asthma
: Coughing Coughing from asthma is often worse at night or early in the morning, making it
. hard to sleep

:wheezing. Wheezing is a whistling or squeaky sound when you breathe


:Severe shortness of breathSome people say they can't catch their breath, or they feel
breathless or out of breath. You may feel like you can't get
.enough air in or out of your lungs

Not all people have these symptoms, and symptoms may vary from one asthma attack
to another. Symptoms can differ in how severe they are: Sometimes symptoms can be
mildly annoying, other times they can be serious enough` to make you stop what you are
. doing, and sometimes symptoms can be so serious that they are life threatening

signs 2.2
:Signs of an asthmatic episode include
,Wheezing ,a rapid heart rate rhonchous lung sound
The presence paradoxical of pulse and over-inflation of the chest

uring very severe attacks, an asthma sufferer


Can turn blue from lack of oxygen, and can experience chest bain or even loss of
consciousness . Just before lss of consciousness, there is a chance that the patient
will feel numbness in the limbs and palms may start to sweat.The person's feet may
become icy cold. Severe asthma attacks, which may not be responsive to standard
. treatments, are life-threatening and may lead to respiratory arrest and death

Causes.3
Asthma is caused by a complex interaction of genetic and environmental factors
there are many genetic and environmental factors have been suggested as, causes of asthma

Environmental causes 3.1


Many environmental risk factors have been associated with asthma

*
*
*
*

Poor air or high quality from traffic pollution ozone levels


Environmental tabacco smoke, especially maternal cigarette smoking
Viral respiratory infections at an early age may be protective against asthma
Psychological stress on the part of a child's caregiver has been associated with asthma

3.2 Genetic causes:

Over 25 genes had been associated with asthma

EX ADRB2 (-2 adrenergic receptor)

Gene-Environment Interactions causes 3.3


Research is now finding that some genetic variants may only causes asthma when they are
combined with specific environmental exposures

EX The CD14 SNP C-159T and exposure are a well-replicated example of a geneenvironment interaction that is associated with asthma. Endotoxin exposure varies from
person to person and can come from several environmental sources, including
. environmental tobacco smoke, dogs, and farms

4. Pathophysiology
Bronchoconstriction 4.1
During an asthma episode, inflamed airways react to environmental triggers such as smoke,
dust, or pollen The airways narrow and produce excess mucus, making it difficult to breathe. In
essence, asthma is the result of an immune response in the bronchial airways .The airways of
asthmatics are "hypersensitive" to certain triggers,, the bronchi contract into spasm (an
"asthma attack").Inflammation leading to a further narrowing of the airways and excessive
mucus production, which leads to coughing and other breathing difficulties

.Inflamed airways and bronchoconstriction in asthma

4.2 stimuli

*
*
*
*
*
*
*
*
*
*

:Allergens from nature such as thehouse dust mite,cockroach and.grass pollen


Medications: including aspirin
Indoor air pollution from volatil organic compounds: including perfumed productes
Examples soap, dishwashing liquid

Food allergies:such asmilk,peanuts, and eggs


Use of fossil fuel related allergnic air
pollution such as ozone, smog
Various industrial compounds and other
chemicals:notably sulfites
, Early childhood infections
Hormonal changes
Emotional stress
Cold weather

Bronchial inflammation 4.3


The mechanisms behind allergic asthma, asthma resulting from an immune response
to inhaled allergens. In both asthmatics and non-asthmatics, inhaled allergens that find their
way to the inner airways are ingested by a type of cell known as antigen presenting cells, or
APCs. APCs then "present" pieces of the allergen to other immune system cells. In most
people, these other immune cells (TH0 cells) "check" and usually ignore the allergen
molecules. In asthmatics, however, these cells transform into a different type of cell (TH2),
the resultant TH2 cells activate an important arm of the immune system, known as the
humoral immune system. The humoral immune system produces antibodies against the
inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies
"recognize" it and activate a humoral response. Inflammation results

4.4Asthma and sleep apnea


It is recognized with increasing frequency, that patients who have both obstructive
sleep apnea (OSA) and bronchial asthma, often improve tremendously when the sleep
apnea is diagnosed and treated

Asthma and gastro-esophageal reflux disease 4.5


If gastro-esophageal reflux disease is present, the patient may have repetitive episodes
. of acid aspiration, which results in airway inflammation and "irritant-induced" asthma

Diagnosis.5
Asthma is defined simply as reversible airway obstruction. Reversibility occurs either
spontaneously or with treatment. The basic measurement is peak flow rates and the
following diagnostic criteria are used by the British Thoracic society

* 20% difference on at least three days in a week for at least two weeks
20% improvement of peak flow following treatment, for example
;minutes of inhaled -agonist (e.g.,salbutamol) 10o

* 20% decrease in peak flow following exposure to a trigger (e.g., exercise).


Testing peak flow at rest and after exercise can be helpful, especially in young
asthmatics
In the Emergency Department doctors may use acapnography which measures the amount
of exhaled carbon dioxide, along with pulse oximetry which shows the amount of oxygen
dissolved in the blood

Treatment 6

most effective treatment for asthma is identifying triggers, such as


.pets or aspirin, and limiting or eliminating exposure to them
Other forms of treatment include relief medication, prevention
.medication, long-acting 2-agonists, and emergency treatment

6.1 Medical
The specific medical treatmen t recommended to patients
with asthma depends on the severity of their illness and the
frequency of their symptoms. Specific treatments for asthma
are broadly classified as relievers, preventers and emergency
treatment.
For those who suffer daily attacks, a higher dose of
glucocorticoid in conjunction with a long-acting inhaled -2
agonist may be prescribed; alternatively, a leukotriene modifier
or theophylline may substitute for the -2 agonist. In severe
asthmatics, oral glucocorticoids may be added to these
.treatments during severe attacks

Pharmaceutical 6.2
Symptomatic control of episodes of wheezing and shortness of breath is
generally achieved with fast-acting bronchodilators. These are typically provided in
.pocket-sized, metered-dose inhalers (MDIs)
an asthma spacer is used. The spacer is a plastic cylinder that mixes the medication
.with air in a simple tube making it easier for patients to receive a full dose
A nebulizer which provides a larger, continuous dose can also be used
that they are more effective than inhalers used with a spacer. Nebulizers may
be helpful to some patients experiencing a severe attack. Such patients may
not be able to inhale deeply

:Relievers include

*
*
*

Short-acting, selective beta2- adrenoceptor agonists, such as salbutamol(albutero)


Older, less selective adrenerigc agonists, such as inhaled epinephrine and ephedrine
.tablets, have also been used
Anticholinergic medications, such as ipratropium bromide may be used instead

Long-acting 2-agonists 6.3


Are similar in structure to short-acting selective beta2-adrenoceptor agonists,
but have much longer side chains resulting in a 12-hour effect, and are used to
give a smoothed symptomatic relief
Currently available long acting beta2-adrenoceptor agonists include salbutamol
formoterol,bambuterol , and sustained-release oral albuterol. Combinations of inhaled
steroids and long-acting bronchodilators are becoming more widespread; the most
common combination currently in use is fluticasone/salmeterol
Found that long-acting beta-agonists increased the risk for asthma hospitalizations and
asthma deaths 2- to 4-fold, compared with placebo
which These agents can improve symptoms through bronchodilation at the same time as
increasing underlying inflammation and bronchial hyper-responsiveness
Three common asthma inhalers containing the drugs salmeterol or formoterol may be
causing four out of five US asthma-related deaths per year and should be taken off the
"market

7.Drugs of Treatment .
Short-acting, selective beta2-adrenoceptor agonists
salbutamo )albuterol(
Salbutamol or albuterol is a short-acting beta2adrenoceptor receptor agonists used for the relief
of bronchospasm in conditions such as asthma

Clinical use
Salbutamol is specifically indicated in the
:following conditions
acute asthma. 1
protection against exercise-induced asthma. 2

OH

H
N

HO
HO

Salbutamol
chemical formula :

C13 H21 NO3

hyperkalaemia, especially in patients with renal failure. 3

Systematic (IUPAC) name


Adverse effects
Common adverse effects include:tremor,palpitations, low
.blood pressure, and headache

4-[2-(tert-butylamino)-1hydroxyethyl]-2(hydroxymethyl)phenol

Salbutamol synthesis
It is prepared from 4-hydroxyacetophenon , the chloromethylation which gives 4hydroxy-3-hydroxymethylacetophenone (1.1) this is acetylated into a diacetyl derivative
(1.2) which is further brominated into the corresponding bromoacetophenone (1.3).
Reacting this with N-benzyl-N-tert-butylamine gives a derivative of amino acatophenone
(1.4) the acetyl group of which is hydrolyzed by hydrochloric acid , and the resulting
product (1.5 ) undergoes a reduction - frist by sodium borohydride for transforming the
keto groub into a hydroxy l group to give (1.6) ,and then by hydrogenation over a
.palladium catalyst for removing the benzyl- protectin group giving salbutamol (1.7)

ClCH2

O
HO

CH3

CH2 O/HCl

HO

(1.1)

CH3

CH3COO Na/
CH3COOH/
(CH3CO)2O

CH3COO-CH2

Br 2

C-CH3

CH3COO

CH2C6H5

C CH2

C CH2 Br

C(CH3)3

HCl

HO CH 2

HO

(1.4)

HO CH2

CH CH2

(1.6)

C(CH3)3

CH2C6H5
CH2

C(CH3)3

NaBH4

(1.5)

OH

HO

H N

(1.3)

CH3COO

CH3COO

(1.2)

CH3COO-CH2

CH 2 C6 H 5

CH3COO-CH2

HO CH2

CH2C6H5
C(CH3)3

H2 Pd C

OH

HO

CH CH2

(1.7)

N H C(CH3)3

Emergency treatment . 8
When an asthma attack is unresponsive to a patient's usual
medication, other treatments are available to the physician or
hospital

*
*

. Oxygen to alleviate the hypoxia that results from extreme asthma attacks
Nebulized slbutamol or terbutline (short-acting beta-2-agonists), often combined with
ipratropium (an anticholinergic).

Systemic steroids, oral or intravenous (prednisone,prednisolone, methylprednisolone


).dexamethasone, or hydrocortisone,

Other bronchodilators that are occasionally effective when the usual drugs fail:
Intravenous salbutamol
Intravenous
salbutamolo
Nonspecific beta-agonists, injected or inhaled (epinephrine,
isoetharine,isoproterenol, metaproterenol

-o

- Methylxanthines (theophylline,aminophylline)o
-

*
*

Inhalation anesthetics that have a bronchodilatory effect o


(isoflurane,halothane,enflurane)

The dissociative anaesthetic ketamine, often used in endotracheal tubeo


induction

Magnesium sulfate, intravenouso

.Intubation and mechanical ventilation, for patients in or approaching respiratory arrest


Heliox, a mixture of helium and oxygen, may be used in a hospital setting. It has a
more laminar flow than ambient air and moves more easily through constricted
.airways

Prevention . 9
Current treatment protocols recommend prevention medications such as an inhaled
corticosteroid, which helps to suppress inflammation and reduces the swelling of the lining of
the airways, in anyone who has frequent need of relievers or who has severe symptoms. If
symptoms persist, additional preventive drugs are added until the asthma is controlled. With
the proper use of prevention drugs, asthmatics can avoid the complications that result from
.overuse of relief medications

Preventive agents include the following


Inhaled glucocorticoids (corticosteroids).1
are the most widely used of the prevention
medications and normally come as inhaler devices
(cicleronide, beclomethasone,,flunisolide,fluticasone,
budesonide and mometasone)

- Long-term use of corticosteroids can have many side


effects including:

A redistribution of fat, increased appetite, blood glucose


problems and weight gain.

Deposition of steroids in the mouth may cause a hoarse or oralthrush (due o


.to decreased immunity)

:Leukotriene modifiers, (montelukast, zafirlukast, pranlukast, and zileuton). 2


:Leukotriene recceptor antagonists have very rare side affects such asHeadshe, dizziness, heartburn, upset stomach, and tirednees

3. Mast cell stabilizers )cromoglicate (cromolyn), and nedocromil(


4. Antimuscarinics/anticholinergics
.which have a mixed reliever and preventer effect), ipratropium,oxitropium, and tiotropium(,

5. Methylxanthines, theophylline and aminophylline(


-There are some side effects of methylxanthines such as:
Diarrhea , nausea ,heartburn ,and loss of appetite And also headaches
nervousness, rabid heart beat, and upset stomach

6. Antihistamines
. often used to treat allergic symptoms that may underlie the chronic inflammation

Prevention Drugs. 10
Drugs on Inhaled glucocorticoids (corticosteroids)

HO

Fluticasone 10.1.1

Side effect of fluticasone


- Hoarseness and sore throat.
-Thrush or yeast infection
(looks like a whitish layer on your tongue).

O
OCOEt
Me

Me

chemical Formula: C22H27F3O4S


Fluticasone is a potent synthetic
corticosteroid often prescribed astreatment
for Asthma and allergic rhinitis

S
Me

O
F

Fluticasone
Systematic (IUPAC) name
S(fluoromethyl) (6S,8S,9R,10S,11S,1
3S,14S,16R,17R)6,9-difluoro-11,17-dihydroxy10,13,16-trimethyl-3-oxo6,7,8,11,12,14,15,16octahydrocyclopenta[a]
phenanthrene-17-carbothioate

Fluticasone synthesis:
The synthesis of fluticasone propionate utilizes commercially available
flumethasone (2.1). by Oxidation of (2.1) with periodic acid gave the etianic
acid (2.2) , whose imidazolide when treated with hydrogen sulphide gas gave
the carbothioic acid (2.3) , treatment with excess propionyl cloride followed by
aminolysis of the mixed anhydride with dimethyl amine gave (2.4) alkylation
with bromochloromethane gave the chloromethyl carbothioate (2.5) which was
converted to iodomethyl ester (2.6) by treatment with sodium iodide .
Convertion to fluticasone was accomplished by treatment with silver fluoride in
acetonitrile . Alternatively . fluticasone was also prepared directly from the
potassium salt of carbothioic acid (2.4) using bromofluoromethane .

O
Me

HO
Me

OH

Me

H
F

CH2OH

Me CO2H
OH

HO

H 5I O6

Me

Me O H

F
O

(2.1)

Me

(2.2)

CDI.DMF
H 2S

HS

Me

OH

1 .ETCOCl.TEA.DCM

Me

HS
Me

Br CH 2Cl
Na H CO3

OCOEt
Me

2 .ET2NH

Et O Ac
(2.4)

(2.3)

BrCH2F
K2CO3.DMF

Cl

S
Me

O
OCOEt
Me

S
Me

NaI

O
OCOEt
Me

acetone

HO

AgF
CH3C

(2.6)

O
OCOEt
Me

Me

(2.5)

S
Me

Trigger avoidance. 10
As is common with respiratory disease, smoking is believed to
adversely affect asthmatics in several ways, including an increased severity
of symptoms, a more rapid decline of lung function, and decreased response
to preventive medications Automobile emission are considered an even more
. significant cause and aggravating factor
Asthmatics who smoke or who live near trafice typically require additional
medications to help control their disease. Furthermore, exposure of both nonsmokers and smokers to wood smoke, gas stove fumes and second-hand smoke is
detrimental, resulting in more severe asthma, more emergency room visits, and more
asthma-related hospital admissions Smoking cessation and avoidance of secondhand smoke is strongly encouraged in asthmatics
For those in whom exercise can trigger an asthma attack(exercise-induced asthma),
higher levels of ventilation and cold, dry air tend to exacerbate attacks. For this reason,
activities in which patients breathes large amounts of cold air, such as skiing and running,
tend to be worse for asthmatics, whereas swimming in an indoor, heated pool, with warm,
.humid air, is less likely to provoke a response

The End