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Contents

1. Defining Asthma . 7.Drugs of Treatment .

2. Signs and Symptoms . 7.1 Short-acting, selective beta2


adrenoceptor agonists .
3. Cause .
7.1.1 Sablutmol (albuterol) .
4.Pathophysiolo .
8. Emergency treatment .
5.Diagnosis .
9.Prevention .
6.Treatment .
10.prevention drugs .
6.1 Medical . 10.1 Drugs on inhaled
6.2 Pharmaceutical . 10.1.1 Fluticasone .

6.3 Long-acting 2-agonist . 11. Trigger avoidance .


1. Defining Asthma .

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.
2. Signs and Smptoms
2.1 Symptoms

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 breath :Some 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.

,
2.2 signs

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

During 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.
3.Causes

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

3.1 Environmental causes

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)

3.3 Gene-Environment Interactions causes

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 gene-
environment 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

4.1 Bronchoconstriction

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
4.3 Bronchial inflammation
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

4.5 Asthma and gastro-esophageal reflux disease

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.
5.Diagnosis

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
10 minutes of inhaled -agonist (e.g.,salbutamol); o

* 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
6 Treatment

The 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.
6.2 Pharmaceutical

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
*
6.3 Long-acting 2-agonists

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
OH
salbutamo (albuterol) H
N
Salbutamol or albuterol is a short-acting beta2- HO
adrenoceptor receptor agonists used for the relief
of bronchospasm in conditions such as asthma
HO

Clinical use Salbutamol


Salbutamol is specifically indicated in the
following conditions :
chemical formula : C13 H21 NO3
1. acute asthma
2. protection against exercise-induced asthma
3. hyperkalaemia, especially in patients with renal failure
Systematic (IUPAC) name
Adverse effects 4-[2-(tert-butylamino)-1-
hydroxyethyl]-2-
Common adverse effects include:tremor,palpitations, low (hydroxymethyl)phenol
blood pressure, and headache.
Salbutamol synthesis
It is prepared from 4-hydroxyacetophenon , the chloromethylation which gives 4-
hydroxy-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) .

O ClCH2 CH3 COO Na/


O CH3 COOH/
HO C HO CH3 (CH3 CO)2 O
CH3 CH2 O/HCl C

(1.1)
CH 2 C6 H 5
CH3 COO-CH2 CH3 COO-CH2
O O H N
C(CH3)3
C-CH3 Br 2 CH3 COO C CH2 Br
CH3COO

(1.2) (1.3)

CH3COO-CH2 HO CH 2
O O
CH2 C6 H5 CH2 C6 H5
CH3COO C CH2 N HCl HO C CH2 N NaBH4
C(CH3)3 C(CH3)3

(1.4) (1.5)

HO CH2 HO CH2
OH OH
CH2 C6 H5
HO CH CH2 N HO CH CH2 N H C(CH3)3
C(CH3)3 H2 Pd C

(1.6)
(1.7)
8 . Emergency treatment

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, o


isoetharine,isoproterenol, metaproterenol
- Methylxanthines (theophylline,aminophylline)o
- Inhalation anesthetics that have a bronchodilatory effect o
(isoflurane,halothane,enflurane)

- The dissociative anaesthetic ketamine, often used in endotracheal tube o


induction

- Magnesium sulfate, intravenous o

* 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.
9 . Prevention

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


1.Inhaled glucocorticoids (corticosteroids)
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).

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


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

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

4. Antimuscarinics/anticholinergics

, (ipratropium,oxitropium, and tiotropium), which have a mixed reliever and preventer effect.
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.
10. Prevention Drugs

F S O
Drugs on Inhaled glucocorticoids (corticosteroids) Me
HO OCOEt

10.1.1 Fluticasone Me H Me

chemical Formula: C22H27F3O4S F H

Fluticasone is a potent synthetic O


corticosteroid often prescribed astreatment F
for Asthma and allergic rhinitis
Fluticasone

Side effect of fluticasone


Systematic (IUPAC) name
- Hoarseness and sore throat.
S-
-Thrush or yeast infection
(fluoromethyl) (6S,8S,9R,10S,11S,1
(looks like a whitish layer on your tongue).
3S,14S,16R,17R)-
6,9-difluoro-11,17-dihydroxy-
10,13,16-trimethyl-3-oxo-
6,7,8,11,12,14,15,16-
octahydrocyclopenta[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 CH2 OH
Me Me CO2 H
HO OH HO OH
Me Me Me
H H 5I O6 Me H
CDI.DMF
F H Me O H F H H 2S

O O
F F
(2.1) (2.2)
HS O HS O
Me OH 1 .ETCOCl.TEA.DCM Me OCOEt Br CH 2Cl
Me Me Na H CO3
2 .ET2 NH
Et OAc

(2.4)
(2.3) BrCH2F
K2 CO3.DMF

F S O
Cl S O I S O Me
Me OCOEt HO OCOEt
Me OCOEt
NaI AgF Me
Me Me H
Me CH3 C
acetone
F H
O
(2.5)
F
(2.6)
10. Trigger avoidance

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 non-
smokers 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 second-
hand 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