Asthna

1. BRONCHIAL ASTHMA

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Bronchial asthma:
• There is airflow obstruction which is
reversible either spontaneously or as a
result of treatment.
• The airflow resistance is due to :-
bronchoconstriction,mucosal oedema
and increased airway secretion.

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• In some patients attacks can be provoked
by specific triggers such as
allergens,some occupational agents or
non steroidal anti-inflammatory drugs.
• Non specific triggers include:-
Exercise,irritants and cold air.
• Cold air will produce asthma in most ,if not
all,asthmatic patients.

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• Asthma developing in childhood is usually
associated with increased levels of
allergen specific IgE antibodies and there
is often a family or personal history of hay
fever or eczema.
• Late onset asthma characteristically
develops in adults,usually after the age of
30 years and symptoms tend to be
persistent.
• Allergen specific IgE levels are usually not
raised.
• This type of asthma is often termed
intrinsic asthma.

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• Treatment of airway obstruction:
• 1. β2-adrenoceptor agonists.
• Albuterol, salbutamol,terbutaline,salmetrol,
metaproterenol and pirbuterol are
available as metered-dose inhalers.
• Albuterol, levalbuterol, bitolterol and
metaproterenol can be diluted in saline for
administration from a hand held nebulizer.
• Nebulized therapy should be reserved for
patients unable to coordinate inhalation
from a metered-dose inhaler.

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Mechanism of action:
• Relaxation of smooth muscle is mediated by
increased intracellular cyclic AMP.
• β2 stimulants are best given by inhalation as this
delivers the drug directly to the site of action
thus minimizing generalised systemic effects
Duration of action:
• Short acting β2 agonists (salbutamol,terbutaline).
• They act for 4-6 hrs.
• Long acting β2 agonists( salmeterol).
• These act for 8-12 hrs.

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• Adverse effects:
• Tremor by stimulating β2-receptors in
skeletal muscle.
• Hypokalaemia by stimulating cell
membrane β2-receptors which in turn
stimulate cell membrane Na+ / K+ pump on
skeletal muscle.
• Tachycardia may result from some β1-
receptor activity.

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Other selective β2 stimulants:
• Isoetharine,rimiterol,reproterol and pirbuterol.
• These agents are either less selective or shorter
acting and have no clear advantages.
2. Theophylline:
• This is a 1,3 dimethyl xanthine.
• The alkyl group at the 3- position is responsible
for its bronchoconstriction.
• The alkyl group at the 1-position (which it shares
with caffeine and theobromine) produces cns
stimulation and diuretic effects

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• The theophylline preparation most
commonly used for therapeutic purposes
is theophylline-ethylene diamine complex
(aminophylline).
• Dyphylline is a synthetic analogue of
theophylline which is both less potent and
shorter acting than theophylline.

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Mechanism of Action:
• In vitro theophylline inhibits the enzyme
phosphodiesterase.
• This enzyme usually hydrolyses cyclic
nucleotides.
• Inhibition of the enzyme results in high
concentration of intracellular cAMP.
• This effect could explain the cardiac
stimulation and smooth muscle relaxation
which is produced by this drug.

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• Another proposed mechanism is the inhibition of
cell surface receptors for adenosine.
• These receptors modulate adenylate cyclase
activity.
• Adenosine has been shown to cause contraction
of isolated airway smooth muscle and to
enhance histamine release from cells in the
lungs.
• These effects are antagonised by theophylline,
an agent generally regarded as a universal
antagonist of cell surface receptors for
adenosine.

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• However xanthine derivatives devoid of
adenosine antagonistic properties (eg
enprofylline) may be many times more
potent than theophylline in inhibiting
bronchoconstriction in asthmatic subjects.
Disposition:
• Totally absorbed from Git but extensively
metabolised by the liver giving wide
variability in pharmacokinetics.

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• Maximum response may be limited by structural
damage to the lungs or by adverse effects at
plasma concentrations in excess of about
25mg/ℓ T½ 8-12hrs.
Adverse effects:
• Tachycardia,palpitations,nausea and
convulsions with plasma concentrations above
25-30mg/ℓ .
• Nausea may occur at therapeutic levels.
• Aminophylline: Contains theophylline and
ethylenediamine (2:1) only the theophylline has
a therapeutic effect.

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3. Anti-allergy drugs:
• Sodium cromoglycate, nedocromil sodium and
kitotifen,
Mechanism of action:
• These drugs are not bronchodilators.
• They stabilise sensitized mast cells and inhibit
the release of bronchoconstriction mediators
such as histamine and prostaglandins.
• Sodium cromoglycate and nedocromil sodium
may also inhibit some neural reflexes in the
lungs as well as having inhibitory effects on
neutrophils and eosinophils.
• Kitotifen has H1-receptor antagonistic properties.

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Clinical use:
• These drugs are used in prophylaxis of asthma.
• They are of no value in patients with airflow
obstruction.
4. Corticosteroids:
• The actions of corticosteroids on the bronchi are
not fully understood but they may contribute to:-
the anti-inflammatory activity.
- modification of immune responses.
- reduction of mucosal oedema.
- increased β-adrenoceptor responses to
agonists.
• Corticosteroids can be given by:-
inhalation,orally or iv.

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Inhalation:
• Generalised adverse effects associated with
systemic routes of administration are minimised.
• Beclomethasone, betamethasone and
budesonide are administered by regular aerosol
inhalation.
Adverse effects:
• Infection of the pharynx and larynx with
candidiasis and laxity of the vocal cords causing
hoarseness.
• High doses (beclomethasone dipropionate and
budesonide) may cause minor degrees of
adrenal suppression.

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Intravenous corticosteroids:
• In severe acute asthma with respiratory
failure hydrocortisone iv is usually given
but there is a delay of effect up to 6hrs.
• Other measures must be persued
aggressively eg nebulised bronchodilators
and supplementary oxygen.
Oral corticosteroids:
• Patients with severe exacerbation of
asthma require high doses of prednisolone
by mouth after intravenous hydrocortisone.

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5.Anticholinergic drugs:
• Ipratropium bromide,oxitropium bromide.
• The anticholinergic effects on the airway
resistance is less than that of sympathetic
agents.
• They abolish the bronchoconstriction due to
vagal tone.
• Ipratropium bromide is a synthetic derivative of
atropine with very few adverse effects.
• Oxitropium bromide is a quaternary ammonium
compound derived from scopolamine.

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6. Leukotriene pathway inhibitors:
• Leukotrienes are produced by the action of
5-lipoxygenase on arachidonic acid.
• They are synthesized by several
inflammatory cells in the airways.
• Inhalation of leukotrienes causes
bronchoconstriction and increased
bronchial reactivity to histamine.
• Leukotriene B4 is a potent neutrophil
chemoattractant.

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• LTC4 and LTD4 cause bronchoconstriction,
increased bronchial reactivity, mucosal
oedema and mucus hypersecretion.
• Zileuton is a 5-lipoxygenase inhibitor.
• Zafirlukast and Montelukast are
inhibitors of LTD4.
• All when taken regularly are effective in
reducing the frequency of exacerbations.
• They are all taken orally and so helpful in
children who comply poorly with inhaled
therapies.

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• Their effects on symptoms, airway caliber,
bronchial reactivity and airway
inflammation are less marked than the
effects of inhaled corticosteroids.
Adverse effects:
• Receptor antagonists appear to be safe.
• Zileuton may occasionally be toxic to the
liver.

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7. Calcium channel blockers:
• These significantly inhibit airway
narrowing induced by various stimuli.
• Nifedipine and verapamil given by
inhalation significantly inhibit
bronchoconstriction induced by various
stimuli.
• But both are much less effective than
inhaled albuterol.

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8. Nitric oxide donors:
• Nitric oxide, which is lipophilic, can be
inhaled as a gas in acute asthma.
• It dilates the pulmonary blood vessels as
well as airway smooth muscles.
• Nitric oxide donors are more useful in
pulmonary hypertension.

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9. Anti-IgE monoclonal antibodies:
• Omalizumab ( anti-IgE Mab) inhibits the
binding of IgE to mast cells but does not
activate IgE already bound to these cells
and thus does not provoke mast cell
degranulation.

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Acute asthma (status asthmaticus):
1. Repeated blood gas measurements and peak
expiratory flow rate should used to assess the
severity of attack and response to treatment.
2. High concentration O2 therapy for hypoxia
3. Aerosol β2-receptor agonist best administered
from a nebuliser in the oxygen flow.
• The combination of nebulised ipratropium
bromide and a β2-receptor agonist may be more
effective than a β2-receptor agonist alone.
4. IV aminophylline as a loading dose, followed by
iv infusion.

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5. IV hydrocortisone as a loading dose
followed by a course of high dose oral
steroids may be required.
6.Exacerbations are rarely due to bacterial
infections and so antibiotics should not be
routinely given.
7. IV fluids to correct dehydration
8. Artificial ventilation may be required if
respiratory failure, exhaustion of the
respiratory muscles or circulatory collapse
is impending.