Drugs Used for Bronchial Asthma

Bronchial Asthma:
Bronchial Asthma is a syndrome in which there is
RECURRENT, REVERSIBLE OBSTRUCTION of the airways
in response to stimuli; which are not in themselves noxious and
do not affect non asthmatic individuals e.g. Exercise , cool air ,
dust , pollen. The airways of these individuals are hyperresponsive to these stimuli.
The pt. has episodes of acute bronchoconstriction causing:
Shortness of breath.
Chest tightness, wheezing & rapid respiration
Cough

Bronchial Asthma.
Incidence of bronchial asthma : 5-10%.
Bronchial Asthma is a chronic disease with an underlying
inflammatory pathophysiology.
There are inflammatory changes in airways; not fully reversible.
If untreated:
May be progressive, airway remodeling may occur.
May be severity and incidence of exacerbations--increased morbidity; increase hospitalizations; absence from
school, offices, work place
Death is rare.

Some patients experience sudden severe attack of

Bronchial Asthma

(Status Asthmaticus), characterized by:

Persistent dyspnea, poorly relieved by
bronchodilators.
Restlessness.
Exhaustion.
High pulse rate.

Classification of Drugs Used for Bronchial Asthma

I.

Bronchodilators/ Relievers

II.

Anti-Inflammatory agents / controllers

Bronchodilators/ Relievers

A. Sympathomimetics
i. 2 Selective Agonists
Short acting:
Salbutamol (Albuterol)
Levalbuterol
Terbutaline
Metaproterenol
Pirbuterol
Bitolterol
Long acting:
Salmeterol
Formoterol

ii. and Agonists

Epinephrine
Ephedrine

iii. ( 1 + 2) Agonists
Isoprenaline
Orciprenaline

Bronchodilators/ Relievers

B. Muscarinic Antagonists
Ipratropium
Tiotropium

C. Methylxanthines
Aminophylline
Theophylline
Dyphylline

2. Anti-Inflammatory agents / controllers

I. Corticosteroids
Oral / Injectable Corticosteroids :
Hydrocortisone
Prednisone
Prednisolone
Methylprednisolone
Betamethasone

Inhaled Corticosteroids :
Beclomethasone
Budesonide
Flunisolide
Fluticasone
Mometasone
Triamcinolone
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II.

Cromolyn & Nedocromil (mast cell stabilizers)

III. Leukotriene Pathway inhibitors

a. Leukotriene Receptors Antagonists

Montelukast
Zafirlukast

b. Leukotriene Synthesis inhibitors

Zileuton

IV.

New approaches:

Anti IgE monoclonal Antibodies:

Other anti-inflammatory therapies:

Omalizumab
Etanercept

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Bronchodilators/ Relievers

A. Sympathomimetics
i. 2 Selective Agonists
Short acting:
Salbutamol (Albuterol)
Levalbuterol
Terbutaline
Metaproterenol
Pirbuterol
Bitolterol
Long acting:
Salmeterol
Formoterol

ii. and Agonists

Epinephrine
Ephedrine

iii. ( 1 + 2) Agonists
Isoprenaline
Orciprenaline

 2 Selective Agonists
Prototype Drug: Salbutamol (Albuterol)
The most widely used sympathomimetics in bronchial asthma.
Synthetic non-catecholamines.
MOA: Bronchodilators/ Relievers
They are 2 selective agonists ,little effect on 1and receptors in
therapeutic doses, so less adverse effects.
The selectivity is lost at higher doses & causes adverse effects.
They relieve symptoms as they reverse the bronchoconstriction--by producing bronchodilation .
No anti-inflammatory effects, no effect on progression of disease.
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1. MOA of Bronchodilatation
They activate 2 receptors in airway smooth muscles

Stimulate adenyl cyclase

cAMP

Rate of inactivation of MLCk --- the enzymes responsible for triggering

the interaction of actin & myosin

Relaxation of smooth muscle Bronchodilatation

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Therapeutic uses:
The most effective, rapidly acting, safe & inexpensive.
1. Bronchial Asthma:
For therapy of acute episodes ---- short acting 2 agonists
(Salbutamol , Metaproterenol, Terbutaline ) are the drug of choice
(DOC).

Alone for mild intermittent asthma.

Combined with Corticosteroids in severe cases.

For prophylaxis and maintenance:

Long acting agents (Salmeterol, Formoterol)

Acute Severe Bronchial Asthma / Status Asthmaticus --- short

acting agents along with other drugs.
2. Chronic obstructive pulmonary disease(COPD).
3. Premature labor ( DOC--- Ritodrine ) to delay labor for 24-48 hrs.
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Administration: Best delivered by inhalation

Short acting
Prototype Drug: Salbutamol (Albuterol)
2 Selective Agonists Albuterol, Terbutaline, Metaproterenol &
Pirbuterol --- available as metered-dose inhalers / nebulizers.
Max. Bronchodilatation --- 15 30 min. DOA: 4-6hrs
Albuterol & Terbutaline ---- also available in tablet form.
Terbutaline --- can be given by S/C injection

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Long acting: Salmeterol & Formoterol ; given by inhalation.

DOA: 12 hrs or more ----- highly lipid soluble dissolve in
smooth muscle cell membranes in high concentration or attach
to mooring molecules in vicinity of the adrenoceptor.
Synergistic with inhaled corticosteroids to improve asthma
control.
Not recommended as the sole therapy for asthma.

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Advantages of Inhalation

Self administration.
The greatest effect in bronchi.
Least systemic effects or toxicity.
Rapid OOA.
Less doses are required.

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Adverse effects:
Relatively few A/E after inhalation.
When given orally ; in sensitive individuals in therapeutic
doses / at high doses, adverse reaction may occur due to
stimulation of 1 receptors ,mainly in heart:
Nervousness, Restlessness.
Tremors
Cardiac arrhythmias.
Worsening of angina.
Decreased response after prolonged treatment.-----due to
down regulation of the 2 receptors Pharmacodynamic
tolerance

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Epinephrine
The most effective & rapidly acting bronchodilator.
Because it stimulates both 1, 2 & receptors , only used in
severe acute asthma / status asthmaticus
0.4 ml of 1:1000 sol. by S/C injection.
Or by inhalation 320 g per puff.
Max. effect after inhalation in 15 min & DOA: 60-90 min.
A/E:
Tachycardia, arrhythmias & worsening of angina.

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Ephedrine
Has been used in china for more then 2000years. Introduced in
western Medicine in 1924
Non catecholamine : Orally active
Longer DOA, low potency.
Crosses BBB.
Acts by dual MOA---direct & indirect sympathomimetic.
A/E: More marked central effects; in addition peripheral effects
due to stimulation of alpha & 1 receptors so not used now.

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Isoproterenol

Synthetic catecholamine
Potent bronchodilator
Stimulates both 1, 2 receptors
Given by inhalation
Maximum bronchodilation in 5minutes.
DOA: 60-90min
A/E: cardiac arrhythmias- increased mortality rate, so
2 selective agonists are used.

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Muscarinic Antagonists
Atropine sulphate: tertiary amine, produces
bronchodilation ,but not used due to systemic anti-muscarinic
adverse effects
Ipratropium A quaternary ammonium compound given by
inhalation--- poor permeation so minimum systemic Atropine
like A/E but maximum effect on bronchi.
Tiotropium: long acting congener of Ipratropium.

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MOA:
Competitive inhibitors of the effect of acetylcholine at
muscarinic M3 receptors in the airway:
They reverse bronchoconstriction in some asthma pts. (specially
children) & in many patients with COPD by blocking the effect
of vagal stimulation / Ach. on bronchial smooth muscles.
the mucus secretion.
No effect on inflammatory aspects of asthma.

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Clinical uses of Ipratropium / Tiotropium:

1. Bronchial asthma:

Effective bronchodilators in 1/3 2/3 patients.

Useful in patients intolerant to inhaled 2 agonists.

In acute severe asthma --- enhance action of 2 agonists

2. COPD : In pts. of chronic obstructive pulmonary disease
(COPD) --- more effective & less toxic than 2 agonists.

3. Ipratropium as a .03% nasal solution sprayed into the nostrils can

reduce Rhinorrhea

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Toxicity:
1. Generally systemic adverse effects are less because:
These agents are quaternary ammonium compound
Are delivered by inhalation directly to the airway
Minimally absorbed.

2. When given in excessive dosage miner atropine like A/E may

occur---dryness of mouth, blurring of vision ,constipation,
tachycardia, urinary hesitancy, in elderly men with BPH--urinary retention, precipitation of attack of acute glaucoma in
patients with narrow angle of anterior chamber.

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Methylxanthines Drugs
Chemistry & Source:
Methylxanthines are methylated xanthines.
Xanthine is a dioxypurine, related to uric acid.
Three important Methylxanthine are:
Major Source
Chemistry
Caffeine
Coffee
1,3,7 Trimethylxanthine.
Theophylline Tea
1,3 Dimethylxanthine
Theobromine cocoa
3,7 Dimethylxanthine

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Theophylline is the most effective Bronchodilator , has low

solubility
So salts of theophylline are used:
Aminophylline: Theophylline & Ethylenediamine
Oxtriphylline: Theophylline& choline

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Mechanism of Action of Methylxanthine Drugs

1. Inhibition of phosphodiesterase enzyme isoform -4
(PDE4)
2. Antagonism of adenosine Receptors.
3. Decrease transcription of inflammatory genes ( via
deacetylation of histone), so theophylline in lower
doses can increase or enhance action of corticosteroids.

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1.

Inhibition of phosphodiesterase enzyme isoform -4 (PDE4);

which degrade /metabolize cAMP.
Inhibition of phosphodiesterase enzyme isoform -4 (PDE4); which
in bronchial smooth muscles & inflammatory cells at high
concentration leads to:
. Bronchodilation :Relaxation of smooth muscles ---- due to
intracellular cAMP because
.
release of cytokines and chemokines in immune
cell migration & activation.

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2.

Antagonism of cell surface adenosine Receptors.

Adenosine receptors modulate adenylyl cyclase activity.
Adenosine provokes contraction of isolated airway SM due
to histamine release from airway mast cells, as histamine is
a powerful bronchoconstrictor.
So inhibition of these receptors leads to:
Bronchodilatation.
release of histamine.

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Pharmacological Actions
Effect on Respiratory System
Bronchial smooth muscles are relaxed---- bronchodilation,
tolerance does not develop on prolonged use.
Antigen induced release of histamine is .
Effect on skeletal muscles:
Improve contractility
Reverse fatigue of diaphragm
In patients with COPD ----improve the ventilatory response
to hypoxia & dyspnea.

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CVS Effects:
Heart: force of contraction & Heart rate.
Low Concentration: due to inhibition of presynaptic adenosine
receptors in sympathetic nerves ---- catecholamine release.
At High Conc: due to inhibition of PDE & cAMP --- Ca++
influx.
Very High Conc: sequestration of Ca++ by SR is impaired

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Blood Vessels:
At low doses: vasoconstriction --- TPR
At large doses: relaxation of smooth muscles (vasodilation) except
cerebral BV ; which are constricted.
Effect on blood flow:
Pentoxifylline:
blood viscosity
May improve blood flow
Useful in intermittent claudications.

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Effect of coffee & other beverages:

Ordinary consumption --- slight heart rate , Cardiac output
& blood pressure.
In sensitive individuals a few cups of coffee may produce
arrhythmias.

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Effect on GIT:
Increase secretion of acid & digestive enzymes----- gastric distress
may occur.
Effect on kidney:
Weak diuretic due to GF & sodium reabsorption.
On CNS:
Specially caffeine
Low & Moderate Doses: alertness, deferral of fatigue due to
mild cortical excitement.
High Doses: Nervousness & tremors in some patients.
At very High Doses: medullary stimulation & convulsions ---may lead to death.

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Pharmacokinetics:
Oral preparations --- microcrystalline form best absorbed,
sustained release preparations longer DOA
Rectal suppositories irregular absorption.
Theophylline should only be used where plasma levels can be
measured because it has narrow therapeutic window.
Therapeutic plasma conc. 5-20 mg/L.
Toxic plasma conc. > 20 mg/L

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 Metabolized in liver to demethylated xanthines which are

excreted in urine
Metabolism by enzyme inducers drugs, cigarette smoking,
changes in diet, by enzyme inhibitors.
Clearance faster in children than adults.
Neonates and young infants ----- slowest clearance.
I/V injection should be slow over 10-20 min.
Plasma half life : 8 hrs

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Therapeutic uses:
Bronchial asthma : Useful both in:
a) Chronic Bronchial asthma.
Theophylline is 2nd line drug with a steroid in patients not
adequately responding to 2 agonists .
b) Acute severe asthma / status asthmaticus. I/V
Chronic obstructive pulmonary disease.
Acute LVF with pulmonary edema (Aminophylline along with
Morphine & Frusemide)
Prolonged apnea of pre- term infants.
Intermittent claudications (Pentoxifylline).
In combination with Analgesics for migraine (Caffeine +
Aspirin for headache, Caffeine + Ergotamine).

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Adverse Effects related to plasma Concentration:

At Plasma conc. 15-20 mg/L.
Nausea, vomiting, anorexia, abdominal discomfort.
Palpitations.
Headache & Insomnia
At Plasma conc. > 40 mg/L: Arrhythmias & Convulsions.
Accidental over dosage- Death
Monitoring of plasma Conc. is required during theophylline
therapy due to narrow therapeutic window.

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Drug Interactions:
Important because of low therapeutic index.
Enzyme inducers metabolism
Phenytoin.
Barbiturates.
Rifampin
Cigarette smoke.
Enzyme inhibitors metabolism
Oral contraceptives, Cimetidine, Erythromycin , Ciprofloxacin ,
calcium channel blockers.

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Precautions:

Hepatic & cardiac disease.

Elderly patients.
Epilepsy
Breast feeding.

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Cromolyn Sodium & Nedocromil Sodium

Source: Synthetic
Chemistry: Stable a extremely insoluble salts.
They are given by inhalation or as eye/drops or nasal
Spray.

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Mechanism of Action

(Mast cells stabilizers)

They produce alternation in function of delayed chloride channels
in the cell membrane and inhibit function / activation of important
cells :
Airway Nerves ---- inhibition of cough.
Mast cells ---- inhibition of early response to antigen challenge,
and degranulation & release of mediators.
Eosinophils ---- inhibit inflammatory / late response to inhalation
of allergens.
No effect on airway smooth muscle tone & are ineffective in
reversing bronchospasm.

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Therapeutic Uses
Primarily Prophylactic , specially in children.
Cromolyn: Used at all ages
Nedocromil: Not below 12 years.
i.
For prophylaxis of Br. Asthma due to:
Exercise.
Sulphur dioxide
Occupational allergens like wood dust.
Other unavoidable allergens.
ii. Allergic rhinitis / Rhino-conjunctivitis

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Administration and Dosage

By inhalation:
i.
In adults by metered dose inhaler 2.4 mg 4 times daily
ii. In children aerosol of 1% solution.
Nasal spray
Eye Drops

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Adverse Effects
Mainly localized

Throat irritation

Cough

Dryness of mouth

Chest tightness and wheezing

Rare A/E:

Dermatitis
Myositis.
Gastroenteritis
Pulmonary infiltration with eosinophilia & anaphylaxis

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Corticosteroids
Oral / Injectable:
Hydrocortisone
Prednisone
Prednisolone
Methylprednisolone
Betamethasone

Inhaled:
Beclomethasone
Budesonide
Flunisolide
Fluticasone
Mometasone
Triamcinolone
Ciclesonide (investigational prodrug)
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MOA:- They do not relax bronchial SM directly but:

a) Br. reactivity
b) Frequency of asthma exacerbations.
Glucocorticoids bind to intracellular receptors & activate GREs in
the nucleus.
Synthesis of substances that provoke the full expression of
inflammation & allergy .
They relieve by :
Anti-inflammatory effects
Contributory mechanisms

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Anti-inflammatory effect:
In asthmatic airways
Inhibit cytokines which initiate inflammation, provoked by
antigen inhalation or viral infection.
Inhibit PLA2 & Arachidonic acid synthesis of LT &
PGs
LTs are extremely potent bronchoconstrictor & may also
participate in the late inflammatory response.
So Inhibit bronchoconstriction ; lymphocytic & eosinophillic
mucosal inflammation.

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Contributory mechanisms:
Potentiate the effect of 2 agonists.
Constriction of engorged BV in the bronchial mucosa ---
obstruction.

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Clinical Use in Bronchial Asthma: They improve all indices of asthma control:
Severity of symptoms
Tests of airways caliber
Bronchial reactivity
Frequency of exacerbation
Quality of life
requirement of 2 agonists.

They are not curative.

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Clinical Use in Bronchial Asthma

1. In chronic severe asthma:

If symptoms persists despite bronchodilator therapy , inhaled
corticosteroids should be started.
Inhaled corticosteroids (Glucocorticoids):
Beclomethasone
Budesonide
Flunisolide
Fluticasone
Mometasone
Triamcinolone
Ciclesonide (investigational prodrug)

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 In severe cases, combination of inhaled & oral therapy 30-60

mg prednisone daily for 5 days or I/V Methylprednisolone
(1mg/kg ) 6 hrly.
After improvement oral dose is gradually over 7 10 days &
inhaled corticosteroid continued.
2. In acute severe Asthma:
I/V Methylprednisolone (1mg/kg ) 6 hrly.
or I/V Hydrocortisone: 200 300 mg
Followed by oral prednisone / Prednisolone. 0.5mg/ kg every
6 hrs.

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Advantages of Inhaled Glucocorticoids

Self administration.
Rapid OOA.
Less doses are required.
The greatest effect in bronchi.
Least systemic effects or toxicity
Better effects when used with spacers

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Spacer: A spacer is a large-volume chamber attached to a

metered-dose inhaler.
Spacers deposition of drug in mouth caused by improper
inhaler technique .
The chamber velocity of aerosol before entering the mouth,
allowing large drug particles to be deposited in the device.
The smaller, higher-velocity drug particles are more likely to
reach the target airway tissue.

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Spacer

 Minimize adrenal suppression by glucocorticoid deposition

in oropharynx.
Improve delivery of drug & are advised for virtually all
patients.
Especially children < 5 yrs & elderly -- who may have
difficulty in using inhaler.
Regular washing and / or rinsing of spacers risk of bacterial
or fungal growth inducing an asthma attack.

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Potential A/E of inhaled Glucocorticoids:

Oropharyngeal Candidiasis.
Hoarseness.
Risk of Osteoporosis & Cataracts.
Transient growth retardation in children --- negligible.
Retardation of vertical bone growth secondary to low oxygenated
blood levels from uncontrolled Asthma can occur in more severe
case.

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Adverse Effects Of oral Glucocorticoids

A.
.
.
.

On Short Term use: less than 2 wks.

Acute peptic ulcers.
Initially Insomnia & euphoria ,subsequently depression.
Large dose may increase intracranial pressure.

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Leukotriene Pathway inhibitors

5- Lipoxygenase inhibitors:

Zileuton
5- Lipoxygenase is found in cells of myeloid origin , such as mast
cells basophils ,eosinophils & neutrophils.
MOA:
Selective inhibitor of 5- Lipoxygenase pathway of arachidonic
acid metabolism .
synthesis of LTB4 & cysteinyl LTs--- LTC4,, LTD4 ,, & LTE4 .
Prevent bronchoconstriction
Inhibit eosinophils & basophil influx due to LTB4.
Hence useful in asthma.

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Receptor Antagonists:
Montelukast , Zafirlukast
MOA:
Competitive Antagonist of LTD4 Receptors.
Prevent bronchoconstriction
Inhibit eosinophils & basophil influx due to LTB4.
Hence useful in asthma.

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Ph. K:
Effective orally.
Food impairs absorption of Zafirlukast
PPB90%
Extensively metabolized.
Excretion: Montelukast , Zafirlukast in urine
& Zileuton in bile.

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Therapeutic uses:
Prophylactic for mild asthma especially in aspirin, exercise &
antigen induced asthma.
They improve asthma control.
bronchial reactivity & airway inflammation, but less than
inhaled corticosteroids.
frequency of asthma exacerbation equal to inhaled
corticosteroids.

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A/E of Leukotriene Pathway inhibitors

Generally receptor antagonists are safe drugs.
Headache , Dyspepsia.
Zafirlukast & Zileuton inhibit cyp450 enzymes-- levels of warfarin
Rarely Churg-Strauss syndrome may occur with all 3 agents
(a systemic vasculitis characterized by worsening asthma, pulmonary infiltrates, and esinophilia).

Zileuton is hepatotoxic

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Anti IgE therapy:

Omalizumab
It is a recombinant-DNA derived humanized monoclonal Antibody
, raised in mice.
It is targeted against the portion of IgE that binds to its receptors
on mast cells & other inflammatory cells.

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MOA:
1: It neutralizes the circulating IgE anti-body . It can lower plasma
IgE significantly when given for more than 10 weeks.
So inhibits / binding of IgE to its receptor on mast cells &
basophils.
degranulation-- release of mediators of the allergic response.
Can early & late bronchospastic responses to antigen challenge.
severity of asthma attacks.
corticosteroids requirement.
2: May inhibit IgE synthesis by lymphocyte .

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Therapeutic Uses:
Give I/V or S/C
Chronic severe bronchial asthma :
With demonstrated IgE-mediated sensitivity.
Inadequately controlled by high dose inhaled corticosteroids &
long acting 2 agonists.
Recurrent or seasonal allergic rhinitis / conjunctivitis .

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No A/E:
Does not produce sensitization because it has been genetically
humanized by replacing almost all amino acids with those
found in human proteins.
It is expensive

77

Severe Acute Asthma (Status Asthmaticus)

It is sudden severe attack of Bronchial Asthma, characterized by:
Persistent dyspnea, poorly relieved by bronchodilators.
Restlessness.
Exhaustion
High pulse rate.

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Management:- Patient should be treated in ICU with

continuous monitoring of lung function & blood gases.

Oxygen inhalations.
Epinephrine 0.4 ml of 1 in 1,000 solution. 0.4 ml by S/C
injection.
Or by inhalation 320 g per puff.
Max. effect after inhalation in 15 min & DOA: 60-90 min.
Frequent / continuous Inhalation of selective 2 receptor
agonist i.e. Albuterol 90 g/Puff aerosol.
I/V Hydrocortisone: 200 300 mg
Or I/V Methylprednisolone (1mg/kg ) 6 hrly.
Followed by oral Prednisolone , 0.5mg/ kg every 6 hrs.

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 Aminophylline 250 mg I/V slowly over 20-40 minutes.

I/V aminophylline - this is only used in patients with near-fatal or lifethreatening asthma with poor response to initial treatment, after
consultation with senior staff. Side-effects, eg arrhythmias and vomiting,
increase with its use.

Ipratropium Bromide by inhalation.

Appropriate antibiotics if bacterial infection is present.
Endotracheal intubation & mechanical ventilation may be
required ; if respiratory failure occurs.

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