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Antiasthmatic Drugs; Uses, Side Effects, Interactions

Antiasthmatic drugs are medicines that treat or prevent asthma attacks. Bronchodilators relax the smooth muscles that line the airway. This makes the airways open wider, letting more air pass through them. These drugs are used mainly to relieve sudden asthma attacks or to prevent attacks that might come on after exercise. They may be taken by mouth, injected, or inhaled. Corticosteroids block the inflammation that narrows the airways. Used regularly, these drugs help prevent asthma attacks. Those attacks that do occur will be less severe. However, corticosteroids cannot stop an attack that is already underway. These drugs may be taken by mouth, injected, or inhaled.

Asthma is the most common respiratory tract infection. It is the reversible obstruction of large and small airways.

Pathophysiology

Bronchial asthma is characterized by hyperresponsiveness of tracheo-bronchial smooth muscle to a variety of stimuli, resulting in narrowing of air tubes, often accompanied by increased secretions, mucosal edema and mucus plugging.

Inflammation
Hyper reactivity
Bronchospasm

Bronchial hyper reactivity results in inflammation of bronchial wall because of increased leakiness from micro circulation, leading to edema of the bronchial wall.

Because of leakage, there is plugging of bronchi with thick mucous, symptoms include wheezing breathlessness.

Parasympathetic innervation is present in fibers of walls of bronchi, when inflammation occurs, increased parasympathetic tone due to the release of acetylcholine leads to bronchospasm.

Vascular smooth muscle has sympathetic innervation. Increased pulmonary blood flow occurs because of vasodilatation, ultimately leading to bronchodilatation.

Hyper reactivity is due to release of chemical mediators.

Mediators are also released from certain cells, storage granules, besides certain other cells are recruited including eosinophils, neutrophils, monocytes, which themselves release mediators contributing to the inflammatory response.

The strategy these days is to address inflammation.

Phases

2 phases are present:

Immediate –release of histamine leading to the antigen-antibody reaction on the surface of mast cells
Late

IgE antibodies are synthesized within mast cells in the lungs. Antigen interacts with IgE on mast cells leading to release of mediators.

IL 4 and IL 13 are mainly responsible for bronchoconstriction and bronchospasm.

Mast cells release platelet activating factors, responsible for late phase eosinophilia.

For control of asthma, antihistamines are the least beneficial especially exercise-induced and allergic asthma and should be avoided. Normally leukotriene antagonists are given because:

Leukotrines are contributing more in process
Antihistamines cause more dryness

Bronchial inflammation differs because here hyper reactivity is the main problem.

The main goal is to treat underlying inflammation by use of anti inflammatory drugs.

Types of Bronchial Asthma

1. Extrinsic Asthma: (allergic)

It is mostly episodic, less prone to status asthmaticus

Atopic (immediate due to IgE antibody).
Nonatopic delayed for some hours, associated with the production of precipitating antibodies

2. Intrinsic Asthma

It tends to be perennial, status asthmaticus is more common. Associated with COPD.

Classification

2 groups are present:

Bronchodilators/relievers –address acute phase
Anti-inflammatory/controllers –address underlying

Bronchodilators

Sympathomimetics

Salbutamol, Albuterol
Terbutaline,
Bambuterol,
Salmeterol,
Formoterol.

Methylxanthines

Theophylline (anhydrous) (oral preparation with erratic solubility)
Aminophylline

500 mg diluted in 5% dextrose is given I/V very slowly, as can cause tachycardia, arrhythmias, having less therapeutic index.

Anticholinergics

Ipratropium bromide (given inhalational, adjuvant therapy)
Tiotropium bromide

Leukotriene Receptor Antagonists

Montelukast,
Zafirlukast

These are 1000 times more potent mediators, they treat underlying infection, the breakthrough for children.

Mast Cell Stablizers

Sodium cromoglycate,
Nedocromil,
Ketotifen (5HT action)

Corticosteroids(main stay)

Systemic

Hydrocortisone,
Prednisolone & others.
Beclomethasone dipropionate,
Budesonide,
Fluticasone- propionate,
Flunisolide

Anti –IGE Humanized Monoclonal Antibodies

Omalizumab

Approaches to Treatment

Prevention of antigen-antibody reaction- avoidance of antigen, hyposensitization – possible in extrinsic asthma and if antigen can be identified

Suppression of inflammation and bronchial hyper reactivity (corticosteroids)
Prevention of release of mediators (Mast cell stabilizers)
Antagonism of released mediators (Leukotriene antagonists, 1000 times potent than histamines)
Blockade of constrictor neurotransmitter, Acetylcholine (anticholinergics)
Mimicking dilator neurotransmitter (sympathomimetics)
Directly acting bronchodilators (Methyl xanthines)

Sympathomimetics

Short Acting

Salbutamol, Terbutaline

Long Acting

Formeterol, Salmetrol, Bambuterol

Preferentially directly into airways by inhalation.

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Onset of action via inhalational route is 1-5 minutes. Action is for 2-6 hours.

Oral administration is not preferred for bronchodilation although having prolonged action, up to 8 hours. Also

Systemic side effects are produced
Metabolic side effects

Although some absorption occurs through inhalational route as well, but there is not much toxicity. Beta2 drugs given in syrup form in children under 5 or elderly chronic asthmatics with symptoms aggravating. Can be given orally. Albuterol syrup

Mechanism of Action

Beta-2 adrenoceptor agonist, when administered binds beta 2 receptors

Stimulation of adenylate cyclase
Increase cAMP
Bronchodilation and decreased muscular tone

Increase potassium conductance leading to hyperpolarization and relaxation of bronchial muscle cells.

Terbutaline subcutaneous preparation is available. Usually, beta 2 agonists are preferred in dyspnea with bronchoconstriction, providing symptomatic relief.
Short term drugs have quick onset of action. Salmetrol reduces possible bronchodilation for 12 hours.
Inhibit release of chemical mediators from mast cells, lymphocytes which have beta 2 receptors in different cells in lungs àincrease cellular cyclic AMP contributing to inflammation by preventing release of cytokines.

Mucociliary action -Increase mucus clearance by an action on cilia

Uses

Acute asthma Inhalation/I/V (short-acting drugs)
Chronic Asthma/ Prophylaxis oral/Inhalation (long-acting drugs)

Chronic treatment decreases receptor sensitization and decreases the action of the drug. Effective in young asthmatics, but desensitization is not observed in beta 2 receptors present on bronchial smooth muslces (resistant). Desensitization is cell specific.

Beta 2 receptors on mast cells are desensitized.

COPD (less benefit due to toxicity)
Salmetrol also has anti inflammatory action. It acts on eosinophils. As controller Salmetrol can be added to corticosteroids, a dose of which is decreased when combined.

There is the risk of side effects due to genetic variations in beta 2 receptors. Patients homozygous for arginine genotype especially African-Americans. Salbutamol, Salmetrol have greater risks, affecting transcription, increasing the mortality rate.

Methylxanthine

Aminophylline, Theophylline
Theophylline is least expensive, very old drug and effective.
It is ethylated xanthine (dioxy purine) structurally related to uric acid.
The solubility of methylxanthine is low and is enhanced by the formation of a complex with ethylene diamine in 1:1
Theophylline + Ethylene diamine = Aminophylline

Mechanism of Action

Inhibit Phosphodiesterase Enzyme (which catalyzes the breakdown of cAMP). Many isoenzymes are present but isoenzyme III and IV are most effective.

Increase cAMP
Dephosphorylation of MLC
Bronchodilation

2. Translocation of intracellular calcium

Increased intracellular calcium lead to increased diaphragmatic contractility

3. Blockade of adenosine receptors

Decrease contractility of bronchiolar smooth muscles

Uses

The drug is slowly given over 20-40 minutes, otherwise, death occurs due to cardiac arrhythmias.

Acute asthma- I/V (slowly)
Chronic asthma (prophylaxis) Oral
Treatment of apnea of preterm infants as metabolized in the liver and:

Converted in caffeine behaving as a stimulant, which is exploited in the treatment
Volume of distribution is very large
2^nd line drug in bronchodilation, having narrow therapeutic window.

Adverse effects

Dose has to be maintained between 5-20 mcg/l if it crosses 20 mcg/l severe CNS toxicity and convulsions occur.
After 15 mcg/l GIT symptoms including pericardial pain occur
Tachycardia, palpitations

Drug monitoring is mandatory, given only in facilities having monitoring facilities.

Still theophylline is preferred in children over corticosteroids as growth retardation occurs by corticosteroids.

Sustained release preparations including 8 hourly, 12 hourly and 24 hourly preparations maintaining plasma levels for peak symptoms.

Pharmacokinetics

Absorbed readily after oral administration, per rectal suppository has erratic absorption.
Peak plasma concentration is achieved within 2 hours
The volume of distribution is 0.4-0.6 l/kg, the important fact is that infants have much larger Vd than adults.

Drug Interactions

Smoking, oral contraceptives, phenytoin, barbiturates increase clearance, dose adjustment is required.

In viral infections, there are chances of toxicity as clearance is decreased.

Antibiotics, macrolides, and cimetidine are not given with methyl xanthine as clearance is decreased

With Anti T.B drug rifampicin clearance of methyl xanthine is increased.

Anticholinergics

Ipratropium
Oxytropium
Tiotropium

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Selective in action, atropine is very potent but not selective so not used because of toxicity.

Mechanism of Action

Blockade of muscarinic receptors present in bronchi and bronchioles
Decrease mucus viscosity
Increase mucociliary clearance

In therapeutic doses, does not overcome bronchoconstriction as nonmuscarinic in nature.

Given as aerosol inhalation.
In lungs relieves bronchospasm.
Duration of action is up to 5 hours.
Minimal systemic effects as poorly absorbed from lungs.

Uses

Chronic asthma/prophylaxis (Inhalation) (More effective & less toxicity)
Limited role in asthma, main role is to decrease bronchoconstriction in bronchitis caused by stimulation of muscarinic receptors. Antibiotics are given for secondary infections.
Mainly for COPD.

Adverse effects

Dry mouth –since not as effective given in combination with beta 2 agonists and corticosteroids, when not controlled by beta agonists alone.

Leukotriene Receptor Antagonists

Montelukast – oral
Zafirlukast – (Cingular) oral administration for control of asthma
Leukotrienes are products of arachidonic acid metabolism. They are released at the site of inflammation producing bronchoconstriction having the contributory effect to inflammation and bronchoconstriction.

Mechanism of Action

Montelukast and Zafirlukast are competitive antagonists.

Inhibits cysteinlyl leukotriene Cys LT₁ receptor relieving bronchospasm and bronchoconstriction.
Inhibit physiologic actions of LTC₄, LTD₄, LTE₄
One drug blocks synthesis of 5 lipooxygenases and is hepatotoxic Zileuton. Half like is 2.5 hours

When Montelukast is administered, it binds cysteine leukotriene 1 receptor

Uses

Prophylaxis & chronic treatment (oral)
(Exercise, antigen, aspirin induced asthma)

Pharmacokinetics

Half life 10 hours
Bioavailability greater than 90%
Peak plasma binding about 99%
Both metabolized by cyt p450
Montelukast is 60-70% metabolized, having plasma life about 3-6 hours.

Side effects

Rare.

Inflammation at the site in lungs
Rarely hypersensitivity reaction
Patients already treated with glucocorticoids have decreased dose.

Chraug Stauss Syndrome

This is not due to the drug but due to pre-existing underlying disease, eosinophilia and vasculitis is seen.

Drug Interactions

Zafirlukast has a drug interaction with warfarin sodium, leading to increased prothrombin time, thus dose has to be monitored.
Increase in theophylline levels, which is itself bronchodilator
Montelukast is commonly used.

Mast Cell Stabilizers

Na chromoglycate inhalation
Nedocromil
Ketotifen- (5HT action) oral

Nedocromil and Ketotifen are not bronchodilators, not having direct effect. They are ineffective once antigen antibody reaction takes place.

Mechanism of Action

Inhibit transmembrance influx of Ca provoked by antigen antibody interaction on the surface of mast cells. this is prophylactic use and have to be given before antigen enters.
Stabilize mast cells membrane and inhibit release of chemical mediators
Depress exaggerated neuronal reflexes triggered by stimulation of irritant receptors
Depress axonal reflexes which release inflammatory neuropeptides.
Inhibit release of cytokines from T-CELLS

Only 5% sodium chromoglycate reaches lungs, rest get accumulated leading to irritation.

Allergic conjunctivitis –nasal sprays, eye drops

Uses

Prophylaxis of allergic exercise, irritant induced asthma.
Adjuvant therapy, dose limited.
Now limited role due to leukotrines was drug of choice in children.

Corticosteroids

Hydrocortisone I/V
Prednisolone oral
Betamethosone
Beclomethasone inhalation
Budesonide
Flucitasone having affinity for glucocorticoids receptors in airways

Mechanism of Action

Anti inflammatory action
Decrease mucosal oedema, mucus secretion and reduce capillary permeability
Stabilize mast cells
Block immune response, decrease antibody formation
Antagonise histaminergic and cholinergic responses
Enhance beta-2 adrenoceptor responsiveness to agonists (Catecholamines)

Effects appear after 1 week, and it takes nearly 10 weeks for control of disease.

Beneficial effects are observed with inhalted 500 mcg.

Maximum therapeutic range is 500 mcg/ml.

Toxicity

Systemic toxicity occurs when steroid is inhaled, more than 1500 mcg.

Even with 500 mcg dose there are chances are

Osteoporosis
Dysphonia
Oropharyngeal candidiasis

Uses and Routes of Administration

A bronchodilator is given immediately because:

It takes about 1 week for effects to appear.
Due to constriction, the drug cannot reach lungs so bronchodilator is given

Acute severe asthma (status asthmaticus)

Hydrocortisone I/V

b. Acute asthma – oral

Prednisolone

c. Chronic asthma –(Prophylaxis) Inhalation

Beclomethasone etc

Ciclesonide

The prodrug, when the absorbed drug is acted upon by esterases in bronchial epithelial cells, less amount of drug absorbed gets bound to glucocorticoid receptors, bones, skin, eyes, and there are less chances of osteoporosis and cutaneous thinning.It has some role in people predisposed to cataract and osteoporosis.

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Status Asthmaticus

Status asthmaticus is an acute exacerbation of asthma that remains unresponsive to initial treatment with bronchodilators.
It is a life-threatening a form of asthma because it can lead to respiratory failure and cardiac arrest.
Status Asthmaticus requires immediate treatment (corticosteroids are essential as immediate treatment)
Air trapping strains on breathing muscle which is fatigue and exhausted
Status asthmaticus is frequently associated with metabolic acidosis, and acidosis reduces the effectiveness of beta agonist.

I/V NaHCo₃added if pH is below 7.5 in a patient with refractory status asthmaticus, but there is risk of hypercapnia, in children.
the decrease in PCO₂level corrected with nasal/Face mask oxygen (Helium)
Continuous nebulization of albuterol for the first few hrs
Switched to intermittent albuterol very 02 hrs. I/V
corticosteroids, inhaled ipratropium every 06 hrs

Treatment of last resort used in status asthmaticus include:-