Pharmacotherapy of

Asthma28/10/2012

What is Bronchial Asthma?

Chronic inflammatory airway disease associated with increased airway responsiveness and reversible airway obstruction.

It can present at any age; majority of cases diagnosed in childhood

Most of them become asymptomatic by adolescence

Disease severity rarely progresses; patients with severe asthma have it at the onset.

Clinical Features

Recurrent episodes characterized by: Breathlessness Wheezing Coughing- especially at night or early morning Tightness in the chest Hyperinflation Increased mucus production

Risk factors

Endogenous

• Atopy• Genetic

predisposition• Obesity • Early infections

Environmental

• Indoor allergens• Outdoor allergens• Occupational

sensitizers• Passive smoking

Triggers

Allergens Respiratory tract infection Exercise Stress Cold Air Drugs- Aspirin Other irritants- SO2 , Household sprays

Pathophysiology

Pathophysiology

Diagnosis

Spirometry Reduced FEV1, FEV1/FVC ratio, and PEF Reversibility - >12% or 200 ml increase in FEV1 15 min after

an inhaled short-acting beta 2-agonist

Airway Responsiveness - increased AHR measured by methacholine or histamine challenge - reduces FEV1 by 20%

Chest X ray- Usually normal; may show hyperinflation

Skin prick test – May be positive but not helpful in diagnosis

Drug Therapy

Relievers

• Beta 2 agonists• Anticholinergics• Methylxanthines

Controllers

• Corticosteroids• Mast cell stabilizers• Anti Leukotrienes• Biological Agents- Omalizumab

β2 Agonists

Classified as:

SABAs(short acting)- Salbutamol, Terbutaline,

Levalbuterol, Fenoterol, Pirbuterol, Metaproterenol

LABAs(Long acting) - Salmeterol, Formoterol

Ultra LABA: Indacaterol (as yet not approved for

asthma)

Mechanism of action

Why are some β2 agonists long acting?

DIFFUSION MICROKINETIC MODEL

Other actions

Acute anti-inflammatory effects by: Inhibition of mast cell mediator release Inhibition of plasma exudation and airway edema Increased mucus secretion and enhanced mucociliary

clearance Reduction in airway cholinergic nerve transmission Chronic inflammation not affected- Rapid

downregulation of inflammatory cell β2 receptors

No effect on airway hyper-responsiveness

SABAs

Albuterol, levalbuterol, terbutaline

Rapid onset of action with effects lasting for 3-6 hrs

Inhaled from pMDI or DPI; very few systemic ADRs

DOC for acute asthma symptoms and exacerbations and for preventing EIA

Regular, long-term use of SABA not recommended; used on ‘as required’ basis.

SABA >2 days a week indicates inadequate control

LABAs

Salmeterol, Formoterol Formeterol: faster onset of action Duration of action: 12 hrs; given BD Do not control underlying inflammation and increase

mortality in asthmatics

NOT TO BE USED AS MONOTHERAPY Used as an adjunct to ICS therapy in persistent asthma May be used before exercise to prevent EIA Dose: Salmeterol- 50μg BD; Formeterol- 12μg BD

Safety issues of LABA

Trials comparing salmeterol with placebo found increased mortality and exacerbations in salmeterol group

Discontiuation of ICS after LABA results in increased markers of inflammation

Black box warning issued by FDA on all LABA

Postulated mechanisms are:

A direct deleterious effect on bronchial smooth muscle

Maintenance of lung function despite worsening inflammation; so that patients tend to delay seeking treatment for an exacerbation

Adverse Effects

Muscle tremor, palpitations- more common in elderly patients

Hypokalemia- clinically insignificant

Metabolic effects(hyperglycemia)- seen after large, systemic doses

Tolerance- Although downregulation is seen after chronic therapy, it does not affect efficacy due to large receptor reserve in airways

Recent Advances

INDACATEROL: Inhaled once-daily β2 agonist

Onset of action faster than salmeterol

Duration of action ~ 24 hrs

Has been approved only for COPD

Clinical trials in asthma underway to test safety and efficacy of once-daily combination of indacaterol with mometasone

Cazzola M, Calzetta L, Matera MG. β(2) -adrenoceptor agonists: current and future direction. Br J Pharmacol. 2011 May; 163(1):4-17

Anticholinergics

Ipratropium Tiotropium Oxitropium

M3 > M1

Prevent cholinergic-nerve induced:Broncho-constrictionMucus secretion

Contd…

Do not reduce mucociliary clearance

Less effective than beta-2 agonists as they inhibit only the cholinergic reflex component of bronchoconstriction

Hence used only as add-on drug

Combined with β2-agonists in treating acute severe asthma

Adverse effects

Bitter taste Dryness of mouth Glaucoma- due to direct effect of nebulized drug

on the eye Paradoxical bronchoconstriction- due to

hypotonic nebulizer solution or additives like benzalkonium chloride/ EDTA

Urinary retention – common in elderly patients

Methylxanthines

AC

CAMPβ2 AMPPDE

Bronchial tone

Contraction

Relaxation

Adenosine

Methylxantines

---------------------------

Anti-inflammatory action

Increased secretion of IL-10 Inhibits the translocation of the pro-inflammatory

transcription factor NK-κB into the nucleus Promotes apoptosis in eosinophils(in-vitro) Activates HDAC2 and enhances the effects of

glucocorticoids All these effects are seen at Cp < 10mg/L Clinically, low oral doses reduce leukocytic infiltration

into the airways and reduce the no. of eosinophils seen in BAL and induced sputum of asthmatic patients

Clinically available compounds

Theophylline

Doxofylline- less potent adenosine receptor antagonist

Enprofylline- no effect on adenosine receptors

Aminophylline- ethylenediamine salt; increases its solubility hence used for i.v. administration

Pharmacokinetics

Therapeutic range is 5-15 mg/L Oral drug rapidly and completely absorbed Metabolized in liver by CYP1A2 Dose has to be individualized because of: Different patients respond differently to the

drug Clearance varies among patients due to the

factors such as….

….Factors affecting clearance

Increased clearance

Enzyme inducers- rifampin, barbiturates

Smoking- which induces CYP1A2

High-protein, low-carb diet

Barbequed meat

In children

Decreased clearance

Enzyme inhibitors- emycin, ciprofloxacin

CCF, liver disease, pneumonia

Viral infection

High-carb diet

Old ageDose reduced to half

Route of administration

Intravenous

Aminophylline is used in dose of 6mg/kg over 20 min f/b 0.5 mg/kg/hr maintenance dose

Indicated in acute severe asthma

Associated with many adverse effects

Hence, currently nebulized β2 agonists preferred over i.v. aminophylline

Oral Preparations

Immediate release formulations give wide fluctuations in plasma levels(Cp)- NOT RECOMMENDED

Sustained-release preparations: Absorbed at a constant rate and provide steady Cp

Twice daily therapy in dose of 8mg/kg is given Once-daily release preparations now available

Single dose given at night for controlling nocturnal asthma symptoms

Indications

Steroid sparing effect: Addition of low dose theophylline to

ICS improves symptom control compared to doubling the

steroid dose

Nocturnal asthma

As add-on therapy: less effective than β2 agonists, but

preferred when cost is a limiting factor

Acute asthma: Used only when patient not responding to

β2 agonists

Adverse Effects

Plasma conc dependent; occur at Cp>15 mg/L

Headache

Nausea, vomiting

Increased gastric acid secretion

Diuresis

Cardiac arrythmias

Seizures

Due to PDE4 inhibition

Due to A1 receptor inhibition

Recent Advances

Most of the adverse effects of theophylline are due to systemic effects on PDE receptors.

Based on this, roflimilast, an oral PDE4 inhibitor, was tested in asthmatic patients but was associated with gastric side effects

Hence, inhaled selective PDE4 inhibitors are in development(phase 2) for asthma treatment

Singh D, Petavy F, Macdonald AJ, Lazaar AL, O'Connor BJ. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res. 2010 Mar 1;11:26.

Corticosteroids

Mechanism of action

Anti-Inflammatory action

Reduce the number of inflm. cells in airway epithelium and submucosa

Induce eosinophil apoptosis Prevent and reverse the increase in vascular

permeability Decease mucus secretion

Reduction in airway hyper-responsiveness and healing Only suppress inflammation and do not cure underlying

disease- recurrence seen after steroid withdrawal

Synergism between steroids and β2 agonists

They interact with each other to potentiate their actions

Steroids: a) Increase transcription of β2 receptor gene in airway

mucosab) Prevent uncoupling of β2 receptors to Gs

c) Prevent downregulation of β2 receptors

β2 agonists:a) Enhance binding of GR to DNAb) Increase in translocation of liganded GR to the nucleus

Inhaled corticosteroids

Beclomethasone dipropionate

Budesonide

Fluticasone

Ciclesonide

Flunisolide

Mometasone furoate

Triamcinolone

Equipotent doses of ICS

Inhaled corticosteroids-PK

Adverse effects-Local

Hoarseness and weakness of voice(dysphonia)- due to atrophy of vocal cords

Oropharyngeal candidiasis

Cough- Common with MDI due to additives

How to reduce these?

Use a large-volume spacer device

Rinsing mouth after use of inhaler

Switch to DPI if cough is troublesome

Systemic ADRs

Adrenal suppression

Growth suppression

Dermal thinning and bruising

Osteoporosis

Cataract, glaucoma

Metabolic abnormalities

How to minimize these?

Budesonide, Fluticasone

High first-pass metabolism

Reduced systemic bioavailability

Ciclesonide

Lung esterases

Active metabolite

Low oral bioavailability and less systemic ADRs

Indications

First line therapy for all patients of persistent asthma(mild, moderate, severe)

In intermittent asthma- use only when β2 agonist (SABA) use is more than twice weekly

Usually administered twice daily- maintain at lowest possible dose that controls symptoms

Dose: < 400 μg/d of beclomethasone or equivalent If >800 μg/d is required, use spacer device Growth suppression in children- usually not seen at

doses < 400 μg/d

Systemic steroids

Oral steroids For patients not controlled on ICS

Prednisolone: 30-40 mg/day usually gives maximal benefit

Maintenance dose: 10-15 mg/day

Given as single dose in the morning: produces less adrenal suppression (matches with diurnal variation)

Alternate day treatment: Control of asthma is suboptimal; hence not preferred

contd…

Intravenous steroids In acute asthma where lung function is < 30% predicted

DOC: Hydrocortisone as it has rapid onset of action

Once control is achieved, switch over to oral prednisolone 40-60 mg/day

New developments

Transrepression – anti-inflammatory activity

Transactivation - Causes side effects

Classical steroids cause both activation and repression so that beneficial effects are accompanied by side effects

SEGRA(selective Glucocorticoid Receptor Agonists)- Less effective in transactivation; selective anti-inflammatory activity

Mapracorat- Undergoing preclinical studies

Mast Cell Stabilizers

Sodium cromoglycate, Ketotifen Inhibit degranulation of mast cells by triggers such as

exercise and pollen Inhibit eosinophil recruitment and decrease inflammatory

response Well tolerated; hence widely used earlier for treatment of

childhood asthma Have short duration of action and hence given QID by

inhalation Less effective than ICS- Rarely used in current

scenario

Anti-Leukotrienes

Indications

Orally administered Improve lung function; however are less effective than

ICS in mild asthma Used as add-on therapy in patients not controlled on

ICS Can also be used in prophylaxis of exercise-induced and

aspirin-induced asthma Doses: a. Montelukast: 10 mg ODb. Zafirlukast: 20 mg BD

Adverse Effects

Well tolerated

Rarely can cause liver dysfunction: monitor liver

enzymes

Churg-Strauss syndrome

Headache, rashes

FLAP inhibitors

Omalizumab

Indications

Reduces no. of exacerbations and improves control in severe asthma

Very expensive

Reserved for use only in patients not controlled on maximal doses of inhaled therapy and having serum IgE within a specified range

Administered as s.c. injection every 2-4 weeks

ADR- anaphylaxis

Types of Inhalers Metered dose inhalers- use a pressurized inert gas (CFC used

earlier now replaced by HFA) “Metered“- amount of dose goes directly to the lungs Coordination during inhalation may be difficult Deposition of 50–80 % of actuated dose in oropharynx Breath actuated MDI- useful for patients unable to coordinate

inhalation

Most common patient errors: Forgetting to shake the canister, inhaling at the wrong time, or forgettingTo hold their breath

Spacer devices/ Holding chambers

Used with pMDIs that act as a reservoir or holding chamber for the drugFitted with 1 way valve- to prevent medication escapeAt pateint end, mouthpiece can be attached- for use in childrenAdvantages:Decrease oropharyngeal deposition and decreased risk of topical side effectsNo need for coordination with breathing

Dry Powder Inhalers Delivers drug in the form of a dry powder Contains no propulsion system/gas Rely on force of patient’s inhalation to trigger delivery of a single

dose(patient-activated) Hence, insuficient inhalational flow rates may reduce drug delivery-

used only in older children & adults Different types are-

Accuhaler DiskhalerTurbohaler

Nebulizer

Turn liquid form of the drugs into a fine mist like an aerosol

Done with the help of compressed oxygen/compressed air (Jet nebulizer/ Atomizer) OR

ultrasonic waves(ultrasonic nebulizer)

Drug delivered during tidal breathing Less dependent on patient coordination and effort Method of choice – In patients with breating fatigue and in severe

asthma where large doses of inhaled drugs need to be administered

Approach to Management of

Asthma

Four pronged approach

•Develop doctor-patient relationship1•Identify and reduce exposure to risk factors2•Assess, treat and monitor asthma3•Manage asthma exacerbations4

Develop doctor-patient relationship

Asthma self-management education is essential

Begin at the time of diagnosis and continue through follow-up care

Involve all members of the health care team

Provide all patients with a written asthma action plan that includes two aspects:

daily management how to recognize and handle worsening asthma

Identify and reduce exposure to risk factors

Clinician should evaluate potential role of allergens, particularly indoor inhalant allergens

Reduce, if possible, exposure to allergens to which the patient is sensitized

Avoid exposure to environmental tobacco smoke and other respiratory irritants

Avoid exertion outdoors when levels of air pollution are high

contd…

Avoid use of nonselective beta-blockers

H/o sensitivity to aspirin or NSAIDs should be counseled -risk of fatal exacerbations from these drugs

Consider inactivated influenza vaccination for adults and children more than 3 yrs of age who have severe asthma.

Asthma Treatment

In children upto 4 yrs of age: Diagnosis is difficult Long term therapy considered in patients who had 4 or

more wheezing episodes alongwith atopic dermatitis/family h/o of asthma

Inhaled ICS(budesonide, fluticasone) in low doses are safe even for extended periods

LABA- Salmeterol is approved for use Montelukast can be given as chewable tablets

contd.. Delivery devices MDI plus valved holding chamber (VHC) with a face mask

Nebulizer with a face mask

Holding the mask or open tube near the infant’s nose and mouth, is not appropriate

If there is a clear and positive response for at least 3 months, step down in therapy should be attempted to identify the lowest dose

If clear benefit is not observed within 4–6 weeks the therapy should be discontinued and alternative diagnoses

In children 5-11 yrs of age

Physical activity at play is an essential part of a child’s life

Full participation in physical activities should be encouraged

Manage moderate or severe exacerbations due to viral RTI, with a short course of oral systemic corticosteroids

Patients > 12 yrs old and adults

Achieving Control Of Asthma

Assess asthma severity

Select T/t that corresponds to the patient’s level of asthma severity

At a follow up visit after starting T/t, asthma is not well controlled ,then T/t should be advanced to the next step

Adjusting Therapy

Once therapy is selected T/t decisions are based on the level of the patient’s asthma control

Step up one step for pts whose asthma is not well controlled

Pts with very poorly controlled asthma, consider increasing by two steps, a course of oral corticosteroids, or both

Regular follow up visits (1-6 months) depending on severity

Special Considerations

Exercise-induced bronchospasm Pretreatment before exercise-

Inhaled beta2-agonists- prevent EIB in more than 80 percent SABA use may be helpful for 2–3 hours LABAs can be protective up to 12 hours

LTRAs can attenuate EIB in up to 50 percent of patients

Cromolyn or nedocromil taken shortly before exercise is an alternative

Contd..

Frequent, severe EIB indicates poorly controlled asthma- Consider long-term control therapy

A warm up period before exercise may reduce the degree of symptoms

A mask or scarf over the mouth may attenuate cold-induced EIB

Surgery and Asthma Attempts made to improve lung function preoperatively

Short course of oral systemic corticosteroids may be required

For patients who have received oral systemic corticosteroids during the past 6 months and for pts on a long-term high dose of ICS

100 mg hydrocortisone every 8 hours i.v during the surgical period & reduce dose rapidly within 24 hours after surgery

Pregnancy and Asthma

Asthma increases risk of preterm birth, IUGR and perinatal mortality.

NEVER WITHHOLD TREATMENT

Monitoring of asthma status during prenatal visits

Albuterol is the preferred SABA because it has an excellent safety profile

ICS are the preferred treatment for long-term control medication

Budesonide is the preferred ICS because more data are available

Bronchial Thermoplasty

Catheter introduced through a bronchoscope

It delivers thermal energy to the airway wall to reduce excess smooth muscle

Increases symptom-free days, improves PEFR and reduces the use of reliever medicines.

FDA approval obtained in 2010 for treatment of severe asthma.

Cho JY. Recent Advances in Mechanisms and Treatments of Airway Remodeling in Asthma: A Message from the Bench Side to the Clinic. Korean J Intern Med 2011; 26:367-383

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