Recent Advances in the Pharmacotherpy of Asthma

Dr. Mohit KulmiPostgraduate resident

Department of PharmacologySAMC & PGI, Indore

History• Asthma : derived from the Greek aazein, meaning "sharp breath.“• In 450 BC. Hippocrates: more likely to occur in tailors, anglers,

and metalworkers. • Six centuries later, Galen: caused by partial or complete bronchial

obstruction.• 1190 AD, Moses Maimonides: wrote a treatise on asthma, describing

its prevention, diagnosis, and treatment• 17th century, Bernardino Ramazzini: connection between asthma

and organic dust. • 1901: The use of bronchodilators started.• 1960s: inflammatory component of asthma was recognized and

anti-inflammatory medications were added to the regimens.

Simple Definition

It’s a reversible chronic inflammatory airway disease which is characterized by bronchial hyper-responsiveness of the airways to various stimuli, leading to widespread bronchoconstriction, airflow limitation and inflammation of the bronchi causing symptoms of cough, wheeze, chest tightness and dyspnoea.

• Bronchial asthma Patients with asthma experience:

• Attacks of severe dyspnea, coughing, and wheezing.

• Rarely, “status asthmaticus” - may prove fatal.

• Patients may be asymptomatic between the attacks.

• In some cases, the attacks are triggered by exercise and cold or by

exposure to an allergen, but often no trigger can be identified.

• There has been a significant increase in the incidence of asthma in

the world in the past three decades.

• Genetic factors• Environmental factors• House dust • Mites• Exposure to tobacco smoke,• to animals, pollens, molds.• Dietary changes• junk food and fast food contain MSG

ETIOLOGY OF ASTHMA

Lack of exercise• Less stretching of the airways

Occupational exposure• Irritants in the workplace : chemicals, dusts, gases, moulds and

pollens. • These can be found in industries such as baking, spray painting of

cars, woodworking, chemical production, and farming. 

• Atopic diseases – eczema and allergic rhinitis.• Maternal status – both physical and mental conditions like

anaemia and depression in the mother are associated with asthmatic stress for the child.

• Early antibiotic use – babies who are given antibiotics may be 50% more likely to develop asthma by the age of six

Pathogenesis

• Complex, not fully understood• Large numbers of cells, mediators are involved and vascular leakage

-activated by expose to allergens or several mechanismInflammation• Eosinophils, T-lymphocytes, macrophages and mast cell Remodeling• Deposition of collagens and matrix proteins-damage• Loss of ciliated columnar cells- metaplasia – increase no of

secreting goblet cells

Inflammation of inner lining of

airways

Muscle around airways tighten

Airways produce mucus due to inflammation

Pathogenesis

Bronchial inflammation

Environment factor Genetic prediposition

Bronchial hyperreactivity + trigger factors

Cough, Wheeze, Breathlessness, Chest tightness

OedemaBronchoconstrictionMucus production

Airways narrowing

Early phase• Inhaled Antigen

Sensitised mast cells on the mucosal surface mediator release.

Histamine bronchoconstriction, increased vascular

permeability.

prostaglandin D 2 bronchoconstriction, vasodilatation.

Leucotriene C4,D4, E4 Increased vascular permeability,

mucus secretion and bronchoconstriction.

Direct subepithelial parasympathetic stimulation

bronchoconstriction.

Late phase

• Starts 4 to 8 hours later

• Mast cell release additional cytokine

• Influx of leukocytes(neutrophil,eosinophil)

• Eosinophils are particularly important- exert a variety of effect

TriggerEg.dust,pollen, animal dander

TH2 cell

IL5

IL4

Eosinophil

IgE B cell

Mast cell

IgE antibody

MediatorsEg.Histamine,

leukotrines

BronchospasmIncrease vascular permeability

Mucus production

Immediate phase (minutes)

Late phase (hours)

Differrence between normal airway and airway in person with asthma

Narrowed bronchioles

(muscles spasms)

Management of Chronic Asthma

Aims of management

• to recognize asthma• to abolish symptoms • to restore normal or best possible long term

airway function • to reduce morbidity and prevent mortality

Approach of chronic asthma

• Education of patient and family• Avoidance of precipitating factors • Use of the lowest effective dose of convenient

medications minimizing short and long term side effects.

• Assessment of severity and response to treatment.

Medication

Bronchodilator drugs

•to relieve bronchospasm and improve symptoms.

Anti inflammatory drugs

•to treat the airway inflammation and bronchial hyper-responsiveness, the underlying cause of asthma, i.e. to prevent attacks.

Drug Delivery

• The inhaled route is preferred for beta2-agonists and steroids as it

produces the same benefit with fewer side effects

• Inhaled medications exert their effects at lower doses

• MDI is suitable for most patients as long as the inhalation technique

is correct

• Alternative methods include spacer devices, dry powder inhalers

and breath-actuated MDI

• Nebulized route is preferred in the management of acute attacks

The Need for New Asthma Therapy• 5-10% have uncontrolled asthma despite effective inhaled therapy.• What we need

– Drugs with similar mechanism but less side effects– New classes of drug to treat asthma– New classes of drug that modify the course of the disease

• Improvement in understanding basic pathophysiology of asthma in molecular level– IgE in pathogenesis of asthma– Cytokines and cell signalling– Immunomodulating pathway

New Bronchodilators

• Ultra-long-acting beta-2 agonists• Muscarinic receptor agonist• Bitter taste receptor agonist

New Bronchodilators

• Bronchodilators use

– Relieving bronchoconstriction (short-acting)

– Preventing bronchoconstriction (long-acting beta-agonist or

LABA: formoterol, salmeterol – lasting 12 hrs)

• Ultra-LABAs in development (lasting > 24 hrs) for once-daily use

• Long-acting muscarinic receptor agonist (LAMA), e.g. tiotropium,

can be a useful add-on for severe asthma.

• Bitter taste receptor (TAS2R) agonist can cause bronchodilation.

Bitter Taste Receptor (TAS2R) Agonist

Bitter taste receptor agonist can cause bronchodilator via G-protein-phosphatidylinositol phosphate pathway resulting in activation of Ca-dependent K channel and subsequent hyperpolarization of smooth muscle cell.

Magnesium sulphate

• Reduces cytosolic calcium in airway smooth muscles leading to

bronchodilatation

• Can be given by IV/nebulisation

• Useful as an additional drug to SABA in acute severe asthma

• Not suitable to be employed alone as clinical benefit is small

• Cheap, well tolerated with minor s/e like nausea and flushing

Potassium channel openers• Potassium channel openers that open calcium activate large conductance

K+ channels in smooth muscles. • Experimental evidence and preclinical models suggest that ATP-dependent

K(+) (K(ATP)) channel openers, big-conductance K(+) (BK(CA)) channel openers, and intermediate-conductance K(+) (IK(CA)) channel blockers may be the most effective agents for treating asthma and COPD.

• Modulation of potassium channels by these agents may produce beneficial effects such as bronchodilation, a reduction in airways hyper-responsiveness (AHR), a reduction in cough and mucus production and an inhibition in airway inflammation and remodelling.

Calcium channel blockers• Nifedipine, verapamil • Prevent calcium entry into smooth muscle• Inhibit stimuli induced bronchoconstriction but no effect on basal airway

caliber• Bronchodilator effect less than SABA.

ANP • Activates membrane guanylyl cyclase cGMP bronchodilatation• Bronchodilator effects comparable to SABA• Useful for additional bronchodilatation in acute severe asthma

VIP analouges• VIP binds to VPAC1 (smooth muscles of blood vessels) & VPAC2

(airway smooth muscles)couple to Gsadenylyl cyclase stimulated smooth muscle relaxation

• VIP potent bronchodilator in vitro studies but in patients it is rapidly metabolised and also has vasodilator S/E

• More stable analouge of VIP (RO25-1533) selectively stimulate VPAC2 produces rapid bronchodilatation.

New Corticosteroids

• Designing new corticosteroids to decrease side effects

• Dissociated steroids• Nonsteroidal selective glucocorticoid receptor

agonists

• ICSs are the most effective anti-inflammatory therapy for asthma.

• Currently available ICSs can be absorbed from the lung, leading to

potential systemic side effects.

• New corticosteroids’ preferred properties

– Reduced absorption from the lungs

– Inactivated in the circulation

– Dissociated steroid (trans-activation vs cis-activation vs trans-

repression)

– Nonsteroidal selective glucocorticoid receptor agonist (SEGRA)

Transcription Mechanism of Corticosteroid

• Most of the anti-inflammatory effects of corticosteroid are due to

trans-repression of the pro-inflammatory gene.

• corticosteroid-GR complex is needed to attach to nuclear factor

leading to inhibition of gene expression.

• Dimerization of corticosteroid-GR complexes is needed for trans-

activation and cis-repression.

• Most of the side effects (osteoporosis, HTN, DM) of steroid are from

gene trans-activations.

Dissociated Steroid/SEGRA

• Dissociated steroid and selective glucocorticoid receptor agonist can

bind to glucocorticoid receptor and prevent dimerization. This will

prevent trans-activation and cis-repression of metabolic gene

products.

• However, trans-activation of anti-inflammatory protein will be

prevented leading to decreased anti-inflammatory effects.

•  Mapracorat, Fosdagrocorat,  Dagrocorat

Targeting Lipid Mediators

• Problems: More than 100 mediators are involved in the complex

inflammatory process in asthma.

• The only mediator antagonists available are cysteinyl-Leukotriene

CysLT1 receptor antagonists e.g. montelukast.

• 5’-lipooxygenase and 5’-lipooxygenase-activating protein inhibitors

are in development.

• Prostaglandin D2 is released from mast cells, Th2 cells and dendritic

cells.

– DP2 receptor (CRTh2) chemotaxis of Th2 and eosinophil

– DP1 receptor vasodilation, enhancing Th2 polarization

– Thromboxane receptor airway smooth muscle constriction

• CRTh2 inhibitors: AMG-853 OC000459 and MK-2746

• DP1/DP2 inhibitors: in development

• PGD2 synthesis inhibitors: in development

Interleukin-4 and Interleukin-13

• Pitrakinra

– Mutated IL-4 (recombinant human IL-4 mutein)

– Blocking IL-4Rα, the common receptor for IL-4 and IL-13

– Reduces the late response to inhaled allergen in mild asthmatics

– Patients with high eosinophil count have a decrease in asthma

exacerbation on pitrakinra.

Interleukin-5• IL-5 is important for eosinophilic inflammation.

• Mepolizumab is a blocking antibody to IL-5.

– Depletes eosinophil from the circulation and the sputum of

asthmatics

– Reduces exacerbation in patients with persistent sputum

eosinophilia despite high dose ICS but no improvement in lung

function.

• IL-5Rα blocker is currently studied.

Other Interleukins• Anti-TNF-α

– No beneficial effect on lung function, symptoms, or exacerbations

– Increased reports of pneumonia and cancer• IL-17

– May be a target in severe asthma with neutrophillic inflammation

• IL-10– Broad spectrum of antiinflammatory effects– Efficacy has not been demonstrated in asthma.

• IL-12 and Interferons– Not effective and results in unacceptable side effects

Phosphodiesterase-4 inhibitors

• PDE 4 inhibitors have wide spectrum of anti-inflammatory effects –

inhibiting T cells, eosinophils, mast cells, airway smooth muscle

• Roflumilast – inhibitory effect on allergen-induced response similar to

low dose ICSs.

• Side effects: nausea/vomiting mediated through PDE4D while PDE4B

decreases inflammation.

• PDE-3 inhibitor can cause bronchodilation.

• Roflumilast can inhibit both the early and late phase response in

patients with mild allergic asthma.

Other novel anti-inflammatory drugs

• Adhesion molecule blockade– Adhesion molecules play important role in recruitment of

inflammatory cells from the circulation to the airways.• PPAR (peroxisome proliferator-activated receptor)-γ agonist

– Wide spectrum of anti-inflammatory effects– Polymorphism of PPARγ gene is linked to increased risk of

asthma– Rosiglitazone marginally improves lung function in smoking

asthmatics.– Rosiglitazone 8 mg/day helps improve FEV1 and FEF in

smokers with asthma.

Anti-IgE therapy

• Omalizumab, monoclonal antibody that blocks IgE, is now used in

treatment of selected patients with severe asthma.

• More potent anti-IgE antibodies are in development.

• Low-affinity IgE receptor (FcεRII or CD23) antagonist seems to be

well tolerated and reduces IgE concentrations in patient with mild

asthma in a phase I study.

Mast cell Inhibitors• Mast cell stabilizers

– Cromones (Sodium cromoglycate, nedocromil sodium)– Furosemide – Short-acting, not effective as long-term controllers

• Stem cell factor (SCF)– Key regulator of mast cell survival

• Masitinib– A potent tyrosine kinase inhibitor. – Reduction in steroid use and symptoms in patients with severe

steroid-dependent asthma.Syk kinase Inhibitors• Spleen tyrosine kinase is involved in activation of mast cells and

other immune cells.• Still in pre-clinical studies for asthma

Targeting Treg and Dendritic cells• Specific immunotherapy increases Treg numbers and their

expression of IL-10 suppressed Th2 responses decrease IgE synthesis

• Several classes of drug have been shown to suppress myeloid

dendritic cell activation

– iloprost

– fingolimod

• In preclinical development

Bronchial thermoplasty

• Bronchial Thermoplasty, delivered by the Alair™ System, is a

treatment for severe asthma approved by the FDA in 2010

• It involves the delivery of controlled, therapeutic radiofrequency

energy to the airway wall,

• thus heating the tissue and reducing the amount of smooth muscle

present in the airway wall..

Conclusion

• With the understanding of pathogenesis of asthma new targets can be found in the drug development.

• Future drugs will be associated with less side effects and toxicity.

• As of now the drugs in current use are possibly the best that can be offered to a asthma patient.