recent advances in the pharmacotherapy of asthma
TRANSCRIPT
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Recent Advances in the Pharmacotherpy of Asthma
Dr. Mohit KulmiPostgraduate resident
Department of PharmacologySAMC & PGI, Indore
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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.
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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.
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• 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.
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• 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
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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.
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• 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
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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
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Inflammation of inner lining of
airways
Muscle around airways tighten
Airways produce mucus due to inflammation
Pathogenesis
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Bronchial inflammation
Environment factor Genetic prediposition
Bronchial hyperreactivity + trigger factors
Cough, Wheeze, Breathlessness, Chest tightness
OedemaBronchoconstrictionMucus production
Airways narrowing
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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.
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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
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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)
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Differrence between normal airway and airway in person with asthma
Narrowed bronchioles
(muscles spasms)
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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
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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.
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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.
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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
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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
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New Bronchodilators
• Ultra-long-acting beta-2 agonists• Muscarinic receptor agonist• Bitter taste receptor agonist
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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.
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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.
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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
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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.
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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.
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New Corticosteroids
• Designing new corticosteroids to decrease side effects
• Dissociated steroids• Nonsteroidal selective glucocorticoid receptor
agonists
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• 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)
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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.
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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
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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.
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• 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
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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.
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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.
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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
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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.
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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.
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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.
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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
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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
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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..
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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.