Asthma Drug
Transcript of Asthma Drug
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Learning Objectives To appreciate the basic pathogenesis and
therapeutic strategies in asthma management
To learn about the pharmacology of the three majorclasses of bronchodilators.
To learn about the various long-term asthmaController drugs
To appreciate the newer therapies for asthma
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Introduction Bronchial asthma is a clinical syndrome
characterized by recurrent bouts of Bronchospasm.
There is hyper-responsiveness of thetracheobronchial smooth muscles accompanied bymucosal odema and mucus plugging
Pathologically, lymphocytic, eosinophilic
inflammation and bronchial mucosa remodeling
Clinically characterized by the triad; recurrentwheezing, cough and dyspnoea
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Bronchial asthma
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Bronchial Asthma
Diagram
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Classification-Aetiological1. Extrinsic or allergic
H/o Atopy in childhood
Fhx of allergies
Positive skin test
Raised IgE levels
Below 30yrs of age
Less prone to status Asthmaticus
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Classification-Aetiological
2. Intrinsic or idiosyncratic
No Fhx of allergies
Negative skin test
No rise in IgE
Middle age
Prone to status asthmaticus
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Asthma TriggersTobacco smoke
Infections e.g. Flu, cold, pneumonia etc
Allergens e.g. dust mite, food, pollen etc
Exercise
Air pollution
Drugs e.g. NSAIDs, Beta Blockers
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Asthma Triggers Emotional stress and anxiety
Singing, Laughing or crying
Smoking, Perfumes or spray
Acid Reflux
Weathers changes
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Bronchial Asthma -Pathogenesis
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Bronchial asthma;-Treatment Strategy
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Antiasthmatics-classification
1. Bronchodilators (Short-term Relievers).
i) B2 Sympathomimetics (agonists):
Salbutamol, Salmeterol, Formeterol,Rimeterol, Bitolterol and Terbutaline (Non-specific) ; adrenaline, ephedrine,
isoproterenol, orciprenaline ii) Methyxanthines: Theophylline and
derivatives aminophylline etc
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Antiasthmatics-classification
1. Bronchodilators (Cont).
iii) Anticholinergics: Ibratropium bromide
and Triotropium bromide
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Antiasthmatics-classification
2. Anti-inflammatory Agents (Long-term Relievers):
i) Mast Cell stabilizer:
Sodium cromoglycate, Nedocromil
Ketotifen
ii) Leukotriene antagonists:
Montelucast,
Zarfirlucast etc
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Antiasthmatics-classification
2.Anti-inflammatory Agents (Long-term Relievers):
iii) Corticosteroids:
Systemic ; Hydrocortisone and prednisolone
Inhalational; Beclomethasone, Budesonide,
fluticasone propionate etc
3. Newer Therapies:
Anti-IgE antibody: Omalizumab
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2-Agonists:-Structures
Structures
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2-Agonists:-Mode of Action
Stimulation of 2 receptor in bronchialsmooth muscle cell membrane activation
of adenyl cyclase cAMP Ca2+ SMrelaxation
Also activate -receptor on mast cell
membranedecrease in mediator release Beta-receptors on mast cells are prone to
desensitizationuncertain beneficial effect
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Beta-2 Agonists contd.
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Beta-2 Agonistscontd.
Results of Beta2 stimulation:
Bronchodilatation without tachycardia
Inhibition of release of chemical mediators bystabilization of mast cell membrane Prevention of mucosal edema Decrease microvascular permeability
Increase ventilatory response to chemoreceptorstimuli Restoration of mucocilliary transport mechanism
in respiratory tract
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Beta-2 Agonistscontd.
Epinephrine,
Stimulates Alpha ,Beta1 and Beta2 receptors
Rapidly acting bronchodilator Maximal bronchodilation in 15 min, lasts 6090
min
SC, 0.4 mL of 1:1000 sol. or 320 mcg/puff
Adverse effects; tachycardia, arrhythmias, andworsening of angina pectoris
Uses; Anaphylaxis, Asthma
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Beta-2 Agonistscontd.
Pharmacokinetics: Undergoes metabolism in gut wall Bioavailability is 50% Duration of action: 4-6 Hrs
Salbutamol: preparation and dosesAvailable as 2,4 and 8 mg tablets, Bd or tid
Syr. As 2mg/5 ml, Bd or tidAs metered dose inhaler100 g-400 g Nebulizer-2.5-5mg
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Beta-2 Agonistscontd
Adverse effects:
Muscle tremor, restlessness, palpitationand nervousness
Vasodilatationreduction in mean arterialpressure with tachycardia and also
exacerbate pulmonary hypoxia due tomismatched of ventilation and perfusion
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Beta-2 Agonistscontd
Adverse effects:
Hyperglycaemia and hyperlacticacidemia
Worsening of asthma on prolongedinhalation (Tachyphylaxis).
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Salmeterol
Long acting Beta-2 agonist (more lipophilic)
Available as inhaler: MDI and rotacaps (25 g)
Weaker than salbutamol but more beta-2 selective Duration of action is 3 Hrs to 12 hrs
Not useful for acute attacks, only for prophylaxis
Usually combined with steroids
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uestions Questions
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Methylxanthines-Chemistry
Three naturally occurring methylxanthinescaffeine, theophylline and theobromine
Theophylline and its derivatives are used inasthma
Chemically, they are purine structured andclose to adenine and uric acid
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Methylxanthines-Chemistry
Many salts of theophylline have been marketed butthe most common one is aminophylline
Aminophyllineis highly water soluble and a stablemixture of theophylline and ethylene diamine
Uses: Bronchial asthma, COPD, infantile apnoea
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Methylxanthines - structures
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MethylxanthinesMode of action
Blockade of adenosine receptorsno contractionof smooth muscles
Inhibition of Phosphodiesterase enzyme:ATP/GTP cAMP/cGMP 5-AMP/5-GMP
(inhibit activity of PDE cAMP Ca2+bronchial relaxation)
Higher doses - Release of Ca++ from sarcoplasmicreticulum
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Methylxanthines - Pharmacokinetics
On prolonged and high doseelimination iszero order from first order
Metabolic products excreted in urine Low therapeutic index: Therapeutic range -
0.2 to 2 mg/100 ml, higher than 4 mg/100mlmay cause arrhythmia, convulsion and coma
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Methylxanthines -Pharmacological actions (PD).
CNS:
Stimulation: improves performance,
sense of well being and allays fatiguethinking become clearer
Higher dosesnervousness, insomniaand restlessness
High dosestremor, convulsion
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Methylxanthines-Pharmacological actions
CVS:
Stimulation of heartincrease in heart rate,cardiac output
Dilatation of blood vessels including coronaryreduced peripheral resistance
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Methylxanthines- Pharmacological actions
CVS:
But, constriction of cerebral vesselsmigraineuse
Transient in normal individual but in cardiacinsufficiency may remain long
Higher dosescardiac arrhythmia
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Pharmacological actions of Methylxanthinescontd.
Kidney:Mild diuretic (decrease in tubularreabsorption of Na and also increase in renal
blood flow)
Stomach:increase in acid-pepsin secretion
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Pharmacological actions of Methylxanthinescontd.
Smooth muscles: relaxedbronchodilatation,but no effect on intestine and urinary tract,
the major therapeutic action in asthma
Metabolic:Increase in BMRplasma fatty
acid level raised
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Methylxanthines-Clinical Uses
1. Bronchial asthma
2. COPD
3. infantile apnoea
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Methylxanthines-Therapeutic Levels
Theophylline has a narrow therapeuticwindow
Improvement in pulmonary functioncorrelates with range of 520 mg/L.
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Methylxanthines-Adverse effects
Anorexia, nausea, vomiting, abdominaldiscomfort, headache, and anxiety occur at
concentrations of 15 mg/L, commoner at>20 mg/L.
Higher levels (> 40 mg/L) may causeseizures or arrhythmias.
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MethylxanthinesPreparation and Dosage
Theophylline: (Unicontin/Theolong)
Poorly water soluble and cannot be injected
Available as tablets 100/200 mg SR
The usual dose is 34 mg/kg, 6hrly. Aminophylline:
Water soluble and can be injected IV
Available as 100 mg tablets and 250 mg/mlinjection
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MethylxanthinesPreparation and Dosage
Hydroxyethyl theophylline: (Derriphylline)
Available as 100/300 mg tablets or 220 mg/2mlinjection
Si l d i h f
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Signal transduction pathway for
Bronchodilatation
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Question
Question
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Anticholinergics-Introduction
Atropine, Ipratropium bromide and tiatropium
Airways are innervated by a supply of efferent,cholinergic, parasympathetic autonomic nerves
Motor nerves derived from the vagus form gangliapredominate in the large and medium-sized airways
Postganglionic fibers supply the smooth muscle andsubmucosal glands of the airways as well as the
vascular structures
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Anticholinergics- Introduction
Atropine, Ipratropium bromide and tiatropium
Release of acetylcholine (ACh) at these sites results instimulation of muscarinic receptors and subsequent airway
smooth muscle contraction and release of secretions fromthe submucosal airway glands
Distinct muscarinic receptors exist within the airways ;M1, M2 and M3 receptors
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Anticholinergicscontd.
M1present in peribronchial ganglion cells wherethe preganglionic nerves transmit to thepostganglionic nerves
M2 receptors are present on the postganglionicnerves - they are activated by the release ofacetylcholine and promote its reuptake into the
nerve terminal
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AnticholinergicsMode of action
M3 receptors are present on smooth muscle
Muscarinic receptor activation of these M3receptors intracellular cAMP levelscontraction of airway smooth musclebronchoconstriction
Anticholinergics compete for M3 receptorresulting in Ach antagonism and smooth musclerelaxation
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Anticholinergicscontd.
Atropineprototype of anticholinergicbronchodilators
Ipratropium is a quaternary amine, which is poorly
absorbed across biologic membranes Both compete for M3 receptor resulting in Ach
antagonism and smooth muscle relaxation
Ipratropium - exclusively by MDI or a nebulizer
Inhaled ipratropium has a slow onset (30 min)and a relatively long duration of action (6 h)
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Anticholinergicscontd.
Tiotropium - a structural analog ofipratropium
High affinity for all muscarinic receptorsubtypes Dissociates from the receptors much more
slowly than ipratropium, esp. M3
receptors. 18 mcg once a day dosing
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Anticholinergics- Clinical Uses
Used as Bronchodilators with salbutamol inrefractory asthma
As a treatment for COPD
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Action of Bronchodilators
Selective b2 agonist
ATP
cAMP
Theophyline
5-AMP
Relaxation
Ach
Ipratopium
Vagus nerve
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Mast cell stabilizers
Examples; Cromolyn Sodium, Nedocromil sodium Synthetic compound and chemically benzopyrone
Stabilizes mast cellsinhibits degrannulation ofmast cells and other inflammatory cells
Mediator release is restricted
Also prevent chemotaxis of eosinophils andneutrophilslocal inflammation is prevented
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Mast cell stabilizersContd
Basis of action may be due an alteration in thefunction of delayed chloride channels in the cellmembrane, inhibiting cell activation
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Mast cell stabilizerscontd
Long term use prevents hyperactivity of bronchialtree
No bronchodilatation or antagonism of constriction
no action on acute cases
Not absorbed orally , given via MDI1 mg/dose2 puffs 4 times daily
Uses: Prophylaxis of asthma, allergic rhinitis andallergic conjunctivitis
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Mast cell stabilizerscontd
Adverse effects
Minor and localized to the sites of deposition.
Includes; throat irritation, cough, and mouthdryness, and, rarely, chest tightness, and wheezing.
Reversible dermatitis, myositis, or gastroenteritisoccurs in less than 2% of patients
Few cases of pulmonary infiltration witheosinophilia and anaphylaxis have been reported..
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Leukotriene Antagonists
Leukotrienes, LTC4, LTD4 and LTB4 areimportant mediators of human asthma
Montelucast and zafirlucast, LTD4-receptorantagonists, zileuton,a 5-lipoxygenaseinhibitor
Benefitsbronchodilatation, reduced eosinophilcounts and suppression of inflammation andhyperactivity
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Leukotriene Antagonists
Montelucast and zafirlucast: Used in mild to moderate asthma as alternative to
inhaled corticostroids
Useful in childrenreduces dose of steroids andbeta agonists Absorbed orally and highly plasma protein bound Half life: montelucast (3-6 hrs), zafirlucast (8-12
Hrs)
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Leukotriene Antagonists
Dosages;
P.O, Zileuton, 400800 Bd, tid, Qid;
P.O, Zafirlukast, 20 mg Bd P.O, Montelukast, 10 mg (Adults) OD or 4
mg (Children)OD
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Leukotriene Antagonists
The receptor antagonists appear to be safe touse
Zileuton is the least prescribed because ofthe QID dosing and occasional liver toxicity.
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Questions
Questions
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Corticosteroids
Mode of Action
Not a bronchodilator but reduces airwayinflammation and bronchial reactivity
The broad anti-inflammatory efficacy is mediated inpart by inhibition of production of inflammatorycytokines
Antiinflammatory actionreduction in mediatorsIL, TNF and PAF etc. and reduction in exudateformation
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Corticosteroids-Contd
Clinical Uses
Systemic steroids are useful in: (Hydrocortisone and Prednisolone)
Acute asthma (status asthmaticus)not relieved orworsening of obstruction inspite of bronchodilatator andinhaled steroid
Chronic asthmafailure of previously optimal regimen
frequent symptoms of progressive severity Systemic therapy - devastating side effects
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Corticosteroids-Contd
Regular or "controller" therapy is maintained
with inhalational corticosteroids.
Inhalation steroids are used regularly arebeclomethasone dipropionate, budesonide,
fluticasone propionate and triamcinoloneacetonide
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Corticosteroids-Contd
Adverse effects: oropharyngel candidiasis and dysphonia. Cataracts and in women osteoporosis, longterm .
Doses: Beclomethasone: available as 50, 100 and 1200
mcg/ml MDIdose is 400 mcg/day
Budesonide: available as 100, 200, 400 mcg/mlMDIdose is 200 mcg BD
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Newer therapies
Anti-IgE Monoclonal Antibodies e.g. Omalizumab
Omalizumab,inhibits the binding of IgE to mast
cells It may also inhibit IgE synthesis by B lymphocytes.
Omalizumab's most important effect is reduction of
the frequency and severity of asthma exacerbations,enabling a reduction in corticosteroid requirements
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Aerosols
Aimto deliver to the alveoli without settling inbigger tubes
Particles > 10 mm are deposited primarily in themouth & oropharynx.
Particles < 0.5 mm are inhaled to the alveoli andexhaled without being deposited in the lungs.
Deposition can be increased by holding the breathin inspiration.
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Treatment - asthma
Step I:When symptoms are less than oncedaily - occasional inhalation of a short actingBeta-2 agonistsalbutamol, terbutaline. If
used more than once dailystep II (Mildepisodic asthma) Step II:Regular inhalation of low-dose
steroids. Alternatively, cromoglycates. Beta-2
agonist as and whenever required (Mildchronic asthma)
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Treatment - asthma
Step III:Inhalation of high dose of steroids (800mcg) + Beta-2 agonist. Sustained releasetheophylline may be added. LT inhibitors may betried instead of steroids (Moderate asthma withfrequent exacerbations)spacers
Step IV:Higher dose of steroid (800 to 200 mcg) +regular beta-2 agonist (long acting salmeterol)
Additional treatment with oral drugsLTantagonist or SR theophylline or oral beat-2 agonist
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Status asthmaticus
May be called acute severe asthma
Hydrocortisone hemisuccinate 100 mg stat
IV and followed by 100-200 mg 4-8 hrly. orInfusion
Oxygen inhalation
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Status asthmaticus
Salbutamol (2.5 to 5 mg) + Ipratropiumbromide (0.5 mg) intermittent inhalationswith oxygen and nebulization
Salbutamol or terbutaline IM or SC (0.4 mg)
Antibiotics
IV saline
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Summary
1. The principles of the therapy of asthma remainsunchanged since long
2. Bronchodilators like short acting beta-2 agonists
are used to reverse bronchospasm of an attack3. Glucocorticoids are used to arrest inflammation
such as to reduce the severity and frequency ofattacks
4. In hospitalized cases short course of systemicsteroids followed by dose tapering is often given
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Summary -contd
1. Long acting beta-2 agonists are added asinhalation agent if steroids cannot suppresssymptoms
2. Methylxanthines are not preferred anymoredue to their modest efficacy and lowtherapeutic index
3. Newer agents like specific PDE4 inhibitorsare under evaluation
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Herbal Products, can they cure asthma?
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Thankyou
Best wishes in your CATS
Thankyou