Asthma Drug

8/13/2019 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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1. Bronchodilators (Cont).

iii) Anticholinergics: Ibratropium bromide

and Triotropium bromide


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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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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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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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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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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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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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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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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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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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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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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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Asthma Drug