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Asthma Drug

GMM

Learning Objectives

To appreciate the basic pathogenesis and therapeutic strategies in asthma management To learn about the pharmacology of the three major classes of bronchodilators. To learn about the various long-term asthma Controller drugs To appreciate the newer therapies for asthma

Introduction

Bronchial asthma is a clinical syndrome characterized by recurrent bouts of Bronchospasm. There is hyper-responsiveness of the tracheobronchial smooth muscles accompanied by mucosal odema and mucus plugging Pathologically, lymphocytic, eosinophilic inflammation and bronchial mucosa remodeling Clinically characterized by the triad; recurrent wheezing, cough and dyspnoea

Bronchial asthma

Bronchial Asthma

Diagram

Classification-Aetiological
1. 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

Classification-Aetiological
2. Intrinsic or idiosyncratic No Fhx of allergies Negative skin test No rise in IgE Middle age Prone to status asthmaticus

Asthma Triggers

Tobacco 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

Asthma Triggers

Emotional stress and anxiety Singing, Laughing or crying Smoking, Perfumes or spray Acid Reflux Weathers changes

Bronchial Asthma -Pathogenesis

Bronchial asthma;-Treatment Strategy

Antiasthmatics-classification
1.

Bronchodilators (Short-term Relievers). i) B2 Sympathomimetics (agonists): Salbutamol, Salmeterol, Formeterol, Rimeterol, Bitolterol and Terbutaline (Nonspecific) ; adrenaline, ephedrine, isoproterenol, orciprenaline ii) Methyxanthines: Theophylline and derivatives aminophylline etc

Antiasthmatics-classification
1. Bronchodilators (Cont). iii) Anticholinergics: Ibratropium bromide and Triotropium bromide

Antiasthmatics-classification
2. Anti-inflammatory Agents (Long-term Relievers): i) Mast Cell stabilizer: Sodium cromoglycate, Nedocromil Ketotifen ii) Leukotriene antagonists: Montelucast, Zarfirlucast etc

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

2-Agonists:-Structures

Structures

2-Agonists:-Mode of Action

Stimulation of 2 receptor in bronchial smooth muscle cell membrane activation of adenyl cyclase cAMP Ca2+ SM relaxation Also activate -receptor on mast cell membrane decrease in mediator release Beta-receptors on mast cells are prone to desensitization uncertain beneficial effect

Beta-2 Agonists contd.

Beta-2 Agonists contd.

Results of Beta2 stimulation: Bronchodilatation without tachycardia Inhibition of release of chemical mediators by stabilization of mast cell membrane Prevention of mucosal edema Decrease microvascular permeability Increase ventilatory response to chemoreceptor stimuli Restoration of mucocilliary transport mechanism in respiratory tract

Beta-2 Agonists contd.


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, and worsening of angina pectoris Uses; Anaphylaxis, Asthma

Beta-2 Agonists contd.

Pharmacokinetics: Undergoes metabolism in gut wall Bioavailability is 50% Duration of action: 4-6 Hrs Salbutamol: preparation and doses Available as 2, 4 and 8 mg tablets, Bd or tid Syr. As 2mg/5 ml, Bd or tid As metered dose inhaler 100 g-400 g Nebulizer-2.5-5mg

Beta-2 Agonists contd

Adverse effects: Muscle tremor, restlessness, palpitation and nervousness

Vasodilatation reduction in mean arterial


pressure with tachycardia and also exacerbate pulmonary hypoxia due to mismatched of ventilation and perfusion

Beta-2 Agonists contd

Adverse effects: Hyperglycaemia and hyperlacticacidemia

Worsening of asthma on prolonged


inhalation (Tachyphylaxis).

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

Questions

Questions

Methylxanthines-Chemistry

Three naturally occurring methylxanthines caffeine, theophylline and theobromine Theophylline and its derivatives are used in asthma Chemically, they are purine structured and close to adenine and uric acid

Methylxanthines-Chemistry

Many salts of theophylline have been marketed but the most common one is aminophylline Aminophylline is highly water soluble and a stable mixture of theophylline and ethylene diamine
Uses: Bronchial asthma, COPD, infantile apnoea

Methylxanthines - structures

Methylxanthines Mode of action


Blockade of adenosine receptors no contraction of 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 sarcoplasmic reticulum

Methylxanthines - Pharmacokinetics

Well absorbed orally, crosses placenta and secreted in milk Metabolized in liver by demethylation and oxidation T1/2 is 6-12 Hrs, but faster in children and slow in elderly (prematures slow)

Methylxanthines - Pharmacokinetics

On prolonged and high dose elimination is zero 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/100ml may cause arrhythmia, convulsion and coma

Methylxanthines -Pharmacological actions (PD).

CNS: Stimulation: improves performance, sense of well being and allays fatigue thinking become clearer Higher doses nervousness, insomnia and restlessness High doses tremor, convulsion

Methylxanthines-Pharmacological actions

CVS: Stimulation of heart increase in heart rate, cardiac output

Dilatation of blood vessels including coronary reduced peripheral resistance

Methylxanthines- Pharmacological actions

CVS: But, constriction of cerebral vessels migraine use Transient in normal individual but in cardiac insufficiency may remain long Higher doses cardiac arrhythmia

Pharmacological actions of Methylxanthines contd

Kidney: Mild diuretic (decrease in tubular reabsorption of Na and also increase in renal blood flow)
Stomach: increase in acid-pepsin secretion

Pharmacological actions of Methylxanthines contd

Smooth muscles: relaxed bronchodilatation, but no effect on intestine and urinary tract, the major therapeutic action in asthma
Metabolic: Increase in BMR plasma fatty acid level raised

Methylxanthines-Clinical Uses

1. Bronchial asthma 2. COPD 3. infantile apnoea

Methylxanthines-Therapeutic Levels

Theophylline has a narrow therapeutic window Improvement in pulmonary function correlates with range of 520 mg/L.

Methylxanthines-Adverse effects

Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety occur at concentrations of 15 mg/L, commoner at >20 mg/L.
Higher levels (> 40 mg/L) may cause seizures or arrhythmias.

Methylxanthines Preparation 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/ml injection

Methylxanthines Preparation and Dosage

Hydroxyethyl theophylline: (Derriphylline) Available as 100/300 mg tablets or 220 mg/2ml injection

Signal transduction pathway for Bronchodilatation

Question

Question

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 ganglia predominate in the large and medium-sized airways

Postganglionic fibers supply the smooth muscle and submucosal glands of the airways as well as the vascular structures

Anticholinergics- Introduction
Atropine, Ipratropium bromide and tiatropium Release of acetylcholine (ACh) at these sites results in stimulation of muscarinic receptors and subsequent airway smooth muscle contraction and release of secretions from the submucosal airway glands

Distinct muscarinic receptors exist within the airways ; M1, M2 and M3 receptors

Anticholinergics contd.

M1 present in peribronchial ganglion cells where the preganglionic nerves transmit to the postganglionic nerves M2 receptors are present on the postganglionic nerves - they are activated by the release of acetylcholine and promote its reuptake into the nerve terminal

Anticholinergics Mode of action

M3 receptors are present on smooth muscle


Muscarinic receptor activation of these M3 receptors intracellular cAMP levels contraction of airway smooth muscle bronchoconstriction Anticholinergics compete for M3 receptor resulting in Ach antagonism and smooth muscle relaxation

Anticholinergics contd.

Atropine prototype of anticholinergic bronchodilators 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)

Anticholinergics contd.

Tiotropium - a structural analog of ipratropium High affinity for all muscarinic receptor subtypes Dissociates from the receptors much more slowly than ipratropium, esp. M3 receptors. 18 mcg once a day dosing

Anticholinergics- Clinical Uses

Used as Bronchodilators with salbutamol in refractory asthma As a treatment for COPD

Action of Bronchodilators
Selective b2 agonist

ATP cAMP Relaxation Theophyline 5-AMP

Ipratopium
Ach

Vagus nerve

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Mast cell stabilizers


Examples; Cromolyn Sodium, Nedocromil sodium Synthetic compound and chemically benzopyrone
Stabilizes mast cells inhibits degrannulation of mast cells and other inflammatory cells Mediator release is restricted Also prevent chemotaxis of eosinophils and neutrophils local inflammation is prevented

Mast cell stabilizers Contd

Basis of action may be due an alteration in the function of delayed chloride channels in the cell membrane, inhibiting cell activation

Mast cell stabilizers contd


Long term use prevents hyperactivity of bronchial tree No bronchodilatation or antagonism of constriction no action on acute cases
Not absorbed orally , given via MDI 1 mg/dose 2 puffs 4 times daily

Uses: Prophylaxis of asthma, allergic rhinitis and allergic conjunctivitis

Mast cell stabilizers contd


Adverse effects Minor and localized to the sites of deposition. Includes; throat irritation, cough, and mouth dryness, and, rarely, chest tightness, and wheezing. Reversible dermatitis, myositis, or gastroenteritis occurs in less than 2% of patients Few cases of pulmonary infiltration with eosinophilia and anaphylaxis have been reported..

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Leukotriene Antagonists

Leukotrienes, LTC4, LTD4 and LTB4 are important mediators of human asthma Montelucast and zafirlucast, LTD4-receptor antagonists, zileuton, a 5-lipoxygenase inhibitor Benefits bronchodilatation, reduced eosinophil counts and suppression of inflammation and hyperactivity

Leukotriene Antagonists
Montelucast and zafirlucast: Used in mild to moderate asthma as alternative to inhaled corticostroids Useful in children reduces dose of steroids and beta agonists Absorbed orally and highly plasma protein bound Half life: montelucast (3-6 hrs), zafirlucast (8-12 Hrs)

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

Leukotriene Antagonists

The receptor antagonists appear to be safe to use Zileuton is the least prescribed because of the QID dosing and occasional liver toxicity.

Questions

Questions

Corticosteroids
Mode of Action Not a bronchodilator but reduces airway inflammation and bronchial reactivity The broad anti-inflammatory efficacy is mediated in part by inhibition of production of inflammatory cytokines Antiinflammatory action reduction in mediators IL, TNF and PAF etc. and reduction in exudate formation

Corticosteroids-Contd
Clinical Uses Systemic steroids are useful in:

(Hydrocortisone and Prednisolone)

Acute asthma (status asthmaticus) not relieved or

worsening of obstruction inspite of bronchodilatator and inhaled steroid Chronic asthma failure of previously optimal regimen frequent symptoms of progressive severity Systemic therapy - devastating side effects

Corticosteroids-Contd

Regular or "controller" therapy is maintained with inhalational corticosteroids. Inhalation steroids are used regularly are beclomethasone dipropionate, budesonide, fluticasone propionate and triamcinolone acetonide

Corticosteroids-Contd

Adverse effects: oropharyngel candidiasis and dysphonia. Cataracts and in women osteoporosis, longterm . Doses: Beclomethasone: available as 50, 100 and 1200 mcg/ml MDI dose is 400 mcg/day Budesonide: available as 100, 200, 400 mcg/ml MDI dose is 200 mcg BD

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

Aerosols

Solid and liquid dispersed particles of 1 to 5 mm in size suspended in gas Do not coalesce and do not sink Aerosols are produced by MDI, Nebulizers and Rotahalers

Aerosols

Aim to deliver to the alveoli without settling in bigger tubes Particles > 10 mm are deposited primarily in the mouth & oropharynx. Particles < 0.5 mm are inhaled to the alveoli and exhaled without being deposited in the lungs.

Deposition can be increased by holding the breath


in inspiration.

Treatment - asthma

Step I: When symptoms are less than once daily - occasional inhalation of a short acting Beta-2 agonist salbutamol, terbutaline. If used more than once daily step II (Mild episodic asthma) Step II: Regular inhalation of low-dose steroids. Alternatively, cromoglycates. Beta-2 agonist as and whenever required (Mild chronic asthma)

Treatment - asthma

Step III: Inhalation of high dose of steroids (800 mcg) + Beta-2 agonist. Sustained release theophylline may be added. LT inhibitors may be tried instead of steroids (Moderate asthma with frequent exacerbations) spacers
Step IV: Higher dose of steroid (800 to 200 mcg) + regular beta-2 agonist (long acting salmeterol) Additional treatment with oral drugs LT antagonist or SR theophylline or oral beat-2 agonist

Status asthmaticus

May be called acute severe asthma Hydrocortisone hemisuccinate 100 mg stat IV and followed by 100-200 mg 4-8 hrly. or Infusion Oxygen inhalation

Status asthmaticus

Salbutamol (2.5 to 5 mg) + Ipratropium bromide (0.5 mg) intermittent inhalations with oxygen and nebulization Salbutamol or terbutaline IM or SC (0.4 mg) Antibiotics IV saline

Questions

Questions

Summary
1. 2. 3.

4.

The principles of the therapy of asthma remains unchanged since long Bronchodilators like short acting beta-2 agonists are used to reverse bronchospasm of an attack Glucocorticoids are used to arrest inflammation such as to reduce the severity and frequency of attacks In hospitalized cases short course of systemic steroids followed by dose tapering is often given

Summary -contd
1.

2.

3.

Long acting beta-2 agonists are added as inhalation agent if steroids cannot suppress symptoms Methylxanthines are not preferred anymore due to their modest efficacy and low therapeutic index Newer agents like specific PDE4 inhibitors are under evaluation

Herbal Products, can they cure asthma?

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