Download - Brochial asthma drugs
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Drugs for Bronchial Asthma
Dr. Sanooz Raheem
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Objectives:• Outline the various groups of drugs used in the management of Bronchial Asthma• Describe the pharmacological properties of the following drugs
SalbutamolTerbutalineSalmeterol
•List the pharmacological actions of Methyl xanthines
• Describe the pharmacological properties of Theophylline• List examples of anticholinergics• Describe the pharmacological properties of Ipratropium Bromide• List examples of Mast cell stabilizers• Describe the role of Mast cell stabilizers in the management of bronchial asthma• Describe the pharmacological properties of Sodium chromoglycate• Explain the role of Corticosteroids in the management of bronchial asthma• List examples & their pharmacological properties of corticosteroids used in the management
of bronchial asthma• Outline the management of Acute severe Asthma (Status asthmaticus)
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Bronchial asthma• An inflammatory condition • Hyper responsiveness of tracheobronchial smooth muscles to variety of stimuli • Results in- Narrowing of air tubes - Increased secretion- Mucosal oedema - Mucus plugging
• Symptoms:- dyspnoea, wheezing, cough, limitation of activity
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Pathophysiology
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Bronchial asthmaTypes of asthma based on etiology:
• Extrinsic asthma: • Allergy-induced• Commonly suffer from other atopic diseases• Mostly episodic, Less prone to status asthmaticus
• Intrinsic asthma: • No immunological basis for their condition• Perennial• More prone to status asthmaticus
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Bronchial asthma• Types of Asthma based on clinical condition:
• Mild episodic asthma:• Seasonal asthma:• Mild chronic asthma:• Moderate asthma with frequent exacerbations:• Severe asthma:• Status asthmaticus/Refractory asthma
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Approach for treatment of Asthma
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Approaches to treatment 1. Prevention of AG:AB reaction- avoid antigen2. Neutralization of IgE- Omalizumab 3. Suppression of inflammation and bronchial hyperactivity-
corticosteroids 4. Prevention of release of mediators- mast cell stabilizers 5. Antagonism of released mediators- leukotriene antagonists,
antihistamines, PAF antagonists 6. Blockade of constrictor neurotransmitter- anticholinergics 7. Mimicking dilator neurotransmitter- sympathomimetics 8. Directly acting bronchodilators- methylxanthines
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Drug administration • Inhalation:- Directly delivers the drug to airways - Dose required is less- Side effects reduced • Oral: - If inhalation is not possible - Systemic side effects• Parenteral: - Beta agonists, corticosteroids, aminophylline can be given- Given when inhalational drugs are inadequate
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Classification of drugs for asthma• BRONCHODILATORS:
1. β2-Sympathomimetics: Salbutamol, Terbutaline, Bambuterol, Salmeterol, Formoterol, Ephedrine
2. Methyl Xanthines: Theophylline, Aminophylline, Choline theophyllinate, Hydroxyethyl theophylline, Doxophylline.
3. Anticholinergics: Ipratropium bromide, Tiotropium bromide• LEUKOTRIENE ANTAGONISTS: Montelukast, Zafirlukast• MAST CELL STABILIZERS: Sodium cromoglycate, Ketotifen• CORTICOSTEROIDS
1. Systemic: Hydrocortisone, Prednisolone2. Inhalational: Beclomethasone, Budesonide, Fluticasone,
Flunisolide• ANTI Ig-E ANTIBODY: Omalizumab
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Sympathomimetics• Bronchodilataion • Minimal effect on airway when inflammation is chronic • Mechanism of action:
• β2 stimulation increased cAMP formation in bronchial muscle cellrelaxation
• Increases cAMP in mast cells and other inflammatory cells • Also decreases mediator release
• Should be used cautiously in hypertensives, IHD, ptn on digitalis • Most effective and fast acting bronchodilator on inhalation • E.g. Salbutamol, Terbutaline, Bambuterol, Salmeterol, Formoterol, Ephedrine• Short acting used for immediate relief and long acting for prophylaxis with steroid
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Short acting: Mild to mod. Symptoms responds rapidly to inhalation Regular treatment with short acting inhalation less effectiveNot appropriate prophylactic TxInhalation before exercise reduces exercise induced asthma EX: salbutamol, Terbutaline
Long acting:Ex: Formoterol, SalmetrolGiven as inhalationUsed only in ptns with regular steroid inhalation Long term control of asthma and nocturnal asthma control Salmetrol no relief in asthma attackFormoterol short term symptom relief and prevention of exercise induced bronchospasm
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Find out the recommendations to use long acting beta2 agonists in BA?
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SympathomimeticsSalbutamol• Highly selective β2 agonist• Less prominent cardiac side effects • Inhaled Salbutamol produces bronchodilatation in 5 min and
action lasts for 2-4 hrs• Side effects: Palpitations, restlessness, nervousness, throat
irritation, ankle edema, muscle tremors, Hypokalaemia • Not suitable for round the clock prophylaxis, but terminates
attacks of asthma • Oral preparations: presystemic metabolism, bioavailability 50%,
duration 4-6 hours• Use of oral salbutamol: Reserved for patients who cannot
correctly use inhalers, Used as an adjuvant in severe asthma
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Dose • OralAdults 4mg 3-4 times/day, max single dose 8mg, elderly start with 2mgChildren 2-6yrs 3-4times/day, 6-12 yrs 2mg 3-4times/day • IV injection- 250mic.g, repeat if necessary • IV infusion- 5mic.g/minute initially, adjust according to response & HR
3-20mic.g/min range • Aerosol- 100-200 mic.g upto 4 times/day, children 100-200mic.g upto
4 times/day • Inhalation of powder- 200-400mic.g upto 4times/day • Nebulize- 2.5-5mg 4times/day or more
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Terbutaline: • Similar to Salbutamol• Dose: Orally 2.5mg tds initially and upto 5mg tds later • Inhaled Salbutamol and Terbutaline are currently the most popular
drugs for quick reversal of bronchospasm• Regular use of both does not reduce bronchial hyperactivity – long
term use reduced responsiveness • Beta2 receptors down regulated on long term use • Long term use - long acting beta2 agonists• Short acting drugs- symptomatic relief of wheezing
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Sympathomimetics
Salmeterol:• It is the first long acting selective β2 agonist (LABA) with slow onset of
action• Used by inhalation on a twice daily schedule• Used for maintenance therapy and nocturnal asthma• Not useful for acute asthma • More beta2 selective than salbutamol • In long term used with corticosteroids Dose: adult 50mic.g – 100mic.g twice daily
child 5-12 yrs 50mic.g twice daily
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Formeterol:• Another LABA• Acts for 12 hrs• Compared to Salmeterol it has faster onset of action
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Preparations • Inhalation:Pressurized MDI- mild to moderate asthma Adding a spacer device improve drug delivery Salbutamol, terbutaline, fenoterol- 3-5 hrs of duration of actionSalmetrol, formoterol- 12hrs Nebulizer- salbutamol/terbutaline solution usedSevere asthma with oxygen• Oral: when inhalations can not be managed by ptns • Parenteral: salbutamol/ terbutaline in severe or life threatening asthma Monitor, adjust dose – response, HR
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Cautions • Hyperthyroidism• Cardiovascular disease • Arrhythmias• Susceptibility to QT prolongation • Hypertension • Diabetes- monitor blood sugar
** can lead to hypokalemia, special concern
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Methyl Xanthines• Naturally occuring Methyl Xanthine alkaloids are Caffein,
Theophylline and Theobromine
• Mechanism of action: • Inhibition of phosphodiesterase (PDE) increased cAMP
Bronchodilatation, cardiac stimulation, vasodilation• Blockade of adenosine receptorsrelaxes smooth muscles• Release of Ca2+ from sarcoplasmic reticulum, especially in
skeletal and cardiac muscle (only at higher concentrations)
• E.g: Theophylline, Aminophylline, Choline theophyllinate, Hydroxyethyl theophylline, Doxophylline
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Methyl Xanthines• Theophylline:
• Well absorbed orally• T1/2 is 7-12 hrs• Distributed in all tissues• 50% plasma protein bound • Metabolized in liver • Toxic dose is close to therapeutic dose • T ½ variation is important • Aminophylline- theophylline+ ethylenediamine, given IV very slowly,
SE- convulsions, arrhythmia• Caution: cardiac disease, Htn, hyperthyroidism, peptic ulcer, elderly, epilepsy,
hypokalemia
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• Dose reduction needed in - Age > 60 yrs- CHF- Pneumonia - Liver failure , viral infections • Has narrow margin of safety • Additive effect with Beta2 agonist- increase SE, hypokalaemia • Side effects: headache, nervousness, nausea, CNS toxicity in children, gastric
pain (with oral), rectal inflammation (with rectal suppositories), pain at site of injection (i.m), Rapid IV can cause precordial pain, syncope and sudden death, hypotension, palpitations, tremor, insomnia
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Interactions: metabolism is induced by smoking, phenytoin, rifampicin, phenobarbitoneMetabolism is inhibited by erythromycin, ciprofloxacin, cimetidine, OCPs, allopurinolTheophylline induces the effects of- furosemide, sympathomimetics, digitalis, oral anticoagulants, hypoglycaemics Reduces the effects of- phenytoin, lithium Uses: Bronchial asthma and COPD, Apnoea in premature infant,
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Anticholinergics• Atropinic drugs cause bronchodilatation by blocking M3 receptor
mediated cholinergic constrictor tone• Short term relief • Act primarily in larger airways• Produce slower response than inhaled sympathomimetics• Better suited for regular prophylactic use• Combination of inhaled Ipratropium with β2 agonists produce more
marked and longer lasting bronchodilatation.• Refractory asthma treated with combination preparations
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• PK: maximal effect by 30-60min use, duration of action 3-6hrs,• Caution: BPH, BOO, angle-closure glaucoma • SE: dry mouth, constipation, cough, paradoxical bronchospasm,
headache, rarely N, AF, urinary retention, • E.g: Ipratropium bromide- shorter acting,Dose- aerosol inhalation20-40mic.g 3-4 times/day, powder inhalation-
40mic.g 3-4times/day, nebulize 250-500 mic.g 3-4 times/day • Tiotropium bromide-longer acting
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Leukotriene antagonists• Cystenyl leukotrienes important mediators in bronchial asthma • Competitively antagonize cysLT1 receptor mediated bronchoconstriction,
increased vasodilatation and recruitment of eisonophils• Indicated for prophylactic therapy of mild to moderate asthma as alternative to
inhaled glucocorticoids- efficacy low • May obviate need for inhaled glucocorticoids• Additive effect with steroids and long acting beta2 agonists • Safe drugs in children • No value in COPD
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• Side effetcs: headache, rashes, Churg-Strauss syndrome • PK: well absorbed orally, highly plasma protein bound, T ½ Monte-3-6
hrs, Zafir- 8-12 hrs • E.g: Montelukast, Zafirlukast• Dose: Montelukast- adult 10mg once/day evening, 6-15 yrs 5mg/day
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Mast cell stabilizersSodium Cromoglycate •Given 4-6wks to assess response , dose adjusted according to response •Dose withdrawal done gradually •Inhibits degranulation of mast cells •Release of asthma mediators inhibited •Chemotaxis of inflammatory cells inhibited •Long term Tx- decreases cellular immunity response, reduced bronchial hyperactivity, •Less effective in prophylaxis compared to steroids •No brochodilatation- not suitable for acute asthma
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• PK: not absorbed orally, given as aerosol, • Use: BA, Allergic rhinitis, Allergic conjunctivitis• AR: systemic toxicity minimal, rarely nasal congestion, headache,
dizziness, arthralgia, rashes• Dose: 10mg 4-8 times/day
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Ketotifen•An antihistamine •Stimulation of immunogenic, inflammatory cells and mediator release are reduced •Not a bronchodilator•Long term use can provide mild symptomatic relief •Use: BA, atopic dermatitis, perennial rhinitis, conjunctivitis, urticaria, food allergy •AR: well tolerated, sedation, dry mouth, dizziness, nausea, weight gain
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Corticosteroids• These do not cause bronchodilatation, • Reduce bronchial hyper-reactivity, mucosal edema, by
supressing inflammatory response to AG:AB reaction• More complete and sustained symptomatic relief than
bronchodilators/ cromoglycate• Improve airflow, reduce asthma exacerbations, influence
airway remodeling and retard disease progression • Increase airway smooth muscle responsiveness to Beta2
agonists • Takes 3-7 days to alleviate symptoms after starting Tx
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Regular corticosteroid inhalation needed• If ptn requires beta2 agonist more than twice a week• If symptoms disturb sleep more than once a week• If the patient has suffered exacerbations in last 2 years requiring a
systemic steroid or nebulized bronchodilator
** regular use of inhaled steroids reduce the exacerbtions
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• Two forms are used Systemic and Inhalational
1. Systemic/Oral Cortico Steroid (OCS)• Used in severe chronic asthma and Status asthmaticus• E.g: Hydrocortisone, Prednisolone
2. Inhalational Cortico Steroid (ICS)• Step one for all asthma patients- airway inflammation and bronchial remodeling
from beginning • Safe during pregnancy• Benefits: suppress bronchial inflammation, increase PEFR, reduce need for rescue
beta2 agonist inhalations, prevent acute episodes of asthma • No role during acute asthma • Peak effect by 4-7 days and effects last for few weeks after discontinuation of Tx • Side effetcs:hoarseness of voice, dysphonia, sore throat, oropharyngeal candidiasis ,
systemic effects if higher doses inhaled for longer duration-adrenal suppression • E.g: Beclomethasone, Budesonide, Fluticasone, Flunisolide
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Oral corticosteroid Tx• Acute attack with short course of oral steroid • If ptn on inhalers can stop oral Tx abruptly • Taper in ptns on several courses of steroids/ period of maintanence • In chronic asthma if response to other drugs inadequate long term
administration of oral corticosteroid • If ptns on long term oral steroid transfer slowly to inhalers • Given as single dose in the morning
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Budesonide:•High topical systemic activity ratio •Small amount absorbed and rapidly metabolized•Less systemic effects•Dose: 200-400mic.g bd-qid
200-400mic.g/day in allergic rhinitis
•SE: nasal irritation, sneezing, crusting, itching of throat, dryness
•CI: presence of infection/nasal ulcers
Fluticasone propionate:•High potency •Longer duration of action•Negligible oral bioavailability •Dose 100-250mic.g bd, max 1000mic.g/day
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Pharmacokinetics of inhaled corticosteroids
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Anti-IgE antibody Omalizumab: Humanized monoclonal antibody against IgE Given S.C Neutralizes free IgE in circulation Useful in severe extrinsic asthma
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What is inhaler?
• An inhaler is a medical device used for delivering medication into the body via the lungs.
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Inhaler devicesDifferent inhaler devices suit different people. Inhaler devices can be divided into four main groups:•Pressurised metered dose inhalers (MDIs).•Breath-activated inhalers - MDIs and dry powder inhalers.•Inhalers with spacer devices.•Nebulisers.
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DevicesMetered-dose inhalers
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PropertiesA liquid propellantInhalation technique is critical for optimal drug delivery
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Common errors include:•Not shaking the inhaler before using it.•Inhaling too sharply or at the wrong time.•Not holding your breath long enough after breathing in the contents.
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How to useWithout chamber
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To use an MDI:
•Shake the inhaler well before use (3 or 4 shakes)•Remove the cap•Breathe out, away from your inhaler•Bring the inhaler to your mouth. Place it in your mouth between your teeth and close you mouth around it.•Start to breathe in slowly. Press the top of you inhaler once and keep breathing in slowly until you have taken a full breath.•Remove the inhaler from your mouth, and hold your breath for about 10 seconds, then breathe out.•Metered Dose Inhaler
•If you need a second puff, wait 30 seconds, shake your inhaler again, and repeat steps 3-6. After you've used your MDI, rinse out your mouth and record the number of doses taken.
•Store all puffers at room temperature
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Cleaning Your MDITo clean your MDI, follow the instructions that came with it. In most cases, they will advise you to:1.Remove the metal canister by pulling it out.2.Clean the plastic parts of the device using mild soap and water. (Never wash the metal canister or put it in water.)3.Let the plastic parts dry in the air (for example, leave them out overnight).4.Put the MDI back together.5.Test the MDI by releasing a puff into the air.
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Advantages Vs DisadvantagesAdvantages
•Rapid application•Handling•Multidose
Disdvantages•Hand-breathe coordinations•İneffective use in poor ventilated patients•Oropharyngeal deposition and local side effects
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SpacersAlso known as aerosol-holding chambers, add-on devices and spacing devices, spacers are long tubes that slow the delivery of medication from pressurized MDIs.
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With chamber
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Using a Spacer:
1.Shake the inhaler well before use (3-4 shakes)2.Remove the cap from your inhaler, and from your spacer, if it has one3.Put the inhaler into the spacer4.Breathe out, away from the spacer5.Bring the spacer to your mouth, put the mouthpiece between your teeth and close your lips around it6.Press the top of your inhaler once7.Breathe in very slowly until you have taken a full breath. If you hear a whistle sound, you are breathing in too fast. Slowly breath in.8.Hold your breath for about ten seconds, then breath out.
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Cleaning Your SpacerTo clean your spacer, follow the instructions that come with it. In most cases, they will advise you to:1.Take the spacer apart.2.Gently move the parts back and forth in warm water using a mild soap. Never use high-pressure or boiling hot water, rubbing alcohol or disinfectant.3.Rinse the parts well in clean water.4.Do not dry inside of the spacer with a towel as it will cause static. Instead, let the parts air dry (for example, leave them out overnight).5.Put the spacer back together.
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Dry powder inhalers
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DISKUS®A DISKUS® is a dry-powder inhaler that holds 60 doses. It features a built-in counter,
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using DISKUS®:1.Open your DISKUS®: Hold it in the palm of your hand, put the thumb of your other hand on the thumb grip and push the thumb grip until it "clicks" into place2.Slide the lever away from you as far as it will go to get your medication ready3.Breathe out away from the device4.Place the mouthpiece gently in your mouth and close your lips around it5.Breathe in deeply until you have taken a full breath6.Remove the DISKUS® from your mouth7.Hold your breath for about ten seconds, then breathe out8.Always check the number in the dose counter window to see how many doses are left.
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If you drop your DISKUS® or breathe into it after its dose has been loaded, you may cause the dose to be lost. If either of these things happens, reload the device before using it.
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Turbuhaler®A Turbuhaler® is a dry-powder inhaler available in an easy-to-use format.
Clean your Turbuhaler® as needed. To do this, first wipe the mouthpiece with a dry tissue or cloth. Never wash the mouthpiece or any other part of the Turbuhaler® - if it gets wet, it won't work properly.
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How to use a Turbuhaler®:1.Unscrew the cap and take it off. Hold the inhaler upright2.Twist the coloured grip of your Turbuhaler® as far as it will go. Then twist it all the way back. You have done it right when you hear a "click"3.Breathe out away from the device4.Put the mouthpiece between your teeth, and close your lips around it. Breathe in forcefully and deeply through your mouth5.Remove the Turbuhaler® from your mouth before breathing out6.Always check the number in the side counter window under the mouthpiece to see how many doses are left.7. When finished, replace the cap.
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Diskhaler®A Diskhaler® is a dry-powder inhaler that holds small pouches (or blisters), each containing a dose of medication, on a disk. The Diskhaler® punctures each blister so that its medication can be inhaled.
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To use your Diskhaler®:1.Remove the cover and check that the device and mouthpiece are clean.2.If a new medication disk is needed, pull the corners of the white cartridge out as far as it will go, then press the ridges on the sides inwards to remove the cartridge.3.Place the medication disk with its numbers facing up on the white rotating wheel. Then slide the cartridge all the way back in.4.Pull the cartridge all the way out, then push it all the way in until the highest number on the medication disk can be seen in the indicator window.5.With the cartridge fully inserted, and the device kept flat, raise the lid as far as it goes, to pierce both sides of the medication blister.6.Move the Diskhaler® away from your mouth and breathe out as much as you can until no air is left in your lungs.7.Place the mouthpiece between your teeth and lips, making sure you do not cover the air holes on the mouthpiece. Inhale as quickly and deeply as you can. Do not breathe out.8.Move the Diskhaler® away from your mouth and continue holding your breath for about 10 seconds.9.Breathe out slowly.10.If you need another dose, pull the cartridge out all the way and then push it back in all the way. This will move the next blister into place. Repeat steps 5 through 9.11.After you have finished using the Diskhaler®, put the mouthpiece cap back on.
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How to use a spacer
1.Take off the cap and shake the inhaler2.Put the inhaler into the end of your spacer3.Breathe out gently as long as feels comfortable4.Put the mouthpiece between your teeth and lips, making a seal so no medicine can escape5.Press the canister to put one puff of your medicine into the spacer6.Breathe in slowly and steadily (not hard and fast) through the mouthpiece7.Remove the spacer from your mouth and hold your breath for 10 seconds (or for as long as is comfortable) then breathe out slowly8.If you need a second dose, wait 30 seconds, remove the inhaler, shake it and repeat the steps above.
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How to help your child use a spacer1.Explain to your child what's going to happen and what they need to do2.Remove the cap and shake the inhaler - your child can help with this3.Put the inhaler into the end of the spacer4.Place the mouthpiece between your child's teeth and lips, making a seal so no medicine can escape5.Press the canister once to put one puff of your child's inhaler medicine into the spacer6.Get them to breathe in and out of the mouthpiece five times7.Repeat from step 2 for each puff of the inhaler needed, remembering to take out the inhaler and shake it before each puff
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1.Remove the cap and shake the inhaler2.Place the inhaler in the end of the spacer3.Put the mask over your child's nose and mouth, making a good seal so no medicine can escape4.Press the canister once so that one puff of medicine goes into the inhaler5.Count to 10 slowly (in your head, say 'One, and two, and three, etc' to get the timing right)6.If you need to give further doses, repeat all the steps again, remembering to remove the inhaler and shake it between puffs7.Wipe your baby's face afterwards, to remove any medicine that might have landed on their skin
How to use a spacer and a mask with your baby
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Cleaning spacerWash your spacer once a month using detergent, such as washing-up liquid. Don't scrub the inside of the spacer as this affects the way it works. Leave it to air-dry as this helps to prevent the medicine sticking to the sides of the chamber and reduces the static. Wipe the mouthpiece clean of detergent before you use it again. Don't worry if your spacer looks cloudy - that doesn't mean it's dirty.
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AEROSOL DELIVERY METHOD AGE OF PATIENTDry powder inhaler Five years or older
MDI Older than five years
MDI with chamber Older than four years
MDI with chamber and mask Four years or younger
MDI with endotracheal tube Neonate
Small-volume nebulizer Two years or younger
General Age Requirements for Correct Use of Various Aerosol Delivery Devices
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