What’s New in Respiratory Medication Delivery?J O E N E KO L A , P H A R M . D. , B C P S

J O S H UA H I T E , P H A R M . D.

L AU R E N P O H R E N , P 4

Objectives

1. Review current developments in the alternative delivery of surfactant

2. Review the variety of inhalers and specific devices currently available

3. Explore the recent pulmonary medications and how they fit into current practice guidelines

Provide a thin film that lowers surface tension in lungs during breathing to prevent alveolar collapse during exhalation, and to minimize work during inhalation.

Consists predominantly of lipids + smaller component of surfactant proteins

Phospholipids: dipalmitoylphosphatidylcholine (DPPC)

Surfactant Proteins A – D

B – hydrophilic protein

In premature infants, formation of lung surfactant is incomplete, leading to increased rates of RDS

Use of antenatal steroids reduce incidence of RDS

AAP recommends prophylactic surfactant be administered primarily to infants that are <30 weeks gestational age

Risk factors: Premature birth

Symptoms: cyanosis, labored and rapid breathing, grunting, retractions, nasal flaring, tachycardia, frequent desaturations

Complications: atelectasis, pneumothorax, sepsis, brain or lung hemorrhage, PDA, developmental delays, chronic lung disease, BPD, longer hospital stays

Oxygen and ventilation◦ CPAP

◦ IMV

◦ Endotracheal intubation

Prophylactic Surfactant Administered if at high risk, before

development of RDS

After initial resuscitation, within 30 minutes after birth

Rescue/Treatment Surfactant

Established RDS

Between 2-12 hours after birth

CPAP – reduced mortality from 18% in 1960s to 7% in 1980s

Exosurf – 30% decrease in mortality

80% of the decline in US infant mortality between 1989 and 1990 is attributed solely to the use of surfactant

What is on the way??? Aerosurf®

Lucinactant (Aerosurf®)

Lucinactant (Aerosurf®)

Now on to the inhalers!

SAMA LAMA ICS SABA LABA

Metered-Dose Inhalers (MDIs)Pressurized canister with metering valve filled with solution or micronized powder aerosols

Delivers particles 1-5 micrometers in size for deposition in lower airway

Requires priming prior to use

Product must to shaken to provide accurate suspension dispersal

Requires coordination of actuation and inhalation

Patient must have slow, deep inspiratory flow

Dry Powder Inhalers (DPIs)Dry micronized powder inhalers

Breath-actuated

Requires minimal hand-lung coordination

Patient must have a deep, forceful inspiratory flow.

◦ Some DPIs require rapid inspiration for activation

Inspiratory flow requirements vary across brands◦ Some DPIs require inspiratory flow of 60 L/min

Multiple brand names◦ Pressair, Respiclick, Flexhaler, Diskus, Ellipta,

Aerolizer, Neohaler, Handihaler, Twisthaler

Soft Mist Inhalers (SMIs)Aerosolized solutions delivered through microelectronic dosimetric systems

Requires cartridge insertion and priming of device prior to use

Provides 2-3x higher pulmonary deposition versus MDI

Sustained duration of medication delivery versus MDI

Patient must have slow, deep inspiratory flow

Asthma

Adapted from The National Asthma Education and Prevention Program: Guidelines for the Diagnosis and Management of Asthma

Asthma InhalersShort Acting Beta Agonists

(SABA)

Drug Device Brand Dose

AlbuterolMDI; RespiClick (DPI)- ProAir

Proair; Proventil; Ventolin

90 mcg/actuation

Levalbuterol MDI Xopenex45 mcg/actuation

Asthma InhalersInhaled Corticosteroids

(ICS)

Drug Device Brand Dose

Beclomethasone MDI QVAR40 or 80 mcg/actuation

BudesonideFlexhaler (DPI)

Pulmicort90 or 180 mcg/actuation

Ciclesonide MDI Alvesco80 or 160 mcg/actuation

Flunisolide MDI Aerospan80 mcg/actuation

Fluticasone priopionate

MDI; Diskus (DPI)

Flovent44, 110, 220;50, 100, 250 mcg/actuation

Fluticasonefuroate

Ellipta (DPI) Arnuity100 or 200 mcg/actuation

MometasoneMDI;Twisthaler(DPI)

Asmanex100 or 200; 110 or 220mcg/actuation

Asthma InhalersInhaled Corticosteroids + Long Acting Beta Agonists

(ICS+LABA)

Drug Device Brand Dose

Fluticasone propionate/salmeterol

MDI; Diskus Advair

Initial 45/21(MDI);100/50 (DPI)mcg/actuation

Fluticasone propionate/salmeterol

MDI; Respiclick

Teva (generic)Initial 55/14 (MDI and DPI) mcg/actuation

Fluticasone furoate/vilanterol

Ellipta Breo100/25 or 200/25 mcg/actuation

Mometasone/formoterol

MDI Dulera100/5 or 200/5mcg/actuation

Budesonide/formoterol

MDI Symbicort80/4.5 or 160/4.5mcg/actuation

COPD

© 2017 Global Initiative for Chronic Obstructive Lung Disease

COPD

© 2017 Global Initiative for Chronic Obstructive Lung Disease

COPD InhalersShort Acting Muscarinic Antagonists

(SAMA) and (SAMA+SABA)

Drug Device Brand Dose

Ipratropium MDI Atrovent17mcg/actuation

Albuterol/ipratropium

Respimat Combivent100/20mcg/actuation

COPD InhalersLong Acting Muscarinic Antagonists

(LAMA)

Drug Device Brand Dose

TiotropiumHandidhaler;Respimat

Spiriva18; 2.5 (2 puff)mcg/actuation

AclidiniumPressair (DPI)

Tudorza400 mcg/actuation

Umeclidinium Ellipta (DPI) Incruse62.5 mcg/actuation

GlycopyrrolateNeohaler(DPI)

Seebri15.6mcg/actuation

COPD InhalersLong Acting Beta Agonists

(LABA)

Drug Device Brand Dose

Salmeterol Diskus (DPI) Serevent50 mcg mcg/actuation

FormoterolAerolizer (DPI)

Foradil12 mcg/actuation

OlodaterolRespimat(SMI)

Striverdi2.5 mcg/actuation

IndacaterolNeohaler (DPI)

Arcapta75mcg/actuation

COPD InhalersLong Acting Muscarinic Antagonists + Long Acting Beta Agonists

(LAMA+LABA)

Drug Device Brand Dose

Tiotropium/ olodaterol

Respimat Stiolto2.5/2.5mcg/actuation

Glycopyrrolate/ indacanterol

Neohaler (DPI)

Utibron15.6/27.5mcg/actuation

Glycopyrrolate/ formoterol

MDI Bevespi9/4.8 mcgmcg/actuation

Umeclidinium/ vilanterol

Ellipta (DPI) Anoro62.5/25mcg/actuation

COPD InhalersInhaled Corticosteroids + Long Acting Beta Agonists

(ICS+LABA)

Drug Device Brand Dose

Fluticasone propionate/ salmeterol

MDI; Diskus (DPI)

AdvairInitial: 45/21; 100/50 mcg/actuation

Budesonide/formoterol

MDI Symbicort80/4.5 or 160/4.5mcg/actuation

Fluticasone furoate/vilanterol

Ellipta Breo100/25 or 200/25 mcg/actuation

Ultra Long Acting Beta Agonists

Require only once-daily dosing

Onset of action similar to albuterol (less than 5 minutes)

Considered for patients with frequent and persistent symptoms and those at higher risk for exacerbation

◦ Gold Guidelines B, C, D

Indacanterol has been shown to have beneficial effects on health care status, frequency of exacerbations and bronchodilation

◦ In direct comparison trials, greater effect on bronchodilation than salmeterol and formoterol

Olodanterol studies have demonstrated similar effects on FEV1 and symptoms compared with other long-acting bronchodilators

◦ Exacerbation frequency has not been evaluated

Indacanterol

Olodanterol

Vilanterol

Ultra Long Acting Beta Agonists

MOA◦ Partial B agonist - high intrinsic efficacy at the B2 agonist receptor

◦ Stimulates intracellular enzyme adenyl cyclase to increase the formation of cyclic adenosine monophosphate (cAMP)

◦ Increased cAMP levels cause relaxation of bronchial smooth muscle

Indacanterol◦ 24-fold greater agonist activity B2 receptor vs B1

◦ 20-fold greater agonist activity B2 receptor vs B3

Olodanterol◦ 241-fold greater agonist activity at B2 receptor vs B1

◦ 2299-fold greater agonist at B2 receptor vs B3

Indacanterol

Olodanterol

Vilanterol

Long Acting Muscarinic Antagonists

Once or twice daily dosing◦ Dissociate slowly from M3 receptor leading to prolong

bronchodilation

Considered for patients with frequent and persistent symptoms and those at higher risk for exacerbation

◦ Gold Guidelines B, C, D

Acts locally with minimal anticholinergic side effects◦ Dry mouth most commonly reported

Aclindium has been shown to demonstrate improvements in spirometry and symptom scores compared to tiotropium.

◦ Reduction in exacerbation frequency has not been observed to date.

Glycopyrrolate has demonstrated equal efficacy to tiotropium in clinical trials for FEV1, dyspnea score, and exacerbation reduction

Umeclindium has primarily been evaluated as part of a combination bronchodilator regimen

Aclidinium

Umeclidinium

Glycopyrrolate

Long Acting Muscarinic Antagonists

MOA◦ Bind to muscarinic receptors (M3) in airway smooth muscle and

mucus glands and antagonize effect of acetylcholine

◦ Inhibit the cholinergic effects of bronchoconstriction and mucus secretion

Aclidinium

Umeclidinium

Glycopyrrolate

Pharmacy TipsBe aware of both drug and device brand names (and different strengths)

Consult patient on appropriate use of medication (storage, expiration, priming)

Use of combination products to increase compliance (ICS-LABA-LAMA?)

Be aware of insurance formularies and manufacturer coupons◦ (https://www.needymeds.org/)

Always reinforce proper technique ◦ (https://www.youtube.com/watch?v=nvwR74XpKUM)

Don’t automatically assume medication compliance

Questions

ReferencesAsthma. In: Wells BG, DiPiro JT, Schwinghammer TL, DiPiro CV. eds. Pharmacotherapy Quick Guide New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.library1.unmc.edu:2048/content.aspx?bookid=2177&sectionid=165474748. Accessed October 15, 2017.

Bourdet, SV, Williams, DM. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.library1.unmc.edu:2048/content.aspx?bookid=1861&sectionid=134126356. Accessed October 15, 2017.

Chronic Obstructive Pulmonary Disease. In: Wells BG, DiPiro JT, Schwinghammer TL, DiPiro CV. eds. Pharmacotherapy Quick Guide New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.library1.unmc.edu:2048/content.aspx?bookid=2177&sectionid=165474800. Accessed October 15, 2017.

Sorkness CA, Blake KV. Asthma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.library1.unmc.edu:2048/content.aspx?bookid=1861&sectionid=146058008. Accessed October 15, 2017.

Global Strategy for the Diagnosis, Management and Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. http://goldcopd.org. Accessed October 15, 2017.

Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) 2017. http://ginasthma.org/. Accessed October 15, 2017.

ReferencesCasarosa P, Bouyssou T, Germeyer S, Schnapp A, Gantner F, Pieper M. Preclinical Evaluation of Long-Acting Muscarinic Antagonists: Comparison of Tiotropium and Investigational Drugs. Journal of Pharmacology and Experimental Therapeutics. 2009;330(2):660-668. doi:10.1124/jpet.109.152470.

Dean Hess, Dhand R. Delivery of Inhaled Medication in Adults. UpToDate.https://library1.unmc.edu/login?url=http://www.uptodate.com/online/content/search.do?unid=^u&srcsys=UTD1178453&eiv=2.1.0. April 24, 2017. February 16, 2017. Accessed October 15, 2017.

Ferguson, Gary, Make B. Management of Refractory Chronic Obstructive Pulmonary Disease. UpToDate.https://library1.unmc.edu/login?url=http://www.uptodate.com/online/content/search.do?unid=^u&srcsys=UTD1178453&eiv=2.1.0. April 24, 2017. February 16, 2017. Accessed October 15, 2017.

Fanta, Christopher. Overview of asthma management. UpToDate.https://library1.unmc.edu/login?url=http://www.uptodate.com/online/content/search.do?unid=^u&srcsys=UTD1178453&eiv=2.1.0. April 24, 2017. February 16, 2017. Accessed October 15, 2017.

Lemanske, Jr, Robert. Beta agonists in asthma: controvery in use. UpToDate.https://library1.unmc.edu/login?url=http://www.uptodate.com/online/content/search.do?unid=^u&srcsys=UTD1178453&eiv=2.1.0. April 24, 2017. February 16, 2017. Accessed October 15, 2017.

Dear Pharmacist. How to use your inhaler. Dearpharmacistinfo. 2017. Available at: https://www.dearpharmacist.info/health-a-to-z/how-to-use-your-inhaler/. Accessed October 19, 2017.

What’s New in Respiratory Medication Delivery?J O E N E KO L A , P H A R M . D. , B C P S

J O S H UA H I T E , P H A R M . D.

L AU R E N P O H R E N , P 4