2023_RS1_Inhalants_LEO.pptx

Pharmacology of Inhalants Dry Powder Inhaler Jet Nebulizer Ultrasonic Nebulizer Goals • Understand the mechanisms and factors affecting deposition of inhaled drugs in the respiratory tract and systemic absorption of inhaled drugs. • Identify specific properties of available pulmonary delivery de...

Pharmacology of Inhalants Dry Powder Inhaler Jet Nebulizer Ultrasonic Nebulizer Goals • Understand the mechanisms and factors affecting deposition of inhaled drugs in the respiratory tract and systemic absorption of inhaled drugs. • Identify specific properties of available pulmonary delivery devices. • Describe the drugs that are available as inhalants. Objectives • Factors affecting drug deposition in the respiratory tract and systemic absorption of inhaled drugs: Particle size, airflow velocity, short diffusion difference, lack of a first-pass effect, role of alveolar macrophages. • Characteristics of pulmonary drug delivery devices: Pressurized metered-dose inhalers, spacer chambers, dry powder inhalers, and jet and ultrasound nebulizers. • Classes of drugs available for pulmonary delivery: Bronchodilators, corticosteroids, mast cell stabilizers, insulin, antibiotics, mucolytic drugs, anesthetic gases. Oldest Known Reference (1554 BC) of Therapeutic Aerosol Delivery Smoke of henbane plants (Hyoscyamus niger) was inhaled through the stalk of a reed. Stein and Thiel, J. Aerosol Med. & Pulmonary Drug Delivery 30(1):20-41, 2017 John S. Patton & Peter R. Byron, Nature Reviews Drug Discovery 6:67-74, 2007 Potter’s Asthma Cigarettes • Cigarettes were made from jimson weed (stramonium) instead of tobacco leaves. • Stramonium contains belladonna alkaloids, including atropine. • Jimson weed seeds or teas may be abused as “legal hallucinogenic drugs”. • Anti-cholinergic side effects include tachycardia, dry mouth, dilated pupils, blurred vision, hallucinations, confusion, constipation, and difficulty urinating. • Coma and seizures can occur, although death is rare. • Treatment: toxin elimination (activated charcoal, gastric lavage), beta-blocker for severe sinus tachycardia. Physostigmine for life-threatening adverse effects. Inhaled Route of Administration • Preferred mode of delivery for many drugs with a direct effect on airways, such as β2-agonists and corticosteroids. • Effective delivery to airways with much lower risk of systemic side effects (e.g., risk of Cushing’s syndrome with inhaled corticosteroids is minimal). • Only way for delivery of some drugs (e.g., cromolyn sodium, anticholinergic drugs, inhalation anesthetics). • Antibiotics may be delivered by inhalation in patients with chronic pneumonia (e.g., cystic fibrosis). • More rapid onset of action than with oral route (importance for bronchodilators). MDI: metered-dose inhaler Deposition Fast ic m te on s y ti S p r o s b A ow l S Source: Goodman & Gilman • Inhalation deposits drugs directly in the lungs (non-exclusive). • Most material will be swallowed and will enter the systemic circulation after undergoing hepatic first-pass metabolism. This effect can be reduced by the use of a large-volume spacer. • Some drug will also be systemically absorbed from the lungs. Deposition and Systemic Absorption of Inhaled Drugs • Drug deposition: determines which segments of the respiratory tract an inhaled drug reaches (e.g., larger bronchi or smaller bronchioles). It is determined by: – Size of particles (MMAD) – Force on particles (e.g., airflow velocity) – Dissolution or disassociation of drug molecules from particles – User error: incorrect use of a device by patients • Factors determining systemic drug absorption: – Surfactant – Alveolar Macrophages (degradation of drugs) – Physicochemical properties of drugs Diameters 5 mm 1 mm 0.4 mm 0.06-0.2 mm Optimal Locations for Inhaled Drugs Based on Location of Target Molecules or Target Cells • β2-receptors are located in the epithelium of the airways between the main bronchi and the terminal bronchioles. • M3 receptors are located in the submucosal glands and smooth muscle cells of the conducting airways. • Inhaled corticoids should be dispersed throughout the lungs, as inflammatory cells (eosinophils, lymphocytes, macrophages) are present throughout the respiratory tract and alveoli in asthma patients. Mechanisms of Inhaled Drug Deposition Impaction: particles (>10µm) hit airway wall Sedimentation: particles are deposited due to the force of gravity. Interception: fibers are deposited by contact with the airway wall. Drug Deliv. Transl. Res., 8(5):1527-1544, 2018. Suspension: particles(<0.5µm) move due to Brownian diffusion. May not result in deposition. Mechanisms of Drug Deposition Interception (fibers) Suspension (diffusion) Nature Reviews Drug Discovery 6:67-74, 2007 Mechanisms for Inhaled Drug Deposition • Impaction: particles >10 µm continue on a trajectory when they travel through the airway and hit the airway wall, instead of conforming to the curves of the respiratory tract. • Interception: Mainly the case for fibers, which due to their elongated shape, are deposited as soon as they contact the airway wall. • Sedimentation: Particles with sufficient mass are deposited due to the force of gravity when they remain in the airway for a sufficient length of time. • Suspension: Particles of an aerosol move erratically as a consequence of Brownian diffusion. This applies for particles <0.5µm when they reach the alveolar space. These particles are generally not deposited, and they are expelled once again upon exhalation. Importance of Particle Size http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2013/NR/c3nr01525d/c3nr01525df5.gif Importance of Particle Size • Definitions: MMAD: Median mass aerodynamic diameter FPF: Fine particle fraction, Fraction of the total drug dose < 5.0 µm • The particle size determines the site of deposition in the respiratory tract. • Optimal size to settle in the airways is 2-5 µm MMAD. • Larger particles (5-10 µm) settle out in the upper airways, whereas smaller particles (<0.5 µm) remain suspended and are, therefore, exhaled. • Delivery of drugs to small airways (e.g., in smallairway diseases such as COPD), requires delivering particles of about 1 µm MMAD, which is possible using drugs formulated in HFA propellant. Determining MMAD Using a Multistage Cascade Impactor Median Mass Aerodynamic Diameter http://www.pharmtech.com/inhaled-product-characterization • At each stage of the cascade impactor, particles with sufficient inertia impact on the collection plate. • Smaller particles remain entrained in the airflow and are carried to the next stage. • Usually, there are 7-8 stages. At each stage particles are collected and then analyzed (e.g., with HPLC). Increasing Air Flow Velocity Importance of Air Flow Velocity Arch Bronconeumol. 48(7):240–246; 2012 Increasing Particle Size Absorption of Inhaled Drugs Is Fast Very Short Diffusion Distance No First-Pass Effect Particles can be Taken up and Degraded by Alveolar Macrophages Drug Deliv. 24(1):891-905, 2017 Inhaled Insulin ? Exubera FDA approved in 2006 Discontinued in 2007 Afrezza FDA approved in 2014 Not (yet) accepted well by patients and physicians: • High cost. • Safety concerns (lung cancer?, cough, decline in FEV1, hypoand/or hyperglycemia). • Competing products. Systemic Absorption Limits the Therapeutic Use of Small Particles in Topical Applications • A small MMAD (1 µm) increases alveolar deposition. • This increases alveolar absorption into the systemic circulation, resulting in more systemic side effects. • In the case of inhaled corticosteroids (ICSs), hydrofluoroalkane- (HFA)-based pressurized metereddose inhalers (pMDIs) can deliver more ICSs to smaller airways. However, there is also increased systemic absorption, so that the therapeutic ratio may not be changed. Delivery Devices Dry Powder Inhaler Jet Nebulizer Ultrasonic Nebulizer Pressurized Metered-Dose Inhalers https://www.saintlukeshealthsystem.org/health-library/discharge-instructions-using-metered-dose-inhaler Pressurized Metered-Dose Inhalers (pMDIs) • Drugs are propelled from a canister in the pMDI with the aid of a propellant. • Particle size is usually between 2 and 4 µm. • The “ozone friendly” HydroFluoroAlkane (HFA) has replaced ChloroFluoroCarbon (CFC, Freon) as a propellant. • These devices are convenient, portable, and typically deliver 50–200 doses of drug. • Require hand-mouth coordination. Soft Mist Inhalers • With the cap closed, hold the inhaler upright and turn the clear base. • Open the cap, then breathe out completely. • Hold the inhaler horizontally and take a slow, deep breath. • As you start to breathe in, press the button on the inhaler to release the medicine. Continue to breathe in until your lungs are full. Distribution of Radiolabeled aerosol delivered by an MDI No Valved Holding Chamber RESPIRATORY CARE • MARCH 2005 VOL 50 NO 3 Effect of Valved Holding Chamber Drug Deposition Without (left) and With Valved Holding Chamber RESPIRATORY CARE • MARCH 2005 VOL 50 NO 3 Oral Thrush (fungus infection) • • • • Risk with inhaled corticosteroids. Spacers and valved holding chamber (VHCs) reduce risk. Rinse mouth with water and spit after each dose. After rinsing, brush teeth. Spacers and Valved Holding Chambers • Spacer devices and valved holding chambers (VHCS) are connected between the pMDI and the patient. • They reduce the velocity of particles entering the upper airways and reduce the size of the particles by allowing evaporation of liquid propellant from the particles. • This reduces oropharyngeal drug deposition and increases the proportion of drug inhaled into the lower airways. • This can reduce local side effects (e.g., oral thrush and hoarseness with inhaled corticosteroids). • Spacer devices are also useful in delivering inhaled drugs to small children who are not able to use a pMDI. Children as young as 3 years of age are able to use a spacer device fitted with a face mask. The First Dry Powder Inhaler Propeller RESPIRATORY CARE • MARCH 2005 VOL 50 NO 3 Dry Powder Inhalers (DPIs) http://www.fairview.org/healthlibrary/Article/86203 Inside a Dry Powder Inhaler Dry Powder Inhalers (DPIs) • Drugs may also be delivered as a dry powder using devices that scatter a fine powder dispersed by air turbulence on inhalation (breath-activated inhaler). • Children less than 7 years of age find it difficult to use a DPI. • DPIs have been developed to deliver peptides and proteins, such as insulin, systemically but have proven to be problematic because of inconsistency of the dosing. Nebulizers Working Principles Jet Nebulizer Ultrasonic Nebulizer World J Methodol 2016 March 26; 6(1): 126-132 Source: UpToDate Nebulizers • Jet nebulizers are driven by a stream of gas (air or oxygen). • Ultrasonic nebulizers use a rapidly vibrating piezoelectric crystal and thus do not require a source of compressed gas. • The nebulized drug may be inspired during tidal breathing. • It is possible to deliver much higher doses of drug compared with a pMDI or dry powder inhaler. • Nebulizers are useful in: – treating acute exacerbations of asthma and COPD. – delivering drugs when airway obstruction is extreme (e.g., in severe COPD). – delivering inhaled drugs to infants and small children who cannot use the other inhalation devices. – giving drugs such as antibiotics when relatively high doses must be delivered. Jet Nebulizer vs. Ultrasonic Nebulizer Jet Nebulizer • Traditional technology • Uses compressed air to generate a fine mist • Offers a range of particle sizes • Can be loud • No medication restrictions • Available in tabletop and handheld models Ultrasonic Nebulizer • Newer technology • Uses ultrasonic vibrations passed through water to generate a fine mist • Offers a very consistent particle size • Virtually silent • Medication restrictions because of heat • Available in handheld models only Inhalation Device Advantages Disadvantages Pressurized Metered-Dose Inhalers (pMDIs) Compact and portable. Multidose (~200 doses). Inexpensive. Sealed environment (no degradation of drug). Reproducible dosing. Inhalation technique and patient co-ordination required. High oral deposition. Limited range of drugs available. Propellant needed. Dry Powder Inhalers (DPIs) Compact and portable. Easy to use. No hand-mouth coordination required. Breath actuated. Dose depends on inspiration. Humidity may cause powder to aggregate and capsules to soften. Dose lost if patient inadvertently exhales into the DPI. Most DPIs contain lactose. Nebulizers (jet, ultrasonic) Delivers large doses. No specific inhalation technique or co-ordination required. Aerosolizes most drugs. Suitable for infants and patients too sick or physically unable to use other devices. Time consuming. Bulky, non-portable. Contents easily contaminated. Relatively expensive. Poor delivery efficiency. Wide performance variation between different models and operating conditions. Drug Deposition with Different Devices MDI MDI plus Spacer RESPIRATORY CARE • MARCH 2005 VOL 50 NO 3 Nebulizer DPI Inhalant Drugs • Short-acting β2 agonists: albuterol (=salbutamol), levalbuterol, metaproterenol, terbutaline (SABA). • Long-acting β2 agonists: formoterol, salmeterol, indacaterol, vilanterol, olodaterol, bambuterol (LABA). • Inhaled corticosteroids: fluticasone, beclometasone, budesonide, ciclesonide, mometasone • Mast cell degranulation blockers: cromolyn sodium, nedocromil sodium (not available in US). • Anticholinergics: ipratropium bromide (SAMA), tiotropium, aclidinium, umeclidinium (LAMA). • Inhaled anesthetics: enflurane, isoflurane, desflurane, sevoflurane, nitrous oxide (=laughing gas). Oral Administration for Pulmonary Diseases • The oral dose is much higher than the inhaled dose required to achieve the same effect (a ratio of ~20:1). • Thus, systemic side effects are more common. • When there is a choice of inhaled or oral route for a drug (e.g., β2 agonist or corticosteroid), the inhaled route is always preferable. • The oral route should be reserved for the few patients unable to use inhalers (e.g., small children, patients with physical problems such as severe arthritis of the hands). • Theophylline is ineffective by the inhaled route and, therefore, must be given systemically. • Corticosteroids may have to be given orally for parenchymal lung diseases (e.g., in interstitial lung diseases). Parenteral Administration for Pulmonary Diseases • The intravenous route should be reserved for delivery of drugs in the severely ill patient who is unable to absorb drugs from the GI tract. • Side effects are generally frequent due to the high plasma concentrations. The End