Aerosol therapy

aerosol therapy physics, applications, hazards

1. DR. RAVIKIRAN H M KIDWAI CANCER INSTITUTE AEROSOL THERAPY

2. INDEX Introduction & Definition Physics: Particle size, motion, and airway characteristics affect aerosol deposition. Advantages & disadvantages. Delivery systems Drugs Bland aerosol therapy

3. INTRODUCTION & DEFINITION Inhalation therapy is often used synonymously with the term respiratory care. In a general, inhalation therapy can be thought of as the delivery of gases for ventilation and oxygenation, as aerosol therapy, or as a means of delivering therapeutic medications. Therapeutic aerosols have been employed in the treatment of pulmonary patients with bronchospastic airway disease, COPD, and pulmonary infection. The basic goals are To improve bronchial hygiene, Humidify gases delivered through artificial airways, and Deliver medications.

4. aerosol is a suspension of solid or liquid particles in gas . occur in nature as pollens, spores, dust, smoke, smog, fog, and mist. The upper airway and respiratory tract filter out larger particles to protect the lungs from invasion by these aerosols Clinically generated with atomizers, nebulizers, and inhalers used to deliver bland water solutions to the respiratory tract or to administer drugs to the lungs, throat, or nose for local and systemic effect. higher local drug concentrations in the lung with lower systemic levels

5. PHYSICS OF AEROSOL THERAPY

6. AEROSOL OUTPUT A large proportion of particles that leave a nebulizer may never reach the lungs. based on numerous variables ranging from particle size to breathing pattern Aerosol output is the mass of fluid or drug produced by an aerosol generator Emitted dose describes the mass of drug leaving the mouthpiece of a nebulizer or inhaler as aerosol. Measured by collecting the aerosol that leaves the nebulizer on filters and measuring either their weight (gravimetric analysis) or quantity of drug (assay-most reliable).

7. PARTICLE SIZE Depends on the substance for nebulization , the method used to generate the aerosol, and the environmental conditions surrounding the particle Unaided human eye cannot see particles < 50 - 100 μ m in diameter Methods to measure : Cascade impactors : are designed to collect aerosols of different size ranges on a series of stages or plates. The mass of aerosol deposited on each plate is quantified by drug assay, and a distribution of drug mass across particle sizes is calculated. Laser diffraction: a computer is used to estimate the range and frequency of droplet volumes crossing the laser beam.

8. Medical aerosols contain particles of many different sizes ( heterodisperse ) Average particle size is expressed with a measure of central tendency: mass median aerodynamic diameter (MMAD) for cascade impaction or volume median diameter (VMD) for laser diffraction. The geometric standard deviation (GSD) describes the variability of particle sizes in an aerosol distribution set at 1 standard deviation above or below the median (15.8% and 84.13%). Greater the GSD, the wider the range of particle sizes, and the more heterodisperse the aerosol. Aerosols consisting of particles of similar size (GSD ≤1.2) are referred to as monodisperse . Used mainly in laboratory research and in nonmedical industries.

9. DEPOSITION A fraction of the inhaled dose is deposited in the lungs ( respirable dose ) Depends on the size, shape, and motion of the particles and on the physical characteristics of the airways and breathing pattern. Key mechanisms Inertial impaction, Gravimetric sedimentation, and Brownian diffusion

10. INERTIAL IMPACTION Occurs when suspended particles in motion collide with and are deposited on a surface. The primary deposition mechanism for particles larger than 5 μm . Greater the mass and velocity of a moving object, the greater its inertia, and the greater the tendency of that object to continue moving along its set path. Turbulent flow and convoluted passageways in the nose cause most particles larger than 10 μm to impact and become deposited. This process produces an effective filter that protects the lower airway from particulates such as dust and pollen. However, particles 5 to 10 μm tend to become deposited in the oropharynx and hypopharynx

11. SEDIMENTATION Occurs when aerosol particles settle out of suspension and are deposited owing to gravity. The greater the mass, the faster it settles During normal breathing, sedimentation is the primary mechanism for deposition of particles 1 to 5 μ m. Occurs mostly in the central airways and increases with time, affecting particles 1 μm in diameter. Breath holding after inhalation of an aerosol increases the residence time for the particles in the lung and enhances distribution across the lungs and sedimentation. 10-second breath hold can increase aerosol deposition 10% and increase the ratio of aerosol deposited in lung parenchyma to central airway by fourfold

12. BROWNIAN DIFFUSION primary mechanism for deposition of small particles <3 μm Mainly in the respiratory region where bulk gas flow ceases and most aerosol particles reach the alveoli by diffusion. These aerosol particles have very low mass and are easily bounced around by collisions with carrier gas molecules. These random molecular collisions cause some particles to contact and become deposited on surrounding surfaces. Particles 1 to 0.5 μm are so stable that most remain in suspension and are cleared with the exhaled gas, whereas particles smaller than 0.5 μm have a greater retention rate in the lungs.

13. AGING Aerosols are dynamic suspensions. Individual particles constantly grow, shrink, coalesce, and fall out of suspension. Process by which an aerosol suspension changes over time is called aging. Depends on the composition, initial size , time in suspension, and the ambient conditions to which it is exposed Result of either evaporation or hygroscopic water absorption. Particle size change is inversely proportional to the size of a particle, so small particles grow or shrink faster than large. Small water-based particles shrink when exposed to relatively dry gas. Aerosols of water-soluble materials, especially salts, tend to be hygroscopic, absorbing water and growing when introduced into a high-humidity environment

14. Particle size is not the only determinant of deposition. Inspiratory flow rate, flow pattern, respiratory rate, inhaled volume, ratio of inspiratory time to expiratory time (I : E ratio), and breath holding Presence of airway obstruction is one of the greatest factors - deposition is greater in smokers and in COPD Prediction of actual aerosol deposition for an individual is difficult

15. QUANTIFYING AEROSOL DELIVERY Precise amount of drug delivered to the patient’s airways can be difficult to determine. It can be measured in terms : Clinical response, pharmacokinetic profile, scintigraphy . Clinical response - desired therapeutic effects and adverse effects. Approach relates the systemic pharmocokinetic profile of a drug delivered by aerosol to an assay of the drug in a patient’s blood or urine over time. This method does not estimate actual lung delivery, but it provides insight into systemic drug levels achieved after aerosol administration. Care must be taken to differentiate drug absorbed through the lungs from drug absorbed through the gastrointestinal tract.

16. Deposition (in vivo) involves scintigraphy In which a drug is “tagged” with a radioactive substance (e.g., technetium), aerosolized, and inhaled. A scanner measures the distribution and intensity of radiation across the device and the patient’s head and thorax. The result is a radiation map of aerosol deposition in the upper airway, the lungs (central and peripheral airways), and the stomach. This information is used to calculate the percentage of drug retained by the device and delivered to various areas in the patient

17. ADVANTAGE & DISADVANTAGE

18. ADVANTAGES OF DELIVERING DRUGS BY INHALATION Safe method for self-administration Easier access Rapid onset of action Reduced extrapulmonary side effects Reduced dosage Coincidental application with aerosol therapy for humidification General psychological support with treatment.

19. HAZARDS OF AEROSOL THERAPY Primary hazard - adverse reaction to the medication being administered Other hazards to the patient Infection Airway reactivity Systemic effects of bland aerosols Drug concentration Eye irritation. In the nonintubated patient, aerosol therapy necessitates the patient’s cooperation and skilled help. Care providers and bystanders risk these hazards as a result of exposure to secondhand aerosol drugs.

20. INFECTION Sources of bacteria are patient secretions, contaminated solutions (i.e., multiple-dose drug vials), and caregivers’ hands Nebulizers should be sterilized between patients, frequently replaced with disinfected or sterile units, or rinsed with sterile water (not tap water) and air dried every 24 hours

21. AIRWAY REACTIVITY Cold air and high-density aerosols Medications such as acetylcysteine , antibiotics, steroids, cromolyn sodium, ribavirin , and distilled water Administration of bronchodilators before or with administration of these agents may reduce the risk

22. PULMONARY AND SYSTEMIC EFFECTS Associated with the site of delivery and the drug being administered For patients unable to clear their own secretions, suctioning or other airway clearance techniques may be indicated as an adjunct to aerosol therapy Airway clearance techniques should accompany any aerosol therapy

23. DRUG CONCENTRATION Although drug use is often reduced, precise titration and dosages are difficult to ascertain During nebulization , the evaporation, heating, baffling, and recycling of drug solutions undergoing jet or ultrasonic nebulization increase solute concentrations Expose the patient to increasingly higher concentrations of the drug over the course of therapy and result in a larger concentration of drug remaining in the nebulizer at the end of therapy Time-dependent; the greatest effect occurs when nebulization of medications occurs over extended periods, as in continuous aerosol drug delivery

24. EYE IRRITATION Via a face mask may deposit drug in the eyes and cause eye irritation. In very rare cases, anticholinergic medications have been suspected to worsen preexisting eye conditions, such as forms of glaucoma. Special mask designs that have been shown to reduce drug deposition in the eyes or mouthpieces should be considered for at-risk patients

25. SECONDHAND EXPOSURE TO AEROSOL DRUGS Exposure to bronchodilators is associated with increased risk of occupational asthma Reduce this by Using systems that introduce less aerosol to the atmosphere (pressurized metered dose inhalers [ pmdis ], dry powder inhalers [ dpis ], and breath-actuated nebulizers) Filtering exhalation to contain aerosol, and Using environmental controls.

26. L/T ratio The ideal aerosol would distribute only to the airway, with none reaching the stomach. The ratio of lung availability to total systemic availability (L/T ratio) quantifies the efficiency of aerosol delivery to the lung L T ratio = Lung availability ÷ (Lung +GI availability)

27. Ideal pattern of inhalation Large volume Slow inspiration (5 to 6 seconds) Accentuated by an inspiratory hold (10 seconds). This breath-holding enhances sedimentation and diffusion. Faster inspiratory inflows increase deposition of particles on oropharyngeal and upper airway surfaces. If airway obstruction is significant, adequate deposition of drugs may be compromised. If the obstruction is not relieved, larger dosages or increased frequency of administration may be necessary. Application of the aerosol early in inspiration allows deeper penetration into the lungs, whereas delivery of medications at the back end of the breath enhances application to slower filling lung units. Concerns are raised in areas of the lung with poor ventilation related to airflow obstruction or low compliance.

28. AEROSOL DRUG DELIVERY SYSTEMS

29. AEROSOL DRUG DELIVERY SYSTEMS Device that quickly delivers sufficient drug to the desired site of action with minimal waste and at a low cost pMDIs (pressurized metered dose inhaler)with or without spacers or VHCs, DPIs(dry powder inhaler) Small and large volume (jet) nebulizers,(SVN, LVN) Hand-bulb atomizers (including nasal spray pumps), Ultrasonic nebulizers (USNs), and Vibrating mesh (VM) nebulizers DPIs and pressurized MDIs are the most common delivery systems because of their low cost and ease of use.

30. PRESSURIZED METERED DOSE INHALERS Portable, compact, and easy to use and provides multidose convenience. A uniform dose of drug is dispensed within a fraction of a second after actuation and is reproducible throughout the canister life. “Press and breathe,” but there is increasing presence of a variation known as breath-actuated pMDIs .

31. Pressurized canister that contains the prescribed drug (a micronized powder or aqueous solution) in a volatile propellant combined with a surfactant and dispersing agent When the canister is inverted (nozzle down) and placed in its actuator, or “boot,” the volatile suspension fills a metering chamber that controls the amount of drug delivered. Pressing down on the canister aligns a hole in the metering valve with the metering chamber. The high propellant vapor pressure quickly forces the metered dose out through this hole and through the actuator nozzle. Aerosol production takes approximately 20 msec.

32. As the liquid suspension is forced out of the pMDI , it forms a plume, within which the propellants vaporize. Initially, the velocity of this plume is high (approximately 15 m/sec). However, within 0.1 second, the plume velocity decreases to less than half its maximum as the plume moves away from the actuator nozzle. At the same time, propellant evaporation causes the initially large particles (35 μm ) generated at the actuator orifice to decrease rapidly in size. The output volume of pMDIs ranges from 30 to 100 mcl . Approximately 60% to 80% by weight of this spray consists of the propellant, with only approximately 1% being active drug (50 mcg to 5 mg, depending on the drug formulation). Chlorofluorocarbon (CFC) pMDI used in a standard actuator

33. CFCs such as Freon were the propellants used in pMDIs . Manufacture of CFCs for most applications has now been prohibited because of the effect of these compounds on global warming Companies developed hydrofluoroalkane (HFA)-134a to be more environment-friendly and possibly clinically safer Dispersal agents to improve drug delivery by keeping the drug in suspension. The most common dispersal agents are surfactants, such as soy lecithin, sorbitan trioleate , and oleic acid. These agents help keep the drug suspended in the propellant and lubricate the valve mechanism but may also cause adverse responses (coughing or wheezing).

34. pMDI should be primed by shaking and actuating the device to atmosphere one to four times (see label for the specific device) before initial use and after storage. Without priming, the initial dose actuated from a new pMDI canister contains less active substance than subsequent actuations. This “loss of dose” from a pMDI occurs when drug particles rise to the top of the canister over time (“ cream ”). particularly with the valve pointed in the downward position. Loss of prime is related to valve design and occurs when propellant leaks out of the metering chamber during periods of nonuse (e.g., 4 hours). Improved designs of metering valves developed for use with HFA propellants reduce these losses. It is recommended that a single dose be wasted before the next dose is inhaled when a CFC pMDI has not been used for 4 to 6 hours. An HFA pMDI requires no wasting of dose for periods exceeding 2 days.

35. New Pressurized Metered Dose Inhaler Technologies Aerospan Breath-Actuated Pressurized Metered Dose Inhaler Tempo Inhaler Dose Counters

36. Aerospan Built-in valveless spacer that improves hand-breath coordination. Also, it does not have a built-in dose counter. Does not need to be cleaned on a regular basis to maintain proper orientation.

37. Breath-Actuated Pressurized Metered Dose Inhaler Incorporates a trigger that is activated during inhalation. Trigger theoretically reduces the need for the patient or caregiver to coordinate pMDI actuation with inhalation. Use should be restricted to older children and adults. Oropharyngeal deposition of steroids using these devices is still very high.

38. Tempo Inhaler Breath actuated with lower force of the plume exiting the mouthpiece Reducing oropharyngeal deposition and increasing lung dose.

39. Dose Counters Limitation of pMDIs is the lack of a “counter” to indicate the number of doses remaining in the canister. After the number of label doses has been administered, the pMDI may seem to give another 20 to 60 doses, which may deliver little or no medications as the doses “tail-off.” The FDA is requiring all new pMDIs to have counter technology to track pMDI actuations remaining.

40. The tail-off effect refers to variability in the amount of drug dispensed toward the end of the life of the canister. The result of tail-off is swings from normal to almost no dose emitted from one breath to the next with no reliable indicator to the user. Without a dose counter, there is no viable method to determine remaining drug in a pMDI other than manually keeping a log of every dose taken.

41. Factors Affecting PMDI Performance Temperature: Low temperature (<10° C) decreases the output of CFC pMDIs . Less serious with the newer HFA pMDIs . Nozzle Size and Cleanliness: As debris builds up on the nozzle or actuator orifice, the emitted dose is reduced Priming Timing of Actuation Intervals: Manufacturers recommend 30sec to 1 min between actuations. When propellants are released, the device cools, changing aerosol output. The pause allows the device to return to room temperature and recover normal output. However, previous research showed that pMDI output is similar at 15-second intervals. Some patients exhibit a “ cold Freon effect ,” which occurs when the cold aerosol plume reaches the back of the mouth and the patient stops inhaling.

42. PMDI Accessory Devices Developed to overcome the two primary limitations of these systems: Hand-breath coordination problems High oropharyngeal deposition. Accessory devices include Spacers Valved holding chambers(VHC)

43. SPACER Simple valveless extension device that adds distance between the pMDI outlet and the patient’s mouth. This distance allows the aerosol plume to expand and the propellants to evaporate before the medication reaches the oropharynx . Larger particles leaving the pMDI tend to impact on the spacer walls. Exhalation after pMDI actuation clears the aerosol from the device and wastes most of the dose to the atmosphere In combination, this phenomenon reduces oropharyngeal impaction and increases pulmonary deposition.

44. VHC VHCs incorporate one or more valves that prevent aerosol in the chamber from being cleared on exhalation. This allows patients with a small VT to empty the aerosol from the chamber over two or more successive breaths. Generally, holding chambers provide less oropharyngeal deposition, higher respirable drug dosages, and better protection from poor hand-breath coordination than simple spacers. VHCs protect the patient from poor hand-breath coordination, with exhaled gas venting to the atmosphere, allowing aerosol to remain in the chamber Allow infants, small children, and adults who cannot control their breathing pattern to be treated effectively

45. Types of Accessory Devices Small volume adapters Open tube designs Bag reservoirs Valved holding chambers

46. Material used Conductive metal or Nonelectrostatic plastic chambers or Washing the plastic chamber periodically with deionizing detergent (liquid dishwashing soap) can overcome the loss of fine-particle mass owing to electrostatic charge and increase the inhaled mass from 20% to 50% of the emitted dose of the pmdi

47. DRY POWDER INHALERS Breath-actuated dosing system. The patient creates the aerosol by drawing air though a dose of finely milled drug powder with sufficient force to disperse and suspend the powder in the air. Inexpensive, do not need propellants, and do not require the hand-breath coordination Depends on the creation of turbulent flow in the inhaler. inhale the powder with a sufficiently high inspiratory flow rate In terms of both lung deposition and drug response, DPIs are as effective as pMDIs

48. Equipment Design and Function Most passive dry powder–dispensing systems require the use of a carrier substance (lactose or glucose) mixed into the drug to enable the drug powder to deaggregate more readily and flow out of the device. Reactions to lactose or glucose seem to be fewer than reactions to the surfactants and propellants used in pMDIs The particle size of the dry powder particles of drug ranges from 1 to 3 μm . However, the size of the lactose or glucose particles can range from approximately 20 to 65 μm , so most of the carrier (≤80%) is deposited in the oropharynx . Types: (1) unit-dose DPI, (2) multiple unit-dose DPI (3) multiple dose drug reservoir DPI.

49. Unit-dose DPIs : dispense individual doses of drug from punctured gelatin capsules. Multiple unit-dose DPIs : contain a case of four or eight individual blister packets of medication on a disk inserted into the inhaler. The Twisthaler and Flexhaler have a multidose reservoir powder system preloaded with a quantity of pure drug sufficient for dispensing 120 doses of medication, and the Diskus incorporates a tape system that contains up to 60 sealed single doses. A and B, Multiple-dose dpi: diskus inhaler C, Unit-dose dpi: aerolizer

50. Factors Affecting Dry Powder Inhaler Performance Intrinsic Resistance and Inspiratory Flow Rate . Optimal performance for each DPI design occurs at a specific inspiratory flow rate. Exposure to Humidity and Moisture . dose of DPI decreases in a humid environment, likely because of powder clumping. The longer the exposure and the greater the level of absolute humidity, the lower the dose emitted. Patient’s Inspiratory Flow Ability . High peak inspiratory flow rates (>60 L/min) are required to dispense the drug powder. Active DPIs use an energy source to deaggregate the powder and suspend the powder into an aerosol, allowing the dose to be suspended independent of patient inspiratory flow rates.

51. JET NEBULIZER Venturi principle Bernoulli principle

52. Application of Venturi principle Sanders jet ventilation and Jet ventilation during bronchoscopy Sprays Venturi mask Atomizers : Fogger Fire extinguisher nozzle Modern Vaporizer Ventilator Pathick test Flowmeter Suction apparatus Gas mixers Aortic regurgitation pulls valve together thus pulsus bisferans Capillary flow  Injectors used to add chlorine gas to water treatment chlorination systems.

53. AERSOLISED DRUGS

54. AEROSOLISED DRUGS ADRENERGIC DRUGS ANTICHOLINERGICS STEROIDS MUCOACTIVE DRUGS ANTIINFECTIVE INSULIN: EXUBERA(dose 5times the normal requirement) PULMONARY VASODILTORS NITRIC OXIDE ILOPROST, TREPROSTINIL BLAND AERSOL THERAPY

55. DRUGS USED ENDOTRACHEALLY FOR SYSTEMIC EFFECT A -Atropine L - Lignocaine A -Adrenaline D -Diazepam I - Isoprenaline N - Naloxone

56. BLAND AERSOL THERAPY Humidity is simply water in the gas phase, whereas a bland aerosol consists of liquid particles suspended in a gas Involves the delivery of sterile water or hypotonic, isotonic, or hypertonic saline aerosols. Bland aerosol administration may be accompanied by O2 therapy. The equipment needed for bland aerosol therapy includes an aerosol generator and a delivery system. Devices used to generate bland aerosols include large-volume jet nebulizers and ultrasonic nebulizers (USNs). Delivery systems include various direct airway appliances and enclosures (mist tents).

57. REFERENCE EGAN’S FUNDAMENTALS OF RESPIRATORY CARE-11 TH EDITION BENUMOF-3 RD EDITION.