Asthma Pharmacology — Salbutamol

Pharmacology of Salbutamol

Delivery systems (Too much information)

• Dosage forms available
  • Aerosol powder – pMDI (DPI not available)
  • Aerosol solution, Inhalation
  • Nebulization solution, Inhalation
  • Solution, Intravenous (Also IM/Subcut)
  • Syrup and Tablets, Oral
• Inhaled Salbutamol is commonly administered via pressured metered dose inhalors and nebulizers (see below for details)
  • Soft mist inhalers and Dry Powder Inhalers are not available for Salbutamol
• Infused intravenously
  • ​​​​​​​Requires no patient effort or breath syncrony
  • Maximal systemic toxicity
• Ingested orally
  • Excellent patient compliance
  • Slower response of a lower magnitude
  • Gastrointestinal absorption is erratic and unreliable

Pressured Metered Dose Inhalers (pMDI)

• A pMDI consists of a pressurized canister, a metering valve and stem, and a mouthpiece actuator.
• Mechanism:
  • The canister contains the drug suspended in a pressurized mixture of propellants, surfactants, preservatives, flavoring agents, and dispersal agents. The propellent is hydrofluoroalkane (HFA)
  • The medication-propellant mixture is released from the pMDI canister through the metering valve and stem into an actuator boot. Lung deposition ranges between 10 and 40 percent of the nominal dose in adults and is very technique-dependent
  • Difficulty precisely coordinating device actuation with inhalation leads to poor drug delivery, suboptimal disease control, and increased inhaler use
• Devices to optimize usage:
  • Spacer or valved holding chamber:
    •  three basic designs: the open tube, the reservoir or VHC, and the reverse-flow design, in which the pMDI, placed close to the mouth, is fired in the direction away from the patient; adding a one-way valve creates a VHC. They can be used with a mouthpiece or mask, and anti-static devices reduce aerosol losses within the device
  • Breath-actuated inhalers
    • better in patients with incoordination of inhalation with device actuation
    • not available for Salbutamol yet

Nebulizers

• Jet (pneumatic), ultrasonic, mesh
• Factors affecting aerosol delivery by nebulizer
  • Technical factors: Mechanism and manufacturer, Flow rate, Fill volume, Solution characteristics, Characteristics of driving gas, Designs to enhance output, Continuous versus intermittent delivery
  • Patient factors: Breathing pattern, Nose versus mouth breathing, Artificial airway, Airway obstruction, Positive pressure level

Jet Nebulizers

• Mechanism:
  • Air compressor or pressurized gas supply (compressed air or O2) acts as driving force for liquid atomizaiton
  • Compressed gas is delivered as a jet through a small orifice, generating a region of negative pressure above medication reservoid
  • Solution is first entrained, or pulled into the gas stream (Venturi effect), then sheared into a liquid film
  • Film is unstable, and rapidly breaks into droplets due to surface tension forces
• Factors affecting drug delivery
  • Respirable dose – function of mass output of nebulizer and size of droplets (mass median aerodynamic diameter) – should be 2 to 5 µm for bronchodilators
  • Nebulization time – determined by volume of drug and flow of driving gas – lesser the better for patient compliance and need for clinical supervision
  • Dead volume – medication trapped inside nebulizer – typically 1-2ml
  • Driving gas – density of gas (improved with heliox)
  • Breathing pattern – best with slow breathing pattern with a normal tidal volume and occasional deep breaths
  • Nebulizer/compressor combination – more important in portable settings
• Continuous nebulizations
  • HEART Nebulizer (Westmed) and the AirLife Misty Finity (Vyaire), Flo-Mist (Smiths Medical), and Hope (B&B Medical Technologies)
  • Issue with need for frequent refilling ~10-15mins
    • avoided by infusion pump and large volume nebulizer
  • drug delivery over time similar to intermittent
  • better with mesh than jet
  • can be delivered via High Flow Nasal Cannula (not available in most centres)

Mesh Nebulizers

• eFlow (Pari), Aeroneb Solo and Aeroneb Go (Aerogen), MicroAIR/NE-U22 (OMRON), InnoSpire Go (Philips) and the I-neb (Respironics)
• use a mesh or plate with multiple apertures to produce a liquid aerosol
  • Solution or suspension of medication is forced through the mesh to produce an aerosol, without need for an internal baffling system or compressed air source
• Able to generate aerosols with a high fine-particle fraction, which results in more efficient drug delivery compared to conventional nebulizers.
• Portable, battery-operated, minimal residual medication volume
• Precise dosing, minimal wastage
• May not give additional benefit for use with Salbutamol (cost-ineffecient)
• May be incorporated with Adaptive Aerosol delivery
• Blockage with particles may impair drug delivery
• More maintenance – disinfection and sterilization

Ultrasonic Nebulizers

• consist of a power unit and transducer, with or without an electric fan.
  • Power unit converts electrical energy to high-frequency ultrasonic waves. A piezoelectric element in the transducer vibrates at the same frequency as the applied wave.
  • Ultrasonic waves are transmitted to the surface of the solution to create an aerosol.
  • The droplets produced by these devices have a slightly higher MMAD than droplets from a jet nebulizer.
  • A fan is used to deliver the aerosol to the patient, or the aerosol is evacuated from the nebulization chamber by the inspiratory flow of the patient.
• Advantages: quieter medication delivery and shorter treatment time than the jet nebulizers.
• Problems include poor battery life and overheating.
• Drug inactivation by increased temperature a potential issue (but not with bronchodilators)
• With suspensions, the drug particles tend to settle and ultrasonic nebulizers are inefficient

ICU patient populations:

• Not on ventilation
  • Mouthpieces and facemasks
  • mouthpiece interface is generally preferred
  • Bronchodilator response similar with either interface
  • may be based on patient preference
  • Face mask – Significant facial and eye deposition of aerosol, important to instruct the patient to inhale through the mouth to minimize nasopharyngeal deposition of medication.
• Patients with tracheostomy
  • Nebulize either via a mask over the tracheostomy opening or using a T-piece
  • T-piece preferred because more aerosol medication is directed into the tracheostomy tube
  • Special T-shaped connectors for T-piece available for pMDI administation. (Not available for direct administration into tracheostomy)
• Mechanically ventilated patients
  • using either a pMDI or a nebulizer
  • Factors affecting aerosol delivery:
    • Nebulizer: position in circuit, type of nebulizer and volume, treatment time, Duty cycle (I:E), Ventilator brand
    • pMDI: Type of actuator, Timing of actuation
    • Nebulizer and pMDI: ETT size, Humidifaction of inspired gas (deposition, Major factor), use of HME (can filter out aerosol)
  • pMDI: special actuator needed, better with a chamber than in-line, should be synchronized with with inspiratory airflow to optimize drug delivery, more consistent dose than nebulizer. HME is removed, or bypassed using commercially available devices
  • Nebulizer
    • affected by large tidal volume, use of an end-inspiratory pause, and use of a slow inspiratory flow
    • Optimized by placing the nebulizer 30 cm from ETT, rather than at the Y-piece, because the inspiratory ventilator tubing acts as a spacer.
    • Breath-actuated delivery: Operates the nebulizer only during inspiration – 5x more efficient than continuous – available in some ventilators
    • When the humidifier is bypassed the delivered dose increases by a factor of nearly four
  • Jet Nebulizer:
    • circuit contamination due to opening the ventilator tubing circuit (Valved T-piece devices available to avoid this)
    • decreased ability of the patient to trigger the ventilator
    • associated increases in tidal volume and airway pressure due to nebulizer flow
    • A filter in the expiratory limb needed to protect the expiratory valve and flow/pressure monitors.
  • Mesh Nebulizer:
    • can be used effectively – placed between the ventilator outlet and the heated humidifier.
    • Does not interfere with ventilator function (eg, no additional gas flow, no effect on triggering).
• Patients receiving noninvasive ventilation
  • during NIV using devices adapted for inline administration
  • the aerosol generator should be placed between the leak port and the interface.