Kompella's stuff Flashcards
What are some agents that are administered by inhalation?
Localized effects:
-Antiasthma agents:
Bronchodilators: Terbulatine sulfate (Brethaire)
Anti-inflammatory: Beclomethasone Dipropionate (Beclovent, Vanceril, Vancenase)
-Mucoinetics: rhDNAse (Pulmozyme)
-Antimicrobials: Tobramycin (Tobix)
Systemic Effects:
- General Anesthetics: Isoflurane (Forane)
- Peptide/Protein drugs: Insulin (Exubera- discontinued; Afrezza), rhDNAse
Describe the respiratory tract
Divided into conducting (zone 0-16; trachea to terminal bronchi) portion and respiratory (zone 17 - 23; respiratory bronchioles to alveolar sacs) portion (where gases get exchanged)
Tracheobronchial region lined with ciliated pseudostratified columnar epithelial cells
Alveoli consists of type I and type II epithelial cells
What are barriers to respiratory delivery?
- Particle clearance: Cilia (in upper airway) clear material toward throat
Mucus layer
goblet cells between columnar cells produce mucus - drug clearance through enzymes: proteases and nucleases
macrophage engulfment & degradation
has to cross membrane barriers (tight junctions)
Why respiratory delivery for systemic effects?
large surface area (140 m2) thin alveolar epithelium high blood supply no hepatic first pass metabolism rapid onset of action in contrast: oral route - high metabolism of some drugs, parenteral route - expensive, painful, poor acceptance, pulmonary route: even proteins are absorbed. can be used for local or systemic effects
How are drugs absorbed through lung epithelium?
passive diffusion through membrane or aqueous pores (useful for most drugs)
carrier mediated transport (useful for small, nutrient-light molecules)
endocytosis (good for large molecules like peptides & proteins)
also openings in capillaries which can allow movement of drugs across barriers (tight junctions in epithelium & fenestrae in capillary endothelium)
What is proper aerosol administration technique?
remove dust cap shake exhale mouth piece into mouth & close lips inhale slowly and deeply while pressing actuator remove the aerosol & hold breath allow 5 minutes between doses
What are some factors influencing particle deposition in lungs?
-Physical properties of the aerosol:
particle size, density, shape, size distribution, charge, and hygroscopicity (readily absorbing moisture - comes into humidified airways, picks up moisture & changes dimension)
propellants used and pressure (dictates droplet size, aerosol velocity, breakup of aerosol jet - important to control this)
solution vs suspension (if in solution, don’t have to deal with hygroscopicity: spread of drug better with solution than suspension, suspension has to dissolve before it spreads, suspension has localized islets of drug)
excipients such as surfactants
temperature of spray
-Device
design of pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs) and nebulizers
use of a spacer device with the above (spacer can take away larger particles - finer particles can go deeper into the lungs)
-Patient related factors
lung geometry & breathing pattern
What are patient related factors influencing particle deposition in lungs?
Lung geometry:
adults vs infants (highest fraction deposition in infants)
Healthy vs disease state (asthma & COPD, small airway resistance to flow increases)
angle of patient’s neck
Breathing pattern:
oral vs nasal inhalation (deep lung deposition not as good with nasal)
respiratory flow rate
tidal volume (amount of air inspired during normal, relaxed breathing)
time for breath hold
Slow, large volume breathing & control of cough improves deposition
what are the mechanisms of particle deposition in lungs?
Impaction (due to inertia): occurs in upper & large conducting airways, favored by high velocities & rapid changes in flow directions, significant for particles > 2 micrometer, increases with particle size
sedimentation (due to gravitational forces): occurs primarily in small conducting airways & in the alveolar region of the lung, favored by deep, slow breathing, becomes negligible for particles < 0.5 micrometer, rate is proportional to the square of the diameter of the particle & the density difference between the particle and air, main mechanism of deposition of respiratory aerosols
diffusion: occurs in the lung periphery w/small airway dimensions, favored by breath-holding, becomes effective for particles < 0.5 micrometer, increases with decreasing particle size, such particles may be exhaled before deposition (e.g., components of cigarette smoke)
areas of respiratory drug delivery and what mechanisms reach them
extrathoracic (nasal/oral passages, pharynx, and larynx) deposition: mainly inertial impaction tracheobronchial deposition: inertial impaction sedimentation (increasing importance as airway get smaller) alveolar deposition: primarily sedimentation diffusion for very small particles
how are drugs removed from respiratory tract?
mucociliary clearance
coughing
permeation across alveolar epithelium into the systemic circulation
metabolism in the lung
What are the kinds of inhalation delivery devices?
Aerosol: a drug delivery system which depends on the power of a compressed or liquefied gas to expel the active ingredients from the container (e.g., pressurized metered-dose inhaler or pMDI)
Inhaler: a drug delivery device from which the drug is inhaled when the patient inhales. That is, it is activated only when the patient breathes in (e.g., dry powder inhaler or DPI)
Nebulizer: generally a mechanical device which generates a very fine mist which is inhaled by the patient using a mask over a period of 10-15 min.
Aerosols (what is dispensed by inhalation devices) are very finely subdivided liquid or solid particles dispersed in and surrounded by air
What are some pMDIs?
Brethaire (terbutaline sulfate)
Vaceril (beclomethasone dipropionate)
both for asthma
What are some DPIs?
Turbohaler DPI for budesonide (Pulmicort)
Rotahaler DPI for albuterol (ventolin)
Classification of aerosol products
based on size of particles:
space sprays: high pressure aerosols which contain approximately 85% propellant and dispense a finely divided spray with particles no larger than 50 microns
surface sprays: contain 30-70% propellant and produce wet or coarse sprays with larger particles: dermatological sprays
foam sprays: contain 6-10% propellant and produce emulsions of propellants with the product concentrate. Medicated foams, vaginals foams, and shaving cream.
pMDI
efficiently delivers consistent, measured dose of medicine into the lungs
proven safe, effective & reliable, mainstay of asthma therapy worldwide
advantages of pMDI
dose can be removed without contamination of contents
stability enhancement for substances sensitive to oxygen & moisture
through use of metered valves, proper formulation & valve control, dosage can be controlled.
essential components of pMDI
Physical components:
- metal can
- elastomers
- valve
- actuator
Formulation:
- drug substance
- propellants (chosen by what solubilize drug, if it can’t solubilize it, choose a suspension)
- surfactants/co-solvents (can choose surfactants & cosolvents that will solubilize drug in propellant - easier formulation because it’s liquid. If there are particles, you have to worry about growth of particles & change in size. Surfactants help stabilize particle suspension)
components of aerosols
Container or canister:
- glass, uncoated or plastic coated
- metal, including tin-plated steel (most widely used metal), aluminum, and stainless steel
- plastics
Valve and actuator assembly
- continuous spray
- metered-valve (pMDI)
- different configurations for different purposes (actuator assembly: e.g., lungs, mouth, nose, skin, vaginal)
Formulation
- propellant
- product concentrate
formulation components of aerosols
Propellant
- liquified gases (fluorinated hydrocarbons: HFA and Freons (11, 12, 114), hydrocarbons: butane, propane, isobutane)
- compressed gases (of minor pharmaceutical importance): carbon dioxide, nitrous oxide, and nitrogen
- solvents (for non-pharmaceutical use): methylene chloride (too toxic for lung delivery - could be used in deodorant sprays)
What is the difference between homogeneous and heterogeneous aerosol formulations?
Homogeneous (two-phase):
single homogeneous liquid in equilibrium with vapor
Heterogeneous (three-phase):
suspension or emulsion in equilibrium with vapor (have liquid, vapor and a solid phase)
have to shake before use
Filling of aerosols
Cold filling:
cool product concentrate and propellant to 30 to -40 degrees F
add above to chilled container
attach spray assembly
disadvantages: aqueous systems cannot be filled as ice is formed. propellant is lost
Pressure filling:
add product concentrate to container
place the valve
add liquefied propellant from a pressurized machine through the valve
Advantages: less danger of moisture contamination. Less propellant is lost
not operating at low temperatures so don’t get moisture from surroundings & don’t lose propellant
testing of aerosols
components
performance (have to meet specifications when released to market per FDA): net contents (total volume or total weight within container), dosage (how much drug is coming out with each actuation), valve discharge rate (how many microliters are coming out per second), spray pattern, particle/droplet size & distribution (important for deposition), foam stability (foam has to stay on surface for a certain amount of time, it can be quantified), leakage (not acceptable for any leaks to be present)
flammability (specs for how much temperature they have to withstand)
biological activity
formulation components of aerosols
product concentrate active ingredients antioxidants surfactants solvent
label warnings of aerosols
avoid inhaling (if not intended for respiratory aerosol therapy)
keep away from eyes and mucous membranes
contents under pressure. Do not puncture or incinerate. Do not expose to heat > 120 F (49C)
Keep out of reach of children
what are problems with pMDIs?
rapid expansion of propellant leads to impaction
Chlorofluorocarbons (CFCs) are toxic to the environment (deplete ozone).
Solutions:
spacer device/expansion chamber: can be used to reduce aerosol velocity, droplet size & impaction in patient (some of the aerosol will be impacted in spacer)
use HFAs instead of CFCs, but they are corrosive & have greenhouse effect.
HFAs don’t solubilize drug as well as CFCs, so it has been difficult formulating with these
Dry-powder inhalers
DPIs don’t dispense a compressed propellant, but a dry powder
most DPIs rely on the energy of patient inhalation for entrainment, aerosolization & delivery
some DPIs use a pump or an electric motor
powder entrainment is a function of the quantity of air that the patient draws through the device and the resistance of the device to the passage of air
Problems: performance largely determined by patient factors, greater the resistance of the device, greater the patient’s discomfort, particle aggregation due to static charge
What is the idea DPI?
one which is able to consistently emit its complete dose of powder within a range of inhalation energy levels produced at a comfortable level and to de-aggregate the powder to the smallest possible particle size
Dry-powder inhaler specifics
- do not contain a propellant, so patient needs to breathe in strongly
- may not be suitable for use during acute attacks
- rotahaler uses capsules of medication powder, which you insert each time
- turbuhaler does not require loading (has a powder reservoir for 200 doses) with capsules. Has a window, which begins to turn red when 20 doses are left
- diskhaler uses medication powder in a blister pack (contains 4 doses), which is pierced to release a dose.
Diskus or Accuhaler uses medication in foil pouches (contains 60 doses), which are pierced. Has a dose number indicator. Doses 5-0 are shown in red.
What is a nebulizer?
a device driven by a compressed air machine or other source of energy for aerosolization. It allows delivery of medicine in the form of a mist (wet aerosol).
It consists of a cup, a mouthpiece attached to a t-shaped part or a mask, and thin, plastic tubing to connect to the compressed air machine
usually used by children under age 5, people who have problem using an MDI, and people with severe asthma
can take more prolonged approach in dosing patient
pattern of drug deposition from various delivery systems:
DPI: 10-15% deposited in lung, 80% in oropharynx, 5% in device = 95% in patient
MDI: 10-15% deposited in lung, 80% in oropharynx, 5% in device = 95% in patient
MDI + spacer: 20% deposited in lung, 15% in oropharynx, 65% in device = only 35% in patient
What does a spacer do?
reduces velocity, droplet size, and impaction in patient
–> more efficient deposition
Innovations in DPIs
Exubera: inhaled insulin (DPI) - used to treat adults w/diabetes. Helps control high blood sugar. Type1 diabetics still need to take some injected insulin in addition to Exubera. Type 2, exubera may be sufficient by itself. Safety information: may lower lung function, so don’t take it if you smoke, start smoking, or quit smoking less than 6 months ago. You will need a breathing test before you start treatment & from time to time as you keep taking exubera.
cough, dry mouth, chest discomfort. only for people 18 years & older.
approved in 2006, withdrawn in 2007
cancer risk because of growth factor in lung that could cause cancer
Afrezza: approved in 2014: very small - once puff comes out it stays there for a while
