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135 Cards in this Set
- Front
- Back
Preparation of inhalers
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comprise solutions of drug in a sealed container containing liquified gas propellant(s) under
pressure. |
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propellants include:
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a. chlorofluorocarbons (CFCs)
e.g., dichlorodifluoromethane (= Freon 12) - being phased out (because of effects on ozone layer) - FDA exempts prohibition of CFC use in specific products if: i. no technically-feasible alternative available ii. substantial health/public benefit unobtainable without use of CFC iii. use does not involve significant release iv. use is warranted by benefits b. non-CFC gases e.g., hydrofluoroalkane 134a (HFA) - currently only a few MDIs use this gas, e.g., Ventolin HFA®, Proventil HFA® - anticipate patients noting a difference in the look, taste and feel of the new MDI c. non-liquified compressed gases e.g., carbon dioxide, nitrogen, nitrous oxide (CO2 is used with lipid soluble drugs) |
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in the pressurized package, drug can be:
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a. dissolved in the propellant
- solubility of drug in propellant b. suspended in propellant e.g., micronized powders (3-5 micron particles of drug that are insouble in the propellant - suspended in propellant - necessary to shake the solution immediately prior to use - used for many bronchodilators c. dissolved in aqueous solution (2 phase solution the propellant is not mixed with the solution) - aqueous solution floats on the propellant - shaking the solution immediately prior to use (therefore mix the propellant into the aqueouse phase) |
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generation of the aerosol
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when depress actuator, propellant vapor pressure forces solution
i. into dip tube ii. through the valve mechanism iii. out the nozzle orifice - increaes vapor pressure causes an increase in force of ejection - decrease orifice diameter decreases the particle size (which better follows the air flow) both of the above influence how the particles are deposited |
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initial velocity from the inhaler influences
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the momentum and the deposition of the particle
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for MDI, similar system operates except only drug from metering chamber is ejected
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therefore there is quatal release of drug from the MDI
the solution gets loaded into a 2 gated chamber so it will not continually be released only the measured volume in the chamber is released |
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Using an MDI
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it is very important that:
a. you know how to use a MDI b. you demonstrate its use to the patient c. the patient shows you how to use an MDI (many physicians don't know how to use them properly!) |
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do you use the floating technique with an MDI
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no
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steps for using an MDI
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1. remove the cap and hold the inhaler upright
2. shake in inhaler to suspend the drug in the propellant 3. tilt head slightly back and breath out 4. position the inhaler 1-2 inches away from the mouth, in the mouth, or use a spacer. 5. press the inhaler down and start to breath in slowly in order to establish an air current. 6. breath in slowly for 3-5 sec 7. hold breath for 10 secs to allow drug to reach deeply into the lungs 8. repeat puffs as direccted, waiting 1 min between puffs to premit sencond puff to better reach the lungs |
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Spacer devices vs. MDI
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depostion of drug in the lungs doubles with the use of a spacer
the larger particles remain in the spacer allowing the smaller particles to penitrate the lungs more deeply |
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are side effects more or less with a spacer
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less
because the large particles remain in the spacer |
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Side efffects of inhalers
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a. oral: candidiasis (thrush)
b. GI (when swallowed) spacers decrease |
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disadvantages of spacers
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they are not practicle they are big and not easy to carry around
especially not practicle for asmatics because they always have to have their inhaler |
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types of spacers
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a. reservoir bag (InspirEase®)
b. tube spacer Aerochamber® |
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Why would spacer devices increase lung deposition?
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because the large particles deposit on the walls of the spacer so less oropharyngeal deposition
velocity of the particles in decreased (inspiration determines the velocity of the particles therefore the inertial impact is decreased |
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resevoir bag spacer
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aerosol paricles end up in the bag and larger particles are left up in the bag
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tube spacer
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injecting into the tube so the large particles remain on the walls of the spacer
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aerochamber
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like a tube spacer, but with a rubber mouth piece/facemask so the particles can be breathed and re-breathed
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is coordination as criticle when using a spacer
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No,
the timing of activation to inspiration is not as critical the patient can inhale the aersol more slowly which is good because the inertial impact is decreased |
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advantages of spacers
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increase pulmonary deposition resulting in a better therapuetic effect
decrease oropharyngeal deposition which decreases SE |
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who are spacers good for
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elderly
children |
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how is the time it takes to from from the inhaler to the mouth effected when using a spacer
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it is increased
and the propellant evaporates causing the particles to get smaller thus decreasing the inertial impaction |
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dry powder inhalers
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• formulations of drug in dry powder form and stored in a capsule or multi-unit blister pack for
delivery • micronized powder (< 5μ) or specifically formulated to have aerodynamic diameter < 5μ • delivery device breaks the capsule or blister pack -->inspiratory flow (± mechanically-assisted activation) disperses powder for inhalation |
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why are the dry powder inhalers medication packaged in blister packs
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to prevent degradation by the humidity
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what are dry poweder inhalers mainly used for
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anti-asthma
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advantages of dry powder inhalers
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increase stability of drugs in powder (less chance of hydrolysis and oxidation)
-->likely to see systemic protein delivery using this technology in the future, e.g., - increase amount of drug/particle - decrease risk of microbial growth - formulation of drugs that are difficult to dissolve in MDIs (not worried about solubilty of the drug) - no issue with CFCs/ozone destruction |
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disadvantages of dry powder inhalers
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- cumbersome equipment needed for delivery (must puncture blister pack to use)
- particles > 5μ cause coughing as a side effect (- technology continues to be developed) patient has to hold up-right so powder doesn't fall out the patient alway has to do something (ie: break the blister pack) before use |
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what breaks up the powder when using a dry powder inhaler
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inspiratory flow
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what gives the particles momentum when using a dry powder inhaler
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inspiration
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nebulizers
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• solutions of drug are placed in the nebulizer reservoir
• "jet" (or air-driven) (used in the hospital) - high velocity gas propels liquid against a baffle creating an aerosol (need air delivery system) ultrasonic - piezoelectric membrane ! aerosol (vibrating membrane creates aerosol) |
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how is dosing based when using a nebulizer
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• dosing is based on time of inhalation
patient is continually exposded to the medication so it is based on time of exposure |
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advantages of nebulizers
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- timing of inhalation not critical because the patient is breathing and re-breathing the aerosol
- inspiratory volume not critical (same reason as above) - deliver larger doses than inhalers (because can get as much as they are breathing - easier to formulate - no issue with CFCs/ozone destruction - often reimbursed by insurance companies as device |
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how much more drug can a powder formulation hold than an aerosol
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5x more
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disadvantages of nebulizers
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- specialized and relatively expensive equipment needed for delivery
- can destroy proteins - variability in perfomance of different nebulizers in relation to particle size some companies recommed a particular nebulizer with their product because of the different profromance characteristics - ultrasonic nebulizers have a relatively short life-span - reservoir needs to be cleaned regularly to prevent bacterial growth |
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advantages of inhaled drugs
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- drug delivered directly to site of action (for pulmonary use)
- by-passes first pass metabolism (for systemic delivery) - acceptable route of administration for patient, e.g., vs. parenteral - relatively few physical or enzymatic barriers to drug absorption into systemic circulation - fast onset (very similar to the rate of an injection) minimal systemic absorption |
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disadvantages of inhaled drugs
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- low efficiency of delivery-->waste a lot of drug (80% of drug is wasted, systemic absorption is even less)
- patient compliance as it relates to timing inhalation with actuation, convenience of carrying - pulmonary toxicity of drug? (in order to get a high concentration of drug to the lungs it may go into systemic circualation, therefore may cause toxcity) |
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upper airway=
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nose/pharynx
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central airways=
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tracheo-bronchial
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peripheral airways=
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alveoli (pulmonary)
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drug deliverly to upper airways local effect
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- vasoconstrictors (decongestants)
- anti-allergy high concentation of drug to control nasal sysptoms |
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drug deliverly to upper airways systemic effect
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by pass 1st pass metabolism
absorbed directly into circulation |
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nasal passgae
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- total surface area " 150 cm2
- olfactory epithelial area " 10 cm2 - ciliated epithelium lines posterior region (back of the nasal passage helps remove mucus) - richly vascularized by fenestrated capillaries (regulates air temp |
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does the nasal passge have a rich supply of blood vessels
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yes
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intranasal drug delvery
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for aerosols or sprays, small particles tend to follow air flow
the big particles are governed by mass and velocity increase in tortuosity--> turbulant air flow--> increase in particle deposition |
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what is the olfactroy region
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the region of the nasal cavity that connects to the CNS
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what kind of airflow does the mouth have
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laminar
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what determines particle deposition
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velocity (speed of inspiration and particle size)
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what size of particles do you want to deliver nasally in oder to remain in the nasal passage
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large
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what size pf particles are delivered to the central airways
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aerosol 1-5 microns
asthma |
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what size of particles are delivered to the peripheral airways
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aerosol <2 micorons
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what size of particles are delivered to the upper airways
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drops
spray (aerosol >10 microns) you can just apply a solution to the nasal passge if it is wanted to stay there |
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drug delivery to the airways is __________
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particle size-dependent
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do you get more lung deposition from inhaling by the mouth or the nose and why
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the mouth because the nose has more turbulant airflow which decreases delevery by 50%
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if a spray is used in the nose where dose it stay
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particles in the spray go in the direction of the spary and are more localized to that area
it coats the surface and has a larger effect |
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if a drop is used in the nose what happens
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more of the nasal passage is affected
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picture of turbulant nose airflow
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Intranasal drug bioavailability
• drug factors: applied drug volume/concentration |
- good distribution/coating
- amount absorbed related to surface area - concentration = "driving force" into the epithelium |
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Intranasal drug bioavailability
• drug factors:distribution in the nasal cavity |
have larger surface area so cleared more quickly
- olfactory epithelium has better CSF access |
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rate of drug clearance from the posterior nasal passage
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6 mm/hr due to the prescence of cilia
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rate of drug clearance in the anterior nasal passage
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2 mm/hr because it is not ciliated
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Intranasal drug bioavailability
• drug factors: density/viscosity of drug solution |
- determines ease of mucociliary clearance (more viscous = decreased CL)
- "bioadhesive" properties (decrease CL because they stick to the epithelium) |
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Intranasal drug bioavailability
• drug factors: physicochemical factors affecting drug absorption |
- molecular size (smaller more more quickly)
- nasal pH and drug pka influence - lipophilicity |
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nasal absorption mechanisms
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a. diffusion ! lipophilic agents
b. aqueous pores ! hydrophilic agents c. active/selective transport (unique to selective drugs such as insulin and propanolol) d. olfactory nerve uptake |
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olfactory nerve uptake happpens by 2 ways
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1. drug is taken up by transcytosis (drug is taken up into the vessicles and released into the CNS)
2. Drug could pass between the nerve and epithlial cells through tight juctions (estradiol) |
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mucociliary escalator
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- mucus + ciliated epithelium
- traps & removes inhaled materials |
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mucociliary escalator
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- mucus + ciliated epithelium
- traps & removes inhaled materials |
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are the peripherial or central airways more efficient in clearing inhaled particles
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the central airways
the peripheral airways aveoli marcophages remove particles |
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airway mucus
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• secreted from mucusal and submucosal glands
• gel-like material |
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properties of mucus
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a. water (90-95%, influences viscosity)
b. proteins, phospholipids c. mucins - glycoproteins - multiple mucins, e.g., MUC5A, MUC5B • impart different physical propertiers to mucus • proportions change in disease |
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what are glycoproteins
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proteins with oligosaccharide side chains
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are the characteristcs of a mucin the same
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no different mucins have different properties
can influence the tenicity and viscosity of the mucus change the properties of the mucins will result in a change in the mucus produced |
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mucuses serves as
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• serves hygienic function
- traps inhaled materials depositing on central airway lumen - cleared from airways by mucociliary escalator & coughing |
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mucus clearance from airways affected by mucus:
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- viscoelasticity: thickness
- tenacity: stickyness.adherance |
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MUCOCILIARY CLEARANCE
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• mucus moved from airways towards pharynx by coordinated beating of cilia on epithelial cells
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• clearance affected by
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a. mucus viscosity
- mucus constituents - water content - extent of xross-linking - pH/ion content b. mucus volume - water content - gland function (determines amount of mucus produced) c. ciliary beat frequency - inflammatory mediators - nerves • clearance mechanisms are affected by mucus characteristics |
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what effects do the PNS have on mucus production
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increased production and increased ciliary function
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what could happen in asthma when an anti-muscurinic is given
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decrease ciliary function so there is a decrease in mucus removal and in asthma there can be an increased production of mucus
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if vicosity of mucus is decreased how are the CL mecanisms affected
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increase mucociliary
no change or decrease in CL through cough |
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how does the volume of mucus affect CL mecanisms
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increased volume will overload the mucociliary CL
increased volume will increase the cough CL |
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how does the ciliary beat frequency affect CL mecanisms of mucus
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increases cause an increase in mucociliary CL
there is not really an effect on cough |
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how does the adhesiveness of mucus affect CL mecanisms
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doesn't affect the mucociliary route of CL
Cough is more effective when the mucus is not adhesive |
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3 phases of cough
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a. inspiratory phase (loading air into the lungs)
b. forced expiration against glottis (creates a large pressure build up and an increase in velocity of airflow) c. glottis opening allowing forced expiration |
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Cough: defensive reflex that clears larynx - main bronchi of:
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- sputum
- foreign particles - infectious organisms |
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cough can be caused by
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- viral infections
- postnasal drip - allergy - asthma - bronchitis - lung cancer - heart failure - pneumonia - foreign particles - drugs |
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can cough volunteraly be controlled
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yes
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sensory nerves for the cough refelx are located...
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in particular areas because it is where particles are more likely to be deposited
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- cough receptors
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receptor
Δ pH Δ tonicity irritant cigarette smoke mechanical stimulation pulmonary congestion C-fiber bradykinin capsaicin stretch mechanical stimulation |
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- ventilatory muscles
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• intercostal muscles
• diaphragm • abdominal muscles • laryngeal muscles to close the glotis |
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uncontrolled, unproductive cough →
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- prevent sleep
- fatigue - muscle pain - rib fractures - pneumothorax - urinary incontinence - syncope |
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disease and cough sensitivity changes in 2 locations
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a. peripheral sensitization (the sensory nerves are more sensitive to irritants)
b. central sensitization (noraml impluses can trigger a cough) both increase cough sensitivity |
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MUCUS CHEMISTRY
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a. covalent (di-sulfide bonds bewteen mucins)
b. ionic bonds c. hydrogen bonds d. van der Waals forces e. intermingling f. interactions with other molecules in mucus, e.g., DNA, F-actin |
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more chemical interactions casue the mucus to become
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thicker
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different mucins have different chemical characteristics which
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→ confers different physical properties because there are differenct chemical reactions between mucin molecules
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disease → ↓ mucus clearance by:
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- ↑ volume
- ↑ viscosity - ↑ tenacity/adhesiveness |
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MUCUS & AIRWAYS DISEASE: ↓ mucus clearance
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→ mucus accumulation in airways
→ airway obstruction airway infection (usually the mucus is cleared now there is a media in which the bacteria can grow) |
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MUCOLYTICS/EXPECTORANTS
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mucus removal facilitated by ↓ mucus viscosity
a. ↓ mucin molecule crosslinking b. degrading DNA or proteins c. ↑ mucus hydration making the mucus more easily flowing and less viscous mucin F-actin DNA • ↓ mucin molecule crosslinking - reduce disulfide bonds |
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N-acetylcysteine
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- contains a free thiol group that reduces the di-sulfide bound between mucins to creae 2 free molecules
an expectorant |
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side effects and considerations of NAC
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• administered by inhalation or intracheal instillation
• bronchospasm (especailly in asthmatics because of low pH) • inactivates some antibiotics (cephlosporins and penicillins) • poor efficacy (not clinically effective) • unpleasant smell (becuase a hydrogen sulfide is produced) • contraindicated in patients with advanced chronic bronchitis (because their mucus is already very fluid therefore it would make it to fluid and hard to move) |
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• degrading DNA or proteins in mucus
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prurulent mucus can contain DNA or F-actin--> from dying neutrophils
degrade DNA or F-actin--> decreases mucus viscosity (mucin molecules are released, they are no longer connected) When the DNA or F-actin are degraded it allows the proteolytic enzymes better access to the mucin molecules in order to break them down |
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dornase alpha (Pulmozyme®)
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- recombinant human DNase
- hydrolyzes extracellular DNA (doesn't get into cells) → DNA detaches from mucus proteins → mucin proteins are degraded by proteases that are in the surrounding enviroment → ↓ mucus viscosity → ↑ mucus CL by clia → decrease airway obstruction and decrease risk of bacterial infection |
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side effects and considerations of dornase alpha (Pulmozyme®)
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• upper airway irritation (hoarseness)
• ↓ antibiotic effects • does not affect DNA in living cells • administered by inhalation (get a high concentration locally) |
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Genentech recommends the use of specific nebulizers with dornase alpha. Why is
this the case? |
nebulizers can damage proteins especailly the jet nebulizers
therefore particular ones are used with certain products becuase studies have been done to determine how much drug is coming out of the nebulizer they choose one that does minimla destruction and creates the desired/optimal sized particle |
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↑ mucus hydration by
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- ↑ water in mucus
→ ↓ mucus viscosity therefore the mucus is easier to remove by the cilary esculator |
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an increase in hydration of mucus is promoted by
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a. osmotic stimuli
b. ion channel inhibition |
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hypertonic saline, mannitol
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- osmotic stimuli
- promotes fluid flow from epithelium into mucus promotes increased mucus hydration |
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side effects and considerations of hypertonic saline, mannitol
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• administered by inhalation (because want to afffect mucus not the blood)
• hypertonic saline may also break ionic bonds between mucin molecules (making the mucus less viscous) • bronchoconstriction • investigational |
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denufosol works on what 2 channels
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inhibits Na channels
Acitvates Ca regulated Cl channels |
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denufosol
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- P2Y2 receptor agonist
→ ↓ Na+ reabsorption → ↑ [Na+] in mucus → activation of Ca++-regulated Cl- channels (on epithelial cells) → ↑ [Cl-] in mucus both of which create a concentration gradient to → promotes fluid flow from epithelium into mucus |
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side effects and considerations of denufosol
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• administered by inhalation
• investigational |
|
guaifenesin MOA
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- irritates gastric mucosa
→ ↑ respiratory secretions (primarily serous fluid from serous glands) → ↓ mucus viscosity approven in 1952 |
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side effects and considerations of guaifenesin
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• po because has to affect the gastric mucosa
• nausea, vomitting, diarrhea, headache |
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cough suppressants/antitussives can be
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a. centrally-acting (increase threshol)
b. peripherally-actin(increase threshold) |
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centrally acting cough supressants
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act in the cough center in the CNS
→ increase cough threshold → depression of cough refelx they have to enter the CNS to alter the threshold |
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what kind of cough supressants are opioids
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centrally acting
|
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opioid cough suprressants drug names
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codeine, hydrocodone
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OPIOID cough suppressants
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- act on μ receptors
- may also act on sensory nerve endings - u receptors are used for analgesia as well, but it maybe a different u receptor - act at doses below those required for analgesia - side effects/considerations • nausea/vomitting • constipation • dizziness, mental clouding • abuse potential *** |
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what do pharmaceutical companies do to decrease the abuse potential of opioids
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add another pharmacological agent that prevents abuse by creating SE (atropine like SE0
so when a person takes more than the recommended amount it causes SE |
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opiate derivative drug names
|
dextromethorphan
levopropoxyphene napsylate |
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what kind of cough supressant are opiate derivatives
|
centrally acting
|
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dextromethoprphan
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- d-isomer of levorphanol
unlike the l-isomer, it has no analgesic or addictive prperties - potency ≈ codeine codine analog acts like codeine without the abuse potential |
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levopropoxyphene napsylate
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no analgesic properties less potenital for addiction
- l-isomer of dextropropoxyphene |
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side effects and considerations of opiate derivatives
|
• drowsiness, sedation
• GI upsets |
|
! Dextromethorphan abuse (CCC, DXM, Skittles, Robo)
High DM doses of metabolized to dextrorphan. Dextrorphan = NMDA receptor antagonist → dissociative hallucinations. Why might you anticipate seeing APAP toxicity in DM abusers? |
combo products, so the patient may be consuming high doses of APAP
|
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peripherally-acting cough suppresants
|
↓ sensitivity of cough receptors to stimulation
→ depression of the cough relfex acting on sensory nerve ending |
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peripherally-acting cough suppresants drug names
|
benzonatate
menthol maybe the below 2: β2-adrenoceptor agonists muscarinic cholinoceptor antagonists |
|
benzonatate
|
- chemically-related to procaine
- inhibits pulmonary stretch receptors periperally acting cough supressant |
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menthol
|
periperally acting cough supressant
- local anesthetic effect on sensory nerves |
|
Cystic fibrosis
|
• affects ≈ 30,000 individuals in U.S.A.
• incidence: caucasian 1/2,500 black 1/17,000 asian 1/90,000 → 95% of cases are in caucasion, which indicates there is a genetic component • autosomal recessive disorder involving defect in the CF transmembrane regulator (chloride transport mechanism in epithelial cells) |
|
what is the main defect in CF
|
Cl channels
defective chloride channels → hyperviscous mucus → airway obstruction |
|
infalmmatory cell death in CF causes
|
hyperviscous mucus
elastase release → ↑ airway injury |
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what does the increased mucus in CF do to ciliary function and what else happens
|
cilia function is decreased therefore the mucus can not be cleard from the airways causing an obstruction and procviding an media for bacterial growth
|
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what kind of inflammatory response is induced in CF
|
the inflammatroy cells respond to the bacterial infection in the mucus
neutrophiiles migrate to the area of infetion |
|
when the neutrophils die when a patient has CF what happens
|
DNA from the dead cells release DNA with causes the mucus to become more viscous
|
|
neutrophils release
|
oxygen free radicals
and elastase both of whichdamage the epithlium causing airway damage |
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PULMONARY THERAPEUTIC OBJECTIVE IN CF
|
• relieve mucus obstruction make it easy to breathe
* decrease mucus viscosty • treat lung infection |