Ios V Test #3 Kuma

Front 1

Preparation of inhalers

Back 1

comprise solutions of drug in a sealed container containing liquified gas propellant(s) under
pressure.

Front 2

propellants include:

Back 2

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)

Front 3

in the pressurized package, drug can be:

Back 3

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)

Front 4

generation of the aerosol

Back 4

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

Front 5

initial velocity from the inhaler influences

Back 5

the momentum and the deposition of the particle

Front 6

for MDI, similar system operates except only drug from metering chamber is ejected

Back 6

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

Front 7

Using an MDI

Back 7

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!)

Front 8

do you use the floating technique with an MDI

Back 8

no

Front 9

steps for using an MDI

Back 9

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

Front 10

Spacer devices vs. MDI

Back 10

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

Front 11

are side effects more or less with a spacer

Back 11

less
because the large particles remain in the spacer

Front 12

Side efffects of inhalers

Back 12

a. oral: candidiasis (thrush)
b. GI (when swallowed) spacers decrease

Front 13

disadvantages of spacers

Back 13

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

Front 14

types of spacers

Back 14

a. reservoir bag (InspirEase®)
b. tube spacer
Aerochamber®

Front 15

Why would spacer devices increase lung deposition?

Back 15

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

Front 16

resevoir bag spacer

Back 16

aerosol paricles end up in the bag and larger particles are left up in the bag

Front 17

tube spacer

Back 17

injecting into the tube so the large particles remain on the walls of the spacer

Front 18

aerochamber

Back 18

like a tube spacer, but with a rubber mouth piece/facemask so the particles can be breathed and re-breathed

Front 19

is coordination as criticle when using a spacer

Back 19

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

Front 20

advantages of spacers

Back 20

increase pulmonary deposition resulting in a better therapuetic effect

decrease oropharyngeal deposition which decreases SE

Front 21

who are spacers good for

Back 21

elderly
children

Front 22

how is the time it takes to from from the inhaler to the mouth effected when using a spacer

Back 22

it is increased

and the propellant evaporates causing the particles to get smaller thus decreasing the inertial impaction

Front 23

dry powder inhalers

Back 23

• 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

Front 24

why are the dry powder inhalers medication packaged in blister packs

Back 24

to prevent degradation by the humidity

Front 25

what are dry poweder inhalers mainly used for

Back 25

anti-asthma

Front 26

advantages of dry powder inhalers

Back 26

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

Front 27

disadvantages of dry powder inhalers

Back 27

- 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

Front 28

what breaks up the powder when using a dry powder inhaler

Back 28

inspiratory flow

Front 29

what gives the particles momentum when using a dry powder inhaler

Back 29

inspiration

Front 30

nebulizers

Back 30

• 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)

Front 31

how is dosing based when using a nebulizer

Back 31

• dosing is based on time of inhalation
patient is continually exposded to the medication so it is based on time of exposure

Front 32

advantages of nebulizers

Back 32

- 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

Front 33

how much more drug can a powder formulation hold than an aerosol

Back 33

5x more

Front 34

disadvantages of nebulizers

Back 34

- 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

Front 35

advantages of inhaled drugs

Back 35

- 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

Front 36

disadvantages of inhaled drugs

Back 36

- 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)

Front 37

upper airway=

Back 37

nose/pharynx

Front 38

central airways=

Back 38

tracheo-bronchial

Front 39

peripheral airways=

Back 39

alveoli (pulmonary)

Front 40

drug deliverly to upper airways local effect

Back 40

- vasoconstrictors (decongestants)
- anti-allergy

high concentation of drug to control nasal sysptoms

Front 41

drug deliverly to upper airways systemic effect

Back 41

by pass 1st pass metabolism
absorbed directly into circulation

Front 42

nasal passgae

Back 42

- 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

Front 43

does the nasal passge have a rich supply of blood vessels

Back 43

yes

Front 44

intranasal drug delvery

Back 44

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

Front 45

what is the olfactroy region

Back 45

the region of the nasal cavity that connects to the CNS

Front 46

what kind of airflow does the mouth have

Back 46

laminar

Front 47

what determines particle deposition

Back 47

velocity (speed of inspiration and particle size)

Front 48

what size of particles do you want to deliver nasally in oder to remain in the nasal passage

Back 48

large

Front 49

what size pf particles are delivered to the central airways

Back 49

aerosol 1-5 microns
asthma

Front 50

what size of particles are delivered to the peripheral airways

Back 50

aerosol <2 micorons

Front 51

what size of particles are delivered to the upper airways

Back 51

drops
spray (aerosol >10 microns)

you can just apply a solution to the nasal passge if it is wanted to stay there

Front 52

drug delivery to the airways is __________

Back 52

particle size-dependent

Front 53

do you get more lung deposition from inhaling by the mouth or the nose and why

Back 53

the mouth because the nose has more turbulant airflow which decreases delevery by 50%

Front 54

if a spray is used in the nose where dose it stay

Back 54

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

Front 55

if a drop is used in the nose what happens

Back 55

more of the nasal passage is affected

Front 56

picture of turbulant nose airflow

Back 56

Front 57

Intranasal drug bioavailability
• drug factors: applied drug volume/concentration

Back 57

- good distribution/coating
- amount absorbed related to surface area
- concentration = "driving force" into the epithelium

Front 58

Intranasal drug bioavailability
• drug factors:distribution in the nasal cavity

Back 58

have larger surface area so cleared more quickly
- olfactory epithelium has better CSF access

Front 59

rate of drug clearance from the posterior nasal passage

Back 59

6 mm/hr due to the prescence of cilia

Front 60

rate of drug clearance in the anterior nasal passage

Back 60

2 mm/hr because it is not ciliated

Front 61

Intranasal drug bioavailability
• drug factors: density/viscosity of drug solution

Back 61

- determines ease of mucociliary clearance (more viscous = decreased CL)
- "bioadhesive" properties (decrease CL because they stick to the epithelium)

Front 62

Intranasal drug bioavailability
• drug factors: physicochemical factors affecting drug absorption

Back 62

- molecular size (smaller more more quickly)
- nasal pH and drug pka influence
- lipophilicity

Front 63

nasal absorption mechanisms

Back 63

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

Front 64

olfactory nerve uptake happpens by 2 ways

Back 64

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)

Front 65

mucociliary escalator

Back 65

- mucus + ciliated epithelium
- traps & removes inhaled materials

Front 66

mucociliary escalator

Back 66

- mucus + ciliated epithelium
- traps & removes inhaled materials

Front 67

are the peripherial or central airways more efficient in clearing inhaled particles

Back 67

the central airways

the peripheral airways aveoli marcophages remove particles

Front 68

airway mucus

Back 68

• secreted from mucusal and submucosal glands
• gel-like material

Front 69

properties of mucus

Back 69

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

Front 70

what are glycoproteins

Back 70

proteins with oligosaccharide side chains

Front 71

are the characteristcs of a mucin the same

Back 71

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

Front 72

mucuses serves as

Back 72

• serves hygienic function
- traps inhaled materials depositing on central airway lumen
- cleared from airways by mucociliary escalator & coughing

Front 73

mucus clearance from airways affected by mucus:

Back 73

- viscoelasticity: thickness
- tenacity: stickyness.adherance

Front 74

MUCOCILIARY CLEARANCE

Back 74

• mucus moved from airways towards pharynx by coordinated beating of cilia on epithelial cells

Front 75

• clearance affected by

Back 75

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

Front 76

what effects do the PNS have on mucus production

Back 76

increased production and increased ciliary function

Front 77

what could happen in asthma when an anti-muscurinic is given

Back 77

decrease ciliary function so there is a decrease in mucus removal and in asthma there can be an increased production of mucus

Front 78

if vicosity of mucus is decreased how are the CL mecanisms affected

Back 78

increase mucociliary
no change or decrease in CL through cough

Front 79

how does the volume of mucus affect CL mecanisms

Back 79

increased volume will overload the mucociliary CL

increased volume will increase the cough CL

Front 80

how does the ciliary beat frequency affect CL mecanisms of mucus

Back 80

increases cause an increase in mucociliary CL

there is not really an effect on cough

Front 81

how does the adhesiveness of mucus affect CL mecanisms

Back 81

doesn't affect the mucociliary route of CL

Cough is more effective when the mucus is not adhesive

Front 82

3 phases of cough

Back 82

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

Front 83

Cough: defensive reflex that clears larynx - main bronchi of:

Back 83

- sputum
- foreign particles
- infectious organisms

Front 84

cough can be caused by

Back 84

- viral infections
- postnasal drip
- allergy
- asthma
- bronchitis
- lung cancer
- heart failure
- pneumonia
- foreign particles
- drugs

Front 85

can cough volunteraly be controlled

Back 85

yes

Front 86

sensory nerves for the cough refelx are located...

Back 86

in particular areas because it is where particles are more likely to be deposited

Front 87

- cough receptors

Back 87

receptor
Δ pH
Δ tonicity
irritant
cigarette smoke
mechanical stimulation
pulmonary congestion
C-fiber
bradykinin
capsaicin
stretch
mechanical stimulation

Front 88

- ventilatory muscles

Back 88

• intercostal muscles
• diaphragm
• abdominal muscles
• laryngeal muscles to close the glotis

Front 89

uncontrolled, unproductive cough →

Back 89

- prevent sleep
- fatigue
- muscle pain
- rib fractures
- pneumothorax
- urinary incontinence
- syncope

Front 90

disease and cough sensitivity changes in 2 locations

Back 90

a. peripheral sensitization (the sensory nerves are more sensitive to irritants)
b. central sensitization (noraml impluses can trigger a cough)

both increase cough sensitivity

Front 91

MUCUS CHEMISTRY

Back 91

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

Front 92

more chemical interactions casue the mucus to become

Back 92

thicker

Front 93

different mucins have different chemical characteristics which

Back 93

→ confers different physical properties because there are differenct chemical reactions between mucin molecules

Front 94

disease → ↓ mucus clearance by:

Back 94

- ↑ volume
- ↑ viscosity
- ↑ tenacity/adhesiveness

Front 95

MUCUS & AIRWAYS DISEASE: ↓ mucus clearance

Back 95

→ mucus accumulation in airways
→ airway obstruction
airway infection (usually the mucus is cleared now there is a media in which the bacteria can grow)

Front 96

MUCOLYTICS/EXPECTORANTS

Back 96

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

Front 97

N-acetylcysteine

Back 97

- contains a free thiol group that reduces the di-sulfide bound between mucins to creae 2 free molecules

an expectorant

Front 98

side effects and considerations of NAC

Back 98

• 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)

Front 99

• degrading DNA or proteins in mucus

Back 99

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

Front 100

dornase alpha (Pulmozyme®)

Back 100

- 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

Front 101

side effects and considerations of dornase alpha (Pulmozyme®)

Back 101

• upper airway irritation (hoarseness)
• ↓ antibiotic effects
• does not affect DNA in living cells
• administered by inhalation (get a high concentration locally)

Front 102

Genentech recommends the use of specific nebulizers with dornase alpha. Why is
this the case?

Back 102

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

Front 103

↑ mucus hydration by

Back 103

- ↑ water in mucus
→ ↓ mucus viscosity

therefore the mucus is easier to remove by the cilary esculator

Front 104

an increase in hydration of mucus is promoted by

Back 104

a. osmotic stimuli
b. ion channel inhibition

Front 105

hypertonic saline, mannitol

Back 105

- osmotic stimuli
- promotes fluid flow from epithelium into mucus

promotes increased mucus hydration

Front 106

side effects and considerations of hypertonic saline, mannitol

Back 106

• 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

Front 107

denufosol works on what 2 channels

Back 107

inhibits Na channels
Acitvates Ca regulated Cl channels

Front 108

denufosol

Back 108

- 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

Front 109

side effects and considerations of denufosol

Back 109

• administered by inhalation
• investigational

Front 110

guaifenesin MOA

Back 110

- irritates gastric mucosa
→ ↑ respiratory secretions (primarily serous fluid from serous glands)
→ ↓ mucus viscosity

approven in 1952

Front 111

side effects and considerations of guaifenesin

Back 111

• po because has to affect the gastric mucosa
• nausea, vomitting, diarrhea, headache

Front 112

cough suppressants/antitussives can be

Back 112

a. centrally-acting (increase threshol)
b. peripherally-actin(increase threshold)

Front 113

centrally acting cough supressants

Back 113

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

Front 114

what kind of cough supressants are opioids

Back 114

centrally acting

Front 115

opioid cough suprressants drug names

Back 115

codeine, hydrocodone

Front 116

OPIOID cough suppressants

Back 116

- 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 ***

Front 117

what do pharmaceutical companies do to decrease the abuse potential of opioids

Back 117

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

Front 118

opiate derivative drug names

Back 118

dextromethorphan
levopropoxyphene napsylate

Front 119

what kind of cough supressant are opiate derivatives

Back 119

centrally acting

Front 120

dextromethoprphan

Back 120

- 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

Front 121

levopropoxyphene napsylate

Back 121

no analgesic properties less potenital for addiction
- l-isomer of dextropropoxyphene

Front 122

side effects and considerations of opiate derivatives

Back 122

• drowsiness, sedation
• GI upsets

Front 123

! 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?

Back 123

combo products, so the patient may be consuming high doses of APAP

Front 124

peripherally-acting cough suppresants

Back 124

↓ sensitivity of cough receptors to stimulation
→ depression of the cough relfex

acting on sensory nerve ending

Front 125

peripherally-acting cough suppresants drug names

Back 125

benzonatate
menthol
maybe the below 2:
β2-adrenoceptor agonists
muscarinic cholinoceptor antagonists

Front 126

benzonatate

Back 126

- chemically-related to procaine
- inhibits pulmonary stretch receptors

periperally acting cough supressant

Front 127

menthol

Back 127

periperally acting cough supressant
- local anesthetic effect on sensory nerves

Front 128

Cystic fibrosis

Back 128

• 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)

Front 129

what is the main defect in CF

Back 129

Cl channels

defective chloride channels → hyperviscous mucus → airway obstruction

Front 130

infalmmatory cell death in CF causes

Back 130

hyperviscous mucus
elastase release → ↑ airway injury

Front 131

what does the increased mucus in CF do to ciliary function and what else happens

Back 131

cilia function is decreased therefore the mucus can not be cleard from the airways causing an obstruction and procviding an media for bacterial growth

Front 132

what kind of inflammatory response is induced in CF

Back 132

the inflammatroy cells respond to the bacterial infection in the mucus

neutrophiiles migrate to the area of infetion

Front 133

when the neutrophils die when a patient has CF what happens

Back 133

DNA from the dead cells release DNA with causes the mucus to become more viscous

Front 134

neutrophils release

Back 134

oxygen free radicals
and elastase

both of whichdamage the epithlium causing airway damage

Front 135

PULMONARY THERAPEUTIC OBJECTIVE IN CF

Back 135

• relieve mucus obstruction make it easy to breathe
* decrease mucus viscosty
• treat lung infection