Pharm Airway Disease

Front 1

an inflammatory disease of the
airways that appears to involve a broad range
of cellular and cytokine mediated mechanisms
of tissue injury.

Back 1

Asthma

Front 2

4 Results in increased
pulmonary resistance

Back 2

– Bronchospasm
– increased produc8on of
airway lining fluid
– mucosal edema
– airway smooth muscle ‐ best treated by pharmacology

Front 3

Severe persistent asthma

PEF % or FEV1

Back 3

< 60% of the predicted
value.

Front 4

Severe Asthma: 10% of all asthmatics Defined as

Back 4

asthma unresponsive to current
treatment including steroids

Front 5

Difficult Asthma:
– Characterized by

Back 5

failure to achieve control despite
maximally recommended doses of inhaled
steroids

Front 6

Brittle Asthma:
– Characterized by

Back 6

sudden acute aKacks occurring
in less than 3 hours, without an obvious trigger in
a previously well controlled asthma8c

Front 7

Nocturnal asthma: (early morning dip)
– Characterized by

Back 7

an early morning (some8mes
evening) deteriora8on paKern in lung func8on.

Front 8

Premenstrual asthma:
– Characterized by

Back 8

a decrease in PEF 2 to 5 days
prior to menstrual period, with improvement once
menstrua8on begins.
– Usually mild and responsive to treatment but can
be severe and steroid resistant.

Front 9

Status Asthmaticus

Back 9

Acute severe asthma that places the patient at risk
of developing respiratory failure.

Front 10

Status Asthmaticus

time frame

Back 10

• Condi8on may develop over several days
– Slow onset
• Can develop in less than 1 hour
– Sudden onset asthma exacerbation

Front 11

Status Asthmaticus

Back 11

Implicated causes include: massive exposure to
common allergens, sensitivity to NSAIDs,
sensitivity of food allergens and sulphites.

Front 12

Fatal Asthma:
– Type 1:

%
occurs in

considered

Back 12

– Type 1: accounts for 80‐85% of deaths from
asthma. Known as slow onset.
– Occurs in pa8ents with severe and poorly
controlled disease who deteriorate over days or
weeks.
– Considered preventable

Front 13

Fatal Asthma;
– Type 2:

Back 13

– Type 2: develops rapidly
– Develop severe hypercapnic respiratory failure
with combined metabolic and respiratory acidosis.
– Succumb to asphyxia
– Responds to treatment faster than type 1 fatal
asthma

Front 14

14 risk factors for asthma death

Back 14

• Past history of sudden severe exacerba8ons
• Prior intuba8on for asthma
• Prior admission for asthma to an ICU
• Two or more hospitaliza8ons for asthma in the
past year
• Three or more emergency care visits for
asthma in the past year.
• Hospitaliza8ons or an emergency care visit for
asthma within the past month
• Use of >2 canisters per month of inhaled short
ac8ng ß2‐agonist.
• Current use of systemic cor8costeroids or
recent withdrawal from systemic
cor8costeroids.
• Comorbidity from cardiovascular diseases or
COPD
• Serious psychiatric disease or psychosocial
problems
• Low socioeconomic status and urban
residence
• Illicit drug use
• Sensi8vity to fungi

Front 15

Asthma
MOA

Back 15

– An inflammatory disease of the airway
– Involves a broad range of cellular and cytokine
mediated mechanisms of tissue injury

Front 16

Asthma –4 Autopsy findings

Back 16

• Occlusion of the bronchial lumen by thick secre8ons
• Thickened smooth muscles
• Bronchial wall inflamma8on and edema
• Peripheral airway occlusion leads to areas of reduced ven8la8on,
(V) but perfusion (Q) is maintained.

Front 17

Asthma pathology Leads to 3X

Back 17

• Hypoxemia
• Hypercapnia
• Lactic acidosis

Front 18

broncial musculature innervation

Back 18

Sympathe8c Nervous System
– Direct control of bronchioles is weak
– Few sympathetic fibers penetrate the central
portions of the lungs

Front 19

broncial musculature

Very much exposed to circulating _________________ released into the blood via sympathetic
stimulation of the adrenal gland

Back 19

norepinephrine and
epinephrine

Front 20

_________ causes dilation of the bronchial tree via
beta receptors

Back 20

Epinephrine

Front 21

Parasympathetic
– Divisions of the _______________ penetrate the lung
parenchyma

Back 21

vagus nerve

Front 22

Parasympathetic

Release acetylcholine when activated causes

Back 22

Causing mild to moderate bronchiole constriction

Front 23

When a disease process (asthma) has already caused some
constric8on, parasympathetic superimposed nervous stimulation
often

Back 23

worsens the condition.

Front 24

Parasympathetic
Release acetylcholine when activated

Explains why drugs like _______________ can relax respiratory passages
enough to relieve the obstruction.

Back 24

atropine

Front 25

Local Cellular Effects‐ 3 substances released
from lung tissue.

Back 25

Released from mast cells during allergic reac8ons.
Especially pollen.
• Histamine
• Slow reacactive substance of anaphylaxis
• Leukotrienes

Front 26

Bronchoconstric8on
– Stimulation of the ACh receptor activates a

Back 26

G
protein

Front 27

Stimulation of the ACh receptor activates a G
protein
– This activates

Back 27

phopholipase C to catalyze the formation of IP3

Front 28

IP3 binds to the sarcoplasmic reticulum and causes

Back 28

the release of calcium

Front 29

Increased intracellular calcium initiates crossbridging of

Back 29

of myosin and actin = muscle contraction

Front 30

receptor signaling pathways - bronchoconstriction 4 steps

Back 30

– Stimulation of the ACh receptor activates a G
protein
– This activates phopholipase C to catalyze the
formation of IP3
– IP3 binds to the sarcoplasmic reticulum and
causes the release of calcium
– Increased intracellular calcium initiates crossbridging
of myosin and actin = muscle contraction

Front 31

Bronchodilation
– Stimulation of a beta 2 receptor activates

Back 31

G
protein

Front 32

Bronchodilation 3 steps

Back 32

– Stimulation of a beta 2 receptor activates a G
protein
– This activates adenylate cyclase and converts ATP
to cyclic AMP
– Cyclic AMP causes muscle relaxation by inhibiting
calcium release from intracellular stores.

Front 33

Asthma
A mul8faceted disease characterized by

Back 33

intermittent, reversible bronchoconstric8on
and chronic airway inflammation.

Front 34

Environmental exposure to repeatedly inhaled
allergens
• Leading to

Back 34

a chronic eosinophilic inflammatory
response

Front 35

inflammatory response

Antigen binds to...

causes 3x

Back 35

immunoglobulin E
(IgE) on the surface
of the plasma cells.

– Causes degranula8on
• Releases Platelet
activating factor
• Prostaglandins
• Leukotriene

Front 36

The IgE released by

Back 36

plasma cells

Front 37

The IgE released by plasma cells circulates in
the blood and binds to

Back 37

IgE receptors on mast
cells.

Front 38

The mast cells in the lungs are then primed to
release 3 inflammatory mediators

Back 38

• Histamine
• Platelet activating factor
• Leukotrienes

Front 39

These 3 inflammatory mediators are major inducers
of bronchoconstric8on in asthma.

Back 39

• Histamine
• Platelet activating factor
• Leukotrienes

Front 40

Mediators released by mast cells histamine,
prostaglandins, bradykinin, platelet
ac8va8ng factor cause 4X

Back 40

– Cause immediate airway smooth muscle
contrac8on
– S8mulate microvascular leakage with edema
forma8on
– Mucous gland secre8on
– Ac8va8on of sensory nerve endings

Front 41

pharm therapies
Controllers

Back 41

Taken on a regular basis to minimize the
occurrence of asthmatic symptoms

Front 42

pharm therapies
Relievers

Back 42

Taken as needed for the rapid relief of asthmartic
symptoms

Front 43

principal receptor
found in airway
smooth muscle

Back 43

Beta2 adrenergic
receptors

Front 44

The therapeutic
effect of beta2
receptor stimulation
is

Back 44

bronchodilation

Front 45

Beta2 Adrenergic Agonists
– Cause

Back 45

an increase in cAMP, activation of protein
kinase A, phosphorylation of intracellular kinases

Leading to a decrease in cytosolic calcium, and
resultant relaxation of the smooth muscle cells

Front 46

Increased levels of cAMP mediate

Back 46

mediate smooth
muscle relaxa8on
– inhibit the release of inflammatory mediators
from cells
• Especially mast cells

Front 47

Adverse effects of beta
agonists are atiributable to

most frequent is

Back 47

increased cAMP levels in
nontarget tissues

• Tremor, nervousness most
frequent


• Tachycardia, hypertension,
palpitations, and nausea/
vomiting can occur

Front 48

epinephrine stimulates

Back 48

Stimulates alpha and beta1 and beta2

Front 49

ephinphrine causes

Back 49

bronchodilation, it is a
potent vasoconstrictor and
cardiac stimulant

Front 50

ephinphrine Oral administration –
rapidly metabolized

Back 50

by COMT and MAO

Available over the
counter as
Primatene Mist

Front 51

isuprel class

causes

Back 51

• Beta1 and Beta2 adrenergic
agonist
• One of the most potent
bronchodilators
• Equal beta 1 and 2
stimulatory effects
• Causes considerable
tachycardia and heart
pounding

Front 52

albuterol
onset

duration

Back 52

Inhalation – onset 5‐7 minutes;

duration 4‐6
hours

Front 53

terbutaline use

Only Beta2 agonist available
for _________ use

Back 53

May be used in acute
exacerbations when inhaled
form has not been effective.

subcutaneous

Front 54

Subq terbutaline used as
tocolytic agent d/t

dose

Back 54

the smooth
muscle relaxing effects on the uterus
dose

Ini8al dose is .25mg sq; can
repeat in 15‐30 minutes. Total dose not to exceed .5 mg/4 hours

Front 55

prophylactic airway resistance

Back 55

Prophylac8c use of ß agonist 1 hour before
induction of general anesthesia results in
reduced airway resistance after endotracheal
intubation.

Front 56

Aminophylline: a water‐soluble salt of

Back 56

theophylline available orally or IV

Front 57

Aminophylline: inhibits

by

Back 57

Inhibits adenosine receptors facilitating release of
catecholamines
– At high concentrations inhibits phosphodiesterase:
the enzyme responsible for the breakdown of
cAMP
– Anti‐inflammatory properties

Front 58

theophylline protein binding

Back 58

40% bound to albumin; may show signs of
toxicity even if in therapeutic range
(10‐20mcg/ml) due to increased levels of
unbound drug

Front 59

theophylline

decreases

increases

Back 59

Decreased peripheral vascular resistance
• Increased cerebral vascular resistance

• Smooth muscle relaxa8on
• Diuresis
• Increased secretion by endocrine and exocrine
tissues

Front 60

Anticholinergic agents
– Promote airway relaxation by

Back 60

inhibiting M2 and
M3 receptors on airway smooth muscle.

Front 61

The release of AcH from parasympathetic nerves
increases during

Back 61

exacerbations of asthma and during endotracheal intubation.

Front 62

The release of AcH from parasympathetic
nerves activates M3 receptors which

Back 62

couple
through the G protein to ac8vate
phospholipase C, which liberates inositol
triphosphates (IP3) increasing intracellular
calcium and causing muscle contraction

Front 63

Mu 2 receptors act through

Back 63

inhibitory G protein and inhibit
adenylyl cyclase and K+ channel activation

Front 64

M2 receptors also exist on

Back 64

the post‐ganglionic
prejunc8onal parasympathe8c nerve where
they act to inhibit further acetylcholine
release

Front 65

The systemic administration of
anticholinergics is limited by

Back 65

systemic side
effects

Front 66

Only inhaled forms of anticholinergics are practical

Back 66

practical anti‐asthma therapy

Front 67

Inhaled anticholinergics have a slower onset
and slower time to peak effect than

Back 67

inhaled
beta agonists.

Front 68

Studies have shown that the combina8on of
_____ and _________more quickly and completely relieved
bronchoconstric8on.

Back 68

inhaled an8cholinergics and beta agonists

Front 69

Viral infections have been
shown to cause

Back 69

dysfunction
of the M2 receptor causing
increased release of
acetylcholine

Front 70

Patients with recent URI
may have a greater benefit
from

Back 70

anticholinergics than
beta agonist therapy

Front 71

VA

Relaxation is facilitated by

Back 71

neural and direct muscle
Thought to impede the entry of
extracellular calcium through
voltage dependent calcium
channels

Front 72

corticosteriods mandated short term use d/t

Back 72

Adverse side effects (weight gain, growth
retarda8on, glucose intolerance,
hypertension, osteoporosis, cataracts,
glaucoma) mandated short term use

Front 73

corticosteriods MOA

also promote and decrease

Back 73

and readily cross the cell membrane
• Once the drug receptor complex enters the
nucleus, it influences the transcription of
genes
• Decreased transcriptoon of genes coding for
proinflammatory cytokines is thought to be an
important mechanism of action


• Promote eosinophil apoptosis and decrease
vascular leakage

Front 74

corticosteriods 4 drugs inhaled

Back 74

Prepara8ons available for inhala8on include
beclomethasone, triamcinolone, flunisolide,
budesonide, and flu8casone

Front 75

The chromone, cromolyn, is an inhaled drug
that inhibits

Back 75

The chromone, cromolyn, is an inhaled drug
that inhibits the release of inflammmatory
mediators from mast cells
• Regular use decreases airway
hyperresponsiveness and improves symptoms
in persistent asthma

Front 76

cromolyn Causes

Back 76

phosphoryla8on of a
cell membrane protein;
mediator release is
inhibited despite an8gen‐
IgE interac8on on the cell
surface
• Inhibits chloride channels,
which decreases
intracellular calcium

Front 77

cromolyn effectiveness

Back 77

Less effective than inhaled steroids for
symptom control and prevention of asthma
attacks
• Is not active in relieving acute asthmatic
symptoms
• It is nearly free of adverse side effects – used
in childhood asthma

Front 78

Leukotienes belong to a family of compounds
known as

Back 78

eicosanoids (which are synthesized
from arachidonic acid

Front 79

Leukotrienes are synthesized from

Back 79

arachidonic
acid which is released from membrane
phospholipids by phospholipase A2 when
inflammatory cells are activated

Front 80

Leukotrienes are synthesized from arachidonic
acid via the ________ pathway

Back 80

5‐lipoxygenase

Front 81

Leukotrienes They are 1000 times more potent than __________ in stimulating airway smooth
muscle constriction

Back 81

histamine

Front 82

Leukotrienes also promote

Back 82

microvascular leakage,
mucous secretion.

Front 83

Leukotrienes

Two types of drugs developed to modify the
pathway

Back 83

Inhibitors of the 5‐lipoxygenase enzyme

• Antagonists of cysteinyl leukotriene receptors

Front 84

Zileuton
Lipoxygenase antagonist
• Exhibits

Back 84

both an acute bronchodilatory effect
and an anti‐inflammatory effect

Short half‐life; dosing 4 8mes daily
• 2‐4% incidence of hepa8c toxicity
• Recently withdrawn from the market

Front 85

Montelukast

Back 85

Cysteinyl leukotriene receptor antagonist
• Administered orally QD or BID
• Metabolized by the liver but no hepa8c
toxicity
• Not all asthma8cs improve with leukotriene
modifiers