Respiratory Lecture (Johnson) Asthma

Front 1

triggers of asthma

Back 1

Allergens (e.g., dust mite antigens, animal dander, pollen)
Exercise
Respiratory infections
Drugs and food additives
Nose and sinus problems
GERD
Emotional stress

Front 2

The pathophysiology is characterized by:

Swelling of mucus membranes caused by:

Back 2

edema

vascular dilation

Front 3

The pathophysiology is characterized by:

Spasm of smooth muscle in bronchioles causing

Back 3

increased airway resistance

Front 4

The pathophysiology is characterized by :

Increased mucus gland secretion causing:

Back 4

increased airflow resistance

Front 5

The pathophysiology is characterized by:

The increased airway resistance causes

Back 5

Increased respiratory rate and work of breathing

Front 6

The pathophysiology is characterized by:

The very severe increased airway resistance causes

Back 6

a decrease in alveolar ventilation resulting in hypercapnea and hypoxemia

Front 7

two phases
first phase:

The first early phase response occurs within

Back 7

30 – 60 minutes because an allergen or irritant activates mast cells.

Front 8

mast cells release:

Back 8

inflammatory mediators including:
-histamine
-bradykinin
-leukotrienes
-acetylcholine
-prostaglandins
-platelet activating factor
-chemotactic factors
-cytokines

Front 9

mast cell release causes inflammation causing:

Back 9

Increased vasodilation and permeability in the airways resulting in edema

Airway epithelial damage

Front 10

there are other factors that contribute
to the acute phase:

Back 10

bronchial smooth muscle contracts-- bronchospasm

increased mucus secretion

Front 11

The latter phase response occurs within 5 – 6 hours there is still inflammation. There can be similar mediators as the early phase.
In addition:

Back 11

there is recruitment/infiltration of leukocytes contributing to the “soup” of inflammatory mediators.

Front 12

these leukocytes could be:

Back 12

Eosinophils (bad guys), neutrophils, lymphocytes & monocytes

Future attacks may be worse because the leukocytes enhance the response; hyper-responsive to specific allergens and irritants

Front 13

the latter phase creates a:

Back 13

chronic condition

Front 14

histamine is:

Back 14

a basic amine released from mast cells and basophiles

Front 15

histamine causes

Back 15

Gastric acid secretion- H2 receptors
Contraction of most GI smooth muscle- H1 receptors
Cardiac stimulation- H2 receptors
Blood vessel smooth muscle relation- H1 receptors
Increased endothelial permeability-H1 receptors
Chemotaxis for neutrophils-H3 receptors
Itching-H1 receptors
Pain-H1, H3 receptors

Front 16

histamine is released from:

Back 16

mast cells and basophils

Front 17

histamine is a primary mediator of:

Back 17

immediate-type allergic reactions (Type I)

Front 18

mast cells reside in:

Back 18

peripheral tissues directly interface with the external environment (e.g., airways)

Front 19

mast cell activation is caused by:

Back 19

cross linking of surface IgE by cognate antigens

Mast cells can also be activated by direct binding of microbial products

Mast cells are activated by complement components

Front 20

mast cells release many inflammatory mediators including:

Back 20

Histamine
Proteases
Prostaglandins
Leukotrienes
Cytokines
TNF-α, GM-CSF, IL-3, IL-4, IL-5, IL-6, IL-10, and IL-13

Front 21

allergies are characterized by:

Back 21

a “local or systemic inflammatory response to allergens”

Front 22

allergies are what type of hypersensitivity?

Back 22

Type 1

Front 23

prevalence of allergies

Back 23

-1 in 4 people
-50 million Americans
-Sixth leading cause of chronic disease
-Healthcare system spends $18 billion a year
-Higher in urban areas

Front 24

allergies

levels of symptoms:

Back 24

Allergic Rhinitis (eyes red & puffy)
Conjunctivitis
Bronchoconstriction
Urticaria (hives)
Atopic Dermatitis
Anaphylaxis

Front 25

anaphylaxis

definintion

Back 25

sudden, severe, potentially fatal, systemic allergic reaction that can involve various areas of the body such as the skin, respiratory tract, gastrointestinal tract and cardiovascular system.

Front 26

anaphylaxis

common cause

Back 26

Food, Insect stings, Medicines, Latex

Front 27

anaphylaxis of the skin:

Back 27

skin there is the wheal, flare and pain

Front 28

anaphylaxis of the respiratory tract

Back 28

there is hypoxia because of larynx edema and broncho-constriction

Front 29

anaphylaxis of the GI tract

Back 29

there is diarrhea because of increased motility

Front 30

anaphylaxis of the cardiovascular system

Back 30

there is vasodilation which causes hypotension and tachycardia. The tachycardia is a reflex to the hypotension and is also by direct H2 activity in the heart.

Front 31

antihistamine

Back 31

Is a competitive antagonist that prevents histamine binding to its receptor

H1 receptor antagonist

Front 32

diphenhydramine

Back 32

-The first generation of an anti-histamine.
-Used to treat allergic rhinitis which should reduce:
Sneezing
Runny nose
Itching
Watery eyes
-Used to treat uncomplicated allergic skin reactions to reduce:
Itching
Swelling
-Used to control coughs during “colds” and allergy

Front 33

Anti H1 antagonist

first generation

Back 33

In the central nervous system the side effect is dizziness, sedation, anti-emetic and anti-motion sickness properties. The is because of anti-H1 and/or anti cholinergic

Front 34

Anti H1 antagonist

first generation-
effect on the neural pathways include in the
Periphery:

Back 34

The non-specific anti-cholinergic effect, by binding to the muscarinic receptor, can cause decreased mucous and salivary secretions
-Drying
--Salivary glands
--Bronchial airways

Front 35

Anti H1 antagonist
first generation

effect on the neural pathways include in the blood brain barrier:

Back 35

First generation anti-histamine is hydrophobic having a high partition coefficient which is characteristic of lipophilicity. This allows blockade of H1-receptor in the CNS

Front 36

Anti H1 antagonist
first generation

kinetics:

Back 36

It is rapidly absorbed with peak levels by 1- 2 hrs

The bioactivity last for 4-6 hr

It is metabolized mostly in liver Cytochrome P450 3A4 (CYP3A4)
-Member of the cytochrome P450 mixed-function oxidase system

It is excreted as metabolites and also unchanged

Front 37

Anti H2 antagonist
second generation

Back 37

The need for greater selectivity for peripheral H1 receptors is indicated because of the side effects for the first generation anti-histamines

The less undesirable CNS effects require that there is reduced ability to cross the blood brain barrier, decreased affinity for central histamine receptors and muscarinic receptors

Front 38

Anti H1 antagonist
second generation has:

Back 38

Greater H1 receptor specificity

Little binding to other species of receptors such as muscarinic. There is less anti-cholinergic side effect.

Front 39

Anti H1 antagonist
second generation

The bulky side groups on the phenol prevents the anti-histamine to cross the blood-brain barrier

Back 39

Polar COOH and OH groups

The polar group causes the molecule to be hydrophilic having a low partition coefficients with increasing lipophobicity.

Therefore there is less nonspecific central effects such as the anti-cholinergic
The second generation in urine 95% unmetabolized

Front 40

next generation antihistamines

Back 40

Metabolite derivatives or active enantiomers (two stereoisomers that are non-superposable complete mirror images of each other) of other anti-histamine drugs

Safer, faster acting, less side effects and/or more potent than Second Generation drugs?

Examples:
Fexofenadine (terfenodine)
Desloratadine (loratodine)
Levocetirizine (ceterizine)

Front 41

asthma is characterized by:

Back 41

Reversible inflammation & obstruction
Intermittent attacks
Sudden onset
Variability
--Minimal symptoms
--Death

Front 42

Asthma:
The are many approaches to treat the symptoms, that is, the regulation of the inflammatory mediators-

Back 42

Corticosteroids which is non-specific; inhibits expression of many proteins possibly some proteins involved in anti inflammatory pathways

Use a beta2-agonists which will causes bronchodilation because of increased cAMP and PKA

Use a phosphodiesterase inhibitor causes bronchodilation because inhibit the degradation of the cAMP; thus, increasing PKA activity

**Use a leukotriene inhibitor that will prevent LTB4 effect on leukocytes and LTC4, LTD4 and LTE4 effect on bronchoconstriction

Front 43

Asthma: Bronchodilators
Characteristic of beta 2-adrenergic agonists:

Back 43

Bronchodilation
Rapid onset used for acute attacks; rescue inhaler
There are adverse events including tremors, anxiety, tachycardia and palpitations
--There are short-acting agonists such as albuterol and metaproterenol
--There are long-acting agonists such as salmeterol. It is more lipophilic and useful for nocturnal asthma

Front 44

The phoshodiesterase inhibitors are the methylxanthines generics are theophylline and aminophylline
They are characterized by:

Back 44

-Bronchodilation
-Inhibition of PDE4
-Used for nocturnal asthma
-There are adverse events such as insomnia, tachycardia, arrhythmias and seizures.

Front 45

The anti-cholinergics block the activity of acetylcholine; generics are

Back 45

atropine and ipratropium

Front 46

ipratropium does not:

Back 46

diffuse into the blood nor the blood brain barrier prevents systemic side effects. A short-acting bronchodilator.
They are characterized by
--Bronchodilation
--Decreased mucus secretion

Front 47

Adenosine and acetylcholine cause

Back 47

bronchoconstriction

Front 48

Muscarinic antagonists, phosphodiesterase inhibitors beta 2-agonists cause

Back 48

bronchodilation

Front 49

Ligands bind to receptor to communicate a signal resulting in coordinated intracellular events

ligands can be:

Back 49

protein, peptide, amino acid, nucleotide, steroid, fatty acid derivatives and dissolved gases (e.g., NO and CO)

Front 50

The response of the cell to the ligand depends on, at least in part, the:

Back 50

Receptor
Intercellular signal
Interaction with other events

Front 51

receptors (quick review)

outcome and effects

Back 51

The outcome of the receptor signaling is multiple and complex

Typical outcomes are effects on metabolism, gene expression, cell shape, cell movement, cell mitosis and cell differentiation

Front 52

Autonomic transmitters: control & outcomes in inflammation

Back 52

--An agonist mimics activity of the natural ligand on the receptor .
--An antagonist is usually constructed similarly to a natural ligand, with some modification, but does not causes the normal activity response. The antagonist blocks the action of the natural ligand.

Front 53

isoproterenol

Back 53

An agonist that binds to beta 2 sympathetic receptors used to treat (i.e., bronchodilation , reduce permeability) asthma

Front 54

epinephrine

Back 54

A natural ligand and a hormone
that acts on sympathetic alpha and beta receptors to treat (i.e., bronchodilation, cardiac contractility, vasoconstriction, decrease permeability) anaphylaxis

Front 55

propranolol

Back 55

A sympathetic beta receptor antagonist

Front 56

If propranolol given first, will block the isoproterenol

Back 56

true

Front 57

how does epinephrine effect cells?

Back 57

1.The beta receptor is a GPCR of Gs
2.The binding of the ligand will cause Gsalpha to activate adenylate cyclase
3.Adenylate cyclase will generate cAMP
4.The cAMP activates protein kinase A (PKA)
5.PKA phosphorylates protein.
6.The ultimate outcome is dilation and anti-permeability
7.cAMP must be regulated by phosphodiesterase to shut the system off

Front 58

Caffeine inhibits

Back 58

phosphodeisterase

Front 59

Epinephrine: cAMP and cAMP dependent protein kinase A (PKA)

In response to epinephrine adenylate cyclase:

Back 59

converts ATP into cAMP = “a second messenger”

Front 60

The cAMP is degraded by phosphodiesterase into 5’-AMP

Back 60

true

Front 61

Cycle of G protein dissociation/association

Back 61

Activation of GPCR causes GTP to displace GDP.
This allows disassociation of alpha-subunit from beta,γ-subunits.
This facilitated by guanine nucleotide exchange factor (GEF) specific for Gs
The active alpha subunit binds to and activates membrane-associated adenylate cyclase
Adeylate cyclase catalyzes conversion of ATP to cAMP
The GTPase activity associated with alpha- subunit hydrolyzes bound GTP to GDP which is facilitated by a GTPase activating protein (GAP) specific for Gs
The alpha subunit/GDP re-associates with beta,γ subunits
Membrane adenylate cyclase returns to basal activity

Front 62

Epinephrine: Activation of PKA

Back 62

cAMP-dependent protein kinase A (PKA) is a tetramer of catalytic and regulatory subunits. It requires cAMP binding for activity
cAMP causes dissociation of regulatory subunits with the release of catalytic subunits
PKA phosphorylates target proteins
PKA is a Ser/Thr kinase

Front 63

There are numerous targets and outcomes of b-adrenergic receptor activation such as

Back 63

membrane proteins, cytoskeletal proteins, enzyme activity and gene expression

Front 64

Protein Kinase A

Back 64

PKA has anti-inflammation effects. PKA causes bronchodilation, vascular barrier enhancement and decreased leukocyte function

PKA activation increases cardiac contractility BUT will vasodilate periphereal blood vessels

Front 65

what type of receptors and what is their function for:

heart

Back 65

beta 1

increased force of contraction
increased rate of contraction

Front 66

what type of receptors and what is their function for:

bronchioles

Back 66

beta 2


dilation

Front 67

b2- via cAMP:

Back 67

Restores vascular barrier function and bronchodilates but will increase cardiac contractility and vasodialate

Front 68

Adenylate Cyclase Activity

Back 68

The complexity of epinephrine is typical of any anti-inflammation agent. The effect of epinephrine is determined by which receptor and which G protein
Epinephrine binds to beta-adrenergic receptors increases cAMP via Gs broncodilation

Epinephrine binds to alpha2 adrenergic receptors decreases cAMP via Gi systemic vasoconstriction

Front 69

Neural Activation of Guanylate Cyclase by Nitric oxide

Back 69

Nitric oxide (NO) is released by neurons.

NO activates guanylate cyclase directly

Guanylate cyclase generates cGMP

cGMP has activates PKG

A typical outcome for PKG activation is vascular relaxation

PKG has variable effects on permeability

Front 70

Neural release norepinephrine in the heart-a model signal transduction pathway- phosphodiesterase

Back 70

Phosphodiesterase (PDE) is a key enzyme in the regulation of inflammation

In cardiac muscle PDE will modify the increased contractility induced by norepinephrine

The cAMP needs to be removed by PDE to control the increased cardiac contractilty induced by norepinephrine
(slide 37 and notes)

Front 71

Phosphodiesterase

Back 71

There are at least 7 isoforms of PDE. Each PDE has a different mechanism of activation and/or target

The PDE will decreases activity of cAMP and cGMP reducing their anti-inflammation effects

Thus, PDE inhibitors are developed to enhance the anti-inflammatory effects of cAMP and/or cGMP

Front 72

PDE Inhibitors
Milrinone

Back 72

inhibits PDE3; Amrinone inhibits PDE3; both used for heart failure

Front 73

PDE Inhibitors
Theophylline

Back 73

--PDE 3, 4 and 5
--Antagonizing Adenosine 1, -2 and -3 receptors ; adenosine releases mediators from sensitized mast cells
--Inhibits the late response to allergen
--Reduce the numbers of eosinophils in bronchial biopsies, bronchoalveolar lavage and induced sputum

Front 74

Phosphodiesterase

Promotes anti-inflammation effects
Bronchodialates:
(cardiopulmonary)

Back 74

-increased contractility and HR
-increased stroke volume and ejection fraction
-decreased ventricular preload (secondary to increased output)
-decreased pulmonary capillary wedge pressure

Front 75

Pro-inflammation: Parasympathetic -receptors

Back 75

Ach-antagonist cause reversible blockade of Ach at muscarinic receptors by competitive binding

The nonselective blockers such as atropine compete for both M1 and M2 receptors

Selective blockers compete for M1 such as pirenzepine can be used for inhibiting gastric acid secretion with less side effects

Front 76

Anti-inflammation: Anti-cholinergics (e.g., atropine)

tissue: GI tract

Back 76

response:Decrease hypermotility and secretions


Use: antispasmotic

Front 77

Anti-inflammation: Anti-cholinergics
(e.g., atropine)

tissue:bronchiolar smooth muscle

Back 77

response:decrease bronchioconstriction

use:asthma

Front 78

Anti-inflammation: Anti-cholinergics
(e.g. atropine)

tissue: glandular tissue

Back 78

response: Decrease gastric secretionsDecrease lung secretions

use: Peptic ulcer
Asthma

Front 79

Anti-inflammation: Anti-cholinergics (e.g. atropine)

tissue: cardiac tissue

Back 79

response: increased cardiac output

use: hypotension

Front 80

Asthma Medications: Other approaches

corticosteroids

Back 80

are good anti-inflammatory agents but not specific and takes longer to have effect = maintenance; generics such as beclomethasone

Front 81

Asthma Medications: Other approaches

mast cell stabilizers

Back 81

alter Ca+2 pathways in mast cells preventing mast degranulation; generics such as cromolyn & nedocromil

Front 82

Asthma Medications: Other approaches

Leukotriene modifiers

Back 82

promote bronchodilation. Interestingly, also are used for maintenance; is this because there is less leukocyte infiltration= no LTB4? The 5-lipoxygenase inhibitor generic is zileuton

Front 83

Asthma Medications: Other approaches

The cysteinyl-leukotriene receptor blockade

Back 83

generic is monteleukast no bronchoconstriction