Term
Conducting Zone:
nose, nasopharynx, larynx, trachea, bronchi, bronchioles
lined with mucus secreting and ciliated cells that function to remove inhaled particles
composed of smooth muscle (trachea also has cartilage)
Respiratory Zone:
respiratory bronchioles, alveolar ducts, alveolar sacs
participates in gas exchange
the alveoli act as primary gas exchange units of the lung
the gas-blood barrier between the alveolar space and the pulmonary capillaries is extremely thin, allowing for rapid and efficient gas exchange
composed of less smooth muscle (none in the alveoli) and no cartilage |
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Definition
| structure of the respiratory system airways |
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Term
skeletal muscle contains thick and thin filaments:
[image]
thick filaments = myosin
myosin is composed of heavy and light chains
light chains: the heads of myosin which contain an actin binding site which is needed for cross bridge formation and also possesses a site which binds and hydrolyzes ATP
heavy chains: the tail
thin filaments = actin, troponin, and tropomyosin
actin: has myosin binding sites
when the muscle is at rest, the myosin binding sites are covered by tropomysin so that actin and myosin cannot interact
if contraction is going to occur, tropomyosin has to be moved out of the way so that actin and myosin can interact
troponin is a complex of 3 proteins: troponin T (for tropomysin), troponin I (for inhibition), and troponin C (for calcium)
troponin T: attaches to troponin complex to tropomyosin
troponin I: along with tropomyosin, inhibits the interaction of actin and myosin by covering the myosin binding site on actin
troponin C: a Ca binding protein that moves tropomyosin out of the way when intracellular Ca increases
when the intracellular Ca concentration increases (through depolarization and opening of L-type voltage gated Ca channels, Ca binds to troponin C and moves tropomyosin out of the way, permitting the binding of actin to the myosin heads to where excitation contraction coupling can occur |
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Definition
| Striated muscle contraction |
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Term
1. Depolarization
2. L-type voltage gated calcium channels open.
3. Intracellular calcium increases.
4. Ca2+ binds to troponin C on the thin filaments, causing a conformational change in the troponin complex and moves tropomyosin out of the way to where actin and myosin can interact.
5. Cross-bridge cycling. With Ca2+ bound to troponin C and tropomyosin moved out of the way, myosin heads can now bind to actin and form so-called cross-bridges. Formation of cross-bridges is associated with hydrolysis of ATP and generation of force. |
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Definition
| Steps in skeletal muscle excitation contraction coupling |
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Term
[image]
CONTRACTION:
in smooth muscle there is no troponin to where the interaction of actin and myosin is controlled by calcium binding to calmodulin
similar to skeletal muscle, depolarization results in opening of L-type voltage gated Ca channels
Ca increases intracellularly
Ca forms a complex with calmodulin, resulting in activation of myosin light chain kinase
activation of MLCK results in phosphorylation of the myosin light chain
when myosin is phosphorylated, it can bind actin, producing cross bridges and contraction
RELAXATION:
when concentrations of intracellular Ca decrease, myosin light chain phosphatase dephosphorylated myosin light chain leading to smooth muscle relaxation
dephosphorylated myosin can still interact with actin, however it produces latch bridges instead of cross bridges
these latch bridges do not result in contraction, but maintain a steady level of muscle tension in smooth muscles
another mechanism of smooth muscle relaxation can occur by increases in cAMP
increased cAMP results in activation of PKA
PKA can phosphorylate MLCK, inactivating it leading to smooth muscle relaxation |
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Definition
| smooth muscle excitation contraction coupling and relaxation |
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Term
[image]
mediated through L-type voltage gated Ca channels, GPCRs, ligand gated Ca channels
GPCRs are coupled with Gq -> activation leads to phospholipase C (PLC) catalyzing the hydrolysis of PIP to IP3 and DAG -> IP3 diffuses into the sarcoplasmic reticulum resulting in increased intracellular Ca |
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Definition
| mechanism to increase intracellular calcium in smooth muscle cells |
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Term
[image]
bronchial smooth muscle is innervated by both the parasympathetic (rest and digest) and sympathetic (fight or flight) nervous systems
parasympathetic nervous system:
preganglionic cell bodies are located in the spinal cord; send their axons to the PNS and release ACh
ACh then binds to nicotinic receptors on the cell bodies of post ganglionic receptors resulting in ACh release
ACh then acts on muscarinic receptors on effector organs
BRONCHIAL SMOOTH MUSCLE
ACh can act on M2 and M3 receptors
M3 receptors: involved in excitation contraction coupling; coupled with Gq resulting in increased Ca and contration
M2 receptors: coupled with Gi which decrease cAMP; cAMP leads to relaxation by inactivation of MLCK; if cAMP decreases, this will cause bronchoconstriction
sympathetic nervous system:
preganglionic cell bodies located in the CNS
sends axons (which are short) to the PNS and releases ACh
ACh binds to nicotinic receptors on the cell bodies of the post ganglionic neurons
post ganglionic neurons (with long axons) release NE which can then bind to adrenergic receptors on effector organs
BRONCHIAL SMOOTH MUSCLE
important to note that NE doesn't have high affinity for B2 receptors on bronchial smooth muscle
adrenal medulla:
preganglionic neurons in the CNS
releases ACh which then binds to nicotinic receptors
adrenal medulla then releases EPI
BRONCHIAL SMOOTH MUSCLE
EPI has high affinity for B2 receptors in bronchial smooth muscle leading to bronchodilation |
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Definition
| nervous system control of bronchial smooth muscle |
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Term
[image]
if resistance increases (due to bronchoconstriction) this results in decreased airflow
if resistance decreases (due to bronchodilation) this results in increased airflow
[image] |
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Definition
| airflow, pressure, and resistance relationships |
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Term
[image]
tidal volume: normal breathing
inspiration reserve volume: maximal inspiration
expiratory reserve voluem: maximal expiration
residual volume: volume of gas remaining in the lungs after the maximal forced expiration; cannot be measured by spirometry
inspiratory capacity: tidal volume + inspiratory reserve volume
functional residual capacity: expiratory reserve volume + residual volume; volume remaining in lungs after a normal tidal volume is expired
vital capacity: inspiratory capacity + expiratory reserve volume; volume that can be expired after maximal inspiration
total lung capacity: includes all lung volumes; vital capacity + residual volume |
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Definition
| lung volumes and lung capacities |
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Term
Forced vital capacity (FVC) is the total volume of air that can be forcibly expired after a maximal inspiration
The volume of air that can be forcibly expired in the first second is called FEV1
, the fraction of the vital capacity that can be expired in the first second, FEV1/FVC, can be used to differentiate among diseases:
in a normal person, FEV1/FVC is approximately 0.8, meaning that 80% of the vital capacity can be forcibly expired in 1 second
in a patient with obstructive lung disease such as asthma, both FVC and FEV1 are decreased, but FEV1 is decreased more than FVC is, as airway obstruction results in increased resistance to expiratory airflow.
Thus, FEV1/FVC is also decreased.
in a patient with restrictive lung disease, such as fibrosis, both FVC and FEV1 are decreased, but FEV1 is decreased less than FVC, resulting in an increased FEV1/FVC ratio |
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Definition
| changes in forced vital capacity (FVC) and forced expiratory volume (FEV) |
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Term
asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, including:
mast cells
eosinophils
T cells
macrophages
neutrophils
epithelial cells
common symptoms are:
acute constriction of bronchial smooth muscle
cough
chest tightness
wheezing
rapid breathing
this inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli |
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Definition
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Term
allergens
respiratory infections
exercise (EIB)
cold air
tobacco smoke
aspirin and other NSAIDs (in susceptible individuals) |
|
Definition
| asthma symptoms can be triggered by: |
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Term
[image]
Increased hygiene and a lack of exposure to various microorganisms may be affecting the immune systems of many populations - particularly in highly developed countries like the US - to the degree that individuals are losing their bodily ability to fight off certain diseases.
Currently, the “hygiene hypothesis” that proposes that genetically susceptible individuals develop allergies and asthma by allowing the allergic immunologic system (Th2-lymphocytes) to develop instead of the immunologic system used to fight infections (Th1-lymphocytes) is being used to explain the increase of asthma in Western countries. |
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Definition
| hygiene hypothesis of asthma |
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Term
airway hyperresponsiveness
reversible airflow obstruction
airway inflammation
airway remodeling |
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Definition
| asthma is characterized by: |
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Term
[image]
airway hyperresponsiveness (AHR) is an increased ability of airway constriction in response to a wide variety of stimuli, including allergens, environmental irritants, exercise, cold air, and infections
in asthmatics, it take significantly less of a constrictor agent to produce a response as compared to a normal individual
also, the response is significantly greater in the asthmatic as compared to a normal individual (greater % change)
AHR has been correlated with certain inflammatory mediators: eosinophils, mast cells, T cells
AHR improves when treated with corticosteroids, suggesting an inflammatory component of AHR |
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Definition
| airway hyperresponsiveness in asthma |
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Term
chronic inflammation results in structural changes to the airway
the degree of structural changes correlates to the severity of asthma
results in:
epithelial changes
subepithelial fibrosis
increased airway smooth muscle mass
globlet cell hyperplasia
vascular changes
structural changes cause airway thickening and decreased diameter, airflow limitation and mucus hypersecretion |
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Definition
| airway remodeling in asthma |
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Term
[image]
NORMAL:
highly regulated and impermeable barrier made possible by tight junctions
ASTHMA:
damaged epithelium is associated with the up-regulation of growth factors
chronic injury and aberrant repair
increased epithelial permeability due to dysfunction of the airway tight junctions
allows easy entry of foreign substances resulting in activationon inflammatory cells |
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Definition
| epithelial cells as a source of inflammatory mediators |
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Term
[image]
dendritic cell activation through toll-like receptors (TLRs) induces NFkB activation and subsequent dendritic cell activation
dendritic cells sample antigens from the airway lumen |
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Definition
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Term
the underlying cause of asthma is an allergic inflammation of the airways
the allergic response is initiated when dendritic cells phagocytize an inhaled allergen
the dendritic cell presents the processed allergen to CD4+ cells and activates them, resulting in development of T cells along the Th2 pathway
the activated Th2 T cells bind and activate B cells
activated Th2 cells also generate IL-4and IL-13, which induce B cell transformation into IgE producing plasma cells
the secreted IgE and subsequent re-exposure to the allergen are critical in the early phase of the asthmatic response |
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Definition
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Term
role in the differentiation of Th2 cells from uncommitted Th0 cells
also important for isotype switching of B cells from producing IgG to producing IgE
short duration |
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Definition
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Term
produced by Th2 cells and mast cells
cytokine involved in stimulating development of eosinophils from bone marrow precursor cells
prolongs the survival of eosinophils |
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Definition
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Term
duration of action for IL-13 is much longer than that of IL-4
isotype switching
when administered to animals, IL-13 induced the cardinal signs of asthma: airway hyperresponsiveness, goblet cell hyperplasia, airway smooth muscle proliferation, and supepithelial fibrosis
induces eotaxin-1 (CCL11) - involved in eosinophil chemotaxis (attacks eosinophils to the lungs)
causes structural changes in airways (fibrosis)
has no effect on Th2 cell differentiation |
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Definition
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Term
when activated, eosinophils release inflammatory mediators:
eosinophil cationic protein (ECP):
creates pores in membranes
has cytotoxic effects against bacteria, parasites, and viruses
however, it can create pores in respiratory epithelial cells too
TGF-beta:
leads to fibrosis
reactive oxygen species (ROS):
result in tissue damage
leukotrienes:
result in bronchoconstriction
results in substantial damage to airway epithelial cells
eosinophils can present antigen to naive T cells and influence lymphocyte function |
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Definition
| role of eosinophils as a key effector cell in asthma |
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Term
mast cell degranulation is important in the early asthmatic response:
bronchoconstriction
mucus secretion
vasodilation
IgE is produced by plasma cells
IgE attaches to high affinity receptors on mast cells (as well as basophils)
mast cell activation occurs when IgE bound to the receptor is cross-linked by an allergen which triggers mast cell degranulation
results in the release of inflammatory mediators |
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Definition
| role of mast cells in asthma |
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Term
1) preformed: histamine, IL-5
2) newly synthesized: prostaglandins, thromboxanes, and leukotrienes from the activation of phospholipase A2
all have bronchoconstrictor activity |
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Definition
| 2 types of inflammatory mediators released after mast cell degranulation |
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Term
histamine is released from mast cells
binds to H1 receptors on bronchial smooth muscle, part of the Gq class of GPCRs
increases intracellular Ca
results in bronchoconstriction and an increase in vascular permeability |
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Definition
| MOA of histamine on bronchial smooth muscle |
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Term
leukotrienes are synthesized from arachidonic acid by the enzyme 5-lipoxygenase (enhanced by FLAP)
arachidonic acid is converted to LTA4 through 5-lipoxygenase
LTA4 is unstable and goes through one of 2 pathways:
1) LTA4 is converted to LTB4
LTB4 binds to BLT1 or BLT2
the BLT1 receptor mediates chemoattraction and pro-inflammatory actions
the BLT2 receptor is involved in airway hyperreactivity and inflammation
2) LTA4 is converted to LTC4 which can then be converted to LTD4 and LTE4
LTC4, LTD4, LTE4 bind to CysLT1 or CysLT2
CysLT1 is responsible for bronchoconstriction, mucus secretion, and edema of airways
CysLT2 does not mediate bronchoconstriction but contributes to inflammation, vascular permeability, and tissue fibrosis
leukotrienes act by binding to specific receptors (GPCRs)
these GPCRs typically increase intracellular Ca and decrease cAMP |
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Definition
| role of leukotrienes in asthma (LTB, LTC, LTD, and LTE) |
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Term
arachidonic acid can be converted by the COX pathway to PGG2, which is then converted to PGH2 by hydroperoxidase
PGH2 results in the formation of different prostaglandins by different sythases |
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Definition
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Term
PGD2
not all prostaglandins are bronchoconstrictors |
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Definition
| which prostaglandin is a potent bronchoconstrictor? |
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Term
RELIEVE BRONCHOCONSTRICTION:
inhaled B2 adrenergic receptor agonists
methylxanthines
inhaled anticholinergics (not FDA approved)
REDUCE AIRWAY INFLAMMATION:
glucocorticoids
leukotriene synthesis inhibitors
leukotriene receptor antagonists
nedocromil sodium and cromolyn
anti-IgE antibodies
macrolides (not FDA approved) |
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Definition
| pharmacologic approaches for asthma |
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Term
agonist at B2 receptors
relax bronchial smooth muscle:
mediated by increased cAMP
increase the conductance of large Ca sensitive K channels in airway smooth muscle - independent of AC and cAMP production - hyperpolarization of the smooth muscle leads to bronchorelaxation
inhibits the release of inflammatory mediators and cytokines (little anti-inflammatory activity and is not sufficient to be used as an anti-inflammatory therapy for asthma) |
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Definition
| MOA of B2 adrenergic receptor agonists |
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Term
[image]
increased levels of bronchoconstriction causes the dose-response curve for B2 agonists to shift to the right (you need more albuterol to provide bronchodilation as asthma severity increases) |
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Definition
| effects of increased bronchoconstriction on the effectiveness of albuterol |
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Term
provides more rapid response
less ADRs
the predominant route of use of B2 agonists is inhalation |
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Definition
| advantages of topical (inhalation) administration of B2 agonists |
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Term
for the treatment of acute bronchospasms more selective B2 agonists are preferred to minimize the potential for cardiac side effects
the major issue with metaproterenol is the B1 receptor agonism, which increases the rate and force of contraction of the heart |
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Definition
| non-selective B1/B2 agonists (metaproterenol) vs. B2 selective agonists (albuterol) |
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Term
short acting provide immediate relief from bronchoconstriction
LABA have a longer duration of action
LABAs cannot be used alone; have to be administered with a corticosteroid to prevent asthma related death
tolerance may develop to LABA due to beta receptor desensitization |
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Definition
| short acting (albuterol) vs. long acting (formoterol) beta agonists |
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Term
levalbuterol is the R isomeric form of albuterol (R isomer is responsible for bronchodilation and for ADRs)
levalbuterol has not shown any advantages over racemic albuterol |
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Definition
| racemic (albuterol) vs. isomeric (levalbuterol) beta agonists |
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Term
| formoterol produces greater side effects, but is able to protect against bronchoconstriction better than salmeterol |
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Definition
| partial beta agonist (salmeterol) vs. full beta agonist (formoterol) |
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Term
albuterol
pirbuterol
terbutaline
ARE FIRST CHOICE FOR RELIEF OF ASTHMATIC SYMPTOMS!!!
produce bronchodilation
quick onset of action
short duration of action |
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Definition
| INHALED short acting B2 adrenergic receptor agonists |
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Term
chronic administration of short acting B2 agonists can lead to tolerance:
down regulation of B2 receptors and decreased affinity for the B2 agonists
cross-tolerance may also occur - there is tolerance to all B2 agonists
can be partially reversed by systemic corticosteroids |
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Definition
| important precautions to keep in mind with short acting B2 agonists |
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Term
prednisone
prednisolone
methylprednisone
systemic corticosteroids are the most effective anti-inflammatory drugs available to treat asthma
indicated in asthmatics not responding well to short acting B2 agonists or in very severe asthmatics whose asthma cannot be controlled well without its use |
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Definition
| oral corticosteroids for asthma |
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Term
fluticasone
beclomethasone dipropionate
budesonide |
|
Definition
| inhaled corticosteroids for asthma |
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Term
increase number of B2 adrenergic receptors and receptor responsiveness
reduce mucus production and hypersecretion
reduce bronchial airway hyperreactivity
decrease pro-inflammatory cytokine release: can inhibit PLA2 to reduce generation of PGs and LTs
prevent and reverse airway remodeling |
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Definition
| actions of corticosteroids in asthma |
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Term
[image]
the GC receptor is normally inactive as it has heat shock proteins which inhibit its translocation into the nucleus
prednisone passes through the plasma membrane into the cytoplasm where it binds to the GC receptor
this causes HSP to dissociate from the GC receptor, leading to the active GC monomer
the monomer then dimerizes where they bind to the GC responsive elements in the DNA to influence transcription
[image]
At higher doses, corticosteroids induce expression of anti-inflammatory genes
GC binds to GC receptor, translocates to the nucleus and influences histone acetyltransferase (HAT) activity
This leads to acetylation of lysines on histone H4, and transcriptional activation of genes encoding anti-inflammatory proteins.
can activate expression of β2 adrenergic receptors |
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Definition
| glucocorticoid receptor signaling - transactivation |
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Term
[image]
Inflammatory stimuli such as IL-1B or TNF alpha, can lead to the activation of inflammatory genes
stimuli (IL-1, TNF) can cause the activation of the transcription factor NFkB
In it’s active form, NFκB is a dimer of p65 and p60 and mobilizes to the nucleus
However, when NF-κB is an inactive state, it is localized to the cytosol and is complexed with the inhibitory protein IκBα
the phosphorylation of IkBa leads the the activation of IkBa (through inflammatory stimuli) results in the dissociation of IkBa from NFkB
activated NFkB goes to the nucleus and binds to co-activators such as CREB binding protein or pCAF: these proteins have histone acetyltransferase activity (HAT)
acetylation of histone results in increased transcription of inflammatory genes
At low doses, corticosteroids bind to the glucocorticoid receptor and translocate to the nucleus where they recruit histone deacetylase-2 (HDAC2), which deacetylates histone H4, leading to repression of inflammatory gene transcription. |
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Definition
| glucocorticoid receptor signaling - transrepression |
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Term
Beclomethasone dipropionate, fluticasone, budesonide
MOA:
provide potent topical anti-inflammatory effects with fewer systemic side effects
reduces bronchial airway hyperreactivity
typical ADRs:
thrush
dry mouth
growth retardation in children
high doses of inhaled corticosteroids may cause:
osteoporosis
cataracts
adrenal insufficiency |
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Definition
| MOA and ADRs of inhaled corticosteroids |
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Term
not completely clear
competitive antagonist of adenosine:
adenosine and theophylline are structurally similar
adenosine can provoke bronchoconstriction
inhibits phosphodiesterase 3 and 4:
responsible for breaking down cAMP
leads to increased cAMP and improved bronchodilation
relaxes smooth muscle of the bronchial airways and pulmonary blood vessels |
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Definition
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Term
narrow therapeutic index:
toxicity:
nausea
vomiting
insomnia
at higher concentrations:
seizures
cardiac arrhythmias
death |
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Definition
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Term
not known: blocking Cl and Ca entry channels
inhibits release of inflammatory mediators from mast cells and other inflammatory cells:
inhibits IgE production
inhibits neutrophil superoxide generation
inhibits mast cell degranulation
inhibits immediate allergic response to allergen challenge or exercise challenge
well tolerated |
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Definition
| MOA of cromolyn sodium and nedocromil sodium |
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Term
leukotriene synthesis inhibitor
inhibits 5-lipoxygenase:
arachidonic acid can travel down 2 different pathways - COX can convert arachidonic acid to prostaglandins and 5-lipoxygenase can convert arachidonic acid to leukotriene A4
thus, by inhibiting 5-lipoxygenase, synthesis of all leukotrienes is blocked
anti-inflammatory
does not replace the use of inhaled short-acting B2 agonists! |
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Definition
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Term
liver toxicitiy
headache
irritation of gastric mucosa
contraindications:
hepatic disease |
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Definition
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Term
cysteinyl leukotriene 1 receptor antagonists
can block the actions of cysteinyl LTs (LTC4, LTD4, LTE4) on CysLT1 receptor (involved in mucus production, bronchoconstriction, and airway edema)
effects of LT receptor antagonists:
anti-inflammatory - inhibit pro-inflammatory actions of LTs, decrease edema, mucus secretion, and eosinophil chemotaxis
decreases bronchial hyperresponsiveness
can produce bronchial relaxation
still need a short acting B2 agonist!
has no effect on CysLT2 receptors or BLT1 or BLT2 receptors |
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Definition
| MOA of montelukast and zafirlukast |
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Term
[image]
monoclonal antibody that binds to IgE preventing the cross linking of IgE by allergen and mast cells
FcεR1 receptor no longer recognizes complexed IgE
FcεR1 receptor found on monocytes, eosinophils, dendritic cells, epithelial cells, and platelets
omalizumab interferes with mediator/cytokine release
prevents degranulation of mast cells
should not be used in patients allergic to hamsters, chimeric not humanized |
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Definition
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Term
NOT AN FDA APPROVED INDICATION
possess anti-inflammatory activity in sub therapeutic doses to treat infections
macrolides increase transepithelial resistance (decreasing the epithelial permeability caused by chronic inflammation)
macrolides can increase the phagocytosis of apoptotic epithelial cells and neutrophils by macrophages reducing the # of inflammatory cells in the airway
reduce production of cytokines
reduce mucus hypersecretion |
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Definition
| MOA of macrolides for asthma |
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Term
chronic inflammatory changes that lead to destruction and development of chronic airflow limitations
inflammation is usually due to exposure to noxious particles and gas through inhalation
collection of conditions characterized by persistent expiratory airflow limitation:
emphysema
chronic bronchitis
in COPD, the bronchi, bronchioles, and alveoli are involved in the pathogenesis
increased resistance in the conducting zone (bronchi and bronchioles) limits the movement of air
chronic bronchitis leads to increased bronchial wall thickness and increased mucus
small airway obstruction is a major factor in airflow obstruction in COPD |
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Definition
| structural changes to respiratory system due to COPD |
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Term
alveolar walls have elastic fibers that are lined with type I and type II pneumocytes
type I pneumocytes are involved in gas exchange
type II pneumocytes synthesize pulmonary surfactant (necessary for reduction of surface tension of alveoli as they would otherwise collapse) |
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Definition
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Term
cigarette smoking
other exposures: pollution, occupational exposures
genetic susceptibility:
deficiency in alpha-1 antitrypsin, an anti-protease for neutrophil elastase
alpha-1 antitrypsin is a protein produced by hepatic cells that protects the lungs by blocking the effects of elastases released by neutrophils
if alpha-1 antitrypsin is not present, these elastases can degrade alveolar wall elastin |
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Definition
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Term
IMBALANCE BETWEEN PROTEINASES AND ANTIPROTEASES
[image]
emphysema is characterized by destruction of gas exchanging air spaces including bronchioles, alveolar ducts, and alveoli
cigarette smoking leads to inflammatory cell recruitment, injury to the extracellular matrix, and cell death
alveolar walls become perforated and in the absence of repair, become obliterated
deficiency in alpha-1 antitrysin associated with emphysema (the anti-protease inhibitor of neutrophil elastase) |
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Definition
| pathophysiology of emphysema |
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Term
elastin: principal component of elastic fibers; important in alveoli
elasticity and lung compliance are inversely related
the greater the amount of elastic tissue, the greater the tendency to "snap back", and the greater the elastic recoil force, but the lower the compliance
with emphysema, the loss of elastic tissue results in greater compliance
because of this, patients with COPD have to breath at higher lung volumes to account for the decrease in elasticity (and increased compliance), resulting in a barrel shaped chest
overproduction of preteinases or not enough anti-proteinases results in alveoli destruction |
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Definition
| compliance and elasticity relationship in COPD |
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Term
alpha-1 antitrypsin (ATT) is a plasma protein that protects cells in the lungs from destruction by elastases released from neutrophils
replacement therapy SLOWS THE PROGRESSION OF COPD
true alpha-1 antitrypsin deficiency accounts for < 1% of COPD cases and replacement therapy can only be used in these patients |
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Definition
| MOA of alpha-1 antitrypsin replacement therapy |
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Term
cigarette smoke activates and recruits inflammatory cells to the lungs:
macrophages
neutrophils: release neutrophil elastases
CD8+ T cells: release granzymes and perforins leading to tissue destruction
B-cells: COPD could possibly be an auto-immune disorder
leads to activation of epithelial cells as well as macrophages to release cytokines such as:
IL-8: chemotactic agent for neutrophils and CD8+ T cells
TNF-a: activates the NFkB pathway leading to transcription of inflammatory mediators
TGF-beta: stimulates fibroblast proliferation, resulting in fibrosis of the small airways
LTB4: chemotactic agent for neutrophils and CD8+ T cells |
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Definition
| cells involved in COPD pathogenesis |
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Term
neutrophils release a wide range of products including LTs, thromboxanes, and cytokines
they also release proteases such as elastase, collagenase, and metalloproteinases
release ROS intermediates
normally these products produce inflammation, but in COPD they cause tissue damage |
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Definition
| neutrophil's role as THE KEY EFFECTORS IN COPD |
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Term
IL-8: chemotactic activity for neutrophils and CD8+ T cells
TNFa: amplifies inflammation through activation of NFkB pathway
LTB4: chemotactic for neutrophils and lymphocytes |
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Definition
|
|
Term
COPD:
cells - neutrophils, large increase in macrophages, increase in CD8+ T cells
mediators - LTB4, IL-8, TNFa
consequences - thickening/fibrosis of epithelium, mucus increases, glandular enlargement
response to treatment - glucocorticoids have variable effects
ASTHMA:
cells - eosinophils, small increase in macrophages, increase in CD4+ Th2 cells, activation of mast cells
mediators - LTD4, IL-4, IL-5, IL-13
consequences - fragile epithelium, thickening of basement membrane, mucus increases, glandular enlargement
response to treatment - glucocorticoids inhibit inflammation |
|
Definition
| comparison of COPD to asthma: cells, mediators, consequences, and response to treatment |
|
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Term
B2 agonists
methylxanthines
muscarinic receptor antagonists
corticosteroids
combination therapy
these therapies do not prevent disease progression nor prolong survival! |
|
Definition
| pharmacologic strategies for treating COPD |
|
|
Term
systemic: only used for acute exacerbations
inhaled: preferred route
actions:
does not alter disease course
*reduces exacerbation frequency
reduce mucus production and hypersecretion
inhibition of PGs
corticosteroid resistance can develop
they do not alter the disease course, but REDUCE EXACERBATION FREQUENCY |
|
Definition
| actions of corticosteroids for COPD |
|
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Term
[image]
HDAC2 is critical in mediating the effects of steroids
acetylation of histone leads to increased expression of pro-inflammatory genes
glucocorticoids bind to their receptors increasing histone DEacetylation through HDAC2 -> leads to transrepression of pro-inflammatory genes
HDAC2 decreases in response to oxidative stress
since HDAC2 can no longer deacetylate histones this leads to higher levels of pro-inflammatory genes
this is thought to underlie corticosteroid resistance
theophylline has been shown to increase HDAC2 activity and possibly restore GC sensitivity |
|
Definition
| theories on corticosteroid resistance in COPD |
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Term
hydrolysis of cAMP
expressed in neutrophils, T cells, and macrophages suggesting they are involved in inflammation |
|
Definition
| role of phosphodiesterase 4 |
|
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Term
PDE4 inhibitor
reduces neutrophils by 36% in COPD patients
improves lung function slightly, but did not reduce exacerbations or improve quality of life |
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Definition
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Term
nausea and vomiting
dose limiting
mediated through PDE4D: inhibition leads to increased cAMP resulting in N/V |
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Definition
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Term
[image]
increases in intracellular Ca (which occurs with activation of M1 and M3 coupled with Gq) leading to smooth muscle contraction
M2 causes decreases in cAMP, PKA cannot phosphorylate MLCK (inactivating it) causing muscle contraction |
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Definition
| smooth muscle contraction by muscarinic receptors (M1, M2, and M3) |
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Term
inhaled
produces bronchodilation
have quaternary structures (do not penetrate cell membranes very well) = less side effects
short acting muscarinic antagonist
superior to albuterol in patients with COPD
blockade of M3 receptors inhibits bronchoconstriction by ACh |
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Definition
| MOA of ipratropium bromide |
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Term
inhaled
produces bronchodilation
have quaternary structures (do not penetrate cell membranes very well) = less side effects
long acting muscarinic antagonist
superior to albuterol in patients with COPD
blockade of M3 receptors inhibits bronchoconstriction by ACh |
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Definition
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Term
| atropine as significant systemic side-effects and does not have the quaternary structure to where it can cross membranes |
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Definition
| why is atropine not used as a muscarinic receptor antagonist for COPD? |
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Term
dry mouth - most common
constipation
urinary retention
tachycardia
blurred vision
precipitation of narrow-angle glaucoma |
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Definition
| ADRs of antimuscarinics (ipratropium, tiotropium) |
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Term
long acting beta 2 receptor agonist
R isomer of formoterol
only used in COPD |
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Definition
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Term
long acting B2 agonist
racemic mixture of R and S formoterol
R = bronchodilating effects and ADRs
S = pro-inflammatory? |
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Definition
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