T5 - IE5 - Pulmonology - TBL + Cumulative

Structural changes in the asthmatic airway

Increased number of goblet cells

Thickened basement membrane

Increased number of smooth muscle cells

Increased size of smooth muscle cells

Structural changes in the asthmatic airway: increased number of _________ cells and ________ ______ cells

- goblet (cells)

- smooth muscle (cells)

Structural changes in the asthmatic airway increased number of goblet cells leads to increased ______ _________

- (increased) mucus production

Structural changes in the asthmatic airway: thickened _______ ______

- (thickened) basement membrane

Myofibroblasts, extracellular matrix

Structural changes in the asthmatic airway: increased size of smooth muscle cells leads to ___________

- (lead to) hypertrophy

Innumerable triggers of asthma include...

environmental exposure

occupational exposure

dust mites

pet dander

cold air

Two phases of asthma

early response --> major problem is bronchospasm

Late response --> major ploblem is "inflammation"; typically more severe than early response

Two phases of asthma attack - bronchospasm: result of immediate release of ____-______ _______, which is contained in granules within the _________ _____ _______

- pre-formed histamine

- (within the) pulmonary mast cells

Two phases of asthma attack - inflammatory reaction: derived from multiple _________ ________ that orchestrates the pathogenesis of asthma in the pulmonary tissue

- cytokines signaling (that orchestrates the pathogenesis)

Pathogenesis of asthma in pulmonary tissue - initial trigger of allergen -> stimulates _________ ______ and _________ ____ ________

- histamine release

- inflammatory cell recruitment

Bronchospasm occurs through activation of sensory nerves and reflexive cholinergic stimulation of bronchial smooth muscle to constrict

Pathogenesis of asthma in pulmonary tissue - bronchospasm occurs through activation of _______ ______ and ____________ _________ stimulation of bronchial smooth muscle to constrict

- sensory nerves

- reflexive cholinergic (stimulation)

As inflammation increases -> there can be hypersecretion of mucus, tissue edema, and shedding of surface epithelial cells

Pathogenesis of asthma in pulmonary tissue - _____________ occurs through activation of sensory nerves and reflexive cholinergic stimulation of bronchial smooth muscle to __________

- bronchospasm (occurs)

- (smooth muscle to) constrict

Pathogenesis of asthma in pulmonary tissue - As inflammation increases -> there can be __________ of mucus, ________ edema, and shedding of _________ ________ cells

- hypersecretion (of mucus)

- tissue (edema)

- surface epithelial (cells)

Chronic inflammation -> remodeling of the pulmonary tissue with increase fibroblast deposition and proliferation of both smooth muscle cells and vascular tissue

Pathogenesis of asthma in pulmonary tissue - Chronic inflammation -> _____________ of the pulmonary tissue with increase __________ deposition and ___________ of both smooth muscle cells and vascular tissue

- remodeling (of the pulmonary tissue)

- fibroblast (deposition)

- proliferation (of both...)

Pathogenesis of asthma in pulmonary tissue: Chronic inflammation -> remodeling of the _________ tissue with increase fibroblast _________ and proliferation of both _________ _________ cells and ________ tissue

- (remodeling of the) pulmonary (tissue)

- (fibroblast) deposition

- smooth muscle (cells)

- vascular (tissue)

To make sure to prevent issue remodeling -> long-term control of inflammation must be achieved in asthmatic patients

Pathogenesis of asthma in pulmonary tissue: To make sure to prevent issue remodeling -> _____-_______ control of inflammation must be achieved in asthmatic patients

- long-term (control of inflammation)

Bronchoconstriction - non-asthmatics: _____-_____ response to stimulus that produces ____, if ____, bronchoconstriction at normal to high doses

- low-level (response)

- low

- (if) any

Asthmatics have HYPER-RESPONSIVE airways

Bronchoconstriction - asthmatics: _________-_______ airways

- hyper-responsive (airways)

In asthmatic bronchoconstriction, there is _________ and _________

- hypersensitivity

- hyperreactivity

Response to abnormally low stimulus (left shift); exaggerated response to normal-high stimulus (upward shift)

Airway smooth muscle is innervated by the __________ ________ ______ ONLY

- parasympathetic nervous system (only)

Bronchial tone - cholinergic action: ____________ (____) receptors located in large bronchial -> _______ innervation

- cholinergic (M3)

- vagal (innervation)

Bronchial tone - adrenergic action: ___ __________ located in small bronchioles; _____ _______ innervation; only stimulated by circulating epinephrine

- β2 receptors (located in small bronchioles)

- no direct innervation

Bronchoconstriction occurs in response to _________ _______ stimulation and through application of exogenous _________ agents like ________

- cholinergic reflexive (stimulation)

- parasympathetic (agents)

- (like) methacholine

Administration of __________ ________ would block the cholinergic bronchoconstrictive response

- muscarinic antagonist (would block)

Conversely, sympathomimetic produce a bronchodilatory action

Administration of muscarinic antagonist (anticholinergic) would block the cholinergic ________________ response

- (cholinergic) bronchoconstrictive (response)

Sympathomimetic produce a _______________ action

- bronchodilatory (action)

______________ produce a bronchodilatory action

- Sympathomimetic

Sympathomimetic produce a bronchodilatory action; β-adrenergic agonist ____________ intracellular Cyclic AMP by stimulating the enzyme ___________ _________ (______)

- increase (intracellular Cyclic AMP)

- adenyl cyclase (AC)

Sympathomimetic produce a bronchodilatory action; ____-____________ _______ increase intracellular Cyclic AMP by stimulating the enzyme adenylyl cyclase (AC)

- β-adrenergic agonist (increase intracellular Cyclic AMP)

Sympathomimetic produce a bronchodilatory action; β-adrenergic agonist increase _____________ __________ ________ by stimulating the enzyme adenylyl cyclase (AC)

- (increase) intracellular Cyclic AMP

Roflumilast MOA

PDE4 inhibitor -> bronchodilation by preventing the breakdown of cyclic AMP

Muscarinic receptors in the lung: M2 receptors are located ___-___________ (___________) on the nerve muscle interface

- pre-synaptically (auto receptors)

Muscarinic receptors in the lung: _____ receptors are located pre-synaptically (auto receptors) on the nerve muscle interface

- M2 (receptors)

Muscarinic receptors in the lung: _____ and _____ are found in bronchial smooth muscle

- M3

- M2

Muscarinic receptors in the lung: M1 receptors found on ____________ __________

- autonomic ganglia

Muscarinic receptors in the lung: Both M3 and M2 are found in ____________ _________ _________

- (found in) bronchial smooth muscle

Muscarinic receptors in the lung: ____ and _____ in submucosal glands responsible for bronchial secretion

- M1

- M3 (in submucosal glands)

Muscarinic receptors in the lung: M1 and M3 in submucosal glands are responsible for _________ __________

- bronchial secretion

Long-acting inhaled anticholinergic drugs

ATROVENT

SPIRIVA

β2RA (SABAS)

β-2 receptor agonists

β2RA (SABAS) MOA

relax smooth muscle and stabilize mast cell preventing histamine release in response to allergen

"RESCUE"

β2RA (SABAS) are used for __________

- (used for) "RESCUE"

SABA drugs

albuterol

levalbuterol

terbutaline

Long-acting β2RA (LABA) MOA

slower onset and longer duration of action (used at night or for exercise induced)

prevents asthmatic attacks

Long-acting β2RA (LABAS) are used to __________

- (used to) prevent

LABAs should ______ ____ the first medicine used to treat asthma and ______ ______ used alone in asthma

- NOT be (the first medicine used to treat asthma)

- NOT be (used alone)

LABAs should be added to the asthma treatment plan only if other medicines do not control asthma, LABAs should be added to a _____________

- (should be added to a) corticosteroid

ICS - low, medium dose etc.

ICS

inhaled corticosteroid

Do NOT use LABA to treat _______________ __________ or sudden ____________

- wheezing exacerbation

- (sudden) wheezing

SABAs are used to treat __________ _______

- (treat) sudden wheezing

i.e., asthma exacerbations

Tachyphylaxis: a major problem with β2RA is the response of the ____-_______ ______ complex due to ___________ by frequent drug dosing

- G-protein receptor (complex)

- overstimulation (by frequent drug dosing)

Tachyphylaxis of β2RA

Repeated stimulation results in phosphorylation of C-terminal amino acids by PKA and/or G protein coupled receptor kinase. B-arrestin binds to phosphorylated domain and blocks Gs bindin, therapy decrease adenylyl cyclase activity

Binding of B-arrestin, also leads to internalization of BAR into endosomes, preventing the agonist from binding and activating the receptor again. The receptor can then be re-cycled and re-inserted in the membrane.

Prolonged receptor occupancy can lead to down-regulation and eventual receptor degradation. Cells can also reduce receptor number by inhibiting transcription or translation of gene encoding receptor.

Tachyphylaxis of β2RA: Repeated stimulation results in _____________ of C-terminal amino acids by PKA and/or G protein coupled receptor kinase. ___-_______ binds to phosphorylated domain and blocks Gs binding, therapy decrease adenylyl cyclase activity

- phosphorylation (of C-terminal amino acids)

- B-arrestin (binds to phosphorylated domain)

Tachyphylaxis of β2RA: Repeated stimulation results in phosphorylation of C-terminal amino acids by _____ and/or ____ _________ _________ ________. B-arrestin binds to phosphorylated domain and blocks Gs binding, therapy decrease adenylyl cyclase activity

- PKA

- G protein coupled receptor kinase

Tachyphylaxis of β2RA: Repeated stimulation results in phosphorylation of C-terminal amino acids by PKA and/or G protein coupled receptor kinase. B-arrestin binds to phosphorylated domain and blocks Gs ________, therapy decrease __________ ________ activity

- (blocks Gs) binding

- adenylyl cyclase (activity)

Tachyphylaxis of β2RA: __________ stimulation results in phosphorylation of C-terminal amino acids by PKA and/or G protein coupled receptor kinase. B-arrestin binds to phosphorylated domain and blocks Gs bindin, therapy ___________ adenylyl cyclase activity

- repeated (stimulation)

- decrease (adenylyl cyclase activity)

Tachyphylaxis of β2RA: Binding of B-arrestin, also leads to ____________ of BAR into endosomes, preventing the agonist from _________ and _________ the receptor again. The receptor can then be re-cycled and re-inserted in the membrane.

- internalization (of BAR)

- binding

- activating (the receptor again)

Tachyphylaxis of β2RA: Binding of ___-_________, also leads to internalization of BAR into endosomes, preventing the agonist from binding and activating the receptor again. The receptor can then be _________ and ___________ in the membrane.

- B-arrestin

- recycled

- reinserted (in the membrane)

Tachyphylaxis of β2RA: __________ receptor occupancy can lead to down-regulation and eventual receptor degradation. Cells can also ___________ receptor number by inhibiting ___________ or _________ of gene encoding receptor.

- prolonged (receptor occupancy)

- reduce (receptor number)

- transcription

- translation (of gene encoding receptor)

Tachyphylaxis of β2RA: Prolonged receptor occupancy can lead to ______-________ and eventual ___________ ___________. Cells can also reduce receptor number by inhibiting transcription or translation of gene encoding receptor.

- down-regulation

- (eventual) receptor degradation

Corticosteroid nuclear receptors: __________ the production of inflammatory cytokines

- decreases (the production)

Corticosteroid nuclear receptors: reduces _______ secretion

- mucus (secretion)

Corticosteroid nuclear receptors: reduces __________ _________

- (reduces) bronchial hyperactivity

CS also reduces mucus secretion

Corticosteroid nuclear receptors: ____________ the effect of β2RA

- enhances (the effect)

Corticosteroid MOA in asthma

decreases the production of inflammatory cytokines

reduces mucus secretion

reduces bronchial hyperactivity

enhances the effect of β2RA

________ glucocorticoids -> most effective agents for ________ attacks unresponsive to bronchodilators

- Oral (glucocorticoids)

- acute (attacks)

Oral glucocorticoids -> most effective agents for acute attacks _____________ to bronchodilators

- unresponsive (to bronchodilators)

Asthma in the elderly often associated with ______________; may have ________ response to β2RA bronchodilators

- comorbidities

- diminished (response)

Asthma in the elderly: some patients may require a __________

- (may require a) nebulizer

Asthma in pregnancy: __________ is the preferred SABA

- albuterol (is the preferred SABA)

Asthma in pregnancy: ______ are the preferred long-term control medications

- ICS (are the preferred long-term control)

More precautions taken in pregnancy

Asthma vs COPD: asthma often diagnosed at a __________ age, whereas COPD is diagnosed _________ usually ____ _______ years old

- young (age)

- older

- > 40 (years old)

Asthma vs COPD: dyspnea

Asthma: variable

COPD: PROGRESSIVE dyspnea

Asthma vs COPD: asthma has _________ dyspnea, whereas COPD is _________

- variable (dyspnea)

- (COPD is) progressive

Asthma vs COPD: treatment response

Bronchodilators in asthma produce a _____________ response

- reversible (response)

Asthma vs COPD: treatment response

Bronchodilators in COPD is only __________ __________

- partially reversible

Asthma vs COPD: treatment response

Corticosteroid use in Asthma

Good outcome

CS can be used in asthma due to the inflammatory pathway

Asthma vs COPD: treatment response

Corticosteroid use in COPD

Poor

Although CS can help, it is not part of the underlying pathophysiology of COPD

Asthma vs COPD:

Smoking status in Asthma: ____________ are also affected

- nonsmokers (are also affected)

Asthma vs COPD:

Smoking status in COPD: usually _______ ____________ ________

- long smoking history

Asthma vs COPD:

Airflow limitation in asthma

can normalize after resolution of episode

Asthma vs COPD:

Airflow limitation in COPD

CANNOT normalize

COPD has progressive deterioration of airflow

Asthma vs COPD: asthma is generally triggered by exposure to ____________, ________ or __________

- allergens

- cold

- exercise

Asthma vs COPD: COPD flare-ups are largely caused by respiratory tract infections like ______________ and ____________

- pneumonia

- influenza

Asthma vs COPD: asthma is treated to __________ __________ _________

- (treated to) suppress chronic inflammation

Asthma vs COPD: COPD is treated to _________ symptoms

Asthma pathology is ___________ whereas COPD is ___________

- reduce (symptoms)

- reversible

- (COPD is) irreversible

COPD: __________ is the major cause

- smoking (is the major cause)

Encourage patients to quit smoking with counseling and NRT

COPD: encourage patients to _______ smoking with counseling and use ________ _______ _______

- quit (smoking with counseling)

- (use) nicotine replacement therapy

COPD pathophysiology - types

emphysema

chronic bronchitis

COPD pathophysiology - emphysema

alveolar walls and septae are destroyed leading to permanently inflated alveolar air spaces.

The alveoli can be destroyed by a genetic deficiency of alpha1 antitrypsin (which inhibits the activity of destructive enzymes during an inflammatory response), cigarette smoking, and certain bacterial infections.

COPD pathophysiology - emphysema: ___________ _____ and _________ are destroyed leading to permanently inflated alveolar air spaces.

- alveolar walls

- septa (are destroyed)

COPD pathophysiology - emphysema: alveolar walls and septae are destroyed leading to ________________ __________ alveolar air spaces.

- permanently inflated (alveolar air spaces)

COPD pathophysiology - chronic bronchitis

fibrosis and thickening of the bronchial wall occurs from constant irritation from smoking or exposure to industrial pollution.

Oxygen levels are low and during coughing episodes cyanosis may occur.

COPD pathophysiology - chronic bronchitis: _________ and ___________ of the bronchial wall occurs from __________ irritation from smoking or exposure to industrial pollution.

- fibrosis

- thickening (of the bronchial wall)

- constant (irritation)

COPD pathophysiology - chronic bronchitis: fibrosis and thickening of the bronchial wall occurs from constant ___________ from __________ or exposure to industrial __________.

- (constant) irritatin

- smoking

- (industrial) pollution

COPD pathophysiology: smoke (particulates, chemicals, reactive oxygen species) causes _____________ which may lead to _________ inflammation or activation of __________

- inflammation

- chronic (inflammation)

- (activation of) neutrophils

COPD pathophysiology: Activation of neutrophils leads to the inactivation of ___________

Thus, increased ________ activity

- (inactivation of) antiproteases

- (increased) elastase (activity)

COPD pathophysiology: increased elate activity can also be elicited by _________ deficiency in α1-antitrypsin

Which leads to _________ ___ ________

- hereditary (defiency)

- destruction of alveoli

β2RA may cause ____________ bronchospasm

- (may cause) paradoxical (bronchospasm)

β2RA (SABA) adverse effects

increase BP / HR

arrhythmias