Respiratory Pharmacology Flashcards Preview

AU 15 - Pharmacology Exam 3 > Respiratory Pharmacology > Flashcards

Flashcards in Respiratory Pharmacology Deck (96):
1

Asthma

A long-term respiratory condition in which the airway may unexpectedly and suddenly narrow, often in response to an allergen, cold air, exercise, or emotional stress

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Asthma symptoms

Wheezing
Shortness of Breath
Chest tightness
Coughing

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COPD

Chronic bronchitis an emphysema, a pair of two commonly co-existing diseases of the lungs in which the airways become narrowed
This leads to a limitation of the flow of air to and from the lungs causing shortness of breath

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What is the cause of asthma (immunologically speaking)

An excessively active immune system

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T effector cells

Critical mediators

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Th cells

Determine the course of an inflammatory response

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What cells are related to antibody-mediated immunity?

B cells

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What cells are related to cell-mediated immunity?

Macrophages

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What is the oversimplified view of the sequence of events leading to infiltration of eosinophils in the lung?

Allergen --> Mast cells --> Th2 --> Infiltration of Eosinophils

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How do Th2 cells mediate inflammatory response in asthma leading to eosinophil infiltration of the lung?

By virtue of cytokines they produce

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Th1 cells

Cell mediated immunity
Intracellular pathogens
Yeast, viruses, intracellular bacteria, cancer

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Th2 cells

Humoral or antibody mediated immunity
Extracellular pathogen
Parasites, normal bacteria, toxins, allergens

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What are the distinct asthma phenotypes?

Eosinophilic Asthma
Non-eosinophilic Asthma

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What is the significance of having distinct asthma phenotypes?

They require distinct pharmacologic treatments

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Eosinophilic Asthma

Eosinophils, basement membrane thickening
Inhalational corticosteroids (ICS) are the first line of defense

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Non-eosinophilic Asthma

No eosinophils, no basement membrane thickening
New treatment regimens needed
Refractory to treatment with ICS

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What Th cells are related to asthma and other inflammatory disorders?

Th1
Th2
Th17

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What disorders are Th1 cells related to?

Chronic inflammatory and autoimmune disorders

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What disorders are Th2 cells related to?

Allergic (atopic) disorders
Eosinophilic asthma

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What disorders are Th17 cells related to?

Chronic inflammatory and autoimmune disorders
Neutrophilic asthma

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What can inflammation of the airway cause?

Bronchoconstriction
Mucus
Airway remodeling

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What signaling molecules causes bronchoconstriciton?

Leukotrines (1000x more potent than histamine in the airway)
Cholinergic stimulation (COPD)
Histamine

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What causes mucus buildup during inflammation?

Mediated by many proinflammatory compounds

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How does airway remodeling occur?

Results from chronic inflammation

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What are the three goals of asthma treatment?

1) Relieve or prevent bronchocontriciton
2) Inhibit airway inflammation (reduce mucus production)
3) Prevent airway remodeling
Theraputic goal: to manage the disease so that the patient is as symptom free as possible

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What can be some cellular responses of COPD?

Fibrosis
Alveolar wall destruction
Mucus Hypersecretion

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What cells are responsible for Fibrosis in COPD?

Fibroblasts

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What cells are responsible for Alveolar wall destruction in COPD?

Tc1 cells and Proteases

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What cells are responsible for Mucus hypersecretion in COPD?

Proteases

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What are the goals of COPD treatment?

Relieve bronchoconstriction
Improve exercise tolerance (keep patient active)
Prevent and treat complications
Slow progress of the disease

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What characteristics of Asthma make it different?

Onset is typically during childhood or adolescence
Bronchoconstriction part of allergic reaction
With treatment, near normal function and symptom-free life is possible
Late stage inflammation usually/sometimes involves eosinophil reqruitment

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What causes mast cell degranulation in asthma?

Allergens

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What does mast cell degranulation produce in asthma?

Release of Histamine, Cystidinyl leukotrines, Prostaglandins, and others
These agents lead to broncho-constriction

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How do asthma drugs work?

Stymie the allergic response
Diminish the number of immune cells in the lung
Alter production of bronchoconstrictors

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What types of drugs can be used to treat asthma?

B2 adrenergic receptor agonists
Corticosteroids
Leukotrine modifiers
Anticholinergics
Anti-IgE

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What does smooth muscle contraction require?

Phosphorylaiton of the myosin light chain

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What do B2 adrenergic receptor agonists produce?

Smooth muscle relaxation

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PKA-mediated activation of K channels causes what?

Attenuation of myosin light chain kinase activity

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How does PKA activation of K channels attenuate MLCK activity?

Activation of K channels leads to hyperpolarization
Hyperpolarization leads to a reduction in cellular Ca
Reduciton in Ca produces smooth muscle cell relaxation because the activity of MLCK is attenuated

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What are the classification os B-agnonists for asthma and COPD treatment?

Short acting B-agonists (SABA)
Long acting B-agonists (LABA)

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Short acting B agonists (SABA)

Administered by inhalation
Provide acute relief, or used as prophylactic for exercise induced asthma
Rapid onset (minutes)
Effects last 4-6 hours

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Long acting B agonists (LABA)

Control persistent asthma and maintenance therapy for COPD
Not for acute treatment
Sometimes combined with corticosteroids
Sometimes combined with anticholinergics
Relatively hydrophobic

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What are some adverse effects of B2 agonists?

Muscle tremor
Tachycardia/palpitations
CNS issues (headache, restlessness, nervousness)

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Inhalational corticosteroids

Critical component of the strategy for managing eosinophilic asthma
Act as general immunosuppresant agents

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What is an important marker of the effectiveness of corticosteroid treatment?

Reduction of eosinophils in the lung of an asthmatic after treatment

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Where are the adrenal glands located?

Above the kidneys
"Suprarenal glands"

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What are the two functionally different regions of the Adrenal gland?

Medulla
Cortex

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Adrenal Medulla

Outer region
Secretes catecholamines (epinephrine, norepi, dopamine)

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Adrenal Cortex

Inner region
Secretes corticoids (Mineralcorticoids, Glucocorticoids, sex steroids)
Regulates many body functions
Essential to life

50

What's the chain of the Hypothalamic-pituitary axis?

Hypothalamus releases CRH, which goes to the pituitary
Pituitary releases ACTH to the adrenal gland
Adrenal gland releases Cortisol/Glucocorticoids

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Cortisol travel characteristics

Highly hydrophobic
Transported by carrier protein - albumin and cortisol binding globulin (CBG)
Only the unbound (2%) hormones are active
Dissociate from binding protein prior to entering target tissue
Readily crosses lipid membranes

52

What effects on the body can cortisol have?
Which is most relevant to this class?

Carbohydrate & Protein metabolism
Lipid Redistribution
Cardiovascular and Respiratory effects
Bone and skin functions
CNS functions
**Anti-inflammatory agent**

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What are the Physiological and Cellular Anti-inflammatory Effects of Glucocorticoids?

1) Attenuate leukocyte trafficking (recruitment of leukocytes to the site of inflammation)
2) Effects on Innate Immunity
3) Effects on Pro-inflammatory mediator

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What is the net result of glucocorticoids on inflammation?

Inhibits vasodilation, chemotaxis, nociception, extravasation
Decreases inflammation and pain
Increases Bronchodilation

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What are the major mechanisms of action of Glucocorticoid-Glucocorticoid Receptor Complexes?

1) Direct activation of gene expression via DNA binding to target genes (via DR dimer)
2) Direct blocking of NFkB mediated transcription by histone deacetylation (via GR monomer)

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The transcription factor NFkB is responsible for which immune response?

Both the innate and acquired immune response

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What are the two types of glucocorticoid therapy?

1) Management of chronic adrenal insufficiency
-replacement therapy (Addison's disease)
-low dose
-may need adjustments

2) Suppress inflammation and immune responses
-Asthma, other inflammatory diseases, transplants, etc
-Higher doses
-Target specific delivery

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What are the two types of corticosteroid therapy?

1) Acute treatment (systemic)
2) Long-term treatment (inhaled)

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Inhaled corticosteroids

Long term management
Patients (children) may have to take these for many years
Effective airway delivery but minimize systemic effects

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What are desired features of inhaled corticosteroids?

High affinity for glucocorticoid receptor
Minimal systemic absorption
Highly serum protein bound
Rapid systemic inactivation

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What are adverse effects of inhaled corticosteroids?

Dysphonia
Oropharyngeal candidiasis
Adrenal suppression (at high doses and systemic absorption)

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Use of ICSs in Asthma treatment

Unless asthma is exercise induced or intermittent, ICSs are usually an integral part of the daily treatment regimen
Doses and use of additional pharmacologic treatments depend on the severity and frequency of asthma symptoms

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What patients with asthma will not respond tp ICS treatment?

Non-eosinophilic asthma
Glucocorticoid resistant

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Use of ICS in COPD treatment

Not monotherapy
40-50% of COPD patients are prescribed ICS for the asthma component
Evidence shows that benefit of ICS is limited in COPD

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What does the increase in vagal tone contribute to?

Broncho-constriction in COPD
Caused by smooth muscle contraction

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In the context of treatment of respiratory diseases, what do anti-cholinergics refer to?

Antagonists of muscarinic acetylcholine receptors

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Blockade of M1 and M3 muscarinic receptors can lead to what?

Bronchodilation

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What is the synopsis of Muscarinic Receptor Physiology in the airway?

Increased parasympathetic activity during airway inflammation
Vagal tone --> acetylcholine
Acetylcholine is also released form other cells
ACh causes contraction of airway smooth muscle
Mucous produciton and secretion

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Anti-cholinergics effect on bronchocontriction

Block the aciton of acetylcholine on muscarinic receptors in the airway
Inhibits smooth muscle contraction
Decreases mucous secretion
First line of defense in treating COPD
ACh-mediated broncho-constriciton is the only reversible component of COPD

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Muscarinic receptor antagonists currently used to treat Asthma/COPD are similar to what?

Atropine (but they have a permanent + charge)

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Use of Anti-cholinergics to treat COPD

First line of defense in maintenance therapy for COPD
Used alone or in combination with SABAs or LABA

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Use of Anti-cholinergics to treat Asthma

Sometimes used as an alternate to LABAs when asthma is not well controlled by corticosteroids alone
Sometimes used in the treatment of exercise-induced asthma
Sometimes used in the treatment of a severe asthma attack (but not alone)

73

T/F - Histmine is a more potent bronchoconstrictor than Leukotrines

False - Leukotrines are 1000x more potent than histamine

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How are leukotrines made?

From arachadonic acid by the enzyme 5'-lipoxygenase

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Asthma treatment with leukotrine modifiers

Alternative therapy to treat mild asthma
Adjunctive therapy with ICS's
Prevention of exercise induced asthma

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COPD treatment with leukotrine modifiers

Leukotrine modifiers have not been adequately tested and are not recommended

77

Omalizumab/Xolair

Humanized monoclonal antibody directed against IgE
For moderate to severe asthma caused by hypersensitivity to environmental substances and poorly controlled by corticosteroids
EXPENSIVE

78

Allergic Rhinitis definition

Hay Fever
Abnormal inflammation of the membrane lining in the nose leading to:
-Nasal congestion
-Rhinorrhea (runny nose)
-Sneeking
-Itching
-Post nasal drip
-Sinus Pain
-Red, watery, itchy eyes
-Symptoms are condined to Nose, eyes, throat

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What causes Allergic Rhinitis?

The same type of excessive reaction of the immune system to allergens as that seen in asthma
Because the nasal passage has different structure and function, the symptoms and pharmacological treatments are not identical

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What is the nasal passage responsible for?

Warming and humidifying the air
-Has extensive blood flow for heat exchange
-Nasal mucosa have high secretory capacity
-Capillary structure facilitates rapid movement of water through the vascular wall to escape into the airway and humidify inspired air
These features of nasal physiology contribute to the symptoms of allergic rhynitis

81

What are the two types of glands in the nose?

Anterior serous glands
-200-300
-watery, non-viscous secretions

Posterior seromucous glands
-100,000
-largely responsibly for nasal discharge

82

What are the major drug classes to treat allergic Rhinitis?

H1 receptor antagonists (antihistamines)
a1-adrenergic reeptor agonists (decongestants)
Intranasal corticosteroids

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Histamine

Biogenic amine
Synthesized and stored by many cells
Abundant in mast cells
H1, H2, H3, H4 GPCRs

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What is H1 responsible for?

Bronchocontriction, vasodilation, rhinitis

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What is H2 responsible for?

Sleep/wake cycles and mood

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What is H3 responsible for?

Stomach acid secretions

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What is H4 responsible for?

Mast cell chemotaxis and activation

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What is another thing Histamine does?

Stimulates nociceptors (C-fibers): itch and pain

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What does Histamine-H1 receptor activity on endothelium do, and what are the two major effects

Increases intracellular Ca++:
1) NO mediated relaxation of smooth muscle, causing vasodilation
2) MLCK mediated contraction of the capillary endothelium

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What physiologic action does Histamine produce?

Produces vasodilation and disrupts capillary seal in

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What physiologic action do Anti-histamines produce?

Vasoconstriction and restores capillary seal

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What forms can H1 antagonists be taken?

Oral for systemic or local relief
Topical for hives
Opthalmic for eye allergies
Intranasal for seasonal rhinitis

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1st generation H1 antagonists

Significant entry into brain
Sedative effect
Anti-emetic, anti-motion sickness effects

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2nd generation H1 antagonists

Limited entry into brain
More selective
Less adverse effects

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a-1 adrenergic receptor agonists

Act directly on smooth muscle to produce vasoconstriction
Relieve congestion

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Nasal corticosteroids

Reduce swelling and inflammation in mucous membranes
Reduce mucous secretions