Respiratory Pharmacology Flashcards
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
Asthma symptoms
Wheezing
Shortness of Breath
Chest tightness
Coughing
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
What is the cause of asthma (immunologically speaking)
An excessively active immune system
T effector cells
Critical mediators
Th cells
Determine the course of an inflammatory response
What cells are related to antibody-mediated immunity?
B cells
What cells are related to cell-mediated immunity?
Macrophages
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
How do Th2 cells mediate inflammatory response in asthma leading to eosinophil infiltration of the lung?
By virtue of cytokines they produce
Th1 cells
Cell mediated immunity
Intracellular pathogens
Yeast, viruses, intracellular bacteria, cancer
Th2 cells
Humoral or antibody mediated immunity
Extracellular pathogen
Parasites, normal bacteria, toxins, allergens
What are the distinct asthma phenotypes?
Eosinophilic Asthma
Non-eosinophilic Asthma
What is the significance of having distinct asthma phenotypes?
They require distinct pharmacologic treatments
Eosinophilic Asthma
Eosinophils, basement membrane thickening Inhalational corticosteroids (ICS) are the first line of defense
Non-eosinophilic Asthma
No eosinophils, no basement membrane thickening
New treatment regimens needed
Refractory to treatment with ICS
What Th cells are related to asthma and other inflammatory disorders?
Th1
Th2
Th17
What disorders are Th1 cells related to?
Chronic inflammatory and autoimmune disorders
What disorders are Th2 cells related to?
Allergic (atopic) disorders
Eosinophilic asthma
What disorders are Th17 cells related to?
Chronic inflammatory and autoimmune disorders
Neutrophilic asthma
What can inflammation of the airway cause?
Bronchoconstriction
Mucus
Airway remodeling
What signaling molecules causes bronchoconstriciton?
Leukotrines (1000x more potent than histamine in the airway)
Cholinergic stimulation (COPD)
Histamine
What causes mucus buildup during inflammation?
Mediated by many proinflammatory compounds
How does airway remodeling occur?
Results from chronic inflammation
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
What can be some cellular responses of COPD?
Fibrosis
Alveolar wall destruction
Mucus Hypersecretion
What cells are responsible for Fibrosis in COPD?
Fibroblasts
What cells are responsible for Alveolar wall destruction in COPD?
Tc1 cells and Proteases
What cells are responsible for Mucus hypersecretion in COPD?
Proteases
What are the goals of COPD treatment?
Relieve bronchoconstriction
Improve exercise tolerance (keep patient active)
Prevent and treat complications
Slow progress of the disease
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
What causes mast cell degranulation in asthma?
Allergens
What does mast cell degranulation produce in asthma?
Release of Histamine, Cystidinyl leukotrines, Prostaglandins, and others
These agents lead to broncho-constriction
How do asthma drugs work?
Stymie the allergic response
Diminish the number of immune cells in the lung
Alter production of bronchoconstrictors
What types of drugs can be used to treat asthma?
B2 adrenergic receptor agonists Corticosteroids Leukotrine modifiers Anticholinergics Anti-IgE
What does smooth muscle contraction require?
Phosphorylaiton of the myosin light chain
What do B2 adrenergic receptor agonists produce?
Smooth muscle relaxation
PKA-mediated activation of K channels causes what?
Attenuation of myosin light chain kinase activity
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
What are the classification os B-agnonists for asthma and COPD treatment?
Short acting B-agonists (SABA)
Long acting B-agonists (LABA)
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
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
What are some adverse effects of B2 agonists?
Muscle tremor
Tachycardia/palpitations
CNS issues (headache, restlessness, nervousness)
Inhalational corticosteroids
Critical component of the strategy for managing eosinophilic asthma
Act as general immunosuppresant agents
What is an important marker of the effectiveness of corticosteroid treatment?
Reduction of eosinophils in the lung of an asthmatic after treatment
Where are the adrenal glands located?
Above the kidneys
“Suprarenal glands”
What are the two functionally different regions of the Adrenal gland?
Medulla
Cortex
Adrenal Medulla
Outer region Secretes catecholamines (epinephrine, norepi, dopamine)
Adrenal Cortex
Inner region
Secretes corticoids (Mineralcorticoids, Glucocorticoids, sex steroids)
Regulates many body functions
Essential to life
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
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
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**
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
What is the net result of glucocorticoids on inflammation?
Inhibits vasodilation, chemotaxis, nociception, extravasation
Decreases inflammation and pain
Increases Bronchodilation
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)
The transcription factor NFkB is responsible for which immune response?
Both the innate and acquired immune response
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
What are the two types of corticosteroid therapy?
1) Acute treatment (systemic)
2) Long-term treatment (inhaled)
Inhaled corticosteroids
Long term management
Patients (children) may have to take these for many years
Effective airway delivery but minimize systemic effects
What are desired features of inhaled corticosteroids?
High affinity for glucocorticoid receptor
Minimal systemic absorption
Highly serum protein bound
Rapid systemic inactivation
What are adverse effects of inhaled corticosteroids?
Dysphonia
Oropharyngeal candidiasis
Adrenal suppression (at high doses and systemic absorption)
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
What patients with asthma will not respond tp ICS treatment?
Non-eosinophilic asthma
Glucocorticoid resistant
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
What does the increase in vagal tone contribute to?
Broncho-constriction in COPD
Caused by smooth muscle contraction
In the context of treatment of respiratory diseases, what do anti-cholinergics refer to?
Antagonists of muscarinic acetylcholine receptors
Blockade of M1 and M3 muscarinic receptors can lead to what?
Bronchodilation
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
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
Muscarinic receptor antagonists currently used to treat Asthma/COPD are similar to what?
Atropine (but they have a permanent + charge)
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
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)
T/F - Histmine is a more potent bronchoconstrictor than Leukotrines
False - Leukotrines are 1000x more potent than histamine
How are leukotrines made?
From arachadonic acid by the enzyme 5’-lipoxygenase
Asthma treatment with leukotrine modifiers
Alternative therapy to treat mild asthma
Adjunctive therapy with ICS’s
Prevention of exercise induced asthma
COPD treatment with leukotrine modifiers
Leukotrine modifiers have not been adequately tested and are not recommended
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
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
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
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
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
What are the major drug classes to treat allergic Rhinitis?
H1 receptor antagonists (antihistamines)
a1-adrenergic reeptor agonists (decongestants)
Intranasal corticosteroids
Histamine
Biogenic amine
Synthesized and stored by many cells
Abundant in mast cells
H1, H2, H3, H4 GPCRs
What is H1 responsible for?
Bronchocontriction, vasodilation, rhinitis
What is H2 responsible for?
Sleep/wake cycles and mood
What is H3 responsible for?
Stomach acid secretions
What is H4 responsible for?
Mast cell chemotaxis and activation
What is another thing Histamine does?
Stimulates nociceptors (C-fibers): itch and pain
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
What physiologic action does Histamine produce?
Produces vasodilation and disrupts capillary seal in
What physiologic action do Anti-histamines produce?
Vasoconstriction and restores capillary seal
What forms can H1 antagonists be taken?
Oral for systemic or local relief
Topical for hives
Opthalmic for eye allergies
Intranasal for seasonal rhinitis
1st generation H1 antagonists
Significant entry into brain
Sedative effect
Anti-emetic, anti-motion sickness effects
2nd generation H1 antagonists
Limited entry into brain
More selective
Less adverse effects
a-1 adrenergic receptor agonists
Act directly on smooth muscle to produce vasoconstriction
Relieve congestion
Nasal corticosteroids
Reduce swelling and inflammation in mucous membranes
Reduce mucous secretions
