Respiratory (Exam 3) Flashcards
Outcome of smoking on public
Loss of tax dollars
Indications of human health
Life expectancy and infant mortality
Indications of human health vary greatly between…
Developed and developing countries
Lower respiratory tract
Includes trachea, bronchi, and alveoli in the lungs
Tuberculosis bacteria settle and cause infection
Upper respiratory tract
Includes nose, throat, and sinuses
Upper respiratory tract infections
Sinusitis, Allergic rhinitis, stridor, tonsillitis, influenza, croup, whooping cough
Lower respiratory infections
Acute bronchitis, pneumonia, SARS, tuberculosis
Structure and function of respiratory system
Surface area
Blood-gas barrier
Cell types
Largest surface area of the body?
Alveolar
Substantial surface for toxicant contact and absorption
Respiratory airways and alveolar epithelium are in…
direct contact with environmental toxicants in air
What separates the blood from contaminated environmental air?
Alveolar epithelium and capillary endothelium
Cells types involved in pulmonary toxicity
Type-I
Type-II
Clara cells
Alveolar macrophages
Endothelial cells
Normal lung
Thin walls in upper and lower airways allow normal exchange of gases between blood vessels and airspace
Diseased upper airway of lungs
Produces influx of inflammatory cells
Increased fibrosis
Constriction of bronchiolar airways
Diseased lower airway of lungs
Fibroblasts and mononuclear inflammatory cells lead to collagen deposits and thickening of lung walls
Clara cells
Non-ciliated rounded secretory cells
Target for pulmonary toxicants
How are Clara cells distinguished?
By smooth rounded “domes” which project into bronchiolar lumen
Function of Type I alveolar cells
Line alveolar spaces
Only barrier between air and capillary endothelium
Where are Clara cells located?
Only in small bronchioles
Functions of Type II alveolar cells
Synthesize surfactant
Serve as Stem cells for Type I alveolar epithelium
Form part of blood-gas barrier
Functions of alveolar macrophages
Phagocytosis
Fibrosis in lungs
How do alveolar macrophages lead to fibrosis?
When overload, they die and release acid hydrolases and phospholipases
These stimulate fibroblasts –> Fibrosis
How do Type II cells serve as stem cells?
Type I cells destroyed
Type II proliferate to cover alveolar surface
How many days to replace type I cells with type II?
2 days
Immature Type II cells
Cuboidal and transfer oxygen more slowly than type I
Functions of Clara cells
Secretions
Xenobiotic metabolism via CYP450
CYP450
Found in high concentration in Clara cells
Functions of endothelial cells (5)
Formation of blood-gas diffusion barrier
Maintenance of active transport
Uptake & metabolism of pesticides
Angiotensin I –> angiotensin II
Synthesis & metabolism of prostaglandins
Upper respiratory disorders
Allergies
Bronchitis
Obstructive Lung Diseases
Asthma
COPD
Cystic Fibrosis
Viruses of Upper Respiratory Tract (CRRABCHIP)
Coxsack
Rhinovirus
Respiratory Syncytial
Adenovirus
Bocavirus
Coronavirus
Herpesvirus
Influenza
Parainfluenza
Viruses of Lower Respiratory Tract (PRAMBIS)
Parainfluenza
Respiratory Syncytial
Adenovirus
Metapneumovirus
Bocavirus
Influenza
SARS-COV-2
How are upper respiratory disorders characterized?
By infection and hypersensitivity of specific areas
Symptoms of upper respiratory disorders
Runny nose
Sore throat
Cough
Breathing difficulty and lethargy
Asthma is triggered by
environmental variables
allergens, pollutants, exercise
Symptoms of asthma
shortness of breath
contraction of bronchiolar smooth muscle
Mechanisms of upper respiratory disorders
Swelling
Increased vascular permeability
Increased secretions
Mechanisms of Asthma
Activation of mast cells
Infiltration of eosinophils and helper T cells (TH2)
Which two disorders are characterized by chronic inflammation of airway?
Asthma
COPD
Symptoms of COPD
Shortness of breath
Progressive destruction of lung parenchyma of small airway
Mechanisms of COPD
Infiltration of Neutrophils, macrophages and cytotoxic T-cells
Respiratory Disease Controlling Agents
Meds used to relieve, treat, or prevent respiratory diseases such as asthma, chronic bronchitis, COPD, or pneumonia
Inhalation Respiratory Agents
Deliver meds directly to lungs
Meds act directly on lung tissues
Minimal systemic side effects
Cystic Fibrosis (CF)
Autosomal-recessive inherited disease
What does CF cause?
Defective Cl- secretion in the lung
What is defective CL- secretion caused by?
Mutations of the CFTR Cl- channel
Result of CFTR mutation
Thick dehydrated mucus and chronic bacterial infections
How many mutations in CFTR gene have been identified?
1600
Therapies for CF target…
downstream consequences that are secondary to loss of CFTR Cl- channel function
Goals of CF treatment
Prevent/control infections
Remove & loosen mucus
Treat/prevent intestinal blockage
Provide nutrition
CFTR modulators
Elexacaftor
Ivacaftor
Tezacaftor
Lumacaftor
Trikafta
(elexacaftor, ivacaftor, tezacaftor)
Approved for age 12 and older
Symdeko
(tezacaftor, ivacaftor)
Approved for age 6 and older
Orkambi
(lumacaftor, ivacaftor)
Approved for age 2 and older
Kalydeco
(Ivacaftor)
Approved for 6 months and older
CFTR modulator therapies correct…
malfunctioning protein made by CFTR gene
Do CFTR medications work for all CF patients?
NO!
Only for specific mutations
Precursor to Histamine
Histadine
Autacoids
Do NOT act on cholinoreceptors or adenoreceptors but have effects on smooth muscle
Most important amine autacoids
Histamine and serotonin
First generation H1 blocker
Diphenhydramine
Ergot alkaloids
Heterogeneous group of drugs that interact with serotonin, dopamine, and alpha receptors
Second generation H1 blocker
Cetirizine
H2 blocker
Cimetidine
5-HT1 agonist
Sumatriptan
5-HT4 partial agonist
Tegaserod
5-HT2 antagonist
Ketanserin
5-HT3 antagonist
Ondansetron
5-HT2 agonist in obesity
Lorcaserin
Classes of histamine receptors
H1-H4
Where are H1 and H2 receptors distributed?
Periphery and central nervous system
H1 receptors
Blocked selectively by classical ‘antihistamines’
Where are H1 receptors found?
Endothelial cells
Are H1 receptors direct or indirect vasodilators?
INDIRECT
Are H2 receptors direct or indirect vasodilators?
DIRECT
H2 receptors
stimulate gastric acid secretion
Where are H2 receptors found?
Gastric mucosa
Cardiac muscle
Mast cells
Brain
H3 receptors are
presynaptic autoreceptors
H3 receptors decrease…
release of histamine
PROMOTE SLEEP
Where are H4 receptors expressed?
Cells of hematopoietic lineage
What do H4 receptors do?
Mediate immune function
Low affinity histamine receptors
H1 and H2
High affinity histamine receptors
H3 and H4
H1 partially selective antagonists or inverse agonists
Mepyramine
Triprolidine
Cetirizine
H2 partially selective antagonists or inverse agonists
Cimetidine
Ranitidine
Nizatidine
H3 partially selective antagonists or inverse agonists
Thioperamide
Iodophenpropit
Clobenpropit
Tiprolisant
Proxyfan
H4 partially selective antagonists or inverse agonists
Thioperamide
Distribution of H1 receptors
Smooth muscle
Endothelium
Brain
Distribution of H2 receptors
Gastric mucosa
Cardiac muscle
Mast cells
Brain
Distribution of H3 receptors
Presynaptic autoreceptor
Distribution of H4 receptors
Eosinophils
Neutrophils
CD4 T cells
H1 receptor antagonists
Competitive inhibition of H1 receptor in blood vessels of nasal mucosa
1st Gen H1 receptor antagonists
Clemastine
Chlorpheniramine
Cyproheptadine
Diphenhydramine
Doxylamine
Hydroxyzine
Ketotifen
Promethazine
2nd Gen H1 receptor antagonists
Terfenadine
Loratadine (Claratin)
Ceterizine (Zyrtec)
3rd Gen H1 receptor antagonists
Desloratadine
Fexofenadine (Allegra)
Levocetirizine
Which H1 receptor antagonists have anti-muscarinic effects?
1st Gens
Diphenhydramine
Bromopheniramine
Chlorpheniramine
Carbinoxamine
Bronchiolar Smooth Muscle Relaxation Pathway
Epinephrine binds to B2-receptor, activates AC, ATP activates cAMP –> Protein Kinase A –> decrease in Ca+
leukotrienes
slow reacting substance of anaphylaxis
examples of leukotriene inhibitors
zileuton
montelukast
pranlukast
zafirlukast
zileuton MOA
inhibitor of 5-lipoxygenase activity in LOX pathway
Adrenergic alpha receptor agonists
Phenylephrine
Ephedrine
Psuedoephedrine
montelukast/pranlukast/zafirlukast MOA
inhibit CYSLTR1 which is a target of cysteinyl leukotrienes
Psuedoephrdrine is a _____ of ephedrine.
Stereoisomer
why is zileuton least prescribed?
due to liver toxicity
does the leukotriene receptor antagonists have toxicity?
little
Ephedrine and Psuedoephedrine Pharmacodynamics
Mixed acting sympathomimetics
Increase NE release
a1 receptor agonist
what happens when cysteinyl leukotrienes bind to CYSLTR1?
constriction of airway smooth muscle
increased vascular permeability
decreased mucocilliary clearance
mucus hypersecretion
Phenylephrine
Selective a1 receptor agonist
inhaled corticosteroid MOA
cortisol transported by glucocorticoid receptor and enters nucleus
GRE interacts with DNA and alters transcription
Sympathomimetic Agents Actions
Decrease resistance to airflow by decreasing volume of nasal mucosa
Activation of alpha receptors that have erectile characteristics
Decrease mucous secretions
examples of inhaled corticosteroids
beclomethasone
flunisolide
fluticasone
budesonide
mometasone
where do inhaled corticosteroids bind?
glucocorticoid receptor
when inhaled corticosteroids bind to the GR, what happens?
induction of anti inflammatory genes
inhibition of pro inflammatory genes
modification of cellular protein transcription
when is peak action of inhaled corticosteroids?
hours to days
are inhaled corticosteroids used for acute relief?
NO
inhaled corticosteroid doses _____ and are initially used to cause _________ for airway clearance
vary
bursts
most important action of inhaled corticosteroids
inhibition of the infiltration of asthmatic airways by lymphocytes, eosinophils, and mast cells
Sympathomimetic Agents therapeutic applications
Used in OTC remedies for upper respiratory tract disorders
therapeutic indications for inhaled corticosteroids
COPD and asthma
short term adverse effects of inhaled corticosteroids
anaphylaxis (beclomethasone)
localized opportunistic infections
SOB
mood alterations
restlessness
dry mouth
Ephedrine adverse effects
CNS effects
Tachycardia
Hypertension
Pseudoephedrine adverse effects
less potent tachycardia
increased BP
CNS stimulation
long term adverse effects of inhaled corticosteroids
moon face
fluid retention
weight gain
osteoporosis
glomerulonephritis
mucokinetic therapy also known as
mucolytics
mucous controlling agents
Phenylephrine adverse effects
Increased BP
Vasoconstriction
example of mucolytics
n-acetylcysteine
Pulmozyme (dornase-a)
Where is histaminergic system localized?
Posterior hypothalamus
MOA of mucolytics
breaks down disulfide bonds in mucoproteins
therapeutic indications for mucolytics
thins abnormally thick mucus in CF and pulmonary fibrosis
adverse effects of mucolytics
wheezing
airway obstruction due to liquefaction of secretions
nausea and rhinorrhea
odor (hydrogen sulfide)
incompatibility with anti infective compounds
Histamine acting via H1 or H3 receptors
Regulation of sleep-wakefulness
omalizumab
recombinant, humanized mAB against human IgE
monoclonal antibody
What induces wakefulness?
Histamine
H1 receptor agonists
omalizumab MOA
binds to free IgE so they cannot bind to mast cell and cause inflammation/trigger an effect
What promotes sleep?
H1 receptor antagonists
Pulmozyme MOA
recombinant human deoxyribonuclease I (rhDNase)
H3 receptor functions as…
Autoreceptor
Regulates synthesis/release of histamine
rhDNAse
selectively cleaves DNA
hydrolyzes the DNA present in sputum/mucus of CF and reduces viscosity in lungs
Histaminergic neurons display max activity during…
State of vigilance
adverse effects of pulmozyme
pharyngitis
laryngitis
rash
chest pain
dimetapp day vs dimetapp night
both have phenylephrine (decongestant)
day - brompheniramine (antihistamine) and dextromethorphan (cough suppressant)
night - diphenhydramine (antihistamine and cough suppressant)
Histaminergic neurons cease activity during
NREM and REM sleep
Classification of beta2 agonists
SABAs
LABAs
ultra-LABAs
DayQuil vs nyquil
both - acetaminophen and dextromethorphan
day - phenylephrine
night - doxylamine
Which class of beta2 agonists has shortest half life?
SABAs
Immediate symptomatic relief
robitussin DM
dextromethorphan (antitussive) and guaifenesin (thins mucus)
Prolonged duration of beta2 agonists is achievable by
decreasing susceptibility of agonists to COMT and MAOs
Robitussin Max strength DM day vs night
both - dextromethorphan
day - guaifenesin
night - doxylamine
Adrenergic beta receptor agonists
Bronchodilators dilate bronchi by direct action on adrenoreceptor on bronchial smooth muscle and relac muscle
Benadryl allergy (my fav)
diphenhydramine (antihistamine)
Benadryl Allergy Plus congestion
diphenhydramine (antihistamine)
phenylephrine (decongestant)
Benadryl Itch Stopping Cream
diphenhydramine (antihistamine)
zinc (skin protectant)
Benadryl itch cooling gel
camphor
besides being an antihistamine, Benadryl is also classified as an
antitussive (cough suppressant)
because you can’t cough when your passed out cold!
Non-selctive Adrenergic beta receptor agonists
Epinephrine
Isoproterenol
Sympathomimetic agents therapeutics indication
Asthma
Sympathomimetic agents adverse effects
Cardiovascular
Tachycardia
Hypertension
Somatic tremor
Nausea and insomnia
Common SABAs
Salbutamol (albuterol)
Terbutaline
Levalbuterol
Pirbuterol
Common LABAs
Salmeterol
Formoterol
Common Ultra-LABAs
Indacaterol
Olodaerol
Vilanterol
Formoterol
Bronchiolar Smooth Muscle Contraction Pathway
ACh binds to M2/M3 receptor to release PLC –> cleaved by PIP2 into DAG and IP3
DAG –> PKC
IP3 –> increases Ca+
Anticholinergic Agents
Ipratropium
Tiotropium
Aclidinium
Anticholinergic Agents MOA
Block M3 on bronchiolar smooth muscles and secretory tissues
Anticholinergic Agents Therapeutic Indications
Asthma
COPD
Anticholinergic Agents Adverse effects
Dry mouth
Ocular
Slow gastric emptying
tremors
Antimuscarinic drugs are contraindicated…
in patients with glaucoma
Methyl Xanthines
Theophylline
Aminophylline
Roflumilast
Methyl Xanthines MOA
Phosphodiesterase inhibitors cause relaxation of smooth muscle and promotes dilation
Methyl Xanthines Therapeutic indications
Asthma
COPD
Emphysema
Methyl Xanthines Adverse Effects
Nausea
Tachycardia, increase CO
increase in TPR
CNS stimulation
Insomnia
Roflumilast MOA
PDE4 inhibitors inhibit inflammatory cytokine and mediator release.
Inhibits neutrophil chemotaxis activity
Promotes apoptosis
Endothelins
Powerful vasoconstrictor produced in endothelial cells
Pathway of Endothelins
Prepro ET (inactive) –> Big ET (inactive) –> ET (active)
Enzymes in endothelins pathways
Furin-like protease
ECE-1 and ECE-2
Most potent vasoconstrictor in cardiovascular system
Endothelin-1
ET-1 and ET-2 act on
ETA and ETB
ET-3 acts on
ETB
ETA
Increases Ca+
Makes receptors more sensitive
ETB
Clearance receptor
Increases NO
Endothelin Receptor Antagonists
Bosentan
Ambrisentan
Macitentan
Bosentan
Dual ETA and ETB antagonist
Ambrisentan
Selective ETA antagonists
Macitentan
Selective ETA antagonists
Endothelin Receptor Antagonists adverse effects
Hypotension
Increased HR
Facial flushing
Edema, headaches
Endothelin Receptor Antagonists to treat pulmonary artery hypertension
Used in conjunction with negative inotropic agents and direct vasodilators
Endothelin Antagonists are contraindicated
in pregnancy
Groups of Prophylactic bronchodilators
Cromolyn Sodium
Leukotriene Inhibitors
Cromolyn Sodium
Low solubility, poorly absorbed
Must be inhaled
Cromolyn Sodium has no effect on
airway smooth muscle tone
Cromolyn Sodium is ineffective in
reversing bronchospasm
Cromolyn Sodium is only of value when
taken prophylactically
Cromolyn Sodium MOA
Alters function of delayed Cl- channels in cells
Inhibits cell activation