Pulmonary Path & Pharm Flashcards
Upper Airways
nose/pharynx
Central Airways
tracheo-bronchial
Peripheral Airways
alveoli (pulmonary)
Airway Pulmonary Function
-Gas exchange -Air conditioning -Defense
Gas exchange
-alveolar surface optimized for gas exchange -short transit distance -large surface area
Air conditioning
-inhaled gas prepared for internal environment -large airway surface area + rich blood supply–>very effective at increasing air temp/humidity 73deg/43% –> 90deg/98% humid
Defense
a. filtration: nose hairs filter out large particles b. mucociliary escalator: trachea down to bronchioles, particles trapped in mucus removed from airways by coordinated ciliary beating toward pharynx c. nerves/reflexes: modulate airway smooth muscle tone, mucus secretion, ciliary beat frequency (mucosal thickness), influcences rate and depth by afferent and efferent nerves
Spirometry
clinical measurement of pulmonary function -measures lung volumes and capacities
total lung capacity
volume of air in lungs at full inspiration
residual volume
volume of air remaining in lungs after maximal expiration
What would you predict to happen to residual volume in a pt experiencing severe bronchoconstriction?
bronchoconstriction in central airways will cause decreased airflow making it harder for air to get into peripheral airways, and exhalation will be harder too, causing an increase in residual volume b/c of gas trapping in lungs
Forced Expiratory Flow Measurements
-FEV-1: forced expiratory volume in 1 second -FVC: forced vital capacity
FEV-1
forced expiratory volume in one second -% predicted FEV-1 = FEV-1 normalized to age, gender, and body weight -estimate of severity of airway obstruction
FEV-1/FVC
useful measure of pulmonary function -estimate of airway obstruction that may not be fully reversible (especially when measured after a bronchodilator)
GOLD classification of COPD
-Mild: FEV-1/FVC 80% -Severe: FEV-1/FVC <30%
Peak Flow Measurements
-simplest measure of expiratory flow -may be used for self-eval and documentation of lung ventilatory function –>patient inhales completely to TLC and then exhales rapidly and completely into a peak flowmeter–> measures maximal (peak) flow rate of expiration
What would you expect to happen to peak expiratory flow rate of a pt experiencing bronchoconstriction?
Flow will decrease! Patients can have airflow obstruction and not realize it, so peak flow meter is good for monitoring peak flow and whether airways are opening up or not
Airway defenses
- Mucociliary clearance
- Ventilatory responses
Mucociliary clearance
- mucus + ciliated epithelium
- traps and removes inhaled material
Ventilatory Responses
- change in rate
- change in depth
- decreased lung penetration
- facilitates mucus removal (reflex parasympathetic nerve activation)
Airway Mucus
- secreted from mucosal and submucosal glands
- influenced by neural and inflammatory mediators
- gel-like material
~water (90-95%), proteins, phospholipids, mucins (elongated glycoproteins)
-nature of the mucus influences treatments (result of different mucins)
Mucins
multiple different mucins
- impart different physical properties to mucus
- proportions change in disease (normal, asthma, COPD, CF)
Interactions between Mucin molecules include:
- covalent
- ionic bonds
- hydrogen bonds
- van der Waals forces
- intermingling
- interaction w/ other molecules in mucus, e.g. DNA, F-actin
Airway mucus function
- serves hygienic function
- traps inhaled material deposited on central airway lumen
- cleared from airways by mucociliary escalatory and coughing
Mucus clearance from airways affected by its:
- viscoelasticity (thickness)
- tenacity/adhesiveness
Mucociliary Clearance
- mucus moved from airways towards pharynx by coordinated beating of cilia on epithelial cells
- mucus floats on a sol layer
Clearance affected by:
a. Mucus Viscosity: water content, mucus constituents, extent of cross-linking, pH/ion content
b. Mucus Volume: water content, gland function
c. Ciliary Beat Frequency: inflammatory mediators, nerves
What could an atropine-like drug do to mucociliary clearance?
Atropine blocks PNS so it would decrease mucociliary clearance, can lead to obstructive and bacterial proliferation and possibly infection
Cough
defensive reflex that clears larynx through main bronchi of:
-mucus, foreign particles, infectious organisms
Cough caused by:
-viral infections, asthma, heart failure, drugs, postnasal drip, bronchitis, pneumonia, allergy, lung cancer, foreign particles
Cough Reflex
cerebral cortex–>cough center-> cough receptor or ventilatory muscles
Cough Receptors and Stimuli
irritant: change in pH, change in tonicity irritant, cig smoke, mechanical stimulation, pulmonary congestion
C-fiber: bradykinin, capsaicin
stretch: mechanical stimulation
ventilatory muscles
intercostals, diaphragm, abs, laryngeal muscles
Uncontrolled, unproductive cough can cause:
-prevents sleeps, rib fractures, syncope, fatigue, pneumothorax, rupture of surgical wounds, muscle pain, urinary incontinence
Disease: change in cough sensitivity
increased coughing to normal stimulus
a. Peripheral Sensitization: increase cough RECEPTOR sensitivity
b. Central Sensitization: change in cough CENTER sensitivity
Mucus and Airway Disease
disease–> decreased mucus clearance by :
- increased volume of mucus secreted
- increased viscosity, harder to clear
- increased tenacity, stickier mucus
Decreased mucus clearance can result in mucus accumulating in the airways. What problems could this cause?
can cause airway obstruction, bacterial proliferation, and infection
Drugs used to treat airways disease target:
A.) Mucus Viscosity (mucolytic) B.) Mucus Hydration (expectorant) C.) Cough (antitussive) D.) Airway Smooth Muscle (Bronchodilator) E.) Inflammation (anti-inflammatory) F.) Neural Mechanisms (anticholinergic) G.) Upper Airway Congestion (vasoconstrictor) H.) Infection (antibiotic)
Mucolytics
mucus removal facilitated by decreased mucus viscosity by:
a. decreased mucin molecule cross-linking
b. degrading DNA or proteins
Mucolytics
- N-acetylcysteine
- Dornase Alpha
N-acetylcysteine
contains a free thiol group
- reduces disulfide bonds (decrease mucin molecule crosslinking) in mucus to make mucus runny and more liquidy (decreased mucin molecule crosslinking)
- SE: bronchospasm, inactivates some antibiotics like PCNs, poor efficacy, unpleasant smell
N-acetylcysteine is contraindicated in patients with advanced chronic bronchitis b/c their mucus is already fairly liquid. Why?
N-acetylcysteine will only make mucus more liquidy and runny, which will only make it harder for mucociliary escalator to clear the mucus, NOT beneficial!
Degrade DNA or proteins
- purulent mucus can contain DNA or F-actin, which increases mucus viscosity
- if you degrade DNA or F-action, it will cause decreased mucus viscosity
Neutrophil myeloperoxidase gives airway secretions a green color (=mucopurulent) why?
excessive infection turns secretions dark yellow, green or brown (=purulent)
Dornase Alpha
degrades DNA/proteins!
- recombinant human DNase
- hydrolyzes extracellular DNA
–DNA detaches from mucus proteins
–proteins broken down by endogenous proteolytic enzymes
–DECREASED mucus viscosity (less thick)
–INCREASED mucus clearance
Dornase Alpha SE/Considerations
- upper airway irritation
- increased antibiotic effects
- does not affect DNA in living cells!
- administered by inhalation (nebulizers used with dornase alpha so correct particle size)
Expectorants
- mucus removal facilitated by increased water in mucus, leads to increased mucus volume (easier to cough up)
- Promoted by: osmotic stimuli, ion channel inhibition
Expectorants
- Hypertonic saline and Mannitol
- Guafenesin
Hypertonic saline, Mannitol
- osmotic stimuli
- promotes fluid flow from epithelium into mucus
- SE/Considerations: administered by inhalation, hypertonic saline may also break ionic bonds between mucin molecules, bronchoconstriction
Guaifenesin
- irritates gastric mucosa
- increased respiratory secretions, decreased mucus viscosity (easier to cough up and clear)
- SE/considerations: N/V/D/HA
Antitussives
can be:
- centrally-acting
- peripherally-acting
Centrally-acting Antitussives
- Codeine & Hydrocodone
- Dextromethorphan
- Levopropoxyphene napsylate
Peripherally-acting antitussives
- benzonatate
- menthol
Centrally-Acting Agents
Act in the cough center in the CNS
- INCREASE cough threshold
- depression of cough reflex
Codeine, Hydrocodone
central-acting
- act on mu-receptors in the CNS
- may also act on sensory nerve ending
- act at doses below those required for analgesia (not the same receptor)
- SE/considerations: N/V/C, dizziness, mental clouding, ABUSE POTENTIAL***!
Dextromethorphan
- opiate derivative, central acting
- D-isomer of levorphanol (codeine analog)
- NO analgesia or addictive properites
- potency= about that of codeine
Levopropoxyphene Napsylate
- opiate derivative, central acting
- L-isomer of dextropropoxyphene
Dextromethorphan/Levopropoxyphene Napsylate SE/Considerations
-drowsiness, sedation, GI upset
Peripherally-acting agents
-decrease sensitivity of cough receptors to stimulation -depression of cough reflex
Benzonatate
- peripherally-acting antitussive
- inhibits pulmonary stretch receptors
Menthol
- peripherally-acting antitussive
- local anesthetic effect on sensory nerves
Bronchodilators
Reverse bronchoconstriction acutely by:
A. Direct relaxation of airway smooth muscle (B2-agonist)
B. Amplification of Relaxation Pathways (Methylxanthines)
C. Inhibition of bronchoconstrictor Stimuli (Muscarinic cholinoreptor antagonists)
B-2 Adrenoceptor Agonists
- RELAX AIRWAY SMOOTH MUSCLE
- inhibit mediator release
- facilitate mucociliary transport (increase ciliary function to clear mucus)
SABA B2-Agonists
SHORT-acting -albuterol -levalbuterol -metaproterenol -pirbuterol -terbutaline
LABA B2-Agonists
LONG-acting (12-18 hrs, BID)
- formoterol
- salmeterol
Ultra-LABA B2-Agonists
Ultra long-acting, once daily
-Indacaterol
Non-selective B2-Agonists
- Epinephrine
- Isoproterenol
B2-Agonists SE/Considerations
- tachycardia
- skeletal muscle tremor (B2): tolerance develops -anxiety/nervousness
- oral,syrup: when pt cannot inhale, but has more side effects
- aerosols (MDIs): rapid onset
- LABAs are not usually used as sole therapy
Methylxanthines
[amplification of relaxation pathways]
- Theophylline
- Aminophylline
Theophylline/Aminophylline act to:
act to: -relax airway smooth muscle by:
1) inhibition of phosphodiesterase type 3 or 4 (increase cAMP)
2) inhibition of adenosine receptors to decrease airway smooth muscle contraction, decrease mast cell degranulation
Theophylline/Aminophylline act to: (con’t)
- improve respiratory muscle performace (i.e. fatigued ventilator muscles)
- facilitate mucociliary transport
- inhibit mediator release (less inflamm. mediators)
Theophylline/Aminophylline SE/considerations
- GI: N/V
- CV: Tachycardia, dysrhythmias
- CNS Stimulation: insomnia, restlessness, alertness (like caffeine), behavioral changes in children, learning impairment, seizures
- Low therapeutic index for theophylline: toxic effects: >30ug/mL **MONITOR serum theophylline levels!
- look @ interacting drugs and conditions
- PK Interactions: hepatic clearance, elimination rate
Muscarinic Antagonists
Ipratopium Bromide
Tiotropium (M1/M3 selective)
Aclidinium (Ultra-long-acting, LAMA)
Muscarinic Antagonists MOA
- act to relax airway smooth muscle by inhibiting parasympathetic bronchoconstriction
- reverses reflex bronchoconstriction
- prevents contracting airway smooth muscle (ACh from PNS)
Muscarinic Antagonists SE/Considerations
- inhalation
- few side effects
- cough
- dry mouth (atropine-like SE, no pee, no see, no spit, no shit)
- worsening of urinary retention and narrow-angle glaucoma (mydriatic agents that dilate pupils make NAG worse)
Anti-inflammatory Agents (prophylactic usually)
- inhibit release and/or synthesis of proinflammatory mediators from mast cells and leukocytes (decreases bronchoconstriction, decreases mucus formation, decreases mucosal edema)
- prevents migration/activation of inflammatory cells (decreases release of inflammatory mediators and cytokines)
- decreases airway hyperreactivity in asthma (decreases inflammation and decreases airway reactivity which is a hallmark of asthma)
Corticosteroids
- Beclomethasone
- Budesonide
- Ciclesonide
- Flunisolide
- Fluticasone
- Mometasone
- Prednisolone
- Triamcinolone Acetanide
Corticosteroids MOA
~Regulate gene transcription to increase anti-inflammatory proteins
~GC-R transrepresses NFkB and AP-1: decreases pro-inflammaotry proteins, decreases inflammatory cytokines and chemokines
~Decreases airway inflammation and decreases # and activation of inflammatory cells in airways
Corticosteroids SE/Consid for Systemic Admin:
- peptic ulcer, Cushings syndrome, fluid retention, decreased linear growth in children**, osteoporosis, cataracts
- HAP axis suppression: inhibits body’s ability to release natural steroids
Corticosteroids SE/Consid. for Inhalation:
- less side effects than systemic
- oral candidiasis, hoarseness (prevented by rinsing mouth and throat or use of a space device)
Mast Cell Stabilizers
- Cromolyn Sodium
- Nedocromil Sodium
Mast Cell Stabilizers MOA
act to: -stabilize mast cells–> DECREASE mediator release
- decrease activation of EOSINOPHILS, neutrophils, and monocytes
- decrease sensory nerve activation (sensory nerves hypersensitive in asthma)
Cromolyn/Nedocromil Sodium Indications
useful in asthmatic children NOTE: NOT effective in everyone
Cromolyn/Nedocromil Sodium SE/Considerations
- coughing/irritation
- unpleasant taste (nedocromil)
- Slow onset of action (4-6wks)
- Inhalation administration
- Used prophylactically
Phosphodiesterase Inhibitors
Roflumilast
Roflumilast
phosphodiesterase inhibitor
-inhibits phosphodiesterase 4 to increase intracellular cAMP
–causes decreased inflammatory mediator release from mast cells and inflammatory cells
–decreased bronchoconstriction (like theophylline)
Roflumilast SE/Considerations
- weight loss
- N/D, dyspepsia
- psychiatric issues (depression, anxiety, insomnia)
- interacts w/ CYP3A4–> drug interactions w/ other CYP3A4-metabolized drugs
Leukotriene Receptor Antagonists/5-Lipoxygenase Inhibitors
- Zafirlukast & Montelukast: leukotriene C4/D4 receptor antagonists
- Zileuton: blocks 5-lipoxygenase
Zafirlukast, Montelukast, Zileuton
- acts to inhibit leukotriene C4/D4 receptors or leukotriene synthesis
- decreased bronchoconstriction, decreased edema, decreased airway hyperreactivity
Zafirlukast, Monetlukast, Zileuton SE/Considerations
- Zafirlukast: HA, Nausea, hepatotoxicity
- Montelukast: HA (less monitoring)
- Zileuton: HA, nausea, dyspepsia, hepatotoxicity
ALL: neuropsychiatric issues (agitation, aggression, hallucinations, depression, insomnia, suicidal thoughts)
Zafirlukast
-99% protein bound (be aware of PK interactions) -metabolized by CYP450 enzymes —>potential for PK interaction
Zileuton
- microsomal CYP3A4 inhibitor (potential for interactions) -
- >inhibits metabolism of warfarin and theophylline
- contraindication in acute liver disease
IgE Binding Antibodies
Omalizumab
Omalizumab
IgE binding antibodies
- humanized murine mAb
- acts by binding to the Fc epsilon R-1 portion of circulating IgE antibodies
- binds to antibody and prevents antibody from binding to mast cell, thus mast cell cannot respond to antigen and release inflammatory mediators (inhibits degranulation)
Omalizumab SE/Consid.
- used prophylactically
- SQ admin–>pain/bruising at injection sites
- anaphylaxis (2%)
- injected Q 2-4wks
