Respiratory Pharmacology

Question 1

Cough

Treatment

Answer 1

• Mainly treat underlying cause
• Productive cough should not be suppressed except in special circumstances and not until cause ID’d
  
  • Exhausts the patient
  • Prevents rest/sleep
  • Sputum needs to be cleared
• Cough medications are antitussives and expectorants

Question 2

Centrally-Acting

Antitussives

Answer 2

Act by suppressing medullary cough centers or associated higher centers.

• Non-narcotic
  
  • Dextromethorphan
  • Chlophedianol
  • Levopropoxyphene
  • Noscapine
• Narcotics
  
  • Codeine
  • Hydrocodone
  • Hydromorphone
  • Methadone
  • Morphine

Question 3

Dextromethorphan

Answer 3

• Centrally-acting antitussive
• Derivative of the narcotic levorphanol
• No significant analgesic or sedative properties
• Does not depress respiration in usual doses
  
  • Extremely high doses may depress respiration
• Non-addictive
• No tolerance

Question 4

Codeine

Answer 4

• Partial agonist of μ and δ-opiod receptors ⇒ narcotic
• Effects:
  
  • Centrally-acting antitussive
  • Analgesic
  • Slight sedative effects
• Especially useful in relieving painful cough
• Exerts a drying action on respiratory mucosa
  
  • Useful ⇒ bronchorrhea
  • Deleterious ⇒ when bronchial secretions already viscous
• Minimal respiratory depression @ dose for cough
• Risk for physical dependence and tolerance
• Potential for abuse low
• Side effects
  
  • Nausea/vomiting
  • Constipation

Question 5

Peripherally-acting

Antitussives

Answer 5

Act by reducing irritation.

Can act on afferent or efferent side of cough reflex:

• Afferent side
  
  • Mild local analgesic or anesthetic on respiratory mucosa ⇒ ↓ input of stimuli
  • Modify output and viscosity of respiratory tract fluid
  • Relax smooth muscle of bronchi in presence of bronchospasm
• Efferent side
  
  • ↑ Efficiency of cough mechanism ⇒ make secretions easier to cough up

Grouped as:

• Demulcents
• Local anesthetics
• Humidifying aerosols and steam inhalations

Question 6

Demulcents

Answer 6

• Forms protective coating over irritated pharyngeal mucosa
• Useful for coughs originating above the larynx
• Usually given as syrups or lozenges
• Includes:
  
  • Acacia
  • Licorice
  • Glycerine
  • Honey
  • Wild cherry syrups

Question 7

Local Anesthetics

Answer 7

• Used to inhibit cough reflex under special circumstances
• Includes:
  
  • Lidocaine
  • Benzocaine
  • Hexylcaine hydrochloride
  • Tetracaine

Question 8

Benzonatate

(Tessalon Perles)

Answer 8

• Local anesthetic
• Similar to tetracaine
• Antitussive effect may be due to a combo of:
  
  • Local anesthesia
  • Depression of pulmonary stretch receptors
  • Nonspecific central depression

Question 9

Humidifying Aerosols & Steam Inhalations

Answer 9

Acts as a demulcent and ↓ viscosity of bronchial secretions

• Inhaling water as aerosol or steam ± medication ⇒ most common method of humidification
• Efficacy of added medications not clearly proven

Question 10

Expectorants

Answer 10

• Help expel bronchial secretions from respiratory tract
  
  • ↓ Viscosity of mucus
  • ↑ Secretion of respiratory tract fluids ⇒ demulcent effect
• Most ↑ secretions via reflex irritation of bronchial mucosa
• Iodides also act directly on bronchial secretory cells
  
  • Excreted into respiratory tract
• Use is controversial ⇒ no data to prove it works
• Use/choice of expectorants based on tradition and widespread clinical impression of effectiveness
• Adequate hydration ⇒ most important measure to encourage expectoration

Question 11

Iodides

Answer 11

• Used to liquefy bronchial secretions
  
  • Late-stages of bronchitis, bronchiectasis, asthma
• ↑ Expectoration
  
  • Reflex irritation of bronchial mucosa
  • Act directly on bronchial secretory cells
• Potassium iodide ⇒ least expensive, most common
• Iodinated glycerol ⇒ better tolerated, less effective
• Usefulness limited d/t low pt tolerance
  
  • Unpleasant taste
  • Side effects
    
    • Acneiform skin eruptions
    • Coryza ⇒ catarrhal inflammation of the mucous membrane in the nose
    • Erythema of face and chest
    • Painful swelling of salivary glands
    • Hypothyroidism w/ prolonged use

Question 12

Guaifenesin

Answer 12

• Mostly commonly used expectorant in OTC cough meds
• No serious adverse effects
• No clear e/o efficacy

Question 13

Mucolytics

Answer 13

• Free -SH group that opens mucoprotein disulfide bonds
  
  • ↓ viscosity of mucus
• Limited use for conditions where mucous is extremely thick
  
  • CF and chronic bronchitis
• Acetylcysteine ⇒ 10-20% solution usually by neb or instillation
  
  • Also used in acetaminophen poisoning
• May aggrevate airway obstruction by causing bronchospasm
  
  • Treat with sympathomimetic bronchodilator or acetylcysteine/isoproterenol before

Question 14

Mucolytic Enzymes

Answer 14

• DNAses ⇒ breaks up DNA resulting from infections
• Useful only when grossly purulent sputum is a major problem
• No advantage over mucolytics
• Side effects
  
  • Local irritation of buccal and pharyngeal mucosa
  • Allergic reactions
• Includes
  
  • Pancreatic dornase
  • Dornase alfa
    
    • New highly purified recomb. human deoxyribonuclease I
      
      • Important in treating CF

Question 15

Decongestants

Overview

Answer 15

• All α-adrenergic agonists
• Vasoconstrict nasal blood vessels
  
  • ↓ Volume of nasal mucosa
  • Opens airways
• Can be used:
  
  • Topically ⇒ short-term relief
  • Systemically ⇒ long-term relief

Question 16

Short-Acting

Topical

Decongestants

Answer 16

• Delivered as nasal sprays
• Avoids systemic side effects e.g. HTN
• Most commonly used:
  
  • Phenylephrine (Neosynephrine)
  • Oxymetazoline (Afrin)
• Repeated use ⇒ down-regulation of receptors ⇒ rebound hyperemia in nasal blood vessels
  
  • Shouldn’t use for more than 2-3 days

Question 17

Long-Acting

Systemic

Decongestants

Answer 17

• Prolonged duration of action
• Increased potential for systemic side-effects
  
  • Caution in pts with HTN
  • Caution in pts taking MAO inhibitors
• Pseudoephedrine (Sudafed) ⇒ most commonly used
  
  • Precursor to meth ⇒ now BTC drug
• Phenylephrine (Sudafed PE) ⇒ OTC version
• Ephedrine & Phenylpropanolamine pulled from market

Question 18

Asthma

Pathophysiology

Answer 18

• Disorder of airway hyper-responsiveness
  
  • Bronchconstriction
  • Mucosal thickening from edema and cell infiltration
  • ↓ FEV₁
• Early stage
  
  • Mediated by IgE bound to airway mast cells
  • Release of mediators from mast cells
    
    • Histamine, LTC₄, LTD₄, prostaglandins
  • Results in bronchoconstriction and vascular leakage
• Late mediators ⇒ GM-CSF, Interleukins (IL-4, IL-5)
  
  • Attract/activate eosinophils
  • Stimulate IgE production
• Mediators also activate neural pathways ⇒ ACh by vagal efferents ⇒ bronchoconstriction

Question 19

Asthma

Therapeutic Approaches

Answer 19

• Prevent mast cell degranulation
• Reduce bronchial responsiveness
• Relax airway smooth muscle

Question 20

Cromolyn (Intal)

&

Nedocromil (Alocril)

Answer 20

• ⊗ Cl^- channels ⇒ ⊗ mast cell degranulation
• Only useful prophylactically
• Cannot reverse bronchospasm or ∆ bronchial tone
• Inhaled as microfine powder
  
  • No systemic effects
• More effective in children than adults
  
  • Does not work in ⅓ of children
  • Usually do 4 week trial
• Other uses:
  
  • Allergic rhinitis
  • Allergic conjunctivitis

Question 21

Sympathomimetic Agents

Answer 21

• β-adrenergic agonists
  
  • ↑ cAMP ⇒ bronchodilation
• β₂-selective preferred
  
  • No chronotropic or inotropic effects of β₁ activation
  • Non-selective agents like Epi, ephedrine, and isoproterenol are no longer used d/t side effects
• β₂-agonists delivered via MDI or nebulizer
  
  • Few systemic side effects

Question 22

Short-acting

β₂-Agonists

Answer 22

Effects last for 3-4 hours.

• Albuterol (Ventolin)
• Metaproterenol (Alupent)
• Terbutaline (Breathaire)
• Pirbuterol (Maxair)

Question 23

Long-acting

β₂-Agonists

Answer 23

Effects last 12 hours ⇒ prophylactic use

Formoterol (Foradil)

Salmeterol (serevent)

• Often used in combo w/ inhaled corticosteroids
• Due to rare exacerbation of asthma attacks, LABAs are not recommended as first line treatment.

Question 24

Theophylline

Answer 24

• Methylxantine PDE inhibitor
  
  • ↓ cAMP breakdown ⇒ ↑ MLCK inactivation ⇒ bronchodilation
• Taken PO ⇒ systemic side effects
  
  • CNS ⇒ nervousness and tremor
  • CV ⇒ ⊕ chronotropic and inotropic effects
  • GI ⇒ ↑ secretion of gastric acid and digestive enzymes
  • Renal ⇒ diuretic activity
• Low therapeutic index
• No longer a first-line therapy

Question 25

Muscarinic Antagonists

Answer 25

* **⊗ Effects of vagal-released Ach @ mAChR** * Atropine cannot be used d/t systemic effects * _Quaternary compounds_ ⇒ poorly absorbed when delivered via inhaler, avoid systemic effects * **Ipratropium bromide (Atrovent)** * Short-acting ⇒ lasts for several hours * Takes 45 mins to work ⇒ bridge with β₂ agonist * **Tiotropium (Spiriva) & Aclidinum (Tudorza)** * Longer-acting ⇒ lasts for 24 hours * Can be used prophylactically * **Rarely used in asthma, commmonly used for COPD**

Question 26

Corticosteroids Mechanism

Answer 26

**⊗ Cytokine production ⇒ anti-inflammatory action ⇒ ↓ airway responsiveness** Does not reverse bronchospasm

Question 27

Oral Corticosteroids

Answer 27

**Used for severe flare-ups** * Systemic effects e.g. **adrenal suppression** * Several days of treatment w/ taper to avoid rebound * Agents: * **Prednisone** * **Methylprednisolone**

Question 28

Inhaled Corticosteroids

Answer 28

**Prophylaxis in children and adults** * Agents: * **Beclomethasone (Beclovent, Vanceril)** * **Triamcinolone (Azmacort)** * **Fluticasone (Flovent)** * Avoids systemic effects * Children who use daily show 0.5" reduction in height as an adult * Most common side effect ⇒ **oropharyngeal candidiasis** * Often used in combo w/ LABA * **Fluticasone + salmeterol (Advair)**

Question 29

Leukotriene Pathway

Answer 29

* Synthesized from arachidonic acid by 5' lipoxygenase * Act via CysLT₁ receptor * **LTC₄ and LTD₄ invovled in asthma response** * Causes bronchoconstriction * Increases sensitivity to histamine

Question 30

Leukotriene Pathway Inhibitors

Answer 30

**Used prophylactically.** **Effective in blocking response to Ag challenge.** Only works in ⅓ of patients. No apparent side effects. * _5' lipooxygenase inhibitors_ * **Zileuton (Zyflow)** ⇒ PO * _CysLT₁R antagonists_ * **Montelukast (Singulair)** ⇒ PO * **Zafirlukast (Accolate)** ⇒ PO

Question 31

Asthma Antibody Treatments

Answer 31

Used when other agents don't work. * _Anti-IgE antibodies_ * **Omalizumab (Xolair)** * Binds to IgE receptor domain on IgE ⇒ prevents interaction with its receptor * Delivered SubQ every 2-4 weeks * _Anti-IL-5 antibiodies_ * **Mepolizumab (Mucala)** * Blocks IL-5 action * Used for eosinophilic asthma * Delivered SubQ every 4 weeks

Question 32

Asthma Management Summary

Answer 32

* Mild asthma w/ occasional sx ⇒ inhaled β₂ agonist PRN * Persistent asthma ⇒ ICS ± cromolyn prophylaxis * Severe asthma ⇒ ICS & salmeterol prophylactically * Severe, prolonged attacks ⇒ oral corticosteroids

Question 33

COPD Treatment Goals

Answer 33

**No drug can affect the natural progression of COPD.** _Treatment geared towards:_ Correction of symptoms Maintenance of lung function Improvement of quality of life

Question 34

COPD Management

Answer 34

* **Bronchodilators** ⇒ first-line therapy * _Mild cases_ * SABA (**albuterol**) + SAMA (**ipratropium**) * **Used PRN or before exercise** * _Severe cases_ * LABA ⇒ **Salmeterol** _or_ * LAMA ⇒ **tiotropium (Spiriva), umeclidinium (Incruse), aclidinium (Tudorza)** * **Theophylline** ⇒ use when LABA or LAMA ineffective, use decreasing * **Inhaled corticosteroids ± LABA/LAMA** * Can result in significant ↑ FEV₁ * Avoid chronic use of oral or systemic corticosteroids * Leukotriene pathway inhibitors not adequately tested in COPD ⇒ not currently recommended