Mucolytics

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Mucolytics

• Module E

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Mucolysis

• Mucolysis is the breakdown of mucus.
• Mucolysis is needed in diseases in which there is
  increased mucus production
• Cystic Fibrosis
• COPD
• Bronchiectasis
• Respiratory Infections
• Turberculosis

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Mucolysis

• These diseases result in a marked slowing of
  mucus transport
• Changes in properties of the mucus
• Decreased ciliary activity
• Both

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Mucolytics

• acetylcysteine
• sodium bicarbonate (NaHCO3)
• dornase alfa
• Pulmozyme

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Airway Anatomy
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Mucus Layer

• Gel (1 to 2 mm) Gelatinous and sticky (flypaper)
• Sol (4 to 8 mm) Watery, Cilia in this layer
• Total layer thickness 5 to 10 mm thick
• Surface Epithelial Cells
• Pseudostratified ciliated columnar
• Surface goblet cells (6,800/mm2)
• Serous cells Sol layer
• Clara cells Unknown function (enzymes?)
• Submucosal Gland
• Bronchial Gland

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Mucus Layer

• Bronchial Gland
• Found in submucosa
• Found down to terminal bronchioles
• Parasympathetic control (Vagus nerve)
• Provide the majority of mucus secretion
• Total volume 40 times greater than goblet cells

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Mucus vs. Sputum

• Mucus is the total secretion from mucous
  membranes including the surface goblet cell and
  the bronchial glands.
• Sputum is the expectorated secretions that
  contains mucus, as well as oropharyngeal and
  nasopharyngeal secretions (saliva).

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Mucociliary Escalator

• Mucosal Blanket
• Sol layer
• Gel layer
• Cilia
• 200 per cell
• 6 mm in length
• Beat 1000/min
• Move mucus 2 cm/min
• Paralyzed by cigarette smoke

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Viscosity and Elasticity

• Rheology
• Viscosity Property of a liquid that measures the
  resistance to movement when a force is applied.
• Increased viscosity, increased resistance to flow
  
• Olive oil vs. Water
• Elasticity Property of solid whereby a solid
  changes shape (deforms) when a force is applied.
• Ideally, a solid is totally elastic, and returns
  to its original shape when force is released.
• The mucus layer is ideally very elastic and has a
  very low viscosity.

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Function of Mucociliary Escalator

• Protective function
• Remove trapped or inhaled particles and dead or
  aging cells.
• Antimicrobial (enzymes in sol/gel)
• Humidification
• Insulation (prevents heat and moisture loss)
• NOTE No cilia or mucus in lower airways
  (respiratory bronchioles on down)
• Mucus also protects the epithelium from toxic
  materials.

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Structure and Composition of Mucus

• Composition
• 95 water
• Need for water intake to replenish
• Mucus doesnt easily absorb water once created
• 3 protein and carbohydrates
• 1 lipids
• Less than 0.3 DNA

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Structure and Composition of Mucus

• Glycoprotein
• Large (macro)molecules
• Strands of polypeptides (protein) that make up
  the backbone of the molecule
• String of amino acids
• Carbohydrate side chains
• Chemical bonds hold mucus together
• Intramolecular Dipeptide links
• Connect amino acids
• Intermolecular Disulfide and Hydrogen bonds
• Connect adjacent macromolecules

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Mucus Production

• Normal person produces 100 mL of mucus per 24
  hour period
• Most is reabsorbed back in the bronchial
  mucosa
• 10 mL reaches the glottis
• Most of this is swallowed
• Mucus production increases with lung disease

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Increased Mucus Production

• Smoking
• Environmental irritants
• Allergy
• Infections
• Genetic predisposition
• Foreign bodies

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Increased Mucus Production

• Viscosity of mucus
• Ciliary effectiveness
• Mucus plugs
• Airway Resistance
• Infections
• Obstructed bronchioles leads to atelectasis

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Diseases that Increase Mucus Production

• Chronic Bronchitis
• Asthma
• Cystic Fibrosis
• Acute Bronchitis
• Pneumonia
• Also some drugs (anticholinergics,
  antimuscarinics)

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Factors that Impair Ciliary Activity

• Endotracheal tubes
• Temperature extremes
• High FiO2 levels
• Dust, Fumes, Smoke
• Dehydration
• Thick Mucus
• Infections

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Facilitation of Mucus Clearance

• Provide adequate hydration
• Increase fluid intake orally or IV
• Remove causative factors
• Smoking, pollution, allergens
• Optimize tracheobronchial clearance
• Use Mucolytics
• Reduce Inflammation

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Dairy Intake

• No evidence to support the common belief that
  drinking milk increases the production of mucus
  or phlegm and congestion in the respiratory tract
• There is a loose cough associated with milk intake

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Secretion Management

• Increase the depth of the sol layer
• Water
• Saline
• Expectorants
• Alter the consistency of the gel layer
• Mucolytics
• Improve ciliary activity
• Sympathomimetic bronchodilators
• Corticosteroids

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Bland Aerosols

• Dilutes mucus molecule
• Also known as wetting agents
• Function may be more of an irritant than a wetter
• Types
• Sterile Distilled Water
• Humectant
• Dense aerosols and asthmatics
• Normal (isotonic) Saline
• Hypertonic Saline
• Increase mucus production
• Hypotonic Saline

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Expectorants

• Iodides
• Unclear function
• SSKI (Saturated Solution of Potassium Iodide)
• Guifenesin
• At high doses, stimulates bronchial gland
  secretion
• Robitussin

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Cough Suppressants

• Vagal stimulation causes a cough.
• Irritation of pharynx, larynx, and bronchi lead
  to a reflex cough impulse.
• If the cough is dry and non-productive, it may be
  desirable to suppress its activity.
• Cough suppressants depress the cough center in
  medulla (?).
• Narcotic preparations (codeine)
• Non-Narcotic preparations (dextromethorphan)
• Caution in patients with thick secretions.

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Function of Mucolytics

• Weakening of intermolecular forces binding
  adjacent glycoprotein chains
• Disruption of Disulfide Bonds
• Alteration of pH to weaken sugar side chains of
  glycoproteins
• Destruction of protein (Proteolysis) contained in
  the glycoprotein core of proteolytic enzymes
• Breaking down of DNA in mucus

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Function of Mucolytics

• Disruption of Disulfide Bonds
• acetylcysteine breaks the bonds by substituting a
  sulfhydril radical HS

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Function of Mucolytics

• Alteration of pH
• 2 NaHCO3 solutions are used to increase the pH
  of mucus by weakening carbohydrate side chains
• Can be injected directly into the trachea or
• aerosolized (2-5 mL)

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Function of Mucolytics

• Proteolysis
• Dornase alfa (Pulmozyme)
• Attacks the protein component of the mucus

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Hazard of Mucolytics

• The problem with all three mucolytics is that
  they destroy the elasticity of mucus while
  reducing the viscosity.
• Elasticity is crucial for mucociliary transport.
• The patient must be able to cough adequately to
  remove the mucus.

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acetylcysteine

• Indications
• Mucolytic by aerosol or direct instillation into
  the ET tube.
• Given orally to reduce liver injury with
  acetaminophen (Tylenol) overdose.
• Mix with cola or given by NG tube.

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Dosage of acetylcysteine

• Concentration
• 10 or 20
• Dosage
• 3-5 mL of a 20 solution TID or QID
• Maximum dose 10 mL
• 6-10 mL of a 10 solution TID or QID
• Maximum dose 20 mL
• 1-2 mL of a 10 or 20 for direct instillation

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Hazards of acetylcysteine

• Bronchospasm
• Asthma may be a problem during an acute asthma
  attack.
• Anecdotal lack of evidence
• If used with asthma, use 10 and mix with a
  bronchodilator (preferably a short-acting agent).
• Increase mucus production
• Be prepared to suction a patient who cannot cough
  or who is intubated.

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Hazards of acetylcysteine

• Do not mix with antibiotics in the same nebulizer
  (incompatible).
• Nausea Vomiting
• Disagreeable odor (smells like rotten eggs) due
  to the hydrogen sulfide.
• Open vials should be used within 96 hours to
  prevent contamination.

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sodium bicarbonate

• Weak base.
• Increasing the pH of mucus weakens the
  polysaccharide chains.
• Available as 1.4, 5, and 7.5 solutions.
• Dosage 2-5 mL of a 2.5 solution Q4-Q8.
• Mix 5 solution with equal volume of sterile
  water.
• Can be irritating (especially the 5 7.5
  solutions).

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dornase alfa

• Pulmozyme
• Clone of the natural human pancreatic DNase
  enzyme which digests extracellular DNA.
• Dornase alfa is a solution of recombinant human
  deoxyribonuclease (rhDNase)
• Approved by FDA in 1994

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dornase alfa Pulmozyme

• Indications
• Reduce viscosity of secretions during an
  infection by breaking down extracellular DNA.
• Used in cystic fibrosis, chronic bronchitis or
  bronchiectasis.
• Maintenance therapy in CF
• Has no effect on non-infected sputum.

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Infection

• Increased WBCs neutrophils
• WBCs contain DNA
• WBCs release DNA when they die which increases
  the viscosity of secretions
• Decreases the effectiveness of antibiotics
• Pancreas produces an enzyme called
  deoxyribonuclease (DNase) which breaks down the
  DNA

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Function of rhDNase
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Concentration and Dosage

• Supplied in single dose vials (unit dose).
• Concentration is 1 mg/mL (0.1 solution).
• Each vial contains 2.5 mg /2.5 mL.
• Administer one unit dose vial (2.5 mL) daily.
• Some patients may benefit from BID
  administration.
• Do not mix or dilute with other drugs.
• Nebulizer specific (per manufacturer).

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Common Side Effect of Pulmozyme

• Voice Alteration
• Pharyngitis/Laryngitis
• Rash
• Chest pain
• Conjunctivitis
• Contraindicated in patients hypersensitive to
  Chinese Hamster Ovary cell products.

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amiloride

• Midamor
• Diuretic that can be given by aerosol for
  patients with cystic fibrosis.
• It is a sodium channel blocker.
• In Cystic Fibrosis, Na is absorbed into the
  epithelium along with H2O, leaving the mucus
  thick and dehydrated.
• By blocking sodium absorption, dehydration of the
  mucus is prevented.
• Drug is dissolved in 0.3 NaCl solution and
  nebulized.
• Bronchial Asthma (?)

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amiloride
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denusfosol tetrasodium

• Experimental drug in CF research
• Phase II as of 8/07
• Enhances mucosal hydration and mucus clearance by
  activating Cl- secretion and inhibiting
  epithelial Na transport.
• 28 days of treatment