Mucolytics Module E

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

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

Mucolytics acetylcysteine sodium bicarbonate (NaHCO 3 ) dornase alfa Pulmozyme

Airway Anatomy

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

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

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).

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

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.

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.

Structure and Composition of Mucus Composition 95% water Need for water intake to replenish Mucus doesn’t easily absorb water once created 3% protein and carbohydrates 1% lipids Less than 0.3% DNA

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

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

Increased Mucus Production Smoking Environmental irritants Allergy Infections Genetic predisposition Foreign bodies

Increased Mucus Production   Viscosity of mucus   Ciliary effectiveness   Mucus plugs   Airway Resistance   Infections  Obstructed bronchioles leads to atelectasis

Diseases that Increase Mucus Production Chronic Bronchitis Asthma Cystic Fibrosis Acute Bronchitis Pneumonia Also some drugs (anticholinergics, antimuscarinics)

Factors that Impair Ciliary Activity Endotracheal tubes Temperature extremes High F i O 2 levels Dust, Fumes, Smoke Dehydration Thick Mucus Infections

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

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

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

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

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

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.

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

Function of Mucolytics Disruption of Disulfide Bonds acetylcysteine breaks the bonds by substituting a sulfhydril radical –HS

Function of Mucolytics Alteration of pH 2% NaHCO 3 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)

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

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.

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.

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

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.

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.

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).

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

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.

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

Function of rhDNase

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).

Common Side Effect of Pulmozyme Voice Alteration Pharyngitis/Laryngitis Rash Chest pain Conjunctivitis Contraindicated in patients hypersensitive to Chinese Hamster Ovary cell products.

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 H 2 O, 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 (?)

amiloride

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