R ESPIRATORY P HARMACOLOGY W EEK 5 A NTICHOLINERGICS AND M UCOLYTICS

A NTICHOLINERGIC A GENTS Only effective if bronchoconstriction exists due to cholinergic activity USED FOR COPD PATIENTS only May also be used for asthmatics during an attack

A NTICHOLINERGIC A GENTS In combination with beta-agonist in patients with COPD on regular treatment regimen who require additional bronchodilation If you give Spiriva, you DO NOT also give Atrovent. Spiriva given QD Kp672Y Kp672Y

A NTICHOLINERGIC A GENTS Adverse effects Dry mouth Cough EXTREMENLY RARE SYSTEMIC SIDE EFFECTS AS IT DOES NOT CROSS BLOOD BRAIN BARRIER Nervousness Headache, dizziness

A NTICHOLINERGIC A GENTS Adverse effects Pharyngitis Dyspnea

A TROVENT “Back door bronchodilator” that is used in conjunction with a front door bronchodilator such as Albuterol or Xopenex. It works by opening up the air passages in your lungs by preventing cholinergic responses. It is not to be used alone for treating an acute attack of breathing problems, as it takes some time to work and is usually given as a maintenance drug that excels the use of Albuterol or Xopenex for people with COPD. Ipratropium is only for inhalation by mouth through an inhaler device or for inhalation by a nebulizer.

A TROVENT Generic Name: Iprtropium Bromide Trade Name: Atrovent Classification: Anticholinergic agent How it works: It relaxes airway muscles by impacting neurotransmitters sent to the autonomic nervous system, a process different than how beta-agonist drugs act. Sometimes given in addition to shorter-acting bronchodilator therapy, if the shorter- acting meds are not doing enough. Tends to have longer-lasting effect than beta-agonist drugs. Delivery Device: As an aerosol used in a nebulizer or as a DPI as SPIRIVA ® HandiHaler ® (tiotropium bromide inhalation powder) Doses: Unit dose is 0.5 mg or 0.02%, usually mixed with Albuterol or Xopenex. Side Effects : Fever, infection, headache, skin rash or hives, swelling of lips, tongue or face, vomiting, cough, blurred vision, dry mouth Contraindications/Percautions- If the following exist take precaution when initiating treatment :

C OMBO D RUGS Albuterol and Atrovent DuoNeb (Nebulizer solution) Combivent (MDI)

A NTICHOLINERGIC A GENTS Ipratropium bromide AtroventMDI: 17 µg/puff, 2 puffs four times daily SVN: 0.02% solution, 0.5 mg, three to four times daily Nasal Spray: 0.03%, 0.06% solution, 2 sprays per nostril, 2 to 4 times daily Onset: 15 minutes Peak: 1 – 2 hours Duration: 4 – 6 hours Ipratropium bromide and Albuterol Combivent DuoNeb MDI: Ipratropium 18µg/puff, Albuterol 90 µg/puff, 2 puffs four times daily SVN: Ipratropium 0.5 mg and Albuterol 2.5 mg. Onset: 15 minutes Peak: 1 – 2 hours Duration: 4 – 6 hours Tiotropium bromide Given with handi haler SpirivaDPI: 18 µg/inhalation, 1 inhalation daily Onset: 30 minutes Peak: 3 hours Duration: 24 hours

M UCUS CONTROLLING DRUGS The general term for medications that are meant to affect mucus properties and promote secretion clearance is “mucoactive.” These include expectorants, mucolytics, mucoregulatory, mucospissic, and mucokinetic drugs Mucoactive medications are intended either to increase the ability to expectorate sputum or to decrease mucus hypersecretion

E XPECTORANTS Expectorants are defined as medications that improve the ability to expectorate purulent secretions. Medications that increase airway water or the volume of airway secretions, including secretagogues that are meant to increase the hydration of luminal secretions (eg, hypertonic saline or mannitol) and abhesives that decrease the adhesivity of secretions and thus unstick them from the airway (eg, surfactants).

M UCOLYSIS 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

M UCOLYSIS These diseases result in a marked slowing of mucus transport Changes in properties of the mucus Decreased ciliary activity Both medical-atlas/237/mucolytics medical-atlas/237/mucolytics

M UCOLYTICS Acetylcysteine sodium bicarbonate (NaHCO 3 ) Dornase alfa Pulmozyme

A IRWAY A NATOMY

M UCUS L AYER 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

M UCUS L AYER 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

M UCUS VS. S PUTUM 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).

M UCOCILIARY E SCALATOR 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

F UNCTION OF M UCOCILIARY E SCALATOR 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.

S TRUCTURE AND C OMPOSITION OF M UCUS 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

S TRUCTURE AND C OMPOSITION OF M UCUS 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

M UCUS P RODUCTION 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

I NCREASED M UCUS P RODUCTION Smoking Environmental irritants Allergy Infections Genetic predisposition Foreign bodies

I NCREASED M UCUS P RODUCTION   Viscosity of mucus   Ciliary effectiveness   Mucus plugs   Airway Resistance   Infections  Obstructed bronchioles leads to atelectasis

D ISEASES THAT I NCREASE M UCUS P RODUCTION Chronic Bronchitis Asthma Cystic Fibrosis Acute Bronchitis Pneumonia Also some drugs (anticholinergics, antimuscarinics)

F ACTORS THAT I MPAIR C ILIARY A CTIVITY Endotracheal tubes Temperature extremes High F i O 2 levels Dust, Fumes, Smoke Dehydration Thick Mucus Infections

F ACILITATION OF M UCUS C LEARANCE Provide adequate hydration Increase fluid intake orally or IV Remove causative factors Smoking, pollution, allergens Optimize tracheobronchial clearance Use Mucolytics Reduce Inflammation

D AIRY I NTAKE 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

S ECRETION M ANAGEMENT Increase the depth of the sol layer Water Saline Expectorants Alter the consistency of the gel layer Mucolytics Improve ciliary activity Sympathomimetic bronchodilators Corticosteroids

B LAND A EROSOLS “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

E XPECTORANTS Iodides Unclear function SSKI (Saturated Solution of Potassium Iodide) Guifenesin At high doses, stimulates bronchial gland secretion Robitussin Not typically given by RTs

C OUGH S UPPRESSANTS 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) Nebulized Xylocain Caution in patients with thick secretions.

F UNCTION OF M UCOLYTICS 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

F UNCTION OF M UCOLYTICS Disruption of Disulfide Bonds acetylcysteine breaks the bonds by substituting a sulfhydril radical –HS

F UNCTION OF M UCOLYTICS Alteration of pH Sodium Bicarbonate 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)

F UNCTION OF M UCOLYTICS Proteolysis Dornase alfa (Pulmozyme) Attacks the protein component of the mucus

H AZARD OF M UCOLYTICS 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.

M UCOMYST Draw up with a syringe and instill into nebulizer

A CETYLCYSTEINE Indicated for treatment of accumulated airway secretions Chronic obstructive pulmonary disease Bronchiectasis Acute tracheobronchitis

A CETYLCYSTEINE Used to treat or prevent liver damage in acetaminophen overdose (patient drinks it) Reduces viscosity of mucus by substituting sulfhydryl group for disulfide group

A CETYLCYSTEINE May be directly instilled during bronchoscopy to remove mucus plugs Normal dosage via SVN: 3 – 5 ml

A CETYLCYSTEINE Side effects Airway obstruction secondary to rapid liquefaction of secretions Disagreeable odor (rotten eggs) Nausea Rhinorrhea Bronchospasm

A CETYLCYSTEINE Discard 96 hours after opening, usually refrigerated Should not be administered in the presence of thin secretions ALWAYS GIVE WITH A BRONCHODILATOR

D OSAGE 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

H AZARDS 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.

H AZARDS 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 – P ULMOZYME 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.

I NFECTION 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

F UNCTION OF RH DN ASE

C OMMON S IDE E FFECT OF P ULMOZYME Voice Alteration Pharyngitis/Laryngitis Rash Chest pain Conjunctivitis Contraindicated in patients hypersensitive to Chinese Hamster Ovary cell products.

C ONCENTRATION AND D OSAGE 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).

M UCUS -C ONTROLLING A GENTS Dornase alfa (Pulmozyne) Indicated for the treatment of cystic fibrosis (CF) to reduce number of infections and improve pulmonary function Breaks down DNA material from neutrophils found in purulent secretions Normal dosage via SVN: 2.5 mg/ampule, 1 ampule daily

D ORNASE A LFA Side effects (does not cause bronchospasm) Pharyngitis Laryngitis Chest pain

S ODIUM B ICARBONATE Not commonly used, but changes the pH of mucus. Aerosolized a. Action: Adjusts the pH of mucus, decreasing the surface tension to facilitate mucolytic action. b. Indication: tracheal irrigation c. Dosage: - irrigation: 2-5 ml of 2-8.4% NaHC03 in 2-5 ml NS d. Precaution: mucosal irritation

E THYL A LCOHOL Ethyl Alcohol 30-50% (Ethanol) a. Indication: - pulmonary edema (OLD treatment) Defoaminant b. Precautions: - mucosal irritation - intoxication - vasodilation

A QUEOUS A EROSOLS ( BLAND AEROSOLS, NON MEDICATED ) Indications Thin secretions Used as diluent for medications May be used to induce sputum (hypertonic saline); >0.9% saline. Normal saline is 0.9% and has no effect in the airway, used a diluent to most medications

A QUEOUS A EROSOLS Distilled water Osmolarity – hypotonic Will be absorbed into interstitial space May cause or contribute to edema Hypotonic rarely given, if it is given, use a ultra sonic nebulizer

A QUEOUS A EROSOLS Isotonic saline (0.9%) Osmolarity – equal to lung tissue Also known as normal saline Used as diluent for medication

A QUEOUS A EROSOLS Hypotonic saline (<0.9%, commonly 0.45% or half normal) Osmolarity – less than that of lung Used in ultrasonic nebulizers – due to evaporation, solution will become isotonic by the time it reaches the airway Can increase resistance due to swelling of secretions

A QUEOUS A EROSOLS Hypertonic saline (>0.9%) Osmolarity – greater than that of lung tissue Used for sputum induction

A QUEOUS A EROSOLS Hypertonic saline (>0.9%) Draws fluid from interstitial space to mucus bed, thinning secretions May cause bronchospasm, especially in hyperactive airways