RESPIRATORY PHARMACOLOGYWEEK 5

ANTICHOLINERGICS AND MUCOLYTICS

ANTICHOLINERGIC AGENTS

Only effective if bronchoconstriction exists due to cholinergic activity

USED FOR COPD PATIENTS only

May also be used for asthmatics during an attack

ANTICHOLINERGIC AGENTS 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

http://www.youtube.com/watch?v=KYS3-Kp672Y

ANTICHOLINERGIC AGENTSAdverse effects

Dry mouth

Cough

EXTREMENLY RARE SYSTEMIC SIDE EFFECTS AS IT DOES NOT CROSS BLOOD BRAIN BARRIER

Nervousness

Headache, dizziness

ANTICHOLINERGIC AGENTS

Adverse effectsPharyngitis

Dyspnea

ATROVENT “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.

ATROVENT 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:

COMBO DRUGS Albuterol and Atrovent DuoNeb (Nebulizer solution) Combivent (MDI)

ANTICHOLINERGIC AGENTSIpratropium bromide

Atrovent MDI: 17 µg/puff, 2 puffs four times dailySVN: 0.02% solution, 0.5 mg, three to four times dailyNasal Spray: 0.03%, 0.06% solution, 2 sprays per nostril, 2 to 4 times daily

Onset: 15 minutesPeak: 1 – 2 hoursDuration: 4 – 6 hours

Ipratropium bromide and Albuterol

CombiventDuoNeb

MDI: Ipratropium 18µg/puff, Albuterol 90 µg/puff, 2 puffs four times dailySVN: Ipratropium 0.5 mg and Albuterol 2.5 mg.

Onset: 15 minutesPeak: 1 – 2 hoursDuration: 4 – 6 hours

Tiotropium bromide

Given with handi haler

Spiriva DPI: 18 µg/inhalation, 1 inhalation daily

Onset: 30 minutesPeak: 3 hoursDuration: 24 hours

MUCUS 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

EXPECTORANTS 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).

MUCOLYSIS

Mucolysis is the breakdown of mucus.Mucolysis is needed in diseases in

which there is increased mucus production:Cystic FibrosisCOPDBronchiectasisRespiratory Infections

Turberculosis

MUCOLYSIS These diseases result in a marked slowing of

mucus transport Changes in properties of the mucus Decreased ciliary activity Both

http://www.nebraskamed.com/health-library/3d-medical-atlas/237/mucolytics

MUCOLYTICS Acetylcysteine sodium bicarbonate (NaHCO3) Dornase alfa

Pulmozyme

AIRWAY ANATOMY

MUCUS LAYERGel (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 thickSurface Epithelial Cells

Pseudostratified ciliated columnarSurface goblet cells (6,800/mm2)Serous cells – Sol layerClara cells – Unknown function (enzymes?)

Submucosal GlandBronchial 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 mm in length Beat 1000/min Move mucus 2 cm/min Paralyzed by cigarette smoke

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 FiO2 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

Not typically given by RTs

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)Nebulized Xylocain

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 MUCOLYTICSDisruption of Disulfide Bonds

acetylcysteine breaks the bonds by substituting a sulfhydril radical –HS

FUNCTION OF MUCOLYTICS Alteration of pH

Sodium Bicarbonate 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)

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.

MUCOMYST Draw up with a syringe and instill into

nebulizer

ACETYLCYSTEINE Indicated for treatment of

accumulated airway secretionsChronic obstructive pulmonary disease

Bronchiectasis

Acute tracheobronchitis

ACETYLCYSTEINEUsed to treat or prevent liver

damage in acetaminophen overdose (patient drinks it)

Reduces viscosity of mucus by substituting sulfhydryl group for disulfide group

ACETYLCYSTEINE

May be directly instilled during bronchoscopy to remove mucus plugs

Normal dosage via SVN: 3 – 5 ml

ACETYLCYSTEINESide effects

Airway obstruction secondary to rapid liquefaction of secretions

Disagreeable odor (rotten eggs)

Nausea

Rhinorrhea

Bronchospasm

ACETYLCYSTEINEDiscard 96 hours after opening,

usually refrigerated

Should not be administered in the presence of thin secretions

ALWAYS GIVE WITH A BRONCHODILATOR

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. http://www.pulmozyme.com/hcp/moa.html

INFECTION Increased WBCs – neutrophilsWBCs contain DNAWBCs 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

COMMON SIDE EFFECT OF PULMOZYME Voice Alteration Pharyngitis/Laryngitis Rash Chest pain Conjunctivitis

Contraindicated in patients hypersensitive to Chinese Hamster Ovary cell products.

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).

MUCUS-CONTROLLING AGENTS 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

DORNASE ALFA

Side effects (does not cause bronchospasm)Pharyngitis

Laryngitis

Chest pain

SODIUM BICARBONATE Not commonly used, but changes the pH of

mucus. Aerosolizeda. 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

ETHYL ALCOHOLEthyl Alcohol 30-50% (Ethanol) a. Indication: - pulmonary edema (OLD treatment) Defoaminant b. Precautions: - mucosal irritation - intoxication - vasodilation

AQUEOUS AEROSOLS (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

AQUEOUS AEROSOLSDistilled 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

AQUEOUS AEROSOLS Isotonic saline (0.9%)

Osmolarity – equal to lung tissue

Also known as normal saline

Used as diluent for medication

AQUEOUS AEROSOLSHypotonic 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

AQUEOUS AEROSOLSHypertonic saline (>0.9%)

Osmolarity – greater than that of lung tissue

Used for sputum induction

AQUEOUS AEROSOLSHypertonic saline (>0.9%)

Draws fluid from interstitial space to mucus bed, thinning secretions

May cause bronchospasm, especially in hyperactive airways