RESPIRATORY PHARMACOLOGY
WEEK 5
ANTICHOLINERGICS AND
MUCOLYTICS
ANTICHOLINERGIC AGENTS
 Only
effective if bronchoconstriction
exists due to cholinergic activity
 USED
 May
FOR COPD PATIENTS only
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=KYS3Kp672Y
ANTICHOLINERGIC AGENTS
 Adverse
effects

Dry mouth

Cough

EXTREMENLY RARE SYSTEMIC SIDE EFFECTS
AS IT DOES NOT CROSS BLOOD BRAIN
BARRIER

Nervousness

Headache, dizziness
ANTICHOLINERGIC AGENTS
 Adverse
effects

Pharyngitis

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 shorteracting 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 AGENTS
Ipratropium
bromide
Atrovent
Ipratropium
bromide
and Albuterol
Combivent MDI: Ipratropium 18µg/puff,
DuoNeb
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
Spiriva
Onset: 30 minutes
Peak: 3 hours
Duration: 24 hours
Given with
handi haler
MDI: 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
DPI: 18 µg/inhalation, 1
inhalation daily
Onset: 15 minutes
Peak: 1 – 2 hours
Duration: 4 – 6
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 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


http://www.nebraskamed.com/health-library/3dmedical-atlas/237/mucolytics
MUCOLYTICS
Acetylcysteine
 sodium bicarbonate (NaHCO3)
 Dornase alfa


Pulmozyme
AIRWAY ANATOMY
MUCUS LAYER
(1 to 2 mm): Gelatinous and sticky
(flypaper)
 Sol (4 to 8 mm): Watery, Cilia in this layer
 Gel

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
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
 10 mL reaches the glottis
 Most of this is swallowed


mucosa
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 MUCOLYTICS
 Disruption

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 secretions

Chronic obstructive pulmonary disease

Bronchiectasis

Acute tracheobronchitis
ACETYLCYSTEINE
 Used
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
ACETYLCYSTEINE
 Side

effects
Airway obstruction secondary to rapid
liquefaction of secretions

Disagreeable odor (rotten eggs)

Nausea

Rhinorrhea

Bronchospasm
ACETYLCYSTEINE
 Discard
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


6-10 mL of a 10% solution TID or QID


Maximum dose 10 mL
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 – 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
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. 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

ETHYL ALCOHOL
Ethyl 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 AEROSOLS
 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
AQUEOUS AEROSOLS
 Isotonic
saline (0.9%)

Osmolarity – equal to lung tissue

Also known as normal saline

Used as diluent for medication
AQUEOUS AEROSOLS
 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
AQUEOUS AEROSOLS
 Hypertonic

saline (>0.9%)
Osmolarity – greater than that of lung
tissue

Used for sputum induction
AQUEOUS AEROSOLS
 Hypertonic

saline (>0.9%)
Draws fluid from interstitial space to mucus
bed, thinning secretions

May cause bronchospasm, especially in
hyperactive airways