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Respiratory Drugs Part 2
V. Leukotriene inhibitors
A. Leukotrienes
• Leukotrienes (LT) are a family of
eicosanoid, formed when arachidonic acid
(released by phospholipids in cell
membranes) is reacted upon by the
lipooxygenase (LOX) enzymes.
• LT’s are synthesized by a number of
different cells (i.e. mast cells,
macrophages) in the airways.
• Three LT’s in particular, LTC4, LTD4, and
LTE4 are responsible for many of the
effects which occur during an attack,
especially bronchoconstriction.
• There are 2 categories of LT inhibitors:
receptor antagonists and LT synthesis
inhibitors.
• Both categories are effective in blocking
antigen induced (grass, cat dander,
ragweed, and mixed antigens),
• as well as exercise-induced airway
responses.
• Neither category is as effective as inhaled
corticosteroids in regard to alleviating
symptoms, airway inflammation and
bronchial reactivity.
• However, they are equal to inhaled
corticosteroids in reducing the frequency
of asthma exacerbation.
• An advantage the LT inhibitors have over
the inhalation corticosteroids is that they
are administered orally.
• This is useful in patients who have poor
compliance with the correct use of a MDI
(children, the elderly).
B. Receptor antagonists
1. montelukast (Singulair)
• This works by blocking the binding of
LT’s.
• It’s safety and effectiveness has been
demonstrated in children as young as 6
months of age. It is generally administered
in the evening (PO 10 mg, children PO 4
mg).
• Adverse effects in adults include
headache, fatigue, cough and rash.
• The same adverse effects, as well as
otitis, sinusitis, nausea and diarrhea are
seen in children.
2. zafirlukast (Accolate)
• This is similar to Singulair in that it is a
receptor antagonist of leukotriene.
• Specifically, it is a selective and
competitive receptor antagonist of
leukotriene D4 and E4 (LTD4 and LTE4),
components of slow-reacting substance of
anaphlaxis(SRSA).
• It is administered either 1 hour before or 2
hours after meals (adults PO 20 mg, bid;
children PO 10 mg bid).
• Headache is the most frequently reported
adverse effect.
• Other adverse effects are similar to those
reported for montelukast.
C. Leukotriene synthesis inhibitor
1. zileuton (Zyflo)
• This drug has a different mechanism of
action, it inhibits formation of leukotrienes
by inhibiting the enzyme 5-lipoxygenase
(5-LO).
• The dosage is 400-800 mg, 2-4 times a
day. It is approved for the prevention and
chronic treatment of asthma in patients
aged 12 years and older.
• In a clinical study, patients receiving Zyflo
were able to reduce their use of inhaled
beta-adrenergic drugs.
• Headache is the most frequently reported
adverse effect. There are also a few
reports of liver toxicity (elevated liver
enzymes) with this drug.
VI. Decongestants
A. Decongestant actions
• Decongestants act as vasoconstrictors to
reduce blood flow to mucous membranes
in the nose, sinuses and pharynx.
• They produce vasoconstriction by
stimulating alpha receptors in the smooth
muscle around blood vessels
B. Oral decongestants
• The most common oral decongestants
are:
• 1. pseudoephedrine (Chlor-Trimeton, Dimetapp,
Drixoral, Sudafed, Suphedrin, Triaminic, many generics).
• Also found in many combination products
(Actifed Cold and Sinus) which contain
antihistamine/pain reliever (aspirin,
acetaminophen, or ibuprofen).
• The dosage is 60 mg every 4-6 hours, or
120 mg extended release every 12 hours,
or 240 mg extended release, once a day.
• As pseudoephedrine has been used in the
illicit manufacture of methamphetamine,
Federal regulations require that all OTC
medications that contain pseudoephedrine
be kept behind the counter in the
pharmacy.
• In addition, people buying these products
must provide a photo ID and sign a
logbook.
2. phenylephrine
• Some drug companies are concerned that
the Federal regulations regarding
pseudoephedrine may keep people from
buying their products, so they have
reformulated their products by removing
the pseudoephedrine and substituting
phenylephrine for it.
• Pseudoephedrine and phenylephrine
• Note the long list of medications that
contain phenylephrine:
• Sudafed PE, PediaCare Children’s decongestant,
Actifed Cold and Allergy, Benadryl Allergy & Cold,
Benadryl Allergy & Sinus, Children’s Sudafed Cough &
Cold, Children’s Tylenol Plus Cold, Children’s Tylenol
Plus Cold & Allergy, Excedrin Sinus Headache, Sudafed
PE Nightime Nasal decongestant, Sudafed PE Sinus &
Allergy, Sudafed PE Cold & Cough, Sudafed PE
Multisymptom, Theraflu Cold & Cough, Theraflu Cold &
Sore Throat, Theraflu Daytime Severe Cold,
• Theraflu Daytime Flu & Sore Throat, Theraflu Nighttime
Severe Cold, Triaminic Cold & Allergy, Triaminic
Daytime Cold & Cough, Triaminic Nighttime Cold &
Cough, Tylenol Allergy MultiSymptom, Tylenol Cold
Head Congestion, Tylenol Cold MultiSymptom, Tylenol
Cold MultiSymptom Daytime, Tylenol Cold
MultiSymptom Nighttime, Tylenol Sinus Congestion &
Pain Daytime, Tylenol Sinus Congestion & Pain
Nighttime, Tylenol Sinus Congestion Severe, Vicks Day
Quil Sinus, Vicks Day Quil Cold/Flu, Vicks Formula 44D
Cough & Head Congestion Relief.
• Congressman Henry Waxman, among
others, have expressed concerns that
these newly formulated drugs are not
working well enough for their intended
purpose.
• In a peer-reviewed letter to the editor
published in late 2006 in the Journal of
Allergy and Clinical Immunology, two
University of Florida researchers
concluded that there is "virtually no
evidence to show that phenylephrine oral
nasal decongestants at the FDAsanctioned dose of 10mg are effective”.
• To address the issue, Waxman has twice
called upon the US Food and Drug
Administration (FDA) to launch an
investigation into the use of phenylephrine
in these drugs, based on a study by
Schering-Plough.
• According to Schering-Plough,
phenylephrine was "not significantly
different from placebo in decreasing nasal
congestion" while pseudoephedrine was
"significantly more effective," in a clinical
trial involving 38 people.
• Both phenylephrine and pseudoephedrine
oral have a prolonged duration of action
compared to topical decongestants, but
they also have more adverse effects.
• These include excitability, nervousness,
and insomnia.
C. Topical decongestants
• 1. Oxymetazoline (Afrin, Dristan 12 hours
nasal, NeoSynephrine 12 hour, various
generics). The recommended dosage for
this 0.05% solution is 2-3 sprays per
nostril, two times a day.
• 2. Phenylephrine containing nasal sprays (Neo
Synephrine)
• This is available in 0.25, 0.5 and 1.0%
solutions. The recommended dosage is 23 sprays per nostril, two times a day. This
nasal spray form of phenylephrine is more
effective than the pill form
• 3. xylometazoline (Otrivin)
• This is available in 0.05 and 0.1%
solutions. The recommended dosage is 23 sprays per nostril, every 8-10 hours.
• These topical decongestants are
recommended for the acute treatment of
congestion related to the common cold.
• They should not be used for longer than 3
days, as they tend to cause rebound
congestion.
VII. Expectorants
A. Expectorant actions
• Expectorants reduce the viscosity or
thickness of sputum so that patients can
more easily cough it up
• The use of expectorants, especially in the
treatment of a common cold, is
controversial.
• Traditional colds involve the upper
respiratory tract, whereas expectorants
are designed to facilitate mucus removal
from the lower respiratory tract.
• In addition, many clinicians have
questioned their effectiveness in actually
facilitating the clearance of mucous.
B. Expectorant agents
• 1. Guaifenesin (Mucinex, Robitussin, numerous
generics)
• Guaifenesin is the only FDA approved
OTC expectorant, 100 – 400 mg every 4
hours.
• It is an ingredient also in many
combination products which come in
several forms, including capsules, tablets,
and liquids.
• It may be combined with antihistamines,
antitussives, or decongestants.
VIII. Antitussives
• Antitussives are agents which suppress a
cough. Their main purpose is to control
nonproductive dry coughs.
• They are not indicated in the treatment of
productive cough as they may allow
accumulation of secretions which lead to
airway obstruction.
A. nonopioid
• 1. dextromethorphan (Benylin, Delsym, Robitussin,
Vicks, various generics)
• Dextromethorphan is a non-opioid
antitussive without analgesic or addictive
properties.
• This is often found in combination
products along with
antihistamine/decongestant/expectorant.
The recommended dosage is 10-20 mg
every 4 hours or 30 mg every 6-8 hours.
B. opioid
• Opioids are the most effective drugs
available for cough suppression. This is
achieved at doses below those used to
produce an analgesic effect.
• The specific mechanism of antitussive
action of opioids is not known, however, it
appears that the receptors involved in their
antitussive effects are different from those
associated with their analgesic effects.
• 1. codeine
• 10-20 mg every 4-6 hours as needed, but
not to exceed 120 mg in 24 hours
2. hydrocodone
• There are a number of FDA approved
hydrocodone-containing antitussives
marketed in the U.S.
• In terms of cough suppression,
hydrocodone is about 3 times more potent
than codeine. It can lead to both physical
and psychological dependence.
• hydrocodone and chlorpheniramine
(Tussionex suspension):
• This formulation contains an antihistamine
(chlorpheniramine) along with the
antitussive hydrocodone.
• The dosage is 5 mL of the suspension
every 8-12 hours. Side effects include dry
mouth, dizziness, drowsiness, euphoria,
nausea, vomiting and constipation.
• hydrocodone and homatropine (Hycodan,
Tussigon): This formulation contains an
anticholinergic, homatropine, which is
effective in drying up secretions.
• It is available both in a suspension and
tablet form: 1 tablet/tsp every 4-6 hours.
Side effects include dizziness, nausea,
vomiting and constipation
IX. Mucolytic agents
• These agents interfere with the chemical
structure of mucous making it less viscous
• 1. acetylcysteine or N-acetylcysteine (Mucomyst)
• Acetylcysteine is used to help break up the
thick, viscous, mucous that is often
present in people suffering from
respiratory ailments.
• It accomplishes this by breaking the
disulfide bonds in mucoproteins thereby
lowering their viscosity.
• It is indicated as an adjuvant treatment for
the following:
•
•
•
•
•
•
•
amyloidosis,
bronchiectasis,
bronchitis,
cystic fibrosis,
emphysema,
pneumonia
tuberculosis
• The usual dosage is 2-20 ml of a 10%
solution via a nebulizer, but high dose oral
N-acetylcysteine has recently been used
to treat inflammation in cystic fibrosis
patients
• 2. dornase alpha (Pulmozyme)
• Dornase alfa is a solution of recombinant
human deoxyribonuclease (rhDNase).
• This is a treatment used by cystic fibrosis
patients to clear the mucus that
accumulates in the airways and leads to
infection (Pseudomonas aeruginosa).
• Their sputum contains a higher
concentration of DNA.
• This is believed to be derived from the
nuclei of degenerating WBC’s, and results
in an increase in viscosity of their sputum.
• It was approved by the FDA in 1993.
• It is administered as a 2.5 mg single
ampule inhaled once a day via a nebulizer.
• It must be kept refrigerated.
• Side effects of its use include cough,
laryngitis and hoarseness.
X. Surfactants
A. Lung surfactant
• In premature infants, a deficiency of lung
surfactant often leads to respiratory
distress syndrome (RDS) of the newborn,
believed to account for approximately 1520% of all neonatal deaths in Western
countries.
• This syndrome is characterized by a 2 to
15 times greater surface tension than
normal, due to a deficiency of lung
surfactant.
• Lung cells which produce surfactant
(arrows)
• Lung surfactant is found in the liquid layer
that lines the alveoli of the lungs.
• The primary role of lung surfactant is to
decrease the surface tension of the liquids
lining the alveoli.
• There are several important physiological
effects of a decrease in surface tension
brought about by the presence of a
surfactant in the alveoli:
• prevention of alveolar collapse;
• a decrease in surface tension increases
compliance (stretching), which means that
less work is needed to expand the alveoli;
• and a decrease in surface tension
prevents water from leaking into the alveoli
from the lung capillaries.
• RDS of the newborn is most common in
infants whose gestational age is less than
34 weeks.
• There is a test which can be performed
before birth, which helps predict the
maturity of the fetal lung.
• In this test, a sample of amniotic fluid is
tested to determine its L/S
(Lecithin/Sphingomyelin) ratio
• (Surfactant is composed of about 85-90%
lipid, and most of this is
dipalmitoylphosphatidylcholine, or lecithin).
• sphingomyelin
• A ratio of 2 or greater is desired, and is
normally found at the gestational age of
about 4 weeks up to term.
• If the ratio is between 1.5 and 1.9, there is
slightly less than a 50% chance of
developing RDS.
• The risk increases greatly to about 75%
when the L/S ration is less than 1.5
B. Treatments
1. Antenatal treatment
• Antenatal treatment with corticosteroids for
women in preterm labor.
• These corticosteroids induce a significant
and rapid acceleration of lung maturation.
• They are currently recommended in a
setting of preterm labor at 24-34 weeks
gestation unless delivery is imminent.
• The treatment with corticosteroids
continues for 48 hours while attempting to
halt labor.
• Generally, either two 12 mg doses of
betamethasone IM, 24 hours apart
• or
• four 6mg doses of dexamethasone IM, 12
hours apart
2. Exogenous surfactant
a. beractant (Survanta, derived from bovine
lung extract)
• 4 ml/Kg of birth weight in four divided
doses through a catheter placed into the
endotracheal tube, with the infant
manually ventilated for a minimum of 30
seconds, or until stable between each
dose.
• Repeated after 6 hours if there is
continuing respiratory distress
• This is specifically recommended by the
manufacturer for prophylactic therapy in
infants weighing less than 1,250 g, within
15 minutes of birth.
• In addition, it is indicated within 8 hours of
birth for infants with evidence of RDS.
b. poractant alfa (Curosurf, derived from
porcine lung extract),
• 2.5 ml/Kg of birth weight in two divided
doses through a catheter placed into the
endotracheal tube, with the infant
manually ventilated with 100% oxygen for
1 minute.
• A 1.25 ml/Kg of birth weight subsequent
dose, is repeated twice at 12 hour
intervals if needed. Maximum dose of 5
ml/Kg of birth weight.
c. calfactant (Infasurf, derived from bovine
lung extract)
• 3 ml/Kg of birth weight to an intubated
infant in two divided doses if administered
by side-port delivery or 4 doses if by
catheter delivery, with the infant
mechanically ventilated for up to 2 minutes
between doses
d. recombinant human surfactant protein D
(rhSP-D)
• In a study published in February 2010 in
the American Journal of Respiratory and
Critical Care Medicine, premature lambs
were treated with either Survanta or
Survanta containing rhSP-D.
• In lambs given Survanta alone, manual
ventilation resulted in pulmonary
inflammation.
• In the group given Survanta with rhSP-D,
there was an inhibition of lung
inflammation. This agent has potential for
use in premature human infants.
C. Adverse effects of surfactant therapy
• Adverse effects of surfactant therapy
include: acute obstruction of the airway
resulting in hypoxemia and bradycardia
with a large volume in a single dose,
rather than small repetitive additions;
• apnea;
• and pulmonary hemorrhage (generally in
infants weighing less than 700 g at birth)
XI. Phosphodiesterase inhibitors
A. Phosphodiesterase
• There are 11 families of
phosphodiesterase, numbered PDE1PDE11. Of particular interest are
phosphodiesterase-3 (PDE3), and
phosphodiesterase-4 (PDE4) found in
airway smooth muscle and epithelial cells.
• PDE4 hydrolyzes cAMP, and there is
compelling scientific rationale (i.e they are
anti-inflammatory in animal models as well
as in in vitro studies) for developing PDE3
and 4 inhibitors for use in the treatment of
COPD.
B. Clinical trials
• A 6 month Phase II trial tested the efficacy
of one of these PDE4 inhibitors, cilomilast
(Ariflo).
• cilomilast (Ariflo)
• It was administered orally, and reached
the most distal portions of the lungs via the
systemic circulation.
• Not all inhaled bronchodilators are capable
of penetrating this deeply, which is
significant in that inflammation is often
continually present in these small airways.
• There was a significant improvement in
airflow, compared to placebo (40 ml
difference in FEV1), as well as a (more
subjective) quality of life improvement, as
measured by a questionnaire.
• Currently, a Phase III clinical trial has been
completed (May 2009) but the results have
not yet been published.
• Similar findings occurred with a different
PDE4 inhibitor.
• In July 2009, an application was filed with
the FDA for approval of once daily oral
roflumilast (Daxas).
• A study from 4 clinical trials with
roflumilast was expected to be published
sometime in 2009 or 2010.
• Patients involved in studies conducted
with both cilomilast and roflumilast
experienced a time delay between
exacerbations of their COPD when
receiving a PDE4 inhibitor.
• The scientists conducting the studies
believe that the systemic distribution of the
PDE4 inhibitors to the distal airways may
be the key to the effectiveness of these
drugs.
• Although resting lung volumes were not
tested in their trials, they believe that
improvement in this parameter would be
seen if measured in future trials.
• Ibudilast (development codes AV-411,
MN-166) does not have FDA approval in
the U.S., but is available in Japan, where it
is used as an anti-inflammatory agent in
the treatment of asthma.
• Studies indicate that it has a better safety
profile and is more potent than
theophylline.
• Some of the adverse effects associated
with PDE inhibitors are GI related (i.e.
dyspepsia, nausea).
• This has limited their development as
potential candidates in the treatment of
COPD.
• Ibudilast has acceptable GI tolerability.
XII. Protease inhibitors
A. Alpha-1 antitrypsin
• Neutrophil elastase is a protease enzyme
which degrades elastic fibers in connective
tissue.
• Alpha-1 antitrypsin (AAT), also known as
Alpha-1-Proteinase is a protein made by
the liver and released into the circulation.
• Alpha-1 antitrypsin is a protease inhibitor
which degrades neutrophil elastase and
therefore plays a protective role in the
places where unchecked neutrophil
elastase activity can have serious
consequences, particularly the lungs and
liver.
• If the breakdown of tissue occurs in the
alveolar wall, it can lead to emphysema.
• Alpha-1 antitrypsin deficiency (AATD) is
an inherited condition that causes low
alpha-1 antitrypsin (AAT) levels in the
blood.
• This predisposes those with the most
severely deficient phenotype (PI*ZZ), to
emphysema and liver disease (neonatal
jaundice, cirrhosis, hepatoma).
• people with normal alleles for AAT are
designated PI*MM
• heterozygotes are designated PI*MZ
• Of the approximately 300 million
Americans, about 100,000 have the
severe AATD (PI*ZZ), and approximately
8 million are heterozygotes.
• This condition is found most often in
Caucasians of European ancestry, the Z
allele is not common in Americans of
Asian and African descent.
• Symptoms of AATD include jaundice in a
newborn or infant that lasts for an
extended period of time (more than a
week or two);
• and wheezing, a chronic cough or
bronchitis, and shortness of breath after
exertion in a person under 40 years of age
(especially when the patient is not a
smoker, and has not been exposed to
known lung irritants).
B. AATD drug therapy
• There are, currently, 4 agents approved by
the FDA for the treatment of AATD.
• These products are derived from human
plasma and are extremely expensive (up
to $100,000 per year, per patient).
• These agents are indicated only for
patients with the PI*ZZ phenotype, and not
for individuals with cigarette-smoking
related emphysema with PI*MM or PI*MZ
phenotypes, or those with liver disease
due to AATD, unless they also have lung
disease.
• The 4 agents are Prolastin, Zemaira,
Aralast and Glassia.
• Glassia is the newest alpha-1 antitrypsin
inhibitor, receiving FDA approval in July
2010. Baxter International in October 2010
received the exclusive distribution rights
for Glassia in the U.S., Canada, Australia,
and New Zealand from Kamada Ltd.
(Israel) for $20 million.
• All 4 of these agents are administered IV,
once a week (recommended dosage of 60
mg/Kg of body weight).
• Clinical trials are currently underway in
Europe for an inhaled version of an alpha1 antitrypsin inhibitor. Approval for this is
expected in 2012 in Europe, with the U.S.
to follow shortly after.
• There is a randomized, placebo-controlled,
double-blind, study conducted by CLS
Bering to assess whether the progression
of emphysema can be halted by
continuous, long term therapy with
Zemaira.
• The study began in January of 2006 and is expected to
end in March 2011. The effect of Zemaira on the
progression of emphysema will be assessed by the
decline of lung density, measured by computerized
tomography (CT).
XIII. Tumor necrosis factor inhibitors
A. Tumor necrosis factor
• During the inflammatory response
triggered normally by infection, but also by
cigarette smoking, macrophages are
activated, and release cytokines.
• Cytokines are proteins which mediate
communication among the cells of the
immune system, as well as between the
cells of the immune system and other
body systems.
• There are 3 major categories of cytokines:
interleukins, tumor necrosis factor (TNF)
and interferons.
• The cytokine of interest here is TNF which
induces programmed cell death, primarily
in tumor cells, but also in any cell with a
receptor.
• The sputum of COPD patients has
increased levels of TNF-α.
• It is believed that an increase in circulating
TNF-α leads to the skeletal muscle
apoptosis that is associated with the
severe wasting in some advanced COPD
patients.
B. TNF blockers
• TNF blockers such as infliximab (Remicade) have been
effective in other chronic inflammatory diseases
(rheumatoid arthritis, inflammatory bowel disease) and,
therefore, may be effective in COPD patients.
• However, in a 6 month study of 234
smokers, 40 years or older, it was shown
that infliximab was not beneficial in
patients with moderate to severe COPD
(based on the Chronic Respiratory
Questionnaire, prebronchodilator forced
expiratory volume in 1 second [FEV1], and
6 minute walk distance.
• This study was published in the May 2007
issue of The American Journal of
Respiratory and Critical Care Medicine.
• It should be noted that infliximab is a
chimeric (mouse/human) recombinant
antibody construct which results in a large
antigenic trigger.
• Newer TNF binding proteins have been
engineered, and trials of anti-TNF
therapies specifically for patients with
COPD are currently underway.
• The anti-TNF-α agents currently available,
include infliximab (Remicade), etanercept
(Enbrel) and adalimumab (Humira).
• Remicade was first approved in the United
States for the treatment of Crohn’s
disease in 1998 and later approved for the
treatment of Ulcerative colitis in
September 2005.
• Enbrel was approved for the treatment of
rheumatoid arthritis in 1998.
• So far, Humira has been approved by the
FDA for the treatment of moderate to
severe rheumatoid arthritis in 2002,
moderate to severe Crohn's disease in
2007 and moderate to severe psoriasis in
2008.
• Before any of these drugs can be
approved for the treatment of COPD,
clinical trials must be completed and the
results, published.
• Another approach may be to target the
enzyme which is responsible for releasing
TNF, TNF-α-converting enzyme (TACE).
C. Other potential therapeutic targets for
drug development in COPD
• A recent study has assessed the ability of
36 different biomarkers to confirm the
presence of COPD exacerbation and
predict its severity.
•
•
•
•
•
This study found that
C-reactive protein (CRP),
IL-6,
myeloid progenitor inhibitory factor (MPIF)-1,
pulmonary and activation–regulated chemokine
(PARC),
• adiponectin (ACRP-30), and
• soluble intercellular adhesion molecule (sICAM)1
• significantly vary between baseline and
exacerbation of COPD.
• These biomarkers are potential
therapeutic targets