Selected Agents Used in Respiratory Disease
I.
α1-Proteinase Inhibitor (Human)
a. Brand Name: Prolastin (Bayer)
b. Status: Orphan Drug
c. Indications
i. Indicated for chronic replacement therapy in individuals with
congenital deficiency of API, with clinically demonstrable
panacinar emphysema
ii. Indicated for those with Pi ZZ, Pi Z-null, or Pi null-null
phenotypes
iii. American Thoracic Society
1. indicated for patients with a serum concentration of API
less than 80 mg/dl
2. indicated if lung function studies become abnormal and
if serial studies show deterioration
iv. The drug cannot reverse lung damage or improve lung
function
d. Dosage and Administration
i. Prolastin is available as single dose vials with
1. 500 mg of active ingredient and 20 ml sterile water
2. 1000 mg active ingredient and 40 ml sterile water
ii. the recommended dose is 60 mg/kg IV weekly
1. usually takes 30 minutes for administration
e. Hazards and Side Effects
i. Well tolerated overall
ii. No evidence of acute or chronic immunologically mediated
rections
iii. Fever
iv. Light-headedness
v. Dizziness
vi. Flulike symptoms
vii. Chills
viii. Dyspnea
ix. Rash
x. Tachycardia
f. Cost
i. $25,000 to $40,000 per year
ii. proven cost effective in individuals who have severe α1antitrypsin deficiency and severe COPD
g. α1-Antitrypsin Deficiency (API)
i. Definition
1. a genetic defect that leads to the development of
severe panacinar emphysema
a. worse in lower lung zones
b. accelerated by cigarette smoking
c. usually accompanied by
i. history of pneumonia
ii. increased cough and sputum
iii. parental history of emphysema
ii. Onset
1. panacinar emphysema usually presents at 30 to 50
years of age
iii. Incidence
1. accounts for 2% of all emphysema in the U.S.
2. 60,000 to 100,000 Americans with severe API
3. most prevalent in individuals of northern European
descent
iv. Pathohysiology
1. an imbalance between proteases (neutrophil elastase)
and antiproteases (α1-proteinase inhibitor)
2. a process of alveolar wall destruction caused by
insufficient protection from the protease neutrophil
elastase
a. the enzyme can cleave all forms of connective
tissue and degrade elastic fibers in the lungs by
solubilizing elastin
b. with inadequate API levels in the lung to balance
protease activity, emphysema results at a
significantly earlier age than normally seen
3. A presentation of severe emphysema at an
unexpectedly young age (third or fourth decade) leads
to al high suspicion of API deficiency
v. Genetics
1. A glycoprotein found on chromosome 14
2. Alleles of the API gene
a. normal
i. individual has normal serum levels of API
1. 150 to 350 mg/dl (20 to 48 µM)
2. Pi MM
b. Deficient
i. Lower than normal serum concentrations
ii. Pi ZZ
1. most common form of deficiency
c. Null
i. Undetectable API levels in the serum
ii. Pi null-null
d. Dysfunctional
i. API is present in normal amounts, but does
not function normally
ii. Pi Z-null
II.
Smoking Cessation Drug Therapy
a. Nicotine
i. The chief alkaloid in tobacco products
ii. Nicotine addiction is the basis for tobacco dependence
iii. Desirable Effects
1. pleasure and cognitive arousal
2. enhanced concentration
3. enhanced alertness and memory
4. decreased tension and anxiety
iv. Undesirable Side Effects
1. GI and urinary tract
a. diarrhea
b. urination
2. Cardiovascular
a. hypertension
b. tachycardia
c. peripheral vasoconstriction
3. Neuromuscular
a. tremor
b. loss of hand steadiness
4. Central Nervous System
a. respiratory stimulation
b. tremors
c. convulsions
d. nausea
e. emesis
b. Symptoms of Nicotine Withdrawal
i. Nicotine craving
ii. Nervousness
iii. Irritability
iv. Anxiety
v. Drowsiness
vi. Sleep disturbance
vii. Impaired concentration
viii. Increased appetite and weight gain
c. Indications for Smoking Cessation Drug Therapy
i. Indicated as an aid to smoking cessation to relieve nicotine
withdrawal symptoms
ii. Should be used as part of a comprehensive smoking cessation
program to increase compliance and reduce relapse
iii. Smokers with signs of high physical dependence on nicotine
may benefit most
Signs of High Physical Dependence on Nicotine
 Smokes more than 15 cigarettes per day
 Prefers brands with nicotine levels above 0.9 mg
 Has habit of inhaling smoke frequently and deeply
 Smokes within 30 minutes of rising
 Finds it difficult to give up the first morning cigarette
 Smokes most frequently in the morning
 Finds it difficult to refrain from smoking in smoke-free
environments
 Smokes even when ill enough to be bed-ridden
d. Drug Formulations
Category
Nicotine transdermal
system
Nicotine polacrilex
Brand Name
Habitrol
Nicoderm
Nicotrol
Prostep
Nicorette (gum)
Nicorette DS (gum)
Nicotrol NS (nasal
spray)
Nicotrol Inhaler
Dosage
21 mg/day for 6 wk, 14 mg/day for
next 2 wk, 7 mg/day for last 2 wk
21 mg/day for first 6 wk, 14 mg/day
for next 2 wk, 7 mg/day for last 2 wk
15 mg/day for first 12 wk, 10 mg/day
for next 2 wk, 5 mg/day for last 2 wk
22 mg/day for 4 to 8 wk, 11 mg/day
for 2 to 4 wk
2 mg if fewer than 25 cigarettes/day;
9-12 pieces/day; maximum of 30
pieces/day
4 mg if 25 or more cigarettes/day; 912 pieces/day; maximum of 20
pieces/day
0.5 mg/spray, one each nostril (1.0
mg); 1-2 doses/hr, up to 5 doses/hr,
or 40 doses/day for 6-8 wk; gradually
reduce over next 4-6 wk
4 mg/use; recommended dosage is
24 to 64 mg per day, up to 12 wk,
with gradual reduction over a period
Bupropion
Zyban
up to 12 wk
150 mg sustained-release tablets;
begin at 150 mg/day for 3 days;
increase to 150 mg/day bid, with
maximum of 300 mg/day, interval of
8 hr between doses; continue
treatment for 7-12 wk
i. Nicotine Transdermal and nicotine polacrilex are nicotine
replacement agents
ii. Bupropion is an antidepressant
1. it may relieve nicotine withdrawal
2. may be used in combination with nicotine replacement
agents
e. Precautions
i. Potentially toxic concentrations of nicotine can occur in the
blood
1. individuals should stop smoking when initiating therapy
ii. transference of nicotine dependency from the tobacco product
to the replacement product can occur
1. replacement formulations should be gradually
withdrawn and stopped by three months
iii. use of nicotine replacement therapy should be carefully
weighed in patients with cardiovascular disease
iv. healthcare workers should avoid handling active nicotine
products
1. nicotine is easily absorbed through the skin
2. wash with water only
a. soap will increase absorption
v. used products must be disposed of properly
1. children and pets should not be exposed
III.
Nitric Oxide (NO)
a. Background
i. Produced by endothelial cells in the body
ii. This endogenously produced vasodilator can be inhaled as a
gas
iii. Investigated for its ability to lower pulmonary vascular
resistance in various states
1. Persistent pulmonary hypertension of the newborn
(PPHN)
2. Acute respiratory distress syndrome (ARDS)
b. Status: Orphan Drug
c. Indications
i. FDA approved on December 23, 1999 for use in neonates with
hypoxic respiratory failure, to reduce pulmonary artery
pressure and increase oxygenation in newborns with
pulmonary hypertension and hypoxia
1. nitric oxide is used in conjunction with ventilatory
support and other critical care in the treatment of term
and near-term neonates (>34 weeks) with hypoxic
respiratory failure associated with clinical or
echocardiographic evidence of pulmonary hypertension
ii. Off-label Uses
1. reduction of pulmonary vascular resistance and
pulmonary artery pressure during neonatal cardiac
surgery
2. treatment of hypoxemia or pulmonary hypertension
after lung transplantation
3. treatment of acute respiratory distress syndrome
(ARDS)
d. Dosage and Administration
i. Nitric oxide is supplied in two sizes of gas cylinder
1. 353 L
2. 1963 L
ii. The recommended dose is 20 ppm
iii. Treatment should be maintained up to 14 days or until the
underlying oxygenation problem has resolved and the
neonate can be successfully weaned from nitric oxide
iv. May be administered with the INOvent system
v. The vasodilating effect of inhaled nitric oxide ends with the
removal of the gas
1. rebound hypertension may occur
2. an increase in FiO2 may be needed
3. close monitoring is critical
e. Effect on Pulmonary Circulation
i. Inhaled NO produces no effect when normal vascular
resistance is present
ii. With increased pulmonary vascular resistance, inhaled NO
dilates pulmonary blood vessels in lung regions that receive
gas flow
1. improved ventilation-perfusion matching
2. increased PaO2
f. Effect on Systemic Circulation
i. No systemic vasodilation or hypotension occurs
1. nitric oxide rapidly combines with hemoglobin making it
inactive
g. Toxicity
i. nitric oxide
1. mediator of lung injury
ii. nitrogen dioxide
1. causes lipid peroxidation in cells
a. causes pulmonary edema
2. exposure to > 150 ppm is usually fatal
iii. methemoglobin
1. unable to carry oxygen
2. usually not a problem at usual inhaled NO doses
3. should be monitored
h. Contraindications
i. Inhaled NO should not be used in neonates who are known to
dependent on right-to-left shunt