Transcript Inhaled Drugs beyond Bronchodilators

Inhaled Drugs beyond
Bronchodilators
China 4000 Years Ago
Bennet’s inhaler
This may be the earliest
published image of
an inhalation device. In
1654 an English
physician, Christopher
Bennet, himself suffering
with consumption,
Bennet experimented on
himself with a number of
different remedies.
First isolation attempts
The Plague doctor
illustration is from Devils,
Drugs & Doctors
(Haggard, 1929). It
depicts the protective
clothing used by doctors
treating the plague in
Marseilles c1720. The
beak was filled with
spices to purify the
inhaled air. At the time it
was believed that plague
was contagious by touch,
hence the leather gloves
and wand.
Kirkwood’s inhaler
This advertisement
from 1874 1888
shows Kirkwood’s
inhaler, an apparatus
for delivering fuming
ammonium chloride. It
was used as an
antiseptic agent, and
was recommended at
times of contagion
and epidemic.
Page's Inhalers
Page's Inhalers were smoked
"for the temporary relief of the
paroxysms of asthma and to
aid in the relief of the
discomforts dust to excessive
secretions in the nasal
passage associated with hay
fever and simple nasal
irritations. Page's Inhalers
were produced by the
Consolidated Chemical
Company of Grand Rapids,
Michigan which was
established in 1892.
Early inhalers
Early Home Care
The ‘Indispensible’
inhaler was created by Dr
Arnold, and was
described as permitting
the sick to follow the
treatment of Dr Arnold at
their own homes.
Treatments while you sleep
First Listed inhaled Medications
The first official formulae of inhalation
medicines were listed in the British
Pharmacopoeia of 1867.
Hydrocyanic acid - which was used
for the treatment of dry cough,
however, in large doses it is lethal as
it can paralyze respiration.
Vapor of hemlock is also described, it
was also used as a treatment for
cough.
Vapor of creosote is also described,
this was used as a treatment for
tuberculosis and bronchitis.
Getting inhaled drugs to work
I Will Make This Work
Cost
Lack of Knowledge
Lack of interest
A Guide to Aerosol Delivery
Devices For Respiratory
Therapists
A Guide to Aerosol Delivery Devices for Respiratory Therapists, 2nd Edition
3 mechanisms usually cited by
which an aerosol particle can
deposit
Inertial impaction, - occurs with larger,
fast-moving particles > 10 μm that are
filtered in the nose and/or oropharynx
Gravitational settling (sedimentation)
is a function of particle size and time,
with the rate of settling is proportional
to particle size generally 5-10 μm
reach the proximal generations of the
lower respiratory tract.
Diffusion occurs with particles
smaller than 1-5 μm reach the lung
periphery
Medical Marihuana
Perception of Marihuana Use
The Real Story
Responsibility for the Medical Marihuana Program is The
Bureau of Health Professions (BHP) within the Michigan
Department of Community Health (MDCH)
A qualifying patient is a person who has been diagnosed by a
physician and have obtain a written certification from a that
physician as having a debilitating medical condition such as
cancer, HIV, AIDS. A primary caregiver means a person who is
at least 21 years old and who has agreed to assist with a
patient’s medical use of marihuana and who has never been
convicted of a felony involving illegal drugs. The caregiver can
assist no more than five patients.
ALBUTEROL FOR
HYPERKALEMIA
Hyperkalemia is classified as mild (5.5 to 6.0),
moderate (6.1 to 6.9) and severe (>7.0).
Definitive management of severe
hyperkalemia is hemodialysis. Temporizing
measures for moderate hyperkalemia,and
severe hyperkalemia, includes
– calcium gluconate
– insulin with glucose
– kayexalate
ALBUTEROL FOR
HYPERKALEMIA Guidelines
Albuterol can be administered in moderate to severe
hyperkalemia.
Mechanism of action is an increased cellular uptake of
potassium, similar to the actions of insulin
Onset of action was within 30 minutes, however the
maximum effect was at 90 minutes after nebulization.
12-40% of the patients were unresponsive to albuterol
and it was recommended that insulin should always be
given in conjunction with the albuterol
Nebulized dose of 10 mg was used in most adults
studies but 20 mg was shown to be more effective at 120
minutes.
The potassium level should be measured 90-120
minutes after the desired dose is given and compared to
the pre-albuterol level;
Heliox
Helium is a colorless tasteless, non-combustible gas
that is biologically inert and insoluble in human
tissue
It is seven times lighter than air.
Combining helium and oxygen (Heliox) results in a
gas with a similar viscosity to air but with a
substantially lower density.
Heliox lowers the resistance of gas flow in the
airways and allows for an increase in ventilation due
to changing turbulent flow into more efficient
laminar flow. It also may decreases the pressure
gradient needed to achieve a given level of turbulent
flow which may decrease work of breathing.
Use of Heliox does not treat the underlying disease,
but is used to reduce airways resistance and
respiratory muscle work until definitive treatments
act.
Heliox History
In 1930’s BarachIt recommended Heliox
as an adjunct therapy for treatment of
respiratory failure from obstructions of the
larynx, trachea, and airways
Use decreased in the 1940s due to the
World War II and the loss of helium
sources and development of
bronchodilators that were more effective.
Heliox resurfaced in the early 1980s
when asthma deaths began to rise
despite advances in medicine
Considerations of Heliox
Heliox usually comes in a 80/20 mixture.
There is little evidence of any severe adverse reactions for patients breathing
Heliox since it is an inert gas that has no effect on human metabolism.
Helium has a high thermal conductivity and may be associated with a lowering of
body temperature when used for prolonged periods.
Administration is best via a closed system as this allows the best concentration
to be delivered to the patient without any mixing of room air to occur.
When using an 80/20 mix FIO2’s >0.45 negate the therapeutic effect of He/O2.
With an 80/20 mix when using an oxygen flow meter multiply by 1.8 to calculate
the actual system flow.
Understanding the effects of heliox on ventilator performance.
Heliox cylinders cost about four times as much as oxygen .
Use of Heliox
Decreases air-trapping in thereby reducing
intrinsic positive end-expiratory pressure
(PEEP).
Decreases dyspnea and work of breathing,
Improves distal-airway deposition of aerosol
particles.
Upper airways obstruction
COPD
Croup
Asthma
Evidence of Heliox
A prospective study by Gluck showed heliox reduced peak airway pressure and PaCO2
and helped correct respiratory acidosis in 7 intubated patients with status asthmaticus.
Schaeffer reported that 11 mechanically ventilated for status asthmaticus receiving
heliox had improved oxygenation in adult and pediatric patients.
A retrospective study by Abd-Allah heliox was used in 28 mechanically ventilated
children with status asthmaticus. Heliox was associated with significantly lower mean
peak pressure and mean PaCO2 , and a improved arterial pH.
Gerbeaux retrospectively studied 81 nonrandomized patients who were admitted for
exacerbation of COPD and respiratory acidosis. 39 patients received 70:30 heliox and
42 did not receive heliox. There were no significant differences in age, gender,
medicalhistory, Among those who received heliox, the intubation rate was lower (8% vs
50%, p 0.01), mortality was lower (3% vs 24%, p 0.01), and intensive-care-unit (ICU)
admissions were lower (46% vs60%, p 0.23). Among the survivors, mean ICU stay was
shorter (8 vs 18 d, p 0.01).
Gross et al found that in children mechanically ventilated for bronchiolitis, heliox did not
improve oxygenation.
The White Elephant in the Room
Inhaled Vasodilators
– The short half-life of inhaled vasodilators
minimizes the systemic effects,
compared to intravenous,
subcutaneous,or oral administration
– Vasodilators that have been
administered via inhalation, clinically and
experimentally, include oxygen, nitric
oxide, milrinone, nitroglycerin,
prostacyclins, nitroprusside, nitric oxide
donors, phosphodiesterase inhibitors,
endothelin receptor antagonists, and
agonists of soluble guanylate cyclase.
Nitric Oxide
Nitric oxide was regarded as a pollutant until 1987.
NO is a free radical, produced by the endothelium, that relaxes
Vascular smooth muscle (via, cGMP) producing vasodilation.
Atmospheric concentrations of nitric oxide typically range between 10
and 500 parts per billion but may reach 1.5 parts per million (ppm) in
heavy traffic and 1000 ppm in tobacco smoke.
In 1991, inhaled nitric oxide was shown to be a selective pulmonary
vasodilator in patients with pulmonary hypertension.
1992 Nitric Oxide was named molecule
1993, inhaled nitric oxide emerged as a potential therapy for the
acute respiratory distress syndrome (ARDS), because it decreased
pulmonary vascular resistance without affecting systemic blood
pressure and improved oxygenation by redistributing pulmonary
blood flow toward ventilated lung units in patients with this condition.
Short half life
Oxidizes to NO2
Almost all cells can produce NO
How does INO Work
Fast acting
INO produces Selective
Pulmonary
Vasodilatation
Does not Cause
Systemic Vasodilatation
Increases cGMP which
causes Vasodilatation
Decrease
intrapulmonary shunt
Pulmonary Effects
– Increased
Oxygenation
– Decreased PVR
NO Action
Mark
J.D. Griffiths, M.R.C.P., Ph.D., and Timothy W. Evans, M.D., Ph.D
NO Effects
Mark J.D. Griffiths, M.R.C.P., Ph.D., and Timothy W. Evans, M.D., Ph.D
Indications
Inhaled Nitric Oxide
Pulmonary Hypertension Treatment Options
Inhaled Nitric vs. Iloprost and Flolan
Ventavis (iloprost)
Synthetic analogue of prostacyclin PGI2
Dilates systemic and pulmonary vascular beds
– 5 mcg @ mouthpiece (10mcg@ chamber) 6-9 times a day while
awake
Affects platelet aggregation
10 mcg/ml
Must use 1 of 2 (AAD) Adaptive Aerosol Systems
Side effects
COMMON
Cardiovascular: Vasodilatation (27%) Dermatologic: Flushing
Musculoskeletal: Trismus (12%) Neurologic: Headache (30%)
Respiratory: Increasing frequency of cough (39%)
SERIOUS
Cardiovascular: Hypotension (11%) Respiratory: Pulmonary edema
I-neb
Prodose
NO vs. ILoprost
CO
(liter/
min)
Before NO NO(40 ppm)
Baseline
2(Before
Iloprost)
Iloprost(14–
17mg)
3.4 +1.1
3.5 +1.2
4.2 +1.2
1,367 + 492
920 + 387
59 + 15
66 + 13
PVR
1,342 +
(dyn
518
eszs
zcm2
5)
SvO2
(%)
58 + 14
3.7 6 + 1.2
1,159 +
587
60 + 13
Hoeper et al. JACC Vol. 35, No. 1, 2000
Aeroneb Pro-X
AEROSOLIZED PROSTACYCLIN
(EPOPROSTENOL, FLOLAN)
Needs
experienced
Caregivers
Prostacyclin
Solution
(20,000 ng/mL)
Normal
saline
Infusion pump
Flow meter
IV extension
ValvedTee
Stop cocks
24 in. aerosol
hose
Connector
Ventilator
12 in.
aerosol hose
nebulizer
Exp
filter
Possibility of Combined Therapy
The treatment with nitric oxide
alone or combined with
prostacyclin or adrenomedullin
(ADM) were effective in
decreasing mean PAP and
improving oxygenation in a
piglet model of PH.
However, nitric oxide plus
prostacyclin and nitric oxide
plus ADM were more effective
than nitric oxide alone.
The combination of
aerosolized prostacyclin and
ADM with nitric oxide might
have a role in the treatment of
infants with PH refractory to
nitric oxide alone.
2007;42:1048-1056 Carlo Dani, MD
Inhaled Opioids
Look at me Now
Reason for Inhaled Opioids
Dyspnea due to Chronic
pulmonary disorders
– Pros
Rapid Absorption
Minimal Systemic effects
Pain management
– Pros
Rapid Absorption
Minimal Systemic effects
– Cons
– Cons
Mixed results
Small sample sizes
Possible Respiratory
Depression
Legal issues of administration
may produce bronchospasm
Recommendations
Not recommended as a
standard treatment option
May be helpful with refractory
cases on patient by patient use
Lack of experience in US
Inhaled Insulin
FDA approved 2006
Rapid Acting
No injections
Works best with type 2
Cost more than injections
Possible pulmonary effects
Dosing can be complicated
Dropped by Pfizer
Several new drugs in pipeline
PENTAMIDINE TREATMENT
ADMINISTRATION
Brand name Pentam 300
Indication: prophylaxis of Pneumoncystis carinii
pneumonia in immune- suppressed patients
Dosage
300 mg every 4 weeks
150 mg every 2 weeks
30 mg every 2 weeks
To prevent possible bronchospasm, patients
should be given 2.5 mg of albuterol via MDI
prior to pentamidine NMT.
Filtered Neb, protection of others
Inhaled CHEMOTHERAPY
(Doxorubicin, Cisplatin )
chemotherapy so it goes
directly into the lungs. The goal
is to maximize the delivery to
the area needing treatment
and minimize the toxicity to the
rest of the body.
Furthermore, researchers
found there was a 25-fold
increase in the amount of
chemotherapy found in the
lungs compared with the level
obtained with traditional
intravenous delivery.
Cisplatin Childhood bone
cancer
Inhaled Alteplase
Dissolve clots
Given to stroke patients
Same safety issues of other Blood
thinners
Used as an inhaled drug to treat fibrin cast
in the lungs
Nose to Brain
OptiNose has developed innovative nasal drug delivery
devices that enable nasal administration of CNS (nose to
brain), systemic and topical nasal formulations. OptiNose’s
unique breath actuated devices deliver intranasal drugs to
targeted regions of the nasal cavity, including the sinuses and
the olfactory region, without lung deposition, unlike
traditional nasal inhalers, nasal sprays or nebulizers. The
Company offers both single and multi-use intranasal delivery
devices for liquid and powder formulations. Founded in 2000,
OptiNose has extensively tested the technology in both invitro and in-vivo deposition studies and concluded Phase I
studies. The Company has recently completed Phase II
clinical studies with rhinosinusitis and migraine therapies.
Surfactant Replacement Therapy
Composed of lipids
(90%) and proteins
(10%).
Instillation directly
into the lung
possibly more
effective at this time
than aerosolized
(Ex-osurf).
Cost for responders
may be to high.
Hypertonic Saline
CF airways lack enough salt and water, researchers thought a
hypertonic saline mist would help clear the thick mucus from
the lungs.
7% hypertonic saline
Presented at the 2004 North American Cystic Fibrosis
Conference published in the New England Journal of Medicine
and University of North Carolina at Chapel Hill.
0.9% vs 7%
Both groups had increased lung function However the
hypertonic group had even better lung function also, the
hypertonic saline group had fewer lung infections.
Average dose 4 mL
You should not mix any other medications with hypertonic
saline.
Side effects that were noted included coughing more, sore
throat and chest tightness. (It is known that hypertonic saline
can irritate the airways.)
Pulmozyme (DNase)
Pulmozyme is a man-made form of naturally occurring DNase.
It works by "cutting up" the DNA left by neutrophils.
Standard dose 2.5 mg
Launched in 1994, Pulmozyme was the first new therapeutic drug for the
management of CF in more than 30 years.
Take every day, whether they have cystic fibrosis symptoms or not. This
may help break the cycle of cystic fibrosis progression.
Must be stored in the refrigerator at 2-8°C (36-46°F) and protected from
strong light.
Pulmozyme should not be diluted or mixed with other drugs,.mixing with
other drugs could lead to adverse physiochemical and/or functional
changes in Pulmozyme or the combined products.
Daily administration of Pulmozyme has also been shown to reduce the
risk of respiratory tract infections requiring less antibiotics.
Pulmozyme should not be used in patients with known allergies to
dornase alfa, Chinese Hamster Ovary cell products, or any component of
the product.
Pulmozyme Action
http://www.pulmozyme.com
Administering Aerosolized Ribavirin
Clinical Indications
Documented symptomatic RSV infection
Recipients of allogeneic stem cell transplant
Recipients of autologenous stem cell transplant
Contraindications
Hypersensitivity to Drug
Pregnant or planning to become pregnant within two weeks of
exposure
Requiring mechanical ventilation
Recommended Dosage
33.3 mL of 60 mg ribavirin/mL aerosolized for 2 hrs every 8 hrs
Total of 6 g/day (100 mL divided into 3 doses)
Given for 5–10 days
NOTE: Administer a Bronchodilator Pre-treatment
C. Haas
Setup
Use Blender, if supplemental O2 is required
Assemble SPAG unit
– Set Drive Pressure to 26 psi
– Set Nebulizer Flowmeter to max (6-10 L/min)
– Set Drying Chamber Flow to 8 L/min (range 3-8)
Attach aerosol tubing to patient face/trach
mask
– Not to be used on vent pts
Place a blue pad under the SPAG
Employee Precautions
The treatment should be given in the Demistifier
2000B HEPA filtration scavenging hood
‘Droplet Precautions’ should be followed for all
patients with RSV (gloves, gown, isolation mask,
face shield/goggles when w/i 3 feet of patient)
– During therapy, wear an N-95 mask or the PAPR unit
Pregnant women should avoid contact
Those wearing contact lenses should avoid
contact (wear goggles or take out)
Patient Preparation
Explain therapy goals and procedure
Administer bronchodilator
Ask if patient needs to use the restroom
If wearing contact lens, ask to take out or
apply goggles
Place a drape sheet over patient
Spag-2 Setup
Drying Chamber
Driving Pressure
(26 psi)
Nebulizer
Nebulizer
Flow 6 to 10
Lpm
(Output is 12.5-15 mL/hr)
Drying Chamber
flow 3 to 8 Lpm
Fightting the Flu
RELENZA (ruh-LENS-uh) is a medicine that can both treat influenza (flu,
infection caused by influenza virus) and help to prevent getting the flu. While
some antiviral medicines only protect against influenza A, RELENZA is
effective against both influenza A and B.
RELENZA belongs to a group of medicines called neuraminidase inhibitors.
These medications target the influenza virus and prevent it from spreading
inside your body. RELENZA treats the cause of influenza at its source, rather
than simply treating the symptoms.
Some patients have had bronchospasm (wheezing) or serious breathing
problems when they used RELENZA. Many but not all of these patients had
previous asthma or chronic obstructive pulmonary disease.
The green Movement
Others That Benefit form Inhaled
Drugs
Inhaled Anesthetics In the ICU
Pro
– May provide better
sedation
– Cost
– Ability to avoid
Hypotension
– Used as last ditch tx.
Cons
– Untrained personal
– Environment
A Gaze Into The Future
Advanced delivery Technology
SPIONSSuperparamagnetic
iron oxide
nanoparticles
Nanobytes
ORBIT-1
Treatment for
Bronchiectasis
First Patient February
Phase 2b study
96 Patients
randomized 100 –
150 mg of Liposomal
Ciprofloxacin
Carbon Monoxide
Carbon monoxide is lethal at certain doses that kills
thousands of Americans every year
"The therapeutic window for carbon monoxide is very
small, it's equivalent to the amount you'd receive sitting
in a traffic jam in Mexico City
May improve transplant out comes-- Hmox expression
goes up, it reduces iNOS expression and suppresses a
key signaling pathway involved in the immune response
Research team focuses on the relationship between
carbon monoxide and nitric oxide.
Love Hormone
University of Haifa has found that the hormone oxytocin, the “love hormone", which affects behaviors such as
trust, empathy and generosity, also affects opposite behaviors, such as jealousy and gloating. "Subsequent to
these findings, we assume that the hormone is an overall trigger for social sentiments: when the person's
association is positive, oxytocin bolsters pro-social behaviors; when the association is negative, the hormone
increases negative sentiments.
Previous studies have shown that the oxytocin hormone has a positive effect on positive feelings. The hormone is
released in the body naturally during childbirth and when engaging in sexual relations. Participants in an
experiment who inhaled the synthetic form of the hormone displayed higher levels of altruistic feelings, and it is
supposed that the hormone plays an important role in the formation of relationships between people.
However, in earlier studies carried out by other investigators with rodents, it was found that the hormone is also
related to higher levels of aggression. Therefore, it was decided to examine whether the hormone also affects
negative social sentiments. The present study, which was published in the journal Biological Psychiatry, included
56 participants. Half of the participants inhaled the synthetic form of the hormone in the first session and were
given a placebo in the second session; the others were given a placebo in the first session and oxytocin in the
second session. Following drug administration each participant was asked to play a game of luck along with
another competitor, who was in fact - and without their knowledge - a computer. Each of the participants was
asked to choose one of three doors and was awarded the sum of money that was hidden behind that door.
Sometimes the participant gained less money than the other player, and sometimes more, creating conditions in
which a person might well develop feelings of envy and gloating.
The findings show that those participants who inhaled the oxytocin displayed higher levels of envy when the
opponent won more money and of gloating when they were ahead. Another interesting result was that as soon as
the game was over, no differences between the participants were evident with regards to these sentiments. This
indicates that the negative feelings were empowered only in the course of the game itself.
Possible use of the hormone as a medication for various disorders, such as autism but the hormone's undesirable
effects must be examined.
New Inhaled Vasodilator
inhaled Treprostinil for the treatment of pulmonary arterial
hypertension. The NDA will be subject to a standard review period of
10 months, with a targeted user fee deadline of April 30, 2009.
United Therapeutics Corporation is a biotechnology company
focused on the development and commercialization of unique
products to address the unmet medical needs of patients with
chronic and life-threatening cardiovascular and infectious diseases
and cancer.
Lung Rx, Inc. is a biotechnology company focused on unmet
medical needs in pulmonary medicine and pulmonary delivery of
innovative therapeutic products.