Pharmacology Is Anything New Out There

1
PharmacologyIs Anything New Out There?

• Bob Spoula, MBA RRT
• Chief Science Officer
• Edward Hospital

2
What Are We Doing?
Objectives

• Examine the historical perspective of Respiratory
  Pharmacology
• Look at recent developments concerning drugs and
  delivery systems
• Provide framework that may help to improve
  clinical practice
• Attempt to provide sufficient stimulation to
  allow for 50 contiguous wakeful minutes

3
A Historical PerspectiveOn Inhalation Therapy
Clearly HMO Prescribed
4
How Far Have We Come?

• Do you remember

And then came
1982!
5
Do you remember 1982?

• No, Bob, of course I dont remember 1982 because
  I wasnt even born yet!
• But for those of us who were around

Michael Jackson released Thriller, ultimately
selling lOO million copies
The Dow closed at an all-time high of 1065up 14
points from January 1973
Time Magazine picked The Computer as their MOTY!
6
Albuterol is FDA Approved!

• Prior drugs not as Beta-2 specific
• Issues with RT related sympathomimetics
• CNS stimulation
• Tachycardia
• Shakiness
• Agitation
• Headaches
• Nausea / Vomiting
• Issues addressed due to Beta-2 specificity

7
When you solve problem No. 1., Number 2 gets a
promotion!

• Montreal Protocol drafted in 1987
• Multi-phase elimination of CFCs and other ozone
  depleting chemicals
• Problem for Healthcare and RTs
• Issue is not the medication
• Issue is how to get the medication OUT!
• All CFC MDIs prohibited in the U.S. starting Jan
  01, 2009

8
CFC vs. HFA

• CFCs found to cause harm as early as 1974!
• Published in Nature journal by Molina and
  Rowland
• Shared Nobel Prize in 1995 for ozone layer
  depletion research
• CFCs unfortunately extraordinarily stable!
• Found that adding a hydrogen molecule causes
  quicker breakdown

To date, there have been virtually no inhalers
that have exploded due to propellants
9
What to Expect

• Smaller plume when delivering actuation
• May cause patients to tell you the inhalations
  feel different, but if it does, somethings
  missing

10
What to Expect

• Warmer puff, softer mist-like spray
• Again, not an issue with good patient education
  and proper equipment
• May be a good opportunity to convert your more
  resistant patients
• HFAs purportedly cause a gummy or sticky feel
  to surfaces
• Clean inhaler/chamber more often

11
Is It Effective?

• Studies from Chest Journal
• Ramsdell, Klinger, Ekholm, and Colice, l999
• HFA Albuterol and CFC Albuterol provided
  comparable bronchodilator efficacy
• Tinkelman, Bleecker, et al.
• Regular use of either Proventil HFA or Ventolin
  did not cause asthma control to deteriorate
• Kleeup, Tashkin, Cline, and Ekholm
• HFA 134a Salbutamol would be a safe and
  effective substitute for CFC Salbutamol

12
But it doesnt work

• Strategies
• Listen (for at least 90 seconds)
• Many patients are frustrated by lack of time
  spent at bedside
• Evaluate patient technique
• Ensure patient has aerochamber
• Make sure inhaler cleaned on regular basis
• Also need to be primed new and after 2 weeks
  inactivity by 3 sprays

13
But it doesnt work

• Provide benefit of your experience
• Nebs may be viable alternative until D/C
• Compare peak flows of nebs vs. HFA MDI
• Maybe an underlying exacerbation requiring more
  puffs for this visit
• Talk about their medication plan
• Are steroids or LABAs included in plan?

14
Try Something Different

• Generic HFA Albuterol will not be available
  until patent expires
• 3 manufacturers offering HFA Albuterol
• Ventolin HFA from Glaxo Smith Kline
• Proventil HFA from Schering Corporation
• ProAir HFA from IVAX (Teva parent corporation)
• Active ingredient/dosage is identical according
  to each package insert
• 120 mcg from canister valve, 108 from mouthpiece
• SO WHATS THE DIFFERENCE?

15
Heres the BIGGEST difference for most

• Research and development cost money
• New formulations allow new patents
• Companies CAN and WILL look to recover
• R D money in the pricing structure
• Typical Scenario
• Generic albuterol monthly - 5
• Brand name albuterol monthly - 40

16
B.O.B.s Quick Quiz

• Which of these drugs are taken by BOTH Britney
  Spears and racehorses?
• A. Pergolide
• B. Xylazine
• C. Clenbuterol

17
B.O.B.s Quick Quiz

• Which of these drugs are taken by BOTH Britney
  Spears and racehorses?
• A. Pergolide
• B. Xylazine
• C. Clenbuterol

Pergolide was withdrawn by the FDA in 2007. It
was previously used as an alternative therapy for
Parkinsons. It is also used for equine Cushings
syndrome (still available in Canada)
18
B.O.B.s Quick Quiz

• Which of these drugs are taken by BOTH Britney
  Spears and racehorses?
• A. Pergolide
• B. Xylazine
• C. Clenbuterol

Xylazine is used for sedation and muscle
relaxation in horses and other large mammals. Of
special note, it is used in combination with
Special K (Ketamine), but we know Britney would
NEVER do that..the only Special K in her life is
the and only K-FED!
19
B.O.B.s Quick Quiz

• The correct answer is Clenbuterol!

Clenbuterol is used worldwide in the tx of
allergic respiratory disease in horses. Due to
its CNS stimulation, it also seems to accelerate
metabolism, making Clen the hottest dietary
supplement in Hollywood. Although you and I
would have to get it through illicit sources on
the internet, Im sure Britneys vetinarian makes
sure she has plenty of Clen available, just in
case her horses start to wheeze.
20
C.O.P.D. and Smoking
21
C.O.P.D. and Smoking

• New initiative at Edward Hospital
• New reports printed from nursing admission
  database
• Therapists go out and talk with patients,
  present literature, answer questions
• Patient responses
• Thank you. I have some literature already.
• I already quit. Its been 3 days now, since my
  admission.
• You people are killing me. You know all the
  answers, dont you?! Give me my treatment and
  leave me the hell alone!
• (Insert your response here)
• Its not their fault..

22
Its Bigger Than All Of Us

• Current population of the U.S?
• 300 Million
• 1 birth every 7 seconds, 1 death every 11 seconds
• Current estimated smokers in U.S.
• 50 Million (about 20 of total)
• 1.5 Billion cigarettes roll off the assembly
  line each day!

How did all this start?
23
Contrary to Popular Belief
Remember Christmas is just around the corner
Did Not Start With These Guys.
How did all this start?
24
A Long, Long Time Ago

• Can be traced back to over 5000 years ago
• Embraced for the longest time

25
The Science of Addiction
Cigarette Smoking Faster than an injection, more
reinforcing than crack cocaine
It all starts with nicotine!
NEVER MIND the formaldehyde, ammonia, hydrogen
cyanide, arsenic, and DDT or 4000 other
identified chemicals
26
The Science of Addiction

• Within six seconds
• Nicotine stimulates the nicotinic Ach receptors
• Causes dopamine release
• Dopamine associated with the reward center
• Influences molecules that control
• Mood
• Energy level
• Memory

Another illustration of the power of
addiction The head of Regent Seven Seas
announced that smokers cancelled bookings worth
US3 million (3.6 million) when the line
announced it would ban smoking in cabins and
balconies.
27
The Science of Addiction
VS.
Millions of years of human physiology
R.T. handing out pamphlets
We Need A BIGGER Weapon!
28
Changing the Game

• Im not going to do it, and you cant make me..

• Unless I can change your attitude from the inside
  out

How many psychoanalysts does it take to change a
light bulb?
Only one, but the light bulb has got to WANT to
change!
29
Enter Chantix! (Varenicline)

• Mechanism of Action
• Blocks nicotine Ach receptor
• Agonist to several types of receptors
• Blocks pleasure response associated with
  smoking
• Shown to be superior to NRT (patch, gum)
• Patients report a response of yuck to smoking
  after a few weeks on Chantix

30
Chantix

• Usage
• Start Chantix 1 week before attempting to quit
• You may smoke during that week and quit by day 8
  of the medication
• Program length is 12 weeks, with an additional 12
  weeks if desired
• Pleasure response should have been negated at
  that point
• Still need motivated patient willing to do what
  is necessary

31
Chantix

• Cautions and Warnings
• Side effects, as reported by Pfizer
• Gastrointestinal upset
• Change in taste
• Vivid or unusual dreams

Whats The Latest?
32
Chantix

• FDA Alert Issued 2/1/08
• Serious neuropsychiatric symptoms
• Agitation, depression, suicide ideation, and
  attempted suicide
• May 2008- FAA bans use of Chantix and instructs
  those affected by the ban (pilots, ATC) to stop
  flying for 72 hours after discontinuing use
• ISMP reported 1001 new cases of adverse effects
  due to Chantix (vs. 17 for NRT and 44 for Zyban)
• ISMP notes that there has been a high degree of
  publicity about the potential side-effects

33
Conclusions

• Like anything else, Chantix is a cost-benefit
  analysis
• Average smoker attempts to quit SIX times before
  succeeding
• Chantix showed 44 success rate when properly
  supported
• Zyban showed 30 success rate
• Primarily used for anti-depression therapy
• Placebo showed 18 success rate

Each patient case needs to be decided based on
individual factors after all available
information has been gathered
34
Conclusions

• Of course, there are exceptions to every rule!

35
B.O.B.s Quick Quiz

• What innovative method of extinguishing a
  cigarette did an angry German man use when his
  girlfriend lit up in their apartment in
  February 2008?
• A. Smothered it with their dog
• B. Doused it with lighter fluid
• C. Dunked her and the smoke in their bathtub
• D. Used a powder-based fire extinguisher

36
B.O.B.s Quick Quiz

• What innovative method of extinguishing a
  cigarette did an angry German man use when his
  girlfriend lit up in their apartment in
  February 2008?
• A. Smothered it with their dog
• B. Doused it with lighter fluid
• C. Dunked her and the smoke in their bathtub
• D. Used a powder-based fire extinguisher

37
B.O.B.s Quick Quiz

• What innovative method of extinguishing a
  cigarette did an angry German man use when his
  girlfriend lit up in their apartment in
  February 2008?
• A. Smothered it with their dog
• B. Doused it with lighter fluid
• C. Dunked her and the smoke in their bathtub
• D. Used a powder-based fire extinguisher

38
B.O.B.s Quick Quiz

• What innovative method of extinguishing a
  cigarette did an angry German man use when his
  girlfriend lit up in their apartment in
  February 2008?
• A. Smothered it with their dog
• B. Doused it with lighter fluid
• C. Dunked her and the smoke in their bathtub
• D. Used a powder-based fire extinguisher

39
B.O.B.s Quick Quiz

• What innovative method of extinguishing a
  cigarette did an angry German man use when his
  girlfriend lit up in their apartment in
  February 2008?
• D. Used a powder-based fire extinguisher

A virulent anti-smoker in Germany was so angry
when his girlfriend lit up he emptied a fire
extinguisher to put out the cigarette, caking her
and their apartment in powder.
40
Surfactant Replacement Therapy

• Surfactant deficiency identified as early as 1959
• Replacement not well understood
• Tried to nebulize Colfosceril 1960s
• Needs proteins and PG to spread, absorb
• Alveolus lined with Type I and Type II cells
• Type II Cells secrete surfactant
• If Type II damaged or immature, may have
  surfactant deficiency
• Mechanical ventilation can lead to Type II damage
  
• (Iatrogenic RDS)

41
Surfactant Replacement Therapy

• Indications for SRT
• Prophylactic use
• Babies less than 28 32 weeks
• Weight less than 1300 grams
• LS Ratio lt 21
• Absence of PG in amniotic fluid
• Rescue use
• Have signs of distress
• Need ventilatory assistance
• CXR shows RDS
• O2 needs increase

42
Effects of Surfactant Therapy

• Reduces surface tension
• Stabilize the alveoli
• Prevents atelectasis at end-expiration
• Decrease work of breathing
• Increases PO2 due to more stable alveoli
• Increase lung compliance
• Avoid complications due to air leak

43
How Do You Choose?

• Exogenous Surfactant Choices
• 1. Natural (animal) options
• Survanta (bovine extract)
• Curosurf (pig lung extract)
• Infasurf (calf lung extract)
• Doctasurf (MD lung extract)
• 2. Synthetic options
• Exosurf
• ALEC (Available in U.K.)
• Surfaxin

44
How Do You Choose?

• Natural Surfactant Choices
• Comes from natural sources
• Proteins present for absorption
• Limited supply
• Time-consuming, expensive

45
How Do You Choose?

• Artificial Surfactant Choices
• Comes from laboratory
• No proteins means less infection
• Unlimited supply
• May not perform as well
• Some components not studied in infants

46
Current Research

• Roger Soll (University of Vermont) published
  several studies in 1999 trying to answer
• Which One?
• How Often?
• When to Give?

47
Conclusions (Not Recommendations)

• Soll concluded that
• Both types are effective
• Quicker response, less barotrauma with natural
• Response is more sustained with multiple natural
  doses
• Prophylactic usage overwhelmingly effective
• Decrease mortality by 40-70

48
Whats the Latest?

• Soll and Pfister, 2005
• Surfactant protein analogs..can ameliorate RDS
  and improve clinical outcome
• Ghodrat, 2006
• Consistent pharmaceutical quality, unlimited
  supply, and no risk of disease transmission
• Moya, et al., Pediatrics - 2005
• Lucinactant (Surfaxin) reduces the incidence of
  BPD compared with colfosceril palmitate
• Decreases RDS-related mortality rates, compared
  with beractant.
• Strongly suggest that administration of
  lucinactant to infants at risk for RDS results in
  neonatal survival that is at least comparable
  with, if not superior to, that of infants given
  the animal-derived surfactants beractant and
  poractant alfa.
• Phase 3 Clinical Trials SELECT and STAR

49
Whats the Latest?

• May 2008
• Discovery Labs received an approvable letter
  from the FDA
• Set forth remaining conditions that must be
  satisfied in order to gain U.S. marketing
  approval for Surfaxin
• 0f Note
• FDA and Discovery Labs agreed on content of the
  package insert
• Letter contained no requirements for additional
  clinical trials
• Discovery Labs addressed quality and
  manufacturing issues raised by the FDA, and are
  prepared for commercial Surfaxin production

50
Nitric Oxide

• Named the Molecule of the Year in 1992
• Common substance in various concentrations
• Present in
• Auto exhaust
• Cigarette smoke
• Room air
• Fireflies
• Plant cells

51
Nitric Oxide

• Nitric Oxide exerts effects on
• Kidney function
• Uterine contraction
• Endocrine glands
• Pancreas, adrenalin, hypothalamus
• Autonomic Nervous System
• Various areas in the brain
• Smooth muscle relaxation most significant in use
  of inhaled Nitric Oxide

52
Nitric Oxide

• NO is NOT a selective pulmonary vasodilator, but
  becomes one when inhaled
• Hess, MacIntyre, et al., Respiratory Care 2002
• Better than systemic agents because
• Inhaled gases never reach unventilated lung units
• NO has an affinity for Hb 106 times vs. O2
• Has a half life of less than 5 seconds

53
Why Neonatal Usage?
Patent Ductus Arteriosus
Areas of High Pressure
Patent Foramen Ovale
Right-to-Left Shunts of Fetal Circulation
54
The Ugliness of PPHN
Blood shunts right to left Bypasses lungs, does
not make pulmonary circuit Oxygen content
decreases,increasing pulmonary vascular
resistance Increased PVR caused more shunting,
more blood bypasses pulmonary circuit Constant
cycle also leads to arteriole remodeling
(hypertrophy), which worsens gas exchange
further
55
Nitric Oxide to the Rescue!

• Inhaled Nitric Oxide used to decrease PVR,
  increase oxygenation
• Since inhaled gas works only in ventilated part
  of lung, avoid V/Q mismatch and worsening hypoxia
• ALSO DILATES THE PULMONARY BEDS AND INCREASES PO2
• Not always so easy to give

56
Early Days of Nitric Oxide

• Early setups involved H-cylinders, multiple
  blenders, industrial scrubbers, flow
  calculations, MetHb poisoning, and lots of
  guessing!

Nitric oxide delivery setup, Childrens Memorial,
early 1990s
57
The Only FDA Approved Indication

• INOmax, in conjunction with ventilatory support
  and other appropriate agents,is indicated for the
  treatment of term and near-term ( gt 34 weeks)
  neonates with hypoxic respiratory failure
  associated with clinical or echocardiographic
  evidence of pulmonary hypertension, where it
  improves oxygenation and reduces the need for
  extracorporeal membrane oxygenation.

58
Nitric Oxide Benefits
Provides immediate benefits, but not without a
downside
Causes pulmonary artery vasodilation, decreased
PVR
Less shunting through PDA and PFO
59
Complications of NO

• Inhibits aggregation of platelets
• Promotes formation of Met Hb
• Not appropriate for everyone
• Forms NO2
• Can be fatal if given to wrong lesion

Biggest Complication of All?
60
As If The Economic Crisis Wasnt Bad Enough
Already
How About An Alternative?
61
How About This?

• Aerosolized prostacyclin (Flolan) for adults
• Potent vasodilator
• Inhalation route provides quick benefits
• Half-life of approx. 2 minutes limits systemic
  effects
• Explored several years prior to inhaled nitric
  oxide

Take the lead from SFGH.
62
SFGH Protocol

• Aersolized prostacyclin is indicated for
  treatment of
• HRF in adult ventilated patients with PO2/FiO2
  ratio of less than 100
• Severe pulmonary hypertension in adults with a
  mean PAP of at least 50 mm Hg
• Response to treatment includes
• 20 or greater increase in PO2
• 20 reduction in PAP
• Clinical signs of improvement
• Response should be apparent within 10 minutes!

63
ButDoes It Work?

• All studies demonstrate that the clinical
  response to inhaled PGI(2)is as good, if not
  better, than INO
• Brian Walsh, University of Virginia Childrens
  Medical Center
• The results of this study suggest that inhaled
  IPGE is a safe and selective pulmonary
  vasodilator in HRF
• Good, Black, Aranda, and Shankaran Childrens
  Hospital of Michigan
• Inhaled prostacyclin induces a selective
  pulmonary vasodilation that is comparable to the
  effect of inhaled nitric oxide
• Haraldsson et al., Sahlgrenska University
  Hospital, Sweden

64
Cost Effectiveness
VS.
130 To 170 Per Day
137 per hour
65
And Now For Something Completely Different
What Defines YOUR Department?

• Blood Gas Responsibilities?
• Airway Management?
• Patient Assessment and Protocols?
• Assistance with Invasive Procedures?
• Full presence in ED but not in NICU?

Strength Through Diversity and Flexibility!
Does it involve the pulmonary system at SOME
point in the process?
66
Yes, but I didnt inhale

• If you inhale a drug, does that make it a
  respiratory drug?
• Not necessarily, but it does make us the EXPERTS
  in the area!

Could you troubleshoot this piece of equipment?
67
Exubera
Inhaled Insulin!
68
Exubera

• Departure from traditional role, but inhalation
  route makes us the instant experts
• Additional RT factors
• Baseline and follow-up PFTs required
• Smokers not eligible must be smoke-free for six
  months
• Smokers show a 2X 5X greater rate of absorption
• Technique is KEY to medication delivery!

69
Exubera

• Pfizer touted benefits starting in the 1990s
• Bought out co-developer for 1B in 2001
• Sales projected to be 1.5B annually by 2010
• Started sales in September 2006
• Stopped sales in Oct 2007 due to poor response

What Happened?
70
Exubera

• Why did Pfizer pull the plug?
• Not cost effective
• Not clinically superior to traditional injections
• May be difficult to dose properly
• Still needs to be covered with long-acting
  insulin such as Lantus
• May be difficult for those with unstable lung
  disease
• Lung cancer concern?
• 1/4292 placebo patients developed lung CA
• 6/4740 Exubera patients developed lung CA
• CA patients were smokers

71
Why did you even bother?

• Other companies continuing research
• Eli Lilly and Company
• Mannkind
• Aradigm
• Size of market drives new competitors
• Problems already identified by Pfizers
  experience!

72
B.O.B.s Quick Quiz

• Inhaling three 1 mg doses of Exubera results in a
  HIGHER dose than inhaling one 3 mg dose

• True
• False

73
B.O.B.s Quick Quiz

• Inhaling three 1 mg doses of Exubera results in a
  HIGHER dose than inhaling one 3 mg dose

• True

Oddly enough, its true. While basic math has not
changed, due to retention of blister
contents,three consecutive 1 mg doses gave more
medication than one 3 mg dose!
74
Summary
HFA Inhalers

• U.S. Law by January 1st
• Different formulations from different companies
• Watch patient technique provide and clean
  equipment

75
Summary

• Dont be upset when the patients throw you out
• Provide information and plant the seed
• Help them make the Chantix decision on an
  individual basis
• Understand that a 44 quit rate is amazing!

76
Summary
Surfaxin

• First artificial surfactant with good peer
  reviews
• Look at the SELECT and STAR studies
• Surfactant will continue to be a mainstay of
  therapy in any NICU

77
Summary
Flolan

• Adult usage for pulmonary hypertension and
  popping oxygen saturations
• Take the lead from SFGH its their protocol
• I dont have an extra 145,000 on me to spend,
  and neither does my hospital

78
Summary
Exubera

• Non-traditional roles for traditional routes
• Blood sugar testing is important, not all that
  difficult
• RTs act with a sense of urgency
• If the patient inhales it, we own it!

79
Thank You!
My assistants will now be glad to answer any
questions you may have!