Transcript Nasal Drug Delivery in EMS - E

Intranasal Medications in clinical
practice
Transmucosal medication
delivery
 Is this really a novel idea?
 Commercially available transmucosal drugs:
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Actiq oral (transmucosal fentanyl lollipop)
Nitroglycerin – Sublingual.
Stadol (butorphanol) - Intranasal opiate.
Fentora - Transmucosal fentanyl tablet
DDAVP - Intranasal delivery route.
Migraine medications – Migranol (DHE), etc.
Influenza Vaccine - Intranasal system is available.
 Active area of pharmacology research
Transmucosal Drug Delivery
 Many IV medications, including analgesics
and sedatives, can be delivered
transmucosally, though not currently
available for that indication commercially:
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Large literature base to support their use.
Generic drugs are available, cutting costs
significantly.
Why Intranasal (IN)
medications?
 This delivery route has several advantages:
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Its easy and convenient
Almost everyone has a nose
The nose is a very easy access point for medication
delivery - even easier to access than IM or IV sites, much
easier than rectal delivery
No special training is required to deliver the medication
No shots are needed
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Painless
Low risk
It eliminates any risk of a needle stick to the medical provider
Intranasal Medication
Administration
 Needleless: Intranasal Medication administration
offers a truly “Needleless” solution to drug
delivery.
 Superior: Intranasal medication administration
generally results in superior drug delivery to the
blood stream compared to other transmucosal
routes.
The remainder of this discussion will surround the
topic of intranasal drug delivery issues.
Lecture Outline
 Part 1:
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Discuss the concept of “Off-label medication”
General principles of intranasal medication delivery
 Part 2: Intranasal medications in clinical practice
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EMS
Emergency Medicine
Anesthesia
Hospice
IN medications: Off-label use
 What is “off-label” use
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Drugs are approved for specific indications in specific
subpopulations by specific route of delivery
All other uses are off label
 Common Examples of “off-label” use:
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IV lorazepam for status epilepsy in children
Most IV drugs given to children (80%), pregnant women
Most antidotes for drug overdoses
ACLS drugs down an endotracheal tube
H2 blockers for allergies
IN medications: Off-label use
 Why are so many common uses “off-label”
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It costs about $650 million to bring a drug to
market for an indication
Once it is on the market, clinicians can use it as
they choose for any indication.
Unless there is a HUGE financial incentive to
seek another indication, the pharma company
will not spend the money to get another
indication
IN medications: Off-label use
 Is it OK to use drugs “off-label”
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Yes – in fact is is expected this will occur and
this actually helps advance medical care
U.S Supreme court on off-label use: “off-label
usage of medical devices is an accepted and
necessary corollary of the FDA’s mission”…
health care practitioners can “prescribe or
administer any legally marketed device to a
patient” without limitation or interference.
IN medications: Off-label use
 Center for drug evaluation and research on off-label
use: “Any approved product may be used by a
licensed practitioner for uses other than those stated
in the product label.”
 FDA on off-label use: “Off-label use is a wellestablished principle that has allowed doctors to
discover new and beneficial uses” for previously
approved drugs.
IN medications: Off-label use
 Nice summary on the topic from and Australian
committee:
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“Routine off-label use (or on-label use) can be justified if there is
high-quality evidence supporting efficacy or effectiveness, and
sufficient evidence about the medicine’s safety profile to suggest and
overall reasonable benefit –risk for a given clinical context”
 Conclusion:
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Off-label use is acceptable.
Most intranasal drugs are off-label – but that is OK if
they provide justifiable benefits.
Understanding IN delivery:
General principles
First pass metabolism
Nose brain pathway
Lipophilicity
Bioavailability
First pass metabolism
 Molecules absorbed through the gut, including all
oral medications enter the “portal circulation” and
are transported to the liver.
 Liver enzymes then break down most of these drug
molecules and only a small fraction enter the body’s
circulation as active drug.
 This process is called “First Pass Metabolism.”
 POINT: Nasally delivered medications avoid the
gut so do not suffer first pass metabolism.
First pass metabolism
Nose brain pathway
 The olfactory mucosa (smelling
Olfactory mucosa, nerve
area in nose) is in direct contact
with the brain and CSF.
 Medications absorbed across the
Brain
olfactory mucosa directly enter
CSF
the CSF.
 This area is termed the nose brain
pathway and offers a rapid, direct
route for drug delivery to the
brain.
Highly vascular nasal mucosa
Lipophilicity
“Lipid Loving”
Non-lipophilic molecules
Lipophilic molecules
 Cellular membranes
are composed of
layers of lipid
material.
Cell Membrane
 Drugs that are
lipophilic are easily
and rapidly absorbed
across the mucous
membranes.
Blood stream
Bioavailability
 How much of the administered medication
actually ends up in the blood stream.
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Examples:
IV medications are 100% bioavailable.
 Most oral medications are about 5%-10% bioavailable
due to destruction in the gut and liver.
 Nasal medications vary, but when the right drug is
delivered in the right way can approach 80%.
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Bioavailability
Naloxone Serum Concentration
1000
Naloxone conc
 Graph demonstrating
naloxone serum
concentrations when
given via IV and IN
routes.
 Note that IV and IN
serum levels are
similar after about 5
minutes.
100
Intravenous
Intranasal
10
1
Time
Intranasal Medication
Administration: Bioavailability
 Not all drugs can be delivered via the nasal mucosa.
 Factors affecting bioavailability:
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Medication characteristics.
Medication volume and concentration.
Nasal mucosal characteristics.
Delivery system characteristics.
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Mucosal surface area coverage.
Medication particle size.
Intranasal Medication Administration:
Factors Affecting Bioavailability
Medication Characteristics:
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Drug characteristics that affect bioavailability
via the nasal mucosa include:
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Molecular size.
Lipophilicity.
pH.
Drug concentration.
Properties of the solution the drug is solubilized
within.
Intranasal Medication Administration:
Factors Affecting Bioavailability
Volume and concentration:
Low volume - High concentration.
Too large a volume or too weak a concentration may
lead to failure because the drug cannot be absorbed in
high enough quantity to be effective.
 Ideal volume for nasal delivery is 1/4 to 1/2 ml per
nostril
 Volumes over 1 ml per nostril are too large and may
result in runoff out of the nostril.
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Intranasal Medication Administration:
Factors Affecting Bioavailability
Nasal mucosal characteristics:
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If there is something wrong with the nasal mucosa it may not
absorb medications effectively.
Examples:
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Vasoconstrictors such as Afrin, cocaine prevent absorption.
Bloody nose, nasal congestion, mucous discharge all prevent
mucosal contact of drug.
 This might be overcome with suction prior to drug delivery
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Destruction of nasal mucosa from surgery or past cocaine abuse –
no mucosa to absorb the drug.
Intranasal Medication Administration:
Factors Affecting Bioavailability
Delivery system characteristics:
Nasal mucosal surface area coverage:
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Larger surface area delivery = higher
bioavailability.
Particle size:
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Particle size 10-100 microns adheres best to the
nasal mucosa.
Smaller particles pass on to the lungs, larger
particles form drop and rapidly run-out of the
nose.
Bioavailability and Particle size
 Compared to drops,
atomized medication
results in:
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Larger surface area of
coverage.
Smaller liquid particle
size allowing thin layer
to cover mucosa.
Less run-off out the
nasal cavity.
Intranasal Medication Administration:
Summary
Points:
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Nasal drug delivery is convenient and easy, but it
may not always be effective.
Nasal drug delivery cannot completely replace
the need for injections.
Being aware of the limitations and using the
correct equipment and drug concentrations will
assist you in predicting times when nasal drug
delivery may not be effective.
IN drug delivery: Requirements
 Appropriate Drug
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Known to be bioavailable across the nasal mucosa
 Appropriate Concentration
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Most concentrated form available
 Appropriate patient
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Requires treatment
Nasal mucosa healthy, free of obvious severe bleeding,
thick mucous, etc
IN drug delivery: Conclusions
 IN drug delivery is:
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Convenient, easy and effective for selected
situations
May result in reduced needlestick risk
Can improve and simplify your practice and your
patients experience
Will NOT replace the need for injections
Nasal Drug Delivery:
What Medications?
There are numerous peer reviewed
articles on this topic is you search
PubMed or other internet sites for
specific indications using key words
such as “intranasal” and the medication
or application you desire.