Intranasal Medications in clinical practice

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Intranasal Medications in clinical practice
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Transmucosal medication delivery

• Is this really a novel idea?
• Commercially available transmucosal drugs
• 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

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Transmucosal Drug Delivery

• Many IV medications, including analgesics and
  sedatives, can be delivered transmucosally,
  though not currently available for that
  indication commercially
• Large literature base to support their use.
• Generic drugs are available, cutting costs
  significantly.

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Why Intranasal (IN) medications?

• This delivery route has several advantages
• 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
• Painless
• Low risk
• It eliminates any risk of a needle stick to the
  medical provider

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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.

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Lecture Outline

• Part 1
• Discuss the concept of Off-label medication
• General principles of intranasal medication
  delivery
• Part 2 Intranasal medications in clinical
  practice
• EMS
• Emergency Medicine
• Anesthesia
• Hospice

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IN medications Off-label use

• What is off-label use
• 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
• 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

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IN medications Off-label use

• Why are so many common uses off-label
• 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

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IN medications Off-label use

• Is it OK to use drugs off-label
• 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 FDAs mission health
  care practitioners can prescribe or administer
  any legally marketed device to a patient without
  limitation or interference.

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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
  well-established principle that has allowed
  doctors to discover new and beneficial uses for
  previously approved drugs.

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IN medications Off-label use

• Nice summary on the topic from and Australian
  committee
• 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 medicines safety
  profile to suggest and overall reasonable benefit
  risk for a given clinical context
• Conclusion
• Off-label use is acceptable.
• Most intranasal drugs are off-label but that is
  OK if they provide justifiable benefits.

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Understanding IN delivery General principles

• First pass metabolism
• Nose brain pathway
• Lipophilicity
• Bioavailability

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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
  bodys 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.

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First pass metabolism
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Nose brain pathway

• The olfactory mucosa (smelling area in nose) is
  in direct contact with the brain and CSF.
• Medications absorbed across the olfactory mucosa
  directly enter the CSF.
• This area is termed the nose brain pathway and
  offers a rapid, direct route for drug delivery to
  the brain.

Olfactory mucosa, nerve
Brain CSF
Highly vascular nasal mucosa
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Lipophilicity
Non-lipophilic molecules

• Lipid Loving
• Cellular membranes are composed of layers of
  lipid material.
• Drugs that are lipophilic are easily and rapidly
  absorbed across the mucous membranes.

Lipophilic molecules
Cell Membrane
Blood stream
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Bioavailability

• How much of the administered medication actually
  ends up in the blood stream.
• 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

• 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.

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Intranasal Medication Administration
Bioavailability

• Not all drugs can be delivered via the nasal
  mucosa.
• Factors affecting bioavailability
• Medication characteristics.
• Medication volume and concentration.
• Nasal mucosal characteristics.
• Delivery system characteristics.
• Mucosal surface area coverage.
• Medication particle size.

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Intranasal Medication Administration Factors
Affecting Bioavailability

• Medication Characteristics
• Drug characteristics that affect bioavailability
  via the nasal mucosa include
• Molecular size.
• Lipophilicity.
• pH.
• Drug concentration.
• Properties of the solution the drug is
  solubilized within.

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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
• If there is something wrong with the nasal mucosa
  it may not absorb medications effectively.
• Examples
• 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
• Destruction of nasal mucosa from surgery or past
  cocaine abuse no mucosa to absorb the drug.

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Intranasal Medication Administration Factors
Affecting Bioavailability

• Delivery system characteristics
• Nasal mucosal surface area coverage
• Larger surface area delivery higher
  bioavailability.
• Particle size
• 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.

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Bioavailability and Particle size

• Compared to drops, atomized medication results
  in
• Larger surface area of coverage.
• Smaller liquid particle size allowing thin layer
  to cover mucosa.
• Less run-off out the nasal cavity.

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Intranasal Medication Administration Summary

• Points
• 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.

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IN drug delivery Requirements

• Appropriate Drug
• Known to be bioavailable across the nasal mucosa
• Appropriate Concentration
• Most concentrated form available
• Appropriate patient
• Requires treatment
• Nasal mucosa healthy, free of obvious severe
  bleeding, thick mucous, etc

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IN drug delivery Conclusions

• IN drug delivery is
• 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

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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.