Intranasal Medications in clinical practice

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

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.

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

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: 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

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

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

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 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 well-established 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:

“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: 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 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

Highly vascular nasal mucosa

BrainCSF

Lipophilicity

“Lipid Loving” Cellular membranes

are composed of layers of lipid material.

Drugs that are lipophilic are easily and rapidly absorbed across the mucous membranes.

Blood stream

Cell Membrane

Non-lipophilic molecules

Lipophilic molecules

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%.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.