Intranasal Medications in clinical practice. Scenario 1: Broken arm A 12 year old fell off his...

$: Intranasal Medications in clinical practice. Scenario 1: Broken arm A 12 year old fell off his bicycle and fractured her distal arm. She is in significant.$
Intranasal Medications in clinical practice

Scenario 1: Broken arm

A 12 year old fell off his bicycle and fractured her distal arm.

She is in significant pain. ED protocols call for IN administration of

sufentanil (0.75 mcg/kg). 10 minutes later the child’s pain gone and she is calm She is taken off to x-ray for diagnostic evaluation of his

fracture

Scenario 2: Frightened child

A 3-year old boy requires head CT scan (or a number of other procedures). He does not have an IV in place and is terrified

of needles. He will not relax and clings to his parent. You administer 0.5 mg/kg of IN midazolam and

10 minutes later he is dozing off and is easily separated from his parent and taken over for his testing.

Scenario 3: Seizing child

EMS is enroute with a 3 y.o. girl suffering a grand mal seizure for at least 15 minutes.

No IV can be established. Rectal diazepam (Valium) is unsuccessful at controlling the

seizure. IV attempts in the ED are also unsuccessful. However, on patient arrival a dose of nasal midazolam

(Versed, Dormicum) is given and within 3 minutes of drug delivery the child stops seizing.

Scenario 4: Epistaxis

A 60 y.o male arrives at the A & E with his third episode of epistaxis in 3 days.

He was cauterized and packed in another A & E the day prior, but started bleeding 5 hours after the packing was removed.

You administer 1 ml of oxymetazoline (Afrin) into the nostril, and insert an oxymetazoline soaked cotton pledget.

15 minutes later his nasal mucosa is dry. You discharge him with instructions to use oxymetazoline

TID for 3 days, and to self treat in the future if possible.

Scenario 5: Heroin Overdose

An unkempt male is dumped in your ambulance bay. He has slow respirations, pinpoint pupils, cool dusky skin and obvious intravenous drug abuse needle track marks on both arms.

After an IV is established, naloxone (Narcan) is administered and the patient is successfully resuscitated.

Unfortunately, the nurse suffers a contaminated needle stick while establishing the IV.

The patient admits to being infected with both HIV and hepatitis C. He remains alert for 2 hours with no further therapy (i.e.- no need for an IV) and is discharged.

Scenario 5: Heroin Overdose

The nurse is given his first dose of HIV prophylactic medications. No treatment for hep C prophylaxis exists.

The next few months will be difficult: He faces the substantial side effects that accompany HIV medications and his personal life is in turmoil due to issues of safe sex with his wife and the mental anguish of waiting to see if he will contract HIV or hepatitis C.

A friend informs him that new evidence suggests that naloxone is effective at reversing heroin overdose if it is given intranasally – with no risk of a needle stick.

Why 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 No special training is required to deliver the medication No shots are needed It is painless It eliminates any risk of a needle stick to the medical

provider

Lecture Outline

Intranasal drug delivery: General principles Intranasal drugs in clinical practice:

Pain control - opiates Sedation - opiates, benzos, ketamine Seizure Therapy - benzos Nasopharyngeal procedures and epistaxis- anesthetics,

vasoconstrictors Opiate overdose - naloxone Other

Understanding IN delivery: General principles

First pass metabolism

Nose brain pathway

Lipophilicity

Bioavailability


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.

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 nasal Narcan approaches

100% - the same as when given intravenously.

Bioavailability

Graph demonstrating naloxone serum concentrations when given via IV and IN routes.

Note that IV and IN serum levels are similar after about 2-3 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.


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.

Volumes over 1/2 to 1 ml per nostril are too large and may result in runoff out of the nostril.


Nasal mucosal characteristics: If there is something wrong with the nasal mucosa it

may not absorb medications effectively. Examples:

Vasoconstrictors such as Afrin prevent absorption.Bloody nose, nasal congestion, mucous discharge all

prevent mucosal contact of drug.Destruction of nasal mucosa from surgery or past

cocaine abuse – no mucosa to absorb the drug.


Delivery system characteristics:Nasal mucosal surface area coverage:

Larger surface area delivery = higher bioavailability.

Particle size: Particle size 10-50 microns adheres best to the

nasal mucosa. Smaller particles pass on to the lungs, larger

particles form droplets and run-out of the nose.


Bioavailability and Particle size: Henry, Ped Dent 1998. Study: Compared IV, IN drops and IN atomization in animal

model. Measured Serum and CSF concentrations. Results:

Serum levels: IV >Atomization > Drops. CSF levels: Atomization>>Drops>IV.

Conclusion: Atomization results in higher serum bioavailability than drops

and higher CSF bioavailability than IV.

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.


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.

Nasal Drug Delivery: What Medications?

Drugs of interest to Emergency Departments: Pain control and Sedation- opiates, benzos, ketamine Seizure Therapy - benzos Nasopharyngeal procedures and epistaxis- anesthetics,

vasoconstrictors Opiate overdose - naloxone Other

Pain control and sedation

Pain Medications Sedatives• Diamorphine • Midazolam

• Fentanyl • Ketamine

• Sufentanil

• Meperidine


Bates et al: A comparison of intranasal sufentanil and midazolam to intramuscular meperidine, promethazine, and chlorpromazine for conscious sedation in children. Ann Emerg Med, 1994 Both methods equally effective in achieving sedation IN sufentanil and midazolam superior in:

Better tolerated by the patients13 minutes faster onset to time of laceration injection

(20 vs 33 minutes)27 minute faster discharge (54 vs 81 minutes)


Borland et al: Intranasal fentanyl reduces acute pain in children in the emergency department: a safety and efficacy study. Emerg Med (Fremantle), 2002

45 Children in acute pain given IN Fentanyl (20 to 40 ug) Titration allowed q 5 minutes Results

Mean VAS score reductions of 18 mm at ten minutesNo negative side effects


Kendall et al: Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. BMJ, 2001.

Randomized trial - 204 IN diamorphine, 200 IM morphine. Results:

IN medication achieved superior pain control at 5, 10 and 20 minutes. Equal at 30 minutes.

IN much better tolerated. IN better accepted by parents and staff.

Conclusion: Nasal opiates should be the prefered method of pain relief in children with painful conditions presenting to the emergency department.


Borland, Ann Emerg Med, 2007.IN fentanyl versus IV morphine for treatment of pediatric

orthopedic fractures - Randomized, double blind, placebo controlled trialResults:

Pain scores identical for IV morphine and IN fentanyl at 5, 10, 20 and 30 minutes

Less time to delivery of medication via nasal route

Conclusion: IN fentanyl is as effective as IV morphine for treating pain associated with broken extremities


Rickard, Am J Emerg Med, 2007.IN fentanyl versus IV morphine for treatment of adult patients

with non-cardiac pain in the prehospital setting - Randomized, open label trialResults:

Pain scores identical for IV morphine and IN fentanyl by the time the hospital was reached

Less time to delivery of medication via nasal route

Conclusion: IN fentanyl is as effective as IV morphine for treating pain in adult EMS patients


Caveats: Borland and Rickard used concentrated fentanyl (150

to 300 mcg/ml) U.S. generic fentanyl comes in 50 mcg/ml

concentrations This lower concentration will likely reduce efficacy

leading to the need to titrate dose Idea - Sufentanil is more potent than fentanyl and is

very effective in adults for controlling pain


Louon et al: Nasal midazolam and ketamine for paediatric sedation during computerised tomography. Acta Anaesthesiol Scand, 1994

30 children < 16 kg requiring CT Dose: Midazolam 0.6 mg/kg, Ketamine 5 mg/kg mixed Results:

83% effective sedation Rapid onset No complications or desaturations

Pre-operative pediatric sedation

Saint-Maurice: The use of midazolam in diagnostic and short surgical procedures in children. Acta Anaesthesiol Scand Suppl 1990“a relatively safe, adaptable, non-invasive method

of inducing sedation in children”

Pre-operative pediatric sedation

Zedie: Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients. Clin Pharmacol Ther 1996 Pre-operative sedation 30 minutes prior to

anesthesia induction with Midazolam or Sufentanil

“Both intranasal midazolam and sufentanil provide rapid, safe, and effective sedation in small children before anesthesia for ambulatory surgery.”

Post-operative pain control

Manjushree: Intranasal fentanyl provides adequate postoperative analgesia in pediatric patients. Can J Anaesth 2002“The intranasal route provides a good alternative

for administration of fentanyl in pediatric surgical patients”

Post-operative pain control

Finkel: The effect of intranasal fentanyl on the emergence characteristics after sevoflurane anesthesia in children undergoing surgery for bilateral myringotomy tube placement. Anesth Analg 2001

“nasally administered fentanyl … was found to reduce the incidence of agitation in these patients”

IN opiates and benzos - My spin

IN opiates and benzos are clearly effective HOWEVER:

Still in its infancy due to: Variable doses in the published studies. Variable delivery devices effecting mucosal coverage. Drug concentrations tend to be too dilute. Lack of titration in most studies.

Opiates and benzos have considerable interindividual variations in effect making titration and mixing of two agents necessary for best effect.

IN opiates and benzos - My spin

We need: Dosing studies that include titration as part of the

administration protocol. Combination drug studies due to interindividual

variations in drug response. More concentrated medications. Standardization of delivery method to optimize

mucosal coverage and improve bioavailability. My personal experience with sufentanil is that it is the

ideal ED opiate for IN delivery

Seizure Therapy

Anticonvulsants Midazolam Lorazepam??

Seizure Therapy

Lahat et al:Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. BMJ, 2000

Prospective study: IN midazolam versus IV diazepam for prolonged seizures (>10 minutes) in children.

Similar efficacy in stopping seizures (app. 90%). Time to seizure cessation:

IV Valium: 8.0 minutes. IN Versed: 6.1 minutes.

Conclusions: IN midazolam controls seizures more rapidly because there is no delay in establishing an IV.

Seizure Therapy

Fisgin et al:Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study. J Child Neurol, 2002

IN midazolam versus rectal diazepam for treatment of pediatric seizure. Prospective trial

Results: IN midazolam effective in 87% of seizures. Rectal diazepam effective in 60%

Conclusion: IN midazolam is more effective for controlling seizures than rectal

diazepam and is more socially acceptable

Seizure Therapy

Scheepers et al: Is intranasal midazolam an effective rescue medication in adolescents and adults with severe epilepsy? Seizure, 2000

IN midazolam for treatment of severe epilepsy in adults.Results:

IN midazolam effective in 94% of seizures.Conclusion:

IN midazolam an effective method for controlling seizures and is a “more acceptable and dignified route” than rectal diazepam.

Seizure Therapy

Holsti, Pediatr Emerg Care, 2007.IN midazolam versus rectal diazepam (PR) for treatment of

pediatric seizure in EMS setting - before an after trialResults:

IN midazolam - 19 minutes less seizure activity on average (11 min IN vs 30 min PR)

Rectal diazepam More likely to re-seize (O.R. 8.4) More likely to need intubation (O.R. 12.2) More likely to require admission to hospital (O.R. 29.3) More likely to require admission to ICU (O.R. 53.5)

Seizure Therapy

Wilson, M. et al: Nasal/buccal midazolam use in the community. Arch Dis Child 2004.

Survey of families with epileptic patients who were prescribed IN midazolam. 83% “effective and easy to use.” 83% “preferred it to rectal diazepam.”

Seizure Therapy

Ahmad. et al: Seizure therapy - IN lorazepam vs IM paraldehyde in rural Africa. Lancet 2006.

RCT of 160 children with status epilepticus. Mean seizure duration 128 minutes 75% controlled with single dose IN lorazepam 61% controlled with IM paraldehyde

Conclusions: IN lorazepam is safe, non-invasive and effective in prehospital setting

Seizure Therapy

Cost (March 7, 2004 Internet search): Rectal diazepam (Diastat brand name)

10 mg: $171 - $194 (£94 - £106)

IN midazolam 10 mg: $4 - $17 (£2- £9)

IN Benzodiazepines for seizures: My spin

IN benzos are very effective for seizure therapy both in children and in adults.

If a seizing patient needs to be treated and does not have an IV established, then administration of IN midazolam should be done without delay. Ideal setting will be home treatment by family and in

EMS settings. Midazolam concentration (5 mg/ml) is marginal and a

higher concentration would be preferred. Other medications such as lorazepam need to be

investigated more thoroughly. (I find lorazepam IN to be quite sedating when compared to midazolam).

Nasopharyngeal procedures and epistaxis

Topical anesthetics Topical vasoconstrictors

• Lidocaine • Oxymetazoline

• Benzocaine • Phenylephrine

• Tetracaine • Cocaine

• Cocaine

• Etc.


Singer et al:Comparison of topical anesthetics and vasoconstrictors vs lubricants prior to nasogastric intubation: a randomized, controlled trial. Acad Emerg Med, 1999

Topical nasal and oral anesthetics with nasal vasoconstrictors result in markedly reduced pain and gagging compared to placebo during NGT placement Pain VAS: 28.6 mm vs 57.5 mm Gagging VAS: 24.1 mm vs 50.9 mm


Wolfe et al:Atomized lidocaine as topical anesthesia for nasogastric tube placement: A randomized, double-blind, placebo-controlled trial. Ann Emerg Med, 2000

Topical nasal and oral anesthetics result in markedly reduced pain compared to topical intranasal 2% lidocaine jelly alone during NGT placement. Pain VAS: 37.4 mm vs 64.5 mm


Krempl et al: Use of oxymetazoline in the management of epistaxis. Ann Otol Rhinol Laryngol, 1995

Retrospective ED study 60 patients with epistaxis Results:

65% controlled with oxymetazoline alone83% success with oxymetazoline plus silver nitrateOnly 17% needed packing


Doo et al: Oxymetazoline in the treatment of posterior epistaxis. Hawaii Med J, 1999

Retrospective study 36 patients with posterior epistaxis Results:

75% controlled with oxymetazoline aloneRemaining 25% treated non-surgically with

recurrent oxymetazoline therapy


Katzet al: A comparison of cocaine, lidocaine with epinephrine, and oxymetazoline for prevention of epistaxis on nasotracheal intubation. J Clin Anesth 1990

3 groups of 14 pateints pretreated with the study drug Following NT intubation, amount of epistaxis scored

Lidocaine with epi: No bleeding in 29% Cocaine: No bleeding in 57% Oxymetazoline: No bleeding in 86%

Vitals: Slightly higher SBP with cocaine, o/w no changes

IN anesthetics and vasocontrictors: My Spin

Nasal instrumentation: Do it every time Proven by multiple RCT’s to reduce pain and

bleeding associated with nasal procedures such as NGT placement and nasal intubation.

Epistaxis: Probably effective, very simple Nasal oxymetazoline for the treatment of epistaxis

is intriguing and appears to be effective Better quality studies are needed.

Treating Opiate overdose

The problem! NEEDLESTICKS Nasal drug delivery of naloxone for opiate overdose

is attractive not because it is BETTER than injectable therapy……

BUT …Because it is SAFER!

..No needle NO needle stick risk!


Hussain et al: Nasal absorption of naloxone and buprenorphine in rats. Int J Pharm, 1984 Naloxone bioavailability is 100% for both IN and IV

delivery.

Loimer et al: (1994). Nasal administration of naloxone is as effective as the intravenous route in opiate addicts. Int J Addict 1994 Nasal naloxone was as effective as IV naloxone in

eliciting opiate withdrawal.


Barton et al: Intranasal administration of naloxone by paramedics. Prehosp Emerg Care, 2002

Prospective prehospital study investigating the efficacy of IN naloxone in treating opiate overdoses 100 patients entered, 52 determined to have opiate overdose Results:

43/52 (83%) = “IN Naloxone Responders.” Conclusions:

IN naloxone is effective most of the timeRoutine use may reduce needle stick injuries

Prehospital IN Naloxone

Results (cont.). 43/52 (83%) = “IN Naloxone Responders.”

Mean time = 3.9 minutes (range 1-11 min.).Median time = 3 min.Mean time from first contact = 9.9 min.Median time from first contact = 8 min.

9/52 (17%) = “IN Non-responders.”4 patients noted to have “epistaxis,” “trauma,” or

“septal abnormality.”Note – no one waited for them to respond, once IV

started they got IV naloxone

IN Naloxone by Paramedics

Other Naloxone Studies…

IV vs. SQ Naloxone: Wanger et al, Acad Emer Med, 1998.

196 patients in Vancouver, BC. IV naloxone (0.4mg) vs. SQ (0.8mg). Response time = crew arrival to RR > 10.

Median response time IV = 9.3 min. Median response time SQ = 9.6 min.

Conclusions = No significant difference. Delay in SQ response offset by time for IV insertion.

*Median response time IN naloxone = 8.0 min.

What if IN naloxone had been available here?

Opiate is gas used at theater By Judith IngramASSOCIATED PRESS

MOSCOW — Russia's top health official said yesterday that the gas used in the storming of a Moscow theater held by Chechen gunmen was based on fentanyl, a fast-acting opiate with medical applications, Russian news agencies reported.

Treatment of opiate overdose with IN naloxone: My spin

Why not? High risk population for HIV, HCV, HBV Difficult IV to establish due to scarring of veins Elimination of needle reduces needle stick risk IV unnecessary for any other therapy in majority of cases IN works as fast or faster than IV naloxone If the treatment is unsuccessful, one can always proceed to

injectable naloxone and no untoward effects should occur (may need 3 minutes of bag ventilation while waiting)

Every EMS system should be utilizing this approach.

Other potential IN medications

IN glucagon for hypoglycemia IN lidocaine for cluster headaches IN saline for severe sinus congestion IN hydroxycobalamine for cyanide treatment? IN antiemetics for N/V, headaches?

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 Is not always effective Will NOT replace the need for injections Can improve and simplify your practice and your

patients experience

Educational Web Links

www.intranasal.net

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