Intranasal Drug Deliver – A new way John Mackenzie, June 2010.

IN drug delivery has an image problem

History of IN Use  Since ancient times, Indian Ayurvedic herbal medicines have used nasal route for drug administration - the process called “Nasya”.  Presently, modern Western medicine uses nasal decongestants, steroids, minirin, sumatriptan, ED.  New developments with nasal drug delivery being trialled for more therapies (drugs, vaccines).

Scenario 1: Broken arm A 12 year old fell off her bicycle and fractured her arm.  She is distressed with pain   Given IN fentanyl 1.5 mcg/kg.  10 minutes later, the child’s pain gone, + calm and composed.  Taken to Xray happy & co-operative.

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 won't relax and clings to his parent.  Given IN midazolam 0.3 mg/kg and 10 minutes later he is dozing off, and easily separated from parent and taken for CT.

Scenario 3: Seizing child 3 y.o. girl seizing 15 minutes.  IV difficult to establish.  Rectal diazepam (Valium) is unsuccessful at controlling the seizure.  Given IN midazolam 0.3 mg/kg, and within 3 minutes the child stops seizing.

Scenario 4: Heroin Overdose Unkempt male with slow respirations, pinpoint pupils, cool dusky skin and obvious IV needle track marks on both arms.  Given IV naloxone (Narcan) and successfully resuscitated.  But medico receives a needle stick injury.  The patient admits to being infected with both HIV and hepatitis C.

So, why IN medications? Quick, easy, convenient, effective. No special training is required to deliver the medication – can be used by family. Easily administered to unconscious patients. Painless – no needles. No needle stick injury. Few c/i: major nasal obstruction/ polyps, or profuse discharge/ rhinorrhoea.

Outline of presentation 1.Intranasal drug delivery: General principles. 2.Intranasal drugs in clinical practice:  Pain control - opiates  Sedation - opiates, benzos, ketamine  Seizure therapy - benzos  Opiate overdose - naloxone  Other

IN delivery: General principles  First pass metabolism  Nose brain pathway  Lipophilicity  Bioavailability

IN avoids 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 Brain CSF

Bioavailability How much of the administered medication actually ends up in the blood stream:  IV medications are 100% bioavailable.  Most oral medications are about 5%-10% bioavailable due to destruction in the gut and liver.  Nasal medications – bioavailability varies. Depends on several factors.

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

Factors Affecting Nasal Absorption Volume and concentration: Low volume + High concentration best  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 run off out of the nostril.

Factors Affecting Nasal Absorption Molecular weight: Absorption of drugs decreases as molecular weight increases. McMartin et al reported a sharp decline in absorption with molecular weight > 1000 Dalton. Atomised particle size and distribution: Particle size microns adheres best to the nasal mucosa, and best distributed to wide area.

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.

IN Medication Administration: Factors Affecting Bioavailability 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.

Nasal Delivery Systems Various delivery systems are possible:  Nasal pump spray  Nose drops  Metered dose inhaler aerosol spray  Nebulizer  Saturated cotton pledget  Insufflators (Rhinochrom)  Mucosal atomizer device (M.A.D)

Mucosal Atomiser Device: MAD300

What IN medications? Current drugs of interest : Naloxone – opiate overdose Narcotic (Fentanyl) – acute pain - palliative care breakthrough pain Midazolam – seizures - sedation/ anxiety - sedation/ acute psychosis Ketamine – acute pain/ shock - sedation/ acute psychosis Other

Naloxone 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 => 100% bioavailable

Naloxone IV vs IN Wanger et al, Acad Emer Med, 1998: 196 patients in Vancouver, BC. IV naloxone (0.4mg) vs. IN (0.8mg). Response time = crew arrival to RR > 10.  Median response time IV = 9.3 min.  Median response time IN = 9.6 min. => No significant difference.

IN Naloxone advantages  Eliminates needle and risk of needle stick injury.  High risk population for HIV, HCV, HBV.  Difficult IV access due to scarring of veins.  IV unnecessary for any other therapy in majority of cases.  IN works as fast as IV naloxone.  If IN is unsuccessful, can always proceed to IV naloxone with no untoward effects (may need 3 minutes of bag ventilation while waiting). => Quiz

IN Opiate Bioavailability Morphine: 10% Diamorphine: High Fentanyl: 70-80% - very lipid soluble Sufentanil: 78% - very lipid soluble Alfentanil: 65% Oxycodone: 46%

IN Fentanyl Borland, Ann Emerg Med, IN fentanyl versus IV morphine for treatment of pediatric orthopedic fractures - Randomized, double blind, placebo controlled trial Results:  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

IN Fentanyl Rickard, Am J Emerg Med, IN fentanyl versus IV morphine for treatment of adult patients with non-cardiac pain in the prehospital setting - Randomized, open label trial Results:  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 non-cardiac pain in adult Emergency Medical Services.

IN Fentanyl Caveats:  Borland and Rickard used concentrated fentanyl (150 to 300 mcg/ml)  In Australia, fentanyl comes in 50 mcg/ml concentrations  This lower concentration will likely reduce efficacy in patients >50kg.  Sufentanil is more potent than fentanyl and is very effective in adults for controlling pain, but not yet available in Oz.

IN Midazolam 83% bioavailability. IN Midazolam can be used for:  Seizures  Sedation for anxiety/ procedures  Adjunct to IM Haloperidol in the sedation of disturbed patients at risk of harm to themselves or others.

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 Midazolam: 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 Holsti, Pediatr Emerg Care, IN midazolam vs rectal diazepam (PR) for treatment of pediatric seizures. Results:  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 Survey of families with epileptic patients who were prescribed IN midazolam.  83% “effective and easy to use.”  83% “preferred it to rectal diazepam.”

IN Midazolam  Sedation for anxiety before CT, procedures.  Sedation of disturbed patients at risk of harm to self or others, as adjunct to IM Haloperidol.

Pre-op IN Midazolam 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.”

IN Ketamine IN Ketamine has good bioavailability. Sedation and pain relief. Minimal respiratory or BP depression. Indications: Pain relief in shock. Sedation for retrieval of disturbed patient.

Other potential IN medications IN glucagon for hypoglycemia IN lidocaine for cluster headaches IN antiemetics IN insulin – molecular weight 5800, poor bioavailability. Vaccines - flu

Key Facts IN drug delivery is: Convenient, easy and effective for selected situations. Eliminates risk of needle stick injury. Potential for more widespread use in future.

Educational Web Site