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Intranasal Medications in clinical practice

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

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Intranasal Medications in clinical practice

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  1. Intranasal Medications in clinical practice

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. Understanding IN delivery: General principles • First pass metabolism • Nose brain pathway • Lipophilicity • Bioavailability

  11. 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.

  12. First pass metabolism

  13. Nose brain pathway Olfactory mucosa, nerve • 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. Brain CSF Highly vascular nasal mucosa

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

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

  20. 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 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.

  21. Intranasal Medication Administration: Factors Affecting Bioavailability Delivery system characteristics: Nasal mucosal surface area coverage: • Larger surface area delivery = higher bioavailability. Particle size: • Particle size 10-50 microns adheres best to the nasal mucosa. • Smaller particles pass on to the lungs, larger particles form droplets and run-out of the nose.

  22. Intranasal 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.

  23. 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.

  24. Intranasal Medication Administration: Factors Affecting Bioavailability • 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.

  25. 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

  26. Pain control and sedation Pain Medications Sedatives • Diamorphine • Midazolam • Fentanyl • Ketamine • Sufentanil • Meperidine

  27. Pain control and sedation 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 patients • 13 minutes faster onset to time of laceration injection (20 vs 33 minutes) • 27 minute faster discharge (54 vs 81 minutes)

  28. Pain control and sedation 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 minutes • No negative side effects

  29. Pain control and sedation 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.

  30. Pain control and sedation Borland, Ann Emerg Med, 2007. 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

  31. Pain control and sedation 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 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 pain in adult EMS patients

  32. Pain control and sedation 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

  33. Pain control and sedation 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

  34. 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”

  35. 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.”

  36. 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”

  37. 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 Analg2001 “nasally administered fentanyl … was found to reduce the incidence of agitation in these patients”

  38. 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.

  39. 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

  40. Seizure Therapy Anticonvulsants • Midazolam • Lorazepam??

  41. 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.

  42. 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

  43. 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.

  44. Seizure Therapy Holsti, Pediatr Emerg Care, 2007. IN midazolam versus rectal diazepam (PR) for treatment of pediatric seizure in EMS setting - before an after trial • 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)

  45. Seizure Therapy Wilson, M. et al: Nasal/buccal midazolam use in the community. Arch Dis Child2004. • Survey of families with epileptic patients who were prescribed IN midazolam. • 83% “effective and easy to use.” • 83% “preferred it to rectal diazepam.”

  46. Seizure Therapy Ahmad. et al: Seizure therapy - IN lorazepam vs IM paraldehyde in rural Africa. Lancet2006. • 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

  47. 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)

  48. 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).

  49. Nasopharyngeal procedures and epistaxis Topical anesthetics Topical vasoconstrictors • Lidocaine • Oxymetazoline • Benzocaine • Phenylephrine • Tetracaine • Cocaine • Cocaine • Etc.

  50. Nasopharyngeal procedures and epistaxis 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

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