1. Modelling and Simulation Group, School of Pharmacy Intranasal Fentanyl in a Nutshell Aaron Basing

2. Modelling and Simulation Group, School of Pharmacy INTRANASAL FENTANYL IN A NUTSHELL PHYSICOCHEMICSTRY PHARMACOLOGY THERAPEUTICS INTRANASAL DRUG DELIVERY PHARMACOKINETICS

3. Modelling and Simulation Group, School of Pharmacy Physicochemistry Molecular Formula C22H28N2O Molecular Weight 336.5 Octanol/Water Coefficient 9550 N-Phenyl-N-[1-(2-phenylethyl) -4-piperidinyl]propanamide 2-hydroxy-1,2,3-propanetricarboxylate

4. Modelling and Simulation Group, School of Pharmacy Pharmacology Member of the Opiod Family Roughly 100 times more potent than morphine Main actions mediated through mu-receptor –Analgesia –Sedation

5. Modelling and Simulation Group, School of Pharmacy Therapeutics Can be administered by many routes –IV, IM, SC, INH, Transmucosal, Transdermal, Rectal, Epidural Can be used for many indications –Pain Chronic, Breakthrough, Post Operative, Trauma, Procedural –Anaesthesia Premedication for induction, Adjunct for maintenance

6. Modelling and Simulation Group, School of Pharmacy Therapeutics (cont) Main Side Effects –CNS depression (drowsiness  coma) –Respiratory Depression –Mood Alteration –Nausea and Vomiting Drug Interactions –Other CNS/Respiratory Depressants –CYP 3A4 Inhibitors/Inducers

7. Modelling and Simulation Group, School of Pharmacy Intranasal Delivery The Nasal Cavities Barash PG, C.B., Stoelting RK, Handbook of clinical anesthesia. 2001, Philadelphia: Lippincott Williams & Wilkins.

8. Modelling and Simulation Group, School of Pharmacy Barash PG, C.B., Stoelting RK, Handbook of clinical anesthesia. 2001, Philadelphia: Lippincott Williams & Wilkins.

9. Modelling and Simulation Group, School of Pharmacy Delivery Devices Wolfe, T.R. and T. Bernstone, Intranasal drug delivery: an alternative to intravenous administration in selected emergency cases. J Emerg Nurs, 2004. 30(2): p. 141-7.

10. Modelling and Simulation Group, School of Pharmacy Nasal Delivery Advantages –Avoidance of injections –Avoidance of first pass metabolism –Socially acceptable CF rectal –Sterile technique not required

11. Modelling and Simulation Group, School of Pharmacy Nasal Delivery (cont) Limitations –Volume –Run off –Formulation/irritation issues –Generally requires drug with good nasal bioavailability

12. Modelling and Simulation Group, School of Pharmacy What circumstances promote good the utility of a drug for nasal administration Drug Characteristics –Small molecular weight –High Octanol Water Coefficient Patient Characteristics –High nasal blood flow Formulation Characteristics –High Potency  Small volume for dose

13. Modelling and Simulation Group, School of Pharmacy Pharmacokinetics Absorption Distribution Metabolism Excretion

14. Modelling and Simulation Group, School of Pharmacy ABSORPTION Time to maxium Concentration –IV>INH>Nasal>SC>Buccal>>>Transdermal Bioavailability –IV 100% –INH 70-90% –Nasal 70- 90% –Buccal 30-70% –Transdermal +90%

15. Modelling and Simulation Group, School of Pharmacy DISTRIBUTION Distribution Studies –Adipose Tissue – some –Skeletal muscle – some –CSF – Minimal erratic –Well Perfused organs – High Has been modelled with both 2 and 3 compartment models 80 – 86% Protein Bound –Predominantly alpha-1-acid glycoprotien

16. Modelling and Simulation Group, School of Pharmacy METABOLISM Liver and Intestinal Mucosa –N-Dealkylation to norfentanyl (inactive) by CYP3A4 –Hydroxylation to other inactive metabolites 4-N-(N- propionylanilino) piperidine and 1-(2-phenethyl)-4-N-(N- hydroxypropionylanilino) piperidine Skin –Neglibile Other Mucosa –?

17. Modelling and Simulation Group, School of Pharmacy EXCRETION Kidney –75% as metabolites, 10% Unchanged Faces –9% Metabolites, 1% Unchanged

18. Modelling and Simulation Group, School of Pharmacy PK SUMMARY Click for Study Comparator spreadsheet

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