Modelling and Simulation Group, School of Pharmacy
Intranasal Fentanyl in a Nutshell
Aaron Basing
Modelling and Simulation Group, School of Pharmacy
INTRANASAL FENTANYL IN A NUTSHELL
• PHYSICOCHEMICSTRY
• PHARMACOLOGY
• THERAPEUTICS
• INTRANASAL DRUG DELIVERY
• PHARMACOKINETICS
Modelling and Simulation Group, School of Pharmacy
Physicochemistry
•Molecular FormulaC22H28N2O
•Molecular Weight336.5
•Octanol/Water Coefficient9550
•N-Phenyl-N-[1-(2-phenylethyl) -4-piperidinyl]propanamide 2-hydroxy-1,2,3-propanetricarboxylate
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
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
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
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.
Modelling and Simulation Group, School of Pharmacy
Barash PG, C.B., Stoelting RK, Handbook of clinical anesthesia. 2001, Philadelphia: Lippincott Williams & Wilkins.
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.
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
Modelling and Simulation Group, School of Pharmacy
Nasal Delivery (cont)
• Limitations– Volume– Run off– Formulation/irritation issues– Generally requires drug with good nasal
bioavailability
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
Modelling and Simulation Group, School of Pharmacy
Pharmacokinetics
• Absorption
• Distribution
• Metabolism
• Excretion
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%
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
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– ?
Modelling and Simulation Group, School of Pharmacy
EXCRETION
• Kidney– 75% as metabolites, 10% Unchanged
• Faces– 9% Metabolites, 1% Unchanged
Modelling and Simulation Group, School of Pharmacy
PK SUMMARY
Click for Study Comparator spreadsheet
Modelling and Simulation Group, School of Pharmacy
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