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

Aaron Basing


INTRANASAL FENTANYL IN A NUTSHELL

• PHYSICOCHEMICSTRY

• PHARMACOLOGY

• THERAPEUTICS

• INTRANASAL DRUG DELIVERY

• PHARMACOKINETICS


Physicochemistry

•Molecular FormulaC22H28N2O

•Molecular Weight336.5

•Octanol/Water Coefficient9550

•N-Phenyl-N-[1-(2-phenylethyl) -4-piperidinyl]propanamide 2-hydroxy-1,2,3-propanetricarboxylate


Pharmacology

• Member of the Opiod Family

• Roughly 100 times more potent than morphine

• Main actions mediated through mu-receptor– Analgesia– Sedation


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


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


Intranasal Delivery

The Nasal Cavities

Barash PG, C.B., Stoelting RK, Handbook of clinical anesthesia. 2001, Philadelphia: Lippincott Williams & Wilkins.


Barash PG, C.B., Stoelting RK, Handbook of clinical anesthesia. 2001, Philadelphia: Lippincott Williams & Wilkins.


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.


Nasal Delivery

• Advantages– Avoidance of injections– Avoidance of first pass metabolism– Socially acceptable CF rectal– Sterile technique not required


Nasal Delivery (cont)

• Limitations– Volume– Run off– Formulation/irritation issues– Generally requires drug with good nasal

bioavailability


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


Pharmacokinetics

• Absorption

• Distribution

• Metabolism

• Excretion


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%


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


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– ?


EXCRETION

• Kidney– 75% as metabolites, 10% Unchanged

• Faces– 9% Metabolites, 1% Unchanged


PK SUMMARY

Click for Study Comparator spreadsheet


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

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