Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

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Anatomy and Physiology of the nose: Key points relating to nasal drug delivery

Nasal Cavity function: Olfaction, filtration, heating and humidification:

The nose has two primary functions. The first is olfaction – the sense of smell. However, the second function is of primary interest to this discussion – filtration, heating and humidification of the inhaled air. Turbinate cross sectional CTTo accomplish the second task, the nasal cavity contains a convoluted set of passageways called the turbinates on the lateral wall of each nasal cavity (see cross-sectional CT scan of turbinates to right). These turbinates interrupt the flow of air into the nasal passage, forcing it through narrow passages that are covered with moist nasal respiratory mucosa. The total surface area available in the nasal mucosa is estimated to be about 180 cm2, of which 10 cm2 is olfactory mucosa and 170 cm2 is the richly vascularized respiratory mucosa. Diagram of the highly vascularized nasal mucosaDuring the passage across this broad mucosal surface, the air is warmed and humidified by a rich vascular capillary bed that is directly beneath the surface see diagram to left). These capillaries are specifically designed for rapid passage of fluids through the vascular wall and out into the dry air.[1-3] The amount of blood flow to this area is considerable – it is higher per unit of tissue than the blood flow to the brain, liver or muscle.[2-4]

Nasal mucosal absorption of medications directly into the blood stream:

Morphine plasma concentrations following IN, IM and oral dosingThis large mucosal surface covered with a rich vascular bed of highly permeable capillaries creates an opportunity for intranasal medication delivery. Not only will fluids cross the capillary bed into the air stream to humidify the air, but fluids delivered in the air stream onto the mucosa will also cross the capillary bed into the blood stream.[1-3] For this reason, when medications of proper concentration and molecular character are delivered onto the nasal mucosa, they are rapidly transported into the capillary bed and delivered to the patient’s circulation. (See diagram comparing nasal morphine plasma concentrations to those of intramuscular and oral morphine).

Nose-brain pathway – nasal mucosal absorption of medications directly into the cerebral spinal fluid and brain:

Olfactory mucosa demonstrating close proximity to brain emphaasizing the nsoe brain pathwayIf the nasally administered medication contacts the olfactory mucosa, there is good evidence that suggests molecule transport can occur directly across this tissue and into the cerebral spinal fluid.[5-8] The olfactory mucosa is located in the upper nasal cavity, just below the cribriform plate of the skull. It contains olfactory cells which traverse the cribriform plate and extend up into the cranial cavity. When medication molecules come in contact with this specialized mucosa they are rapidly transported directly into the brain, skipping the blood-brain barrier, and achieving very rapid cerebrospinal fluid levels (often faster than if the drug is given intravenously). CSF levels of drug following IN versus Sublingual vs subcutaneous administrationThis concept of transfer of molecules from the nose to the brain is referred to as the nose-brain pathway and has implications when centrally acting medications such as sedatives, anti-seizure drugs and opiates are delivered nasally. Multiple authors demonstrate that the nose-brain pathway leads to nearly immediate delivery of some nasal medications to the cerebral spinal fluid, by-passing the blood brain barrier.[5-8]

Summary:

In summary, the nasal mucosa consists of a highly vascularized surface that easily absorbs many medications directly into the venous circulation. This medication is then transported to the heart and pumped out to the body where it can have its therapeutic effect. Because the absorptive surface is not the intestinal mucosa, the drug never enters the portal circulation and is not subjected to hepatic metabolism – thereby leading to far higher drug levels than oral or rectal medications. In addition, the nose brain pathway across the olfactory mucosal transports some of the nasally delivered medication directly into the CSF and brain – leading to early effects of centrally acting medications.

References (Click here for abstracts):

1. Hussain, A.A., Mechanism of nasal absorption of drugs. Prog Clin Biol Res, 1989. 292: p. 261-272.

2. Dale, O., R. Hjortkjaer, and E.D. Kharasch, Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand, 2002. 46(7): p. 759-70.

3. Chien, Y.W., K.S.E. Su, and S.F. Chang, Chapter 1: Anatomy and Physiology of the Nose. Nasal Systemic Drug Delivery, 1989. Dekker, New York: p. 1-26.

4. Mygind, N. and S. Vesterhauge, Aerosol distribution in the nose. Rhinology, 1978. 16(2): p. 79-88.

5. Henry, R.J., et al., A pharmacokinetic study of midazolam in dogs: nasal drop vs. atomizer administration. Pediatr Dent, 1998. 20(5): p. 321-6.

6. Sakane, T., et al., Transport of cephalexin to the cerebrospinal fluid directly from the nasal cavity. J Pharm Pharmacol, 1991. 43(6): p. 449-51.

7. Banks, W.A., M.J. During, and M.L. Niehoff, Brain uptake of the glucagon-like peptide-1 antagonist exendin(9-39) after intranasal administration. J Pharmacol Exp Ther, 2004. 309(2): p. 469-75.

8. Westin, et al., Direct nose-to-brain transfer of morphine after nasal administration to rats. Pharm Res, 2006. 23(3): p. 565-72.