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Mucosal Surfaces for Noninvasive Drug Administration

King, Brent R. MD

Pediatric Rounds: Last in a Series

Dr. King is an associate professor of emergency medicine and pediatrics, and the chairman of the department of emergency medicine at the University of Texas-Houston Medical School.

Figure. B

Figure. B

Mucosal surfaces offer many advantages as routes of noninvasive drug administration. There are a great many of them, and as with the respiratory tract, the mucosal surface is vast. Although they are only slightly less accessible than the skin surface, mucosal surfaces lack the thick stratum corneum layer that impedes drug absorption through the skin, allowing many agents to be quite readily absorbed. This is aided in part by their generally excellent blood supply, which tends to ensure that the absorbed agents enter the systemic circulation relatively quickly.

Of course, the poster child for mucosal administration is inhalational anesthesia, which has been employed successfully for decades. Emergency physicians use this method of drug delivery on an almost-daily basis. Beta-agonist medications are frequently given by nebulization or metered dose inhalation. Other agents are introduced through the respiratory mucosal surface by direct instillation (e.g., surfactant, epinephrine, atropine) and in powder form. Most agents administered into the respiratory tract never make it beyond the upper airway. Some particles are too large to reach the lower airways, and some are too small. Particles of intermediate size (1-4 micrometers) are most likely to reach the lower airways as are more lipid-soluble particles. Lipid-soluble drugs are also more likely to be absorbed quickly.

In addition to the pulmonary mucosa, the respiratory tract also includes the nasal mucosa. Anyone who lived through the 1980s remembers the lethal combination of money and hedonism that fueled cocaine addiction. Back in those days, cocaine addicts favored snorting cocaine into their noses. Drugs administered via the nasal mucosa can enter the circulation in a variety of ways, but the most rapid is direct absorption into the nasal capillary bed. Interestingly, in the case of some agents, nasal administration seems to represent a back door through the blood-brain barrier, and these agents actually reach higher CNS concentrations when administered by this route than when they are given intravenously. This fact should make us proceed with caution in our attempts to administer drugs in this way. We need to be certain that the agents we are using and their preservatives are not neurotoxic.

Although many medications (e.g., vasopressin) are routinely given intranasally, most of the attention in recent years has focused on two issues: the administration of agents for procedural sedation and the control of status epilepticus. In fact, one agent — midazolam — is most often employed for both indications. The problems associated with intranasal midazolam have primarily been that when the liquid preparation is administered nasally, it seems to be uncomfortable, and at least some of the medication is swallowed before it can be absorbed from the nose.

Whether administration is inhalational, intranasal, or oral, mucosal surfaces provide an excellent way to ensure that agents enter the system quickly

In the seizing child, there is the added risk of aspiration as the medication enters the hypopharynx. More recently, some investigators have been administering an aerosolized form instead of the liquid into the nose. This route of administration may avoid some problems, and allow for more widespread use.

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Oral Mucosa

The other mucosal site is, of course, located in the mouth. Once again, there is nothing novel about administration of medications with the intention of being absorbed from the oral mucosa. Nitroglycerine is administered thousands of times a day in this fashion.

In pediatrics, however, there has been a great deal of interest in the mucosal absorption of pain medications and sedatives. Most of us have heard of oral transmucosal fentanyl lozenges, aka the fentanyl lollipop. This ingenious medication places three different doses of fentanyl in flavored, sweetened lozenges that are both palatable and effective. A weight-appropriate lozenge is given to the child, and he partakes until a clinical effect is achieved.

Oral transmucosal administration is not the same as oral administration. In fact, while most orally administered medications are ultimately swallowed and then subjected to digestion and potentially to first-pass metabolism, medications absorbed from the oral mucosa avoid these problems. Absorption from the oral mucosa is not as simple as it sounds. First, the agent must be palatable because absorption requires a period of contact with the mucosal surface. Few adults and very few if any children will hold an unpleasant-tasting substance in their mouths long enough for absorption to occur unless they are contestants on Fear Factor.

Secondly, even if the substance does not taste bad, it must be in a form that is conducive to oral absorption rather than swallowing. Older cooperative children can be given small aliquots of a substance, and be instructed to hold the substance in their mouths for as long as possible. Even better, however, are agents placed in a vehicle that dissolves slowly like the transmucosal fentanyl lozenge. And because saliva is slightly acidic, drugs with a high pKa are absorbed more readily.

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Suggested Reading:

1. Barton ED, Ramos J, Colwell C, et al. Intranasal administration of naloxone by paramedics. Prehosp Emerg Care 2002;6:54.
2. Lahat E, Goldman M, Barr J, Bistritzer M. Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: Prospective randomized study. Brit Med J 2000; 321:83.
3. The American Academy of Pediatrics, Committee on Drugs. Alternative Routes of Drug Administration. Pediatrics 1997;100:143.
    © 2005 Lippincott Williams & Wilkins, Inc.