Medicating cats: Transdermal drugs and more (Proceedings)

Long term administration of oral medications can be problematic in cats. Unfortunately, relatively few drugs have received FDA approval for cats and "cat friendly" drug formulations (e.g., small size and strength, attractive flavorings) are less common than desired by practitioners. In recent years, veterinarians and cat owners have sought alternative drug formulations, and compounding pharmacies have stepped in to fill the gap. But do they work?

Problems with Pills

Many cats resent the invasiveness of receiving oral medications, making it difficult or impossible for owners to be compliant with medication instructions. Even liquid medications may be difficult to administer to some cats as they may find the taste unpleasant, and salivate profusely. Adding medication to the cat's food may simply induce food aversion, or in a multi-cat household, the wrong cat may receive the drug.

Another significant problem is the risk of esophageal damage. Certain drugs given in tablet or capsule form, such as doxycycline and clindamycin, may induce esophagitis or esophageal stricture in cats (Melendez, Twedt et al. 2000; German, Cannon et al. 2005; Beatty, Swift et al. 2006). Studies have revealed a delayed transit time (longer than 30-60 seconds) in most cats that are dry-pilled (Graham, Lipman et al. 2000; Westfall, Twedt et al. 2001). More than 50% of cats in one study experienced entrapment of capsules in the mid-cervical region of the esophagus (Graham, Lipman et al. 2000). Cats given a water bolus or fed a small amount of food after a tablet or capsule do not experience prolonged retention of the drug in the esophagus and the risk of esophagitis is reduced or eliminated.

Flavored Suspensions and Chewables

Many pharmacies now offer compounding of a long list of drugs into flavored suspensions or chewables. In a commercial licensed formulation, the active ingredients and the excipients are tested and must meet FDA specifications to ensure the stability of the drug and uniform performance in the patient. In compounding, the addition of chemicals, flavorings, or vehicles may interfere with the stability of a drug, decrease potency, change distribution of the drug in the product, cause precipitation, compromise absorption, and thereby reduce efficacy or compromise safety. The same is true when the protective coating found on some tablets is disrupted to crush the tablets and make a suspension. Compounding pharmacists should be able to provide information to clinicians about the stability, safety and potency of any formulations offered. When veterinarians compound drugs in their own practices, the same standards apply.

Bitter tasting pills are a common problem in feline medicine. Flavored treats formulated to hide pills or capsules (e.g., Greenies® Pill Pockets®) are an alternative to crushing pills and adding a flavoring or vitamin/mineral supplement. Another option is to place the tablet inside an empty gelatin capsule to hide the taste. Empty gelatin capsules of various sizes are readily available from most pharmacies.

Transdermal Drug Administration

Transdermal administration of medications to cats appears to be an ideal solution to the difficulties with oral medications. This route of administration may also avoid gastric and intestinal irritation associated with some drugs. However, this is a relatively new area of veterinary therapeutics, and in many cases, scant information is available on safety and efficacy. In human medicine, a number of drugs are available as transdermal patches, such as fentanyl, scopolamine and nicotine. In veterinary medicine, there are several FDA-approved "pour-on" or "spot-on" antiparasitic drugs approved for cats.

Many factors influence transdermal drug absorption. Patient factors include skin thickness and lipid content, density of hair follicles, skin pH, blood flow, and integrity of stratum corneum. Drug factors include molecular weight, ionization, and the carrier vehicle. Drugs are developed for transdermal application in humans only if they are effective at doses under about 50 mg per day.

In order to evaluate a transdermal formulation, these questions must be answered:

1 Is the drug bioavailable – does it get absorbed?

2. Is the bioavailability consistent from patient to patient?

3. Does the drug require biotransformation for efficacy?

4.Is the formulation stable?

Dozens of compounding pharmacies offer a plethora of drugs in transdermal formulations to veterinary practitioners. While research is ongoing into the safety and efficacy of drugs via the transdermal route, there is still very limited data available, and many of the published studies are single-dose studies. There may be significant differences between single-dose and multiple-dose studies, as multiple dosing allows for saturation of the stratum corneum and dermis to form a depot of the drug that delivers it slowly to the systemic circulation over time. An excellent example of this is methimazole, which showed poor bioavailability in single-dose studies (Hoffman, Yoder et al. 2002). Long term studies have shown that transdermal methimazole is an effective treatment for feline hyperthyroidism, although it may take longer to reach a euthyroid state than using an oral formulation (Hoffman, Marks et al. 2003; Sartor, Trepanier et al. 2004; Lecuyer, Prini et al. 2006). Transdermal methimazole has a lower risk of GI irritation than the oral formulation.

The most commonly used drug in a transdermal patch in the cat is fentanyl. Transdermal patches provide sustained plasma concentrations of fentanyl for a 5-day period (Lee, Papich et al. 2000). Several studies have demonstrated effective analgesia using fentanyl transdermal patches for various surgical procedures (Franks, Boothe et al. 2000; Glerum, Egger et al. 2001; Gellasch, Kruse-Elliott et al. 2002). However, fentanyl is not effectively absorbed when formulated using a common carrier, pluronic lecithin organogel (PLO) (Robertson, Taylor et al. 2005).

Data is available on several other drugs showing poor absorption and variable bioavailability in PLO transdermal formulations in cats. Fluoxetine is only 10% bioavailable in PLO gel compared to the oral route, with slower absorption and lower peak serum concentrations (Ciribassi, Luescher et al. 2003). Several drugs have shown undetectable or very low absorption levels in single-dose studies, such as dexamethasone (Willis-Goulet, Schmidt et al. 2003), buspirone and amitriptyline (Mealey, Peck et al. 2004), and diltiazem (DeFrancesco 2003).

Transdermal absorption of glipizide was low and inconsistent in a single-dose study, although it did affect plasma glucose concentrations (Bennett, Papich et al. 2005). One prospective study evaluated the efficacy of transdermal amlodipine for control of hypertension in cats (Helms 2007). Transdermal amlodipine administered at doses comparable to oral amlodipine was able to maintain a reduction in blood pressure in hypertensive cats previously stabilized on the oral drug. However, the degree of reduction in blood pressure was less than that achieved with the oral route. Plasma concentrations showed that the bioavailability of transdermal amlodipine is less than that of the oral drug.

The topical anesthetic EMLA cream (lidocaine/prilocaine) is an interesting product in that systemic absorption is undesirable and is not the goal of therapy. One study evaluated the safety of EMLA cream in 31 ill cats for placement of jugular catheters (Wagner, Gibbon et al. 2006). Neither lidocaine nor prilocaine was absorbed systemically, and no adverse clinical signs were noted. A 4% liposome-encapsulated lidocaine cream (ELA-Max), was also found to be safe in a study using 6 health cats (Fransson, Peck et al. 2002). The maximum plasma concentrations of lidocaine remained well below the toxic levels for cats.

Since no data is available for most of the drugs offered to veterinary practitioners in transdermal formulations, certain guidelines should be used to determine whether to choose this formulation for a given drug or patient. Ideally, the condition being treated should have a measurable end-point to assess efficacy, such as heart rate or blood glucose concentration. Only drugs with wide therapeutic windows should be used, and the proven routes must be ruled out for a given patient. Unfortunately, there is no useful rule to extrapolate from an oral dose to a transdermal dose. The transdermal dose for a given drug may need to be greater than the oral dose (if transdermal absorption is poor), equal to the oral dose (if transdermal absorption is equivalent to oral), or lower than the oral dose (if the oral drug undergoes extensive first pass metabolism). It would seem wise to start with a low dose and titrate to effect.

In the absence of supporting data, transdermal drugs should not be used to treat serious medical conditions, particularly those where an immediate drug effect is desired (e.g., congestive heart failure, hypertension, seizures). At this time, there is insufficient evidence to support the use of the transdermal route for antimicrobials and sub-therapeutic levels may induce pathogen resistance. Given all the potential pitfalls, informed owner consent is very important when using transdermal drugs.

Adverse Effects

Mild local inflammation from PLO gels is reasonably common; it usually resolves when the drug is discontinued. Soy lecithin is a common allergen in people. The potential to induce a serious adverse reaction in cats is unknown.

It is important that owners are instructed carefully in the use and handling of transdermal drugs to avoid unintentional self-application. The person applying the drug should wear gloves. Caution should be used in prescribing transdermal drugs for pets in households with small children to avoid inadvertent exposure.

References

Beatty, J. A., N. Swift, et al. (2006). "Suspected clindamycin-associated oesophageal injury in cats: five cases." J Feline Med Surg 8(6): 412-9.

Bennett, N., M. Papich, et al. (2005). "Evaluation of transdermal application of glipizide in a pluronic lecithin gel to healthy cats." Am J Vet Res 66(4): 581-588.

Ciribassi, J., A. Luescher, et al. (2003). "Comparative bioavailability of fluoxetine after transdermal and oral administration to healthy cats." Amer J Vet Res 64(8): 994-998.

DeFrancesco, T. C. (2003). Transdermal cardiac therapy in cats: the NCSU experience. 21st Annual ACVIM Veterinary Medical Forum, Charlotte, NC.

Franks, J., H. Boothe, et al. (2000). "Evaluation of transdermal fentanyl patches for analgesia in cats undergoing onychectomy." J Amer Vet Med Assoc 217(7): 1013-1018.

Fransson, B., K. Peck, et al. (2002). "Transdermal absorption of a liposome-encapsulated formulation of lidocaine following topical administration in cats." Amer J Vet Res 63(9): 1309-1312.

Gellasch, K., K. Kruse-Elliott, et al. (2002). "Comparison of transdermal administration of fentanyl versus intramuscular administration of butorphanol for analgesia after onychectomy in cats." J Amer Vet Med Assoc 220(7): 1020-1024.

German, A., M. Cannon, et al. (2005). "Oesophageal strictures in cats associated with doxycycline therapy." J Fel Med Surg 7(1): 33-41.

Glerum, L., C. Egger, et al. (2001). "Analgesic effect of the transdermal fentanyl patch during and after feline ovariohysterectomy." Vet Surg 30(4): 351-358.

Graham, J., A. Lipman, et al. (2000). "Esophageal transit of capsules in clinically normal cats." Am J Vet Res 61(6): 655.

Helms, S. R. (2007). "Treatment of Feline Hypertension With Transdermal Amlodipine: A Pilot Study." J Am Anim Hosp Assoc 43(3): 149-156.

Hoffman, G., S. Marks, et al. (2003). "Transdermal methimazole treatment in cats with hyperthyroidism." J Fel Med Surg 5(2): 77-82.

Hoffman, S., A. Yoder, et al. (2002). "Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats." J Vet Pharmacol Ther 25(3): 189-193.

Lecuyer, M., S. Prini, et al. (2006). "Clinical efficacy and safety of transdermal methimazole in the treatment of feline hyperthyroidism." Can Vet J 47(2): 131-5.

Lee, D. D., M. G. Papich, et al. (2000). "Comparison of pharmacokinetics of fentanyl after intravenous and transdermal administration in cats." Am J Vet Res 61(6): 672-7.

Mealey, K. L., K. E. Peck, et al. (2004). "Systemic absorption of amitriptyline and buspirone after oral and transdermal administration to healthy cats." J Vet Intern Med 18(1): 43-6.

Melendez, L., D. Twedt, et al. (2000). "Suspected doxycycline-induced esophagitis with esophageal stricture formation in three cats." Fel Pract 28(2): 10-12.

Robertson, S. A., P. M. Taylor, et al. (2005). "Relationship between plasma concentrations and analgesia after intravenous fentanyl and disposition after other routes of administration in cats." J Vet Pharmacol Ther 28(1): 87-93.

Sartor, L., L. Trepanier, et al. (2004). "Efficacy and safety of transdermal methimazole in the treatment of cats with hyperthyroidism." J Vet Intern Med 18(5): 651-655.

Wagner, K., K. Gibbon, et al. (2006). "Adverse effects of EMLA (lidocaine/prilocaine) cream and efficacy for the placement of jugular catheters in hospitalized cats." J Fel Med Surg 8(2): 141-144.

Westfall, D., D. Twedt, et al. (2001). "Evaluation of esophageal transit of tablets and capsules in 30 cats." J Vet Intern Med 15(5): 467-470.

Willis-Goulet, H., B. Schmidt, et al. (2003). "Comparison of serum dexamethasone concentrations in cats after oral or transdermal administration using pluronic lecithin organogel (PLO): a pilot study." Vet Dermatol 14(2): 83-89.