Pharmacotherapeutics in small mammals (Proceedings)

Pharmacokinetic studies in exotic small mammals are lacking and, therefore, most of the dosages used in these species are based on empirical data, observations, and experience. Because drug uptake depends on factors such as age, sex, physiology, disease state, diet, etc., it is important for us as veterinarians to know some of the pharmacobiologic, physiologic, and anatomic characteristics of these species. It should also be noted that most of the drugs used in exotic small mammals are extralabel, so very few drugs are approved by the U.S. Food and Drug Administration (FDA) for use in these animals. The U.S. Animal Medicinal Drug Use Clarification Act enables veterinarians to use drugs approved for human and other animal use on animals other than those for which they are approved, if the reasoning is sound. This act requires that owners sign an informed consent form for extralabel drug use. Because most drugs are not approved by the FDA for use in these animals, it may be warranted for the owners to sign a consent form when registering their pet.1

This review will outline drug administration sites, compounding, and some of the issues involved in selecting an antibiotic, analgesic, or nonsteroidal, anti-inflammatory drugs for use in exotic small mammals.

Compounding

Exotic animal practitioners face daily challenges to meet the pharmaceutical needs of their small mammal patients. Because there are few approved medications for use in these patients, attempts to meet these challenges include: extralabel use of human and domestic animal products; compounding by the practitioner; use of compounding service; using medicated feeds; and using imported pharmaceutical productions.2 There may be both legal and ethical issues that the practitioner must be aware in using any of the aforementioned strategies.

In the U.S., compounding of animal drugs is only permitted if it is conducted in accordance with established laws. These laws require that compounding be done by or on an order of a licensed veterinarian, within the context of a valid veterinarian/client/patient relationship, and from approved human or veterinary drugs. Compounded products must be prescription only.

Although compounding is a useful tool for exotic practitioners, it can sometimes lead to incompatibilities between active and nonactive ingredients. A well trained pharmacist can help avoid pitfalls of incompatibilities.

In small mammal medicine, the most common indication for compounding is the preparation of medications for per os administration. In cases when animals refuse to take a medication because of the taste, compounding using various flavor additives may be useful. For example, flavors which rabbits generally accept include: lettuce, carrot, parsley, celery, banana crème, vanilla butternut, and pineapple.

Antibiotics

Antibiotics are probably the most commonly used medications in small mammal medicine. Because pharmacokinetic studies are lacking in these pet species and are often empirical, it is helpful to know the basic pharmacologic features and the side effects of the drugs being used for maximum safety and efficacy.

Because rabbits are herbivorous animals, their intestinal microflora consists mainly of gram positive bacteria and anaerobic bacteria. Antibiotic choices in rabbits, however, are limited because many antibiotics suppress the healthy flora and allow pathogens to proliferate, resulting in welldocumented enteric disorders. Antibiotics which have been reported to cause dysbiosis/enteritis/enterotoxemia in rabbits include amoxicillin, amoxicillin/clavulanic acid, ampicillin, cephalosporins, clindamycin, erythromycin, lincomycin, and penicillin.3 There have also been some reports of antibioticrelated colitis in rabbits given penicillin/streptomycin, trimethoprim/sulfamethoxazole, tetracycline, tylosin, and gentamicin. It should also be noted that, in some cases, enteritis can develop weeks after the antibiotic has been discontinued. Oral use of these medications generally is contraindicated in rabbits; however, penicillin is occasionally used parenterally on a limited basis.4

Unfortunately, there is a lack of data (based on clinical trials) on the use of most antibiotics in rabbits. Very few antibiotics have been evaluated for their therapeutic effectiveness, and, therefore, dosages in rabbits often rely largely on empiric data. Antibiotics that are generally considered safe in rabbits include the fluoroquinolones, sulfonamides, chloramphenicol, and metronidazole. Antibiotics that do not cause problems with normal usage can cause diarrhea when given in large doses.4 Even when presumably "safe" agents are used, rabbits on antibiotics should be monitored for signs of gastrointestinal distress.

A unique characteristic in rabbits is their property to produce granulomatous abscesses with caseous pus which are impenetrable for many antibiotics.5 In these cases, therefore, successful treatment involves surgical excision of the lesions as well as use of appropriate antimicrobials.

Inappropriate antibiotic treatment can also result in enteritis and antibiotic-associated clostridial enterotoxemia in rodents, especially when antibiotics with a primary gram-positive spectrum are given. Incidence is higher when agents are given orally. Chinchillas, guinea pigs, and hamsters are most susceptible. Also, direct toxicity from streptomycin and dihydrostreptomycin occurs in gerbils, guinea pigs, hamsters, and mice. Procaine, included in some penicillin preparations, can be toxic to mice and guinea pigs. Guinea pigs and chinchillas are highly susceptible to the ototoxic effects of chloramphenicol and aminoglycosides at dosages above those recommended clinically. Antibiotics implicated in antibiotic associated clostridial enterotoxemia in rodents include:3

• Chinchillas: penicillins (including ampicillin, amoxicillin), cephalosporins, clindamycin, erythromycin, lincomycin.

• Guinea pigs: penicillins (including ampicillin, amoxicillin), cefazolin, clindamycin, erythromycin, lincomycin, dihydrostreptomycin, streptomycin, bacitracin, chlortetracycline, oxytetracycline, tetracycline, tylosin.

• Hamsters: penicillins (including ampicillin, amoxicillin), cephalosporins, clindamycin, erythromycin, lincomycin, vancomycin, dihydrostreptomycin, streptomycin, bacitracin, oral gentamicin, tylosin.

When selecting an appropriate antimicrobial agent for use in a small mammal, there are a number of issues one needs to consider: patient's clinical/pathologic condition (specific pathogens?); organ system involved; patient's nutritional and hydration status; the antimicrobial most likely to be effective against the known (based on culture and sensitivity results) or suspected pathogen (bacteriostatic vs. bacteriocidal, with the latter being preferred when the immune system is not capable of destroying the organism or in cases of sepsis); dose and route of administration of the antimicrobial; potential adverse effects; and owner compliance. The concentration of an antimicrobial in a tissue is dependent upon the dose administered, frequency of administration, route of administration, and formulation and physicochemical characteristics of the drug.6 For appropriate tissue concentrations, the minimum inhibitory concentrations (MICs) for the target pathogen should be attained.

Use of antimicrobial-impregnated polymethyl methacrylate beads

Antibioticimpregnated polymethyl methacrylate beads (AIPMMA) are used in rabbits to provide controlled, local release of antimicrobials for the treatment of infection (generally osteomyelitis or abscesses, especially those of the head).7,8 In addition, local release is associated with a lower risk of toxicoses than is parenteral administration.8 Also, effective concentrations of antimicrobials can be achieved and maintained even if the site of infection is difficult to reach, and AIPMMA can be used to help manage infections in intractable animals in which systemic administration may be difficult.8 The beads are reasonably easy to make, and may be sterilized with ethylene oxide gas.

The ideal antimicrobial for incorporation in a AIPMMA bead would be bactericidal, have a broad spectrum of activity, and be effective at how concentrations; have low tissue toxicity; be heat stable (up to 100°C); have high water solubility; and results in low serum concentrations but high concentrations in adjacent bone and soft tissue.8

Ideally the antibiotic should come as a sterile powder. Liquid antibiotics have been used, but they may reduce the mechanical strength of the PMMA. Although most practitioners usually leave the beads in until the site is no longer infected, others have left them in indefinitely. Some of the antibiotics which have been used include amikacin and ceftiofur.

In treating abscesses, it is essential to remove the abscess as completely as possible before placing the beads.7 The AIPMMA should not be placed within the abscess capsule.

Analgesics

Because small mammals are increasingly considered by their owners to be part of the family unit rather than just possessions, more clients are expecting appropriate pain relief post surgically, post trauma, etc., for their pets. Likewise, veterinarians are much more aware and proactive in providing pain management for their patients. Analagesia results in smoother recoveries, a decrease in systemic stress and resultant stress-related diseases (i.e., gastric ulcers), and a more rapid return to normal behavior and function. Preemptive analgesia, or the administration of analgesic drugs during premedication, is now the standard when performing painful procedures.9,10

Assessing pain in exotic small mammals is often difficult and requires knowledge of the animal's normal behavior which can then be compared to their postoperative/post trauma condition. Subtle changes in the level of activity and shifting of body position may be indications that the animal is experiencing significant discomfort. Vocalization is unusual but may occur, while bruxism or hypersalivation are seen more commonly. A decreased appetite or lack of grooming may also be seen. 9,10

The two main groups of analgesic medications are opiates and nonsteroidal anti-inflammatory drugs (NSAIDS).11 These can be combined or used alone. Opioids produce both central and peripheral alleviation of pain and have advantages of being efficacious, safe, reversible, and versatile. Of the opioid receptors, the one that has been demonstrated to be extremely important in pain control is the mu receptor.

Although opioids provide the most effective analgesia for most types of pain, they can also cause sedation and can be difficult to prescribe for home use. Potent muagonists (i.e., morphine, meperidine, and oxymorphone) can cause respiratory depression in small mammals. Mixed opioid agonistantagonists (i.e., buprenorphine, butorphanol) have fewer sideeffects and are most commonly used. The effects of opiates on the cardiovascular system are variable, depending on the species. In ferrets and rats, opiates tend to produce hypotension, whereas in rabbits and mice, they are hypertensive. Use of opiates may also result in ileus.

Butorphanol and buprenorphine, both synthetic opiate partial agonists, are, therefore, the most common opiates used in small mammals. They have minimal respiratory effects and do not cause significant CNS depression. Butorphanol acts mostly at kappa and sigma opioid receptors, whereas buprenorphine acts at mu receptors, which may explain its relatively long duration of action. Mammals have more mu receptors, hence an advantage to buprenorphine.

Butorphanol (a synthetic opiate partial agonist that is 4-7 times as potent an analgesic as morphine) has a faster onset of action and shorter duration compared to buprenorphine's slower onset of action and longer duration. Some clinicians use both drugs concurrently in exotic animals to provide rapid analgesia (butorphanol) and longer duration (buprenorphine). However, it is probably preferable to give butorphanol (i.e., as a preanesthetic) followed by buprenorphine at least 2-3 hours later. Butorphanol can produce profound sedation in ferrets, so often lower doses are used in this species compared to other small mammals.

Buprenorphine is 30 times more potent than morphine and exhibits many of the same actions as the opiate agonists. Although few adverse effects of this drug have been reported, on rare occasions patients have developed respiratory depression.

Nonsteroidal, antiinflammatory drugs

Nonsteroidal, antiinflammatory drugs (NSAIDS) are increasingly being used in small mammals because of the analgesia they provide in response to pain associated with inflammation (i.e., arthritis and dental problems). However, NSAIDs are not considered adequate for treating severe pain and are usually contraindicated in the patient that has received corticosteroids because of the potential for gastrointestinal ulceration or bleeding. Other characteristics of NSAIDs include their antipyrectic actions and many have a long duration of action (i.e., at least 12-24 hours). Although there is little information concerning the safety and appropriate dosages of NSAIDS in these animals (an offlabel species), these drugs have been reported to cause gastric ulceration in some species. Sucralfate has been shown to protect gastric cells in vitro. 12

Meloxicam is probably the most commonly used NSAID used in exotic small mammals, and is available in both oral and injectable forms. Its primary action is the inhibition of cyclooxygenase-2, which mediates inflammation. Meloxicam at 1 mg/kg SC dose reduced acute post-laparotomy pain behaviors in rats, but a 0.5 mg/kg SC dose was not effective. In another study, the pharmacokinetics of single or repeated PO doses (daily for 5 days) of either 0.3 or 1.5 mg/kg meloxicam in female rabbits showed that after single oral dosing of either dose, maximal plasma concentrations were achieved at 6-8 hr and were nearly undetectable by 24 hr. No drug plasma accumulation was identified at either dose after 5 days, and meloxicam was rapidly eliminated after drug discontinuation. Meloxicam administered 0.5 mg/kg PO produced significant analgesia in visceral pain tests in guinea pigs. These studies suggest that some rodents and rabbits may need higher meloxicam doses, but further research is necessary to determine appropriate meloxicam analgesic doses and dosing frequency in small mammal patients.

Carprofen is also more selective for COX-2 activity, and is also routinely used to provide analgesia in exotic pet mammals. Carprofen is available in both injectable and PO forms. The half-life of carprofen varies considerably amongst the mammalian species, which may affect dosing intervals. Very little work has been performed to date evaluating this drug in exotic species. Some clinicians have use 1-4 mg/kg PO, SC, and IM q12-24h term in many small mammal species.

Ketoprofen is a potent non-selective COX inhibitor. Ketoprofen is used parenterally in exotic patients because of limited oral pharmacokinetic data and difficulty in accurately dosing oral formulations. Ketoprofen administered 5 mg/kg SC pre-operatively in rats undergoing exploratory laparotomy showed an effect for at least 5 hours, but this dose was not effective PO, suggesting higher doses may be needed for PO dosing.

Tramadol hydrochloride is an analgesic that has become popular recently despite minimal evidence as to its efficacy. It is active at opiate, alpha-adrenergic, and serotonergic receptors. In the United States, only the PO formulation is available. The pharmacokinetics of tramadol have been evaluated in rats and rabbits, but analgesic plasma concentrations have not yet been established. Clinically insignificant isoflurane-sparing effects have been shown in both rats and rabbits administered 10 and 4.4 mg/kg tramadol PO, respectively. Results of several studies in rats have shown that it can be an effective analgesic for acute pain. In rats, tramadol provided analgesia for osteoarthritis, but efficacy decreased with increased duration of pain. Anecdotally, doses of 2-5 mg/kg PO have been well tolerated in rabbits and rats. While this analgesic holds great promise for use in small mammals, much work is still needed to evaluate appropriate dosing, efficacy, and safety of this drug in different species.

There are, however, potential risks associated with the use of NSAIDS.13 The four most commonly reported clinical signs in domestic animals are vomiting, anorexia, depression, and diarrhea. 13 Less commonly, gastric ulceration, intestinal ulceration, renal failure, hepatic failure, and death may result.

Recommendations for reducing the adverse sideeffects of NSAIDS in animals include:13

• Animals should undergo a thorough history and physical examination before the initiation of NSAID therapy.

• Appropriate laboratory tests (i.e., serum biochemical analysis) should be considered prior to, and periodically during the administration of any NSAID (i.e., monitor for gastrointestinal, hepatic, and renal toxicosis).

• Concomitant use with other antiinflammatory drugs (i.e., other NSAIDS or corticosteroids) should be avoided or closely monitored.

• Ensure patients are hydrated during NSAID therapy.

Corticosteroids

Glucocorticosteroids, which have both anti-inflammatory and potential analgesic effects, are still used too commonly in practice. For example, the rabbit is considered to be a very corticosteroidsensitive species. Steroids in rabbits cause two types of adverse reactions: severe immune suppression and liver toxicity.14 Small, onetime doses of a corticosteroid have been reported to have an adverse effect in a rabbit and even topical or ophthalmic doses can cause gastrointestinal ulceration and immunosuppression in this species. Because the adverse effects of corticosteroids in rabbits may be overstated, though, more research and clinical observations on the effects of these drugs in this species are needed.

Typical hepatic changes caused by steroid administration in rabbits include lipid deposits, glycogen deposition, vacuolization, and hydropic degeneration.15 These changes were seen whether the steroids were given orally, subcutaneously, or ocularly. Studies have also shown that steroid use can cause immunosuppression (atrophy and disappearance of lymphoid tissue in Peyer's patches and in the spleen) and a decreased survival in rabbits.

There are very few indications for steroids in rabbits, and extreme caution should be observed when steroids are administered. Even for dermatologic conditions in rabbits, corticosteroids are not generally recommended. Many veterinary and human critical care specialists do not currently recommend the use of glucocorticoids for treating shock or head trauma in other species. If corticosteroids are indicated, concurrent use of a gastric protectant is recommended.

Formulary for small mammals

The Exotic Animal Formulary (2005) and Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery (2004) list the antimicrobial and antifungal agents, antiparasitic agents, chemical restraint/anesthetic/analgesic agents, ophthalmic drugs, and miscellaneous agents used in exotic small mammals.

References

1. Morrisey, J.K., J.W. Carpenter. 2004. Formulary. In: Quesenberry, K.E., J.W. Carpenter, eds. Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery. 2nd ed. Philadelphia, WB Saunders, pp. 436444.

2. Spenser, E.L. 2004. Compounding, extralabel drug use, and other pharmaceutical quagmires in avian and exotics practice. Sem. Avian Exotic Pet Med. 13(1):1624.

3. Carpenter, J.W., T.Y. Mashima, D.J. Rupiper. 2000. Exotic Animal Formulary. 2nd ed. Philadelphia, WB Saunders, pp. 299326.

4. Ivey, E.S., J.K. Morrisey. 2000. Therapeutics for rabbits. Vet. Clin. N. Am.: Exotic Anim. Pract. 3(1):183220.

5. Goebel, T. 1999. Antimicrobial therapy in small mammals. Proc. N. Am. Vet. Conf.: 829830.

6. McKeller, Q.A. 1995. Applications of pharmacokinetics in clinical practice. N. Am. Vet. Conf. Proc. Int. Symp. on Antimicrobial Therapy in Caged Birds and Exotic Pets: 310.

7. Bennett, R.A. 1999. Management of abscesses of the head in rabbits. Proc. N. Am. Vet. Conf.: 826828.

8. Tobias, K.M.S., R.K. Schneider, T.E. Besser 1996. Use of antimicrobialimpregnated polymethyl methacrylate. J. Am. Vet. Med. Assoc. 208(6):841845.

9. Eisel, P.H. 1997. Signs of pain in small mammals: Analgesia in small mammals. Proc. N. Am. Vet. Conf.: 795799.

10. Hawkins, M.G. 2006. The use of analgesics in birds, reptiles, and small exotic mammals. J. Exotic Pet Med. 15(3):177-192.

11. Heard, D.J. 2004. Anesthesia, analgesia, and sedation of small mammals. In: Quesenberry, K.E., J.W. Carpenter, eds. Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery. 2nd ed. Philadelphia, WB Saunders, pp. 356369.

12. Takahashi, S., S. Okabe. 1996. Effects of sucralfate and its components on indomethacininduced damage to cultured rabbit gastric mucosa cells. J. Physiol. Pharmacol. 47:611619.

13. Moskal, T.J. 2004. Minimizing the risk factors associated with veterinary NSAIDS. J. Am. Vet. Med. Assoc.: 12301231.

14. Rosenthal, K.L. 2004. Therapeutic contraindications in exotic pets. Sem. Avian Exotic Pet Med. 13(1):4448.

15. Borgmann, A.R., D. Bogle, C.A. Robb, et al. 1976. Comparative toxicity of twodexamethasone derivatives following topical ocular instillation to rabbits. II. Systemic histopathological changes. Toxicology 6:7784.