CHAPTER 1
Horse of a different color: Peculiarities of equine pharmacology

Lara Maxwell

Oklahoma State University, Stillwater, OK, USA

Introduction

Horses are different. Practitioners expect such differences, given the unique anatomy and physiology of the many species encountered within veterinary medicine. Nonetheless, the appropriate use of therapeutic agents can be particularly challenging in the horse. Small animal practitioners have an advantage over other veterinary clinicians when novel therapeutics are investigated for veterinary use, as the pharmacology of investigational drugs is often described in dogs before they are used in people. However, if the dog is the prototypical species of basic pharmacological research, then the horse is just the opposite. The many idiosyncrasies of equine anatomy and physiology can make the behavior of drugs in this species highly unpredictable. Drugs that are well absorbed after oral administration, safe, and efficacious in other species may be poorly absorbed, toxic, or ineffective in horses. This chapter will investigate the sources of some of these pharmacological peculiarities and address strategies for using drugs safely and effectively in horses despite these inherent challenges.

Idiosyncrasies related to route of administration

Enteral absorption

Administration of drugs per os is the most natural route in companion animals. Administering foreign material to the gastrointestinal tract (GIT) is safer than parenteral administration, since the immunological and physical defenses in the GIT are designed to cope with all manner of foreign substances. Particulates, excipients, bacteria, fungi, endotoxins, and other toxins can be devastating if inadvertently administered parenterally, but most of these contaminants will have little impact if inadvertently delivered to the GIT. The cost of a drug formulated for oral administration is often less than its injectable counterpart, because of the stringent requirements needed to prepare safe injectable formulations. In addition, owner and patient compliance is usually better when oral drug administration is employed, especially when the duration of therapy encompasses days, weeks, or even for the remaining life of the patient. For all of these reasons, the oral route of administration is generally preferred in the nonhospitalized equine patient. In counterpoint to all of the advantages of oral drug administration, there are certainly disadvantages that the equine practitioner will recognize. First, getting the drug into the stomach of the horse can be challenging. Some small capsules and powders can be administered as a topdressing to highly palatable feed. For horses that don't avoid top-dressed drugs and drugs that are palatable, this method of administration probably represents the most effective and convenient method of oral administration. Capsules, tablets, and powders may be hidden in pieces of carrot or apple with space carved or drilled by drug placement. Capsules and powders can also be mixed with applesauce, molasses, or syrup and mixed with feed, bran, or beet pulp. These methods can all be effective but require that the feed bucket be observed after administration to confirm that the entire dose was ingested. For unpalatable drugs and horses that avoid top-dressings, a powder can be mixed with applesauce, syrup, or molasses and placed in a syringe. A catheter-tipped syringe can be used for thinner mixtures, or the tip of the syringe can be removed and surfaces sanded smooth for the administration of thicker mixtures. Tablets can be crushed with a mortar and pestle, coffee grinder, or hammer to make a powder for administration. Some tablets and capsules can also be dissolved in a small volume of water. However, not all drugs are soluble and stable in water, so knowledge of the drug's aqueous stability is necessary if the drug does not quickly dissolve and is not immediately administered. Drugs should not be heated to speed solubilization unless aqueous and thermal stability is known, since heating will also speed hydrolysis of an unstable drug. Drugs with beta-lactam rings, including penicillins and cephalosporins, as well as some drugs with ester bonds, such as valacyclovir, have poor aqueous stability (see Chapter 2) [1, 2]. Some tablets and capsules that are insoluble in water will instead dissolve in the acidic pH of lemon juice [3]. The volume of lemon juice should be minimized to limit administration of the acidic solution, and it should be mixed with syrup or feed prior to administration.

Administration of drugs by a nasogastric tube is sometimes employed clinically and is often the route used when the oral absorption of a drug is being investigated. However, nasogastric intubation requires the presence of the veterinarian and is poorly tolerated for chronic dosing regimens. The bioavailability, or the total amount of the drug that reaches systemic circulation, of an orally administered drug is often reported in the initial assessments of a drug's utility in horses. As described in the following text, the knowledge of a drug's oral bioavailability will assist the practitioner with decisions regarding selection of the best available drug for a particular condition, dose modifications, and the likelihood of therapeutic failure with a particular drug. Since bioavailability is often known from studies detailing the drug's pharmacokinetic properties, the presentation of bioavailability after nasogastric administration to a fasted horse represents the best possible bioavailability of that drug in the horse. However, the actual bioavailability in the field, where fasting is difficult and nasogastric administration is seldom used, may be considerably lower than the reported value.

Although we expect that cattle and other ruminants will exhibit unique absorption patterns when drugs are administered per os, we may conversely expect that horses will absorb drugs in a similar manner to other monogastric species. Certainly, this expectation is met for some therapeutics, with drugs such as fluconazole being nearly completely absorbed after oral administration to horses and other species [4]. If the bioavailability is less than 100% but still adequate, an increase in dose can be used to obtain therapeutic results comparable to that of intravenous (IV) administration [5]. However, other drugs, such as acyclovir and azathioprine, are subject to abysmal oral bioavailability in horses [6, 7]. There are numerous pharmacological examples of drugs, such as furosemide, tramadol, metformin, ciprofloxacin, and amoxicillin, that are adequately absorbed after oral administration to other monogastric species but are poorly absorbed in horses, with average bioavailability of less than 10% [8–13]. Such drugs are rarely if ever administered orally to adult horses due to the recognition that their bioavailability is too low to allow a predictable therapeutic effect at doses that are practical to administer.

Parallels may be drawn between ruminants and horses, with ruminants often exhibiting very poor oral absorption of therapeutics due to the propensity of ruminal microbes to cleave xenobiotics to an inactive form and the dilution of drugs by the tremendous volume of the ruminal fluid [14]. Although horses have a monogastric digestive system, the poor bioavailability of some drugs in horses can also be attributed to their herbivorous diet. Whereas horses do not maintain the full complement of cellulolytic gastric bacteria as ruminants, both ruminants and horses do ingest a large volume of herbaceous feed, and horses do maintain some fermentative bacteria as part of the normal stomach flora [15]. Although the effect of the equine gastric flora on drug stability is poorly understood, it has been shown that some drugs, such as ampicillin, will specifically bind to equine ingesta, limiting their bioavailability [16]. Although feeding status also impacts some drug absorption profiles in other species, the presence of feed can be even more important to the absorption of orally administered drugs in horses. For example, the rate of flunixin absorption is greatly affected by fasting in horses, with the time of maximal plasma drug concentration occurring much later in fed horses (7 h) than in fasted ones (<1 h) [17]. Interestingly, whereas the rate of flunixin absorption was dependent on feeding, the extent of absorption was not, so efficacy is probably unaffected. However, a decrease in the maximal plasma drug concentration that occurs with slower absorption can reduce the efficacy of drugs that must reach some threshold concentration to obtain the desired effect, since a slower rate of absorption will produce a lower peak plasma concentration. Alternatively, the presence of feed may affect both the rate and extent of absorption of some drugs, such as moxidectin [18]. It should also be noted that the presence of feed does not affect the absorption of some orally administered drugs. For example, the absorption of orally administered meclofenamic acid is not affected by feeding status [19].

For those drugs that are poorly absorbed after feeding, strategic fasting can increase the peak concentration, the extent of absorption, or both properties. However, fasting can be difficult to implement with a prolonged multiple-dose regimen. Complicating the design of a strategic fasting schedule, the amount of fasting time required to enhance drug absorption in horses is poorly defined, with some studies reporting enhanced absorption with fasting for as little as a few hours before and after oral drug administration and others after fasting overnight...