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Vascular Perfusion and Subcutaneous Space

Unlike humans, carnivores such as dogs and cats typically have large, vascular subcutaneous spaces under loose skin. This anatomical feature helps to guard against serious injury to underlying muscle and hasten healing if the animal is bitten by live prey that it captures as food. The large subcutaneous spaces also can accommodate large fluid volumes, enabling owners of dogs and cats to administer drugs and fluids easily by the subcutaneous route without ever having to develop venipuncture skills. This is particularly useful for dogs and cats that develop renal insufficiency; owners can rehydrate their pets at home with several hundred milliliters of subcutaneous fluid (as instructed by the attending veterinarian) instead of taking pets to the veterinary clinic for intravenous fluids every few days. Many cats that resist administration of unpalatable oral drugs (eg, clindamycin) do not object to subcutaneous injections. Indeed, the subcutaneous route can be an ideal alternative whenever oral administration is not feasible—for example, in animals with mandibular fractures, cervical spine disorders, or oral neoplasia.

Herbivores such as horses and cattle do not have a large subcutaneous space, but they do have large superficial veins that can be accessed easily by trained caregivers for administration of intravenous drug and fluid therapy.

Gastrointestinal Tract

There are significant anatomical differences between humans and non-human species in the structure and function of the GI tract and the corresponding influence of diet on GI characteristics.¹¹ In addition, gastric pH and average GI transit time (from mouth to anus) vary widely across species (Table 2).

Like humans, cats and dogs are monogastric species (ie, they have a simple, single-chambered stomach). However, GI transit time is somewhat shorter in cats and considerably shorter in dogs than it is in humans, and the stomach contents are about 10 times more acidic due to increased gastric secretion of hydrochloric acid.¹⁸ Human gastric pH typically is in the range of 4 to 5—a pH at which bacteria such as E. coli, Campylobacter, and Salmonella species can survive. Humans must cook or acidify their food to decrease risk of food poisoning. Gastric pH in carnivores can drop as low as 1 when food is in the stomach, to facilitate digestion of meat and kill pathogenic bacteria that might be ingested through raw food.¹⁹ Although it is possible for carnivores to suffer infection from contaminated ingesta (food or medications), such infections are far less likely than they are in humans.

Differences in pH and average GI transit time have important implications for drug therapy. The low gastric pH in carnivores may increase the bioavailability of drugs that are weak acids. Enteric-coated dosage forms designed to release their contents in the distal GI tract of humans most likely will release in the duodenum of cats, where the pH (5.7) approximates that of the distal human colon.²⁰ Consequently, enteric-coated dosage forms designed for humans are not likely to achieve the desired effect in cats. Also, because GI transit time is much shorter in dogs than it is in humans, delayed-release wax matrix tablets designed to release drugs during the long journey through the human GI tract likely will be excreted in the feces of a dog before any drug is released.

Horses and rabbits also are monogastric species. However, compared with cats and dogs, they have a longer GI tract and a more developed hindgut (cecum) in which large populations of microflora break down the herbivorous diet of grasses and other fibrous plants into nutritionally valuable carbohydrates.²¹ Herbivore saliva is alkaline due to the presence of enzymes that facilitate digestion of carbohydrates, so drugs with higher pKa values may be bioavailable when administered via buccal routes. GI transit times in hindgut fermenters are considerably longer than they are in humans, dogs, or cats, and some drugs are vulnerable to degradation during long transit times. Certain drugs may be inactivated by cecal microflora. Alternatively, some antibiotics (eg, macrolides) should be avoided entirely in hindgut fermenters, because they decimate beneficial microflora and can lead to endotoxemia from overgrowth of gram-negative bacteria.²²

Ruminant animals such as cattle and sheep have complex stomachs with four separate chambers to facilitate digestion: rumen, reticulum, omasum, and abomasum. The first three compartments (rumen, reticulum, and omasum) are colonized by microflora that digest complex carbohydrates and produce volatile fatty acids. The slightly acidic pH (5.5-6.5) in the rumen and reticulum favors absorption of nonionized forms of weakly acidic drugs; however, the bioavailability of many drugs is reduced substantially by passage through the rumen due to degradation or long residence times (eg, prednisolone).²² The last compartment, the abomasum, is most similar to the stomach in monogastric species. Abomasal pH typically is around 3, which is comparable to gastric pH in monogastrics.¹¹ Absorption of weak acids is favored in the abomasum.

GESTATION

Approximate gestational periods vary considerably by species (Table 3). Although animal pregnancies are not typically divided into trimesters, the known gestational periods can be divided by 3 to draw comparisons with human pregnancy trimesters.

Before any drug is used in a pregnant woman, its pregnancy category and safety data are considered carefully, based on the trimester in which the drug will be used. If safety information regarding the use of a particular drug in a pregnant animal is not available—but safety data exist for its use in a pregnant woman—the human safety data should be extrapolated to the pregnant animal. For example, folate antagonists cause congenital malformations in human fetuses when used during the first trimester of pregnancy. It stands to reason that folate antagonists should not be administered to animals during the first trimester of pregnancy.

VITAL SIGNS

Normal vital signs vary significantly from species to species. It is important for pharmacists and pharmacy technicians to be familiar with normal body temperature, heart rate, and respiratory rate in different types of animals, so they can recognize clinically important variations and counsel pet owners about appropriate monitoring parameters.

Temperature

Fever can be a sign of infection or an adverse drug effect. However, a body temperature that would be considered a fever in humans may be considered normal temperature, or even a low normal temperature, in a cat or rabbit. For example, a temperature of 102°F is considered normal in a cat, and unless cat owners are given a threshold for what temperature constitutes a fever, they may be concerned with a temperature of 102°F. Figure 1 depicts comparative values for what most veterinarians consider to be clinically significant fever by species.

Figure 1. Comparative Fever Thresholds in Selected Species

Heart Rate and Respiratory Rate

In some instances, pet owners may need to monitor their pets for abnormalities in heart rate (ie, bradycardia or tachycardia) or breathing (ie, dyspnea or tachypnea). Those thresholds typically are very different in animals than they are in humans. For example, a resting heart rate of 60 beats per minute (bpm) would not be cause for concern in a healthy human. In contrast, the normal resting heart rate for a horse typically is 28 to 40 bpm. A horse with a resting heart rate of 60 bpm should be evaluated by a veterinarian immediately, especially if the animal exhibits other signs of discomfort or distress. Owners of cats with cardiomyopathies are counseled to monitor their pet’s pulse to ensure that it ideally stays below 150 bpm.²³

Comparative heart rate thresholds for various species are shown in Figure 2. Normal respiratory rates are listed in Table 4.

Figure 2. Comparative Heart Rate Thresholds in Selected Species

DRUG DISPOSITION

Important considerations for drug disposition in non-human species include body composition, protein binding, blood volume, metabolism, urinary pH, glomerular filtration rate, and variations in first-pass effect.

Distribution

Distribution of drugs in non-human species is affected significantly by body composition. Compared with humans, some animals (eg, marine mammals) normally have a greater body adipose tissue percentage, and some (eg, Greyhound dogs) normally have a lower one. Lipophilic drugs that distribute to adipose tissue (eg, thiobarbiturates) will remain in the bloodstream of lean animals, causing dangerously high levels of drug and abnormally long recovery times. Individual animals may undergo dramatic fluctuations in adipose tissue in response to hormonal, seasonal, or dietary variations (eg, egg-laying birds, hibernating mammals, starved animals); all of these conditions can affect lipophilic drug distribution.

Unbound drugs in plasma generally are free to enter tissues and exert an effect, while protein bound drugs generally have a longer duration of effect. Differences in protein binding among species can account for substantial differences in potency and duration of action of certain drugs. For example, the long-acting cephalosporin antibiotic cefovecin is highly protein bound (98.5%–99.8%);²⁵ it is approved for administration once every 14 days to dogs and once every 7 days to cats. In non-human primates, the half-life of cefovecin is only a few hours, presumably because of a much lower degree of protein binding.²⁶

Blood volume per unit of body weight also varies widely across species and contributes to differences in dosage and frequency of administration for non-human species. If all other factors are equal, peak blood concentrations following intravenous administration of a drug (on a mg/kg body weight basis) will be dependent on the blood volume per kilogram of the animal. Table 5 lists approximate values for blood volume per weight by species and the likely relationship to maximum blood concentrations achieved after intravenous administration to humans.

Metabolism

Variation in drug metabolism is the most important aspect of comparative drug disposition for pharmacists, pharmacy technicians, and veterinary technicians filling prescriptions for non-human patients or consulting with veterinarians.

Phase I Metabolism. Hepatic microsomal enzymes vary significantly across species and may be affected by diet, gender, or age. It is important to note that cytochrome P-450 (CYP) nomenclature is based on species-specific amino acid sequences. It is not possible for non-human species to share a named microsomal enzyme with humans. For example, although CYP3A4 (human) may be functionally similar to CYP3A12 (canine), they are not the same enzyme because of differences between the human and canine amino acid sequences.

Extrapolations from human cytochrome P-450 mediated drug metabolism may or may not accurately predict drug elimination or drug interactions in non-human species. Although rabbits once served as a primary laboratory model for preclinical human drug studies, rabbits do not have a counterpart to the human CYP2D6 microsomal enzyme that is involved in the metabolism of about one-third of drugs used in humans.²⁸ Conversely, dogs share many cytochrome P450 enzyme subfamilies with humans (eg, 3A), and these similarities can be used to predict both useful and harmful drug interactions. For example, cyclosporine A is cleared by the CYP3A subfamily of microsomal enzymes in both dogs and humans. Cyclosporine A is used widely in dogs for a variety of indications, but it is expensive and causes many dose-related adverse effects. Veterinarians often will take advantage of the well-documented drug interaction between ketoconazole and cyclosporine to boost blood levels of cyclosporine in dogs, allowing administration of smaller systemic doses.²⁹

Phase II Metabolism. Differences in phase II metabolism (conjugation) across species are the most well-known and best documented. There are seven major metabolic conjugation reactions in mammals: glucuronidation, sulfation, methylation, acetylation, glutathione conjugation, amino acid conjugation, and fatty acid conjugation.²² Four of these reactions may be deficient or absent in non-human species:

• Glucuronidation
• Sulfation
• Methylation
• Acetylation

It is commonly stated that cats lack the ability to conjugate with glucuronide. This is not completely true; cats do have the ability to conjugate with glucuronide, but lack some of the major glucuronyl transferase enzymes. Domestic cats are unable to conjugate phenol, morphine, acetaminophen, carprofen, some benzodiazepines, and propofol, but they are able to conjugate endogenous substances such as bilirubin, some steroids, and thyroxine.³⁰ Pharmacists, pharmacy technicians, and veterinary technicians should be aware of drug classes that are metabolized through conjugation with glucuronide (eg, opioids, benzodiazepines, steroids, acetaminophen, salicylates, nonsteroidal anti-inflammatory drugs) and recognize that if these drugs are used at all in cats, the dose may be substantially smaller than the human dose, or the drug may be administered less frequently.

Differences in demethylation and hydroxylation also have been described in cats and are responsible for serious hepatotoxicity that may arise following administration of chloramphenicol or oral diazepam.³¹ Oral diazepam therapy can cause idiosyncratic hepatic failure in some cats; if the benefit of oral diazepam therapy outweighs risk in a feline patient, serum chemistries should be performed 5 days after therapy is initiated to monitor for elevated transaminase.³²

Many drugs that are conjugated with glucuronide also are cleared through sulfation. Conjugating agents for glucuronidation are abundant in most species, but the endogenous moieties to conjugate with sulfate are in low supply. For example, pigs have a very low capacity for synthesizing sulfate substrates, so the primary conjugation reaction in pigs is glucuronidation.

Acetylation involves transfer of an acetyl group from acetyl coenzyme A to the amino group of the metabolized drug. This can transform a drug into an active metabolite or (more commonly) render it pharmacologically inactive for renal elimination. Because canine species lack specific transacetylase enzymes, acetylation is completely absent in dogs. The inability to acetylate has several major consequences:

• Failure to produce active metabolites necessitates more frequent administration of affected drugs (eg, N-acetylprocainamide)
• More rapid excretion of the parent drug necessitates more frequent administration of affected drugs
• Inability to detoxify certain drugs (eg, isoniazid) increases susceptibility to drug toxicity

On the positive side, the inability to acetylate sulfanilamide to the less soluble and more toxic acetylsulfanilamide tends to protect dogs from the renal toxicity of sulfanilamide.³³

Methylation involves the transfer of a methyl group from methionine to the metabolized drug. It is a relatively minor pathway for the biotransformation of drugs. One important deficiency in methylation is seen in cats. Because cats lack thiopurine methyltransferase, azathioprine and 6-mercaptopurine can be quite toxic.³⁰

Table 6 describes species deficiencies in conjugation capability and the targeted functional groups and important drugs for each conjugation reaction.

Elimination

Metabolism of drugs usually produces a more water-soluble metabolite that can be eliminated easily by urinary excretion. The pH of human urine generally is in the range of 5 to 7, favoring the reabsorption of weak acids but promoting final elimination of many drugs. Drugs that typically are excreted or reabsorbed through renal tubules in humans may have a very different elimination profile in other species. Table 7 lists the typical urinary pH for selected mammalian species and the general impact on drug disposition.

The glomerular filtration rate (GFR) is another critical aspect of drug disposition and monitoring. For drugs and active metabolites that are eliminated via renal excretion, the GFR can dramatically affect mean residence time and half-life—and, subsequently, the dose and frequency of administration of drugs. Logically, the higher the GFR of a given species is compared with human GFR, the less time the drug will persist in that animal’s system relative to humans.

As an example of this concept, canine GFR is approximately 3 times greater than human GFR. The daily dosage of levothyroxine in dogs (0.02 mg/kg/d) is approximately 10 to 15 times higher than the human dosage. This is due largely to decreased oral bioavailability in dogs, but also to faster renal elimination in dogs vs humans.

Table 8 shows the average GFR and predicted effect on the half-life of renally eliminated drugs for selected species.

Humans and other mammals have a hepatic portal system, in which drugs and nutrients are directed to the liver via blood vessels draining the gut. Pharmacists and pharmacy technicians are aware of the significant effect of hepatic first pass on bioavailability, toxicity, and dosage regimens for drugs in humans; the hepatic first-pass effect is similar in non-human mammals. In addition, birds, amphibians, reptiles, and some fish also have a renal-portal system that returns blood directly to the kidneys from the hindlimbs and/or caudal body, theoretically resulting in a first-pass effect in the kidneys.³⁴ In birds and reptiles, drugs that may be nephrotoxic (eg, aminoglycosides) or renally eliminated (eg, cephalosporins) have thus typically been injected in the anterior portion of the body (eg, the pectoral muscles for birds or the forelimbs of turtles) to avoid nephrotoxicity or rapid elimination before therapeutic effect is achieved. Some drugs, including opioids, aminoglycosides, and beta-lactam antimicrobials undergo a significant hepatic first-pass effect or a significant renal portal system effect after being injected into the hindlimb of reptiles.^37,38 Nevertheless, if a veterinarian prescribes injection in a specific region on a given animal patient, pharmacists, pharmacy technicians, and veterinary technicians should emphasize the importance of administering the drug in that site.

SPECIES PHARMACOGENETICS

Long before veterinary pharmacogenetics was an active field of research or a viable clinical approach, veterinarians often followed the adage “white feet, don’t treat” when dosing certain drugs, including chemotherapy agents, antidiarrheals, and heartworm preventatives. Herding canine breeds (many of which have white feet) were known to suffer severe, often fatal, central nervous system toxicity from typical doses of drugs that were not observed to be toxic in other breeds. It is now well established that this increased susceptibility to drug toxicity in certain breeds of dogs is caused by a genetic polymorphism in the ATP binding cassette (ABC) transporter protein, also known as the p-glycoprotein (P-gp) transporter protein, resulting in failure of the P-gp pump at the blood–brain or other blood–compartment barriers.³⁹ A four-base pair deletion mutation in the ABCB1 gene occurs at a very high incidence in many herding breed dogs, including Collies, Australian Shepherds, and Shetland Sheepdogs. The problematic chemotherapy agents (doxorubicin and vinca alkaloids), antidiarrheal (loperamide), and macrocyclic lactone heartworm preventatives (avermectins and milbemycin) all are substrates for P-gp.

The approximate frequency of genetic polymorphism of the ABCB1 gene in high-risk dog breeds is shown in Table 9. For mixed-breed dogs, genetic testing is easily accessible at a nominal fee—a simple cheek swab can determine a dog’s risk for multidrug sensitivity due to genetic polymorphisms. Pharmacists, pharmacy technicians, and veterinary technicians should know which drugs are likely to cause adverse events in susceptible breeds (Table 10) and perform drug use evaluation accordingly. Health care professionals providing pharmaceutical products for dogs should also encourage dog owners to learn more about this important issue by referring them to the Canine Multidrug Sensitivity Testing website (http://vcpl.vetmed.wsu.edu/).

Genetic deficiencies in protein transporters also may occur at the species level. For example, the unique susceptibility of cats to dose-related retinal toxicity from the fluoroquinolone antibiotic enrofloxacin recently was attributed to failure of the ABCG2 blood–retinal barrier protein transporter. Failure of the ABCG2 P-gp pump in cats results in accumulation of photoreactive fluoroquinolones in the retina;⁴¹ exposure of the retina to natural light (through the pupil) generates reactive oxygen species that cause retinal degeneration and blindness. Pharmacists, pharmacy technicians, and veterinary technicians should consider the possibility that pharmacological inhibition of ABCG2—in cats in particular, but also in other species (through genetic polymorphism or drug interactions)—could result in retinal damage if photoreactive drugs are administered concomitantly. Table 10 lists drugs that have the potential to cause adverse effects in animal patients with genetic polymorphisms in P-gp protein transporter pumps.

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