CHAPTER 27 Pharmacologic Considerations in the Young Patient
Treatment of neonates in small animal medicine presents challenges for clinicians because of the marked anatomic and physiologic differences between puppies and kittens and adult animals. Current guidelines for the treatment of puppies and kittens have been extrapolated from other species, including human neonates, and from a small number of studies. Therefore many of the recommendations in this chapter are provided to make practitioners aware of pharmacological considerations that may require dosage adjustments in young animals.
Puppies and kittens can be exposed to drugs in utero through placental transfer. Neonates can also be exposed by ingesting compounds in their mother’s milk during nursing or through direct administration. Each source of exposure can be problematic for a developing fetus or a young animal because of differences in proportions and physiology compared with more mature animals. Although current veterinary drug reference handbooks provide little guidance for administration of medications to young animals, there are some basic considerations that are helpful for clinicians when administering drugs to pregnant or nursing mothers and young puppies or kittens.
The transfer of drugs from mother to fetus has been demonstrated for a number of drugs, which is a greater concern for drugs with high lipid solubility or that reach high systemic concentrations. The main forces that favor drug transfer from mother to fetus are the lipid solubility of the drug and a steep maternal-fetal drug concentration. However, other properties of the drug may also affect the extent of drug transfer; a list of properties and effects are presented in Table 27-1.
|Drug property||Effect on drug exposure to the fetus|
|Molecular weight (MW)|
|Lipid solubility||Only lipid-soluble drugs cross the placental barrier.|
|Ionization||Only nonionized drugs are able to cross the placenta. Weak acid drugs are more likely to transfer.*|
|Protein binding||Only unbound substances are likely to cross the placenta. Decreased maternal albumin increases the amount of free drug and may increase fetal exposure for highly bound drugs.|
Data from Syme MR, Paxton JW, Keelan JA: Drug transfer and metabolism by the human placenta, Clin Pharmacokinet 43(8):487-514, 2004.
Like transplacental transfer of drugs to the fetus, the transfer of drugs from mother’s milk to the neonate can also be a concern. The transfer of the drug to milk is similar to placental transfer of drugs. Weakly acidic drugs that are nonionized and nonprotein bound rapidly transfer from the maternal circulation to milk. Animal milk tends to be more acidic than the plasma pH, therefore drugs that make their way into milk may accumulate because they become ionized and “trapped” in the milk. The neonate may receive a significant dose of drug while nursing, although the amount of drug is generally less than 2% of the maternal dose. It is important to note, however, that the drug present in milk is not necessarily bioavailable and depends again on possible interactions in the neonate’s gastrointestinal tract that might limit drug absorption. Examples of drugs that cross the placenta include anesthetics, such as lidocaine; salicylates and nonsteroidal antiinflammatory drugs (NSAIDs); beta-lactam antibiotics; many narcotics; and anticonvulsants, including phenytoin and diazepam (Table 27-2).
Within the absorptive region of the neonatal small intestine, the surface area is sufficiently large relative to the size of the animal to allow a highly bioavailable drug to be rapidly absorbed. This absorption may lead to higher-than-anticipated peak plasma drug concentrations after oral administration of a medication. The increase in the rate of absorption combined with increased intestinal permeability in young animals can produce plasma concentrations that may reach toxic levels with some drugs. Drugs that normally have limited oral bioavailability can reach systemic circulation in the neonatal animal. These drugs include aminoglycosides, carbenicillin (and other acid-sensitive beta-lactams), and enteric sulfonamides. However, the practitioner should also consider other factors that may limit absorption of drugs in puppies and kittens. For example, intestinal permeability will be substantially reduced after the ingestion of colostrum or exogenous supplementation of either hydrocortisone or adrenocorticotropic hormone (ACTH) in the mother before giving birth.
Very young animals also have decreased gastric emptying time and irregular peristalsis that can partially protect against the increase in maximum systemic drug concentrations. Decreased gastric emptying in young dogs has been observed in multiple breeds, independent of size. Reduced gastric emptying may decrease the likelihood of reaching toxic drug concentrations by slowing the rate of absorption and thus reducing peak plasma concentrations. However, gastric emptying time has been shown to be shorter in puppies 12 weeks of age compared to older animals, so it may not be prudent to assume that decreased gastric emptying time will provide protection from high peak plasma concentrations. As a puppy develops, the rate increases to become higher than would be expected in an adult animal. This means that the practitioner should be aware that oral drugs with a narrow therapeutic index may present a problem for neonates, particularly when toxicity occurs because of peak plasma concentrations. Further, the practitioner must consider that if the peak concentration is reduced because of gastric emptying time, the net effect may result in increased steady-state plasma concentration and a reduced dose or dosing interval may be warranted.
Gastric pH is also a consideration for oral administration of drugs to newborns. Although pH in adult animals is quite acidic, the pH of newborns is closer to neutral. Mean gastric pH has been found to be stable at 5.85 until the seventh day of life. After day 7, gastric pH was shown to decrease to 3.45 and then increase to a mean of 4.95 through the eighteenth day. These types of changes will likely affect absorption of mildly acidic or basic drugs and either limit or increase bioavailability depending on pKa. For example, when pH is less acidic, drugs, such as beta-lactam antibiotics (weak acids), will be ionized and thus less bioavailable. Also, high gastric pH may decrease the bioavailability of drugs, such as ketoconazole and itraconazole, that require an acid environment for absorption. In contrast, weak bases, including the aminoglycoside antibiotics and fluconazole, have greater bioavailability. It is ultimately up to the practitioner to weigh the margin of safety versus the likelihood that the drug absorption might be significantly different from that expected in the adult.
A consideration for giving medications to nursing puppies and kittens includes the reduced absorption of concomitant administration of drug when milk may be present in the stomach. Milk can both decrease gastric emptying time and may also interact with drugs directly. Drugs likely to have reduced bioavailability include enrofloxacin and doxycycline. These interactions may lead to reduced absorption and result in lower peak plasma concentrations.
Newborn puppies and kittens can also be expected to have reduced hepatobiliary function, reduced capacity for drug metabolism through the cytochrome P-450 system, and reduced glucuronidation up to 4 to 6 weeks of age. These differences in phase I and II metabolism tend to lower absorption of fat-soluble drugs and vitamins. Also, reduced metabolism reduces the clearance of some drugs, including lidocaine and theophylline, that rely on P-450 metabolism. Other drugs, including morphine and many NSAIDs, may have reduced clearance as a result of reduced glucuronidation. Neonatal puppies and kittens also require time for their intestinal flora to be fully colonized; therefore an altered response to drugs that require activation in the intestine can be expected.
A common route of administration of drugs in puppies and kittens is by subcutaneous (SC) injection. This is often a preferred route because of the reduced muscle mass in young animals, which can make intramuscular (IM) injections more problematic. As muscle mass develops, the accompanying increase in blood flow also contributes to a more rapid absorption after IM injection. There are a number of physiologic differences between puppies and kittens relative to adult animals that contribute to changes in the absorption of drugs. Reduced fat and increased total body water may enhance SC drug absorption. Absorption likely decreases after either SC or IM administration if the animal is hypothermic.
Topical formulations are becoming more common in small animal medicine. These formulations are often designed to provide the drug at a rate that depends on the hydration state of the skin. Because skin hydration is greatest in the neonate, the rate of absorption will be higher and these patients may reach higher than expected peak plasma concentrations. This increase in peak plasma concentrations in neonatal and young animals could result in adverse effects with drugs that have a low therapeutic index.
One obvious difference between neonates and adult animals is the difference in proportion of head-to-body sizes. Body weight is also distributed differently in puppies and kittens, and these differences lead to changes that can present challenges to drug therapy. For example, the proportion of extracellular fluid as a percentage of total body weight changes significantly during the life of a maturing puppy. As seen in Figure 27-1, the changes occurring in the growing puppy (and similarly in the kitten) are a result of the total water alterations as a proportion of body weight. This water is found primarily in the extracellular fluid compared to percent intracellular fluid and will have significant effects on the absorption and distribution of drugs within the animal, including decreased plasma concentrations and longer half-lives. Plasma concentrations of water-soluble compounds are lower in pediatric patients compared with adults because the volume into which the compound is distributed is greater in the young. Unbound lipid-soluble compounds have the same type of distribution because they are distributed into the total body of water.
(Adapted from Boothe DM, Hoskins JD: Drug and blood component therapy. In Hoskins JD: Veterinary pediatrics: dogs and cats from birth to six months, ed 3, Philadelphia, 2001, Saunders, Table 3-2.)
A second factor important to the distribution of lipid-soluble drugs is the relative lack of fat in neonates and puppies compared to adult animals. Because fat acts as a reservoir for many lipid-soluble drugs, the absence of significant fat stores results in higher plasma concentrations of these types of drugs.
A number of biologic functions are reduced in young animals and will contribute to differences in drug distribution compared to adult animals. Hepatic gluconeogenesis, glycogenolysis, protein synthesis, and bile acid metabolism are reduced in neonates, with adult values occurring after 8 weeks of age. These decreases can contribute to the changes observed in drug metabolism and will alter the distribution of drugs that are protein bound in the circulation.
Kidney function and therefore drug clearance may be attenuated in puppies and kittens. The glomerular filtration rate (GFR) and renal tubular function increase as the puppy or kitten matures, increasing from about 20% of adult values at birth to full adult values over a period of 2 to 3 months. Reduced kidney function results in reduced drug clearance of drugs that undergo renal elimination. Under these conditions, with multiple-dose therapies, reduced clearance will produce a higher steady-state drug concentration for drugs with a sufficiently long half-life. The impact of reduced renal clearance can require the practitioner to adjust the neonate’s recommended drug regimen.
For example, consider the effect that reduced clearance might have on beta-lactam antibiotics such as amoxicillin. The beta-lactam antimicrobials are often the drug of choice for puppies and kittens because of their high therapeutic index. The peak plasma concentrations will be lower than expected because of the greater volume of distribution in puppies compared to adults, and the practitioner may need to select a higher dose for a puppy or kitten. Lower rate of renal clearance and reduced hepatic function will affect the amount of circulating drug and will have its greatest impact on steady-state concentrations. Therefore, to compensate for the reduced clearance, the clinician may have to consider giving an adult dose of the drug and extending the dosing intervals.
Adverse responses to drugs and drug formulations are more likely in puppies and kittens than in their adult counterparts. For example, administration of a drug formulation likely to cause a large shift in osmolality can result in a number of clinically significant adverse effects. Intravenous (IV) administration of hypertonic solutions containing sodium bicarbonate and radiocontrast materials in young animals can result in intraventricular hemorrhage and necrotizing enterocolitis.
Although pharmacokinetic differences contribute significantly to therapeutic failure in puppies and kittens, pharmacodynamic differences are also important to drug response in this population. A lack of response from drugs, such as atropine, isoproterenol, dopamine, and dobutamine, as well as anticholinergic drugs, has been demonstrated. The lack of drug response may be due in part to the immaturity of innervation in the developing animal.
There is relatively little information on the risks to the fetus associated with giving medications during pregnancy; much of the information available is limited to human medicine. However, there are some general guidelines that have been developed that may be helpful in assessing the impact of drug therapy in this population. Table 27-3 shows drug categories and a description of the effects of the different categories. Table 27-4 lists the general safety of a variety of drugs for use in neonates.
|A||Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities.|
Animal studies have revealed no evidence of harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women.
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