CHAPTER 28 Toxicologic Considerations in the Young Patient*
Pups and kittens may be exposed to toxins through various routes: ingestion (including the ingestion of mother’s milk), topical exposure, inhalation, and ocular exposure. In dogs and cats, the first 12 weeks of life is a time of significant developmental changes. Physiologic alterations associated with these maturation stages can predispose the pediatric patient to be more susceptible to adverse reactions. All aspects of drug disposition—absorption, distribution, metabolism, and excretion—are affected by these dramatic developmental changes as the neonate matures (Table 28-1).
|Increased intestinal permeability||Increased oral uptake, toxic plasma concentrations|
|Increased gastric pH||Increased oral uptake of weak bases and acid-labile compounds, prolonged and elevated plasma levels, toxic plasma concentrations|
|Altered peristalsis (decreased gastric emptying time)||Decreased absorption, lower plasma levels of toxin|
|Decreased plasma proteins||Toxin may accumulate, leading to more unbound compound and thus a potentially longer half-life|
|Decreased body fat||Increased plasma levels; decreased accumulation of lipid-soluble toxins|
|Increased total body water (more extracellular fluid)||Decreased plasma concentrations, longer half-life|
|Increased uptake of volatile gases||High plasma concentrations, increased response and toxicity|
|Increased dermal absorption||Higher or prolonged plasma exposure levels, toxicity increased|
|Immature P-glycoprotein system||Poor ability to clear toxins with this system|
After oral exposure, toxin absorption occurs primarily in the small intestine. The pediatric patient has a decreased gastric emptying time and irregular intestinal peristalsis and therefore tends to have a slower rate of absorption. These factors may result in the development of lower peak plasma toxin concentrations. The decreased rate of absorption may actually protect against toxic drug concentrations. However, these protective mechanisms may not be present in neonates before colostrum is absorbed. Before colostrum absorption, the permeability of the intestinal mucosa is increased, which also increases the rate of toxin uptake, including the uptake of compounds that normally would not reach the systemic circulation. Intestinal permeability rapidly decreases after colostrum ingestion. This closure may be induced by endogenous release of hydrocortisone or adrenocorticotropic hormone (ACTH). Exogenous supplementation of these hormones to the mother within 24 hours prepartum prevents the increase in permeability and uptake of colostrum.
Several other factors may affect small intestinal drug absorption in pediatric patients. Newborns have a neutral gastric pH, and the rate of progression to adult levels depends on the species involved. Achlorhydria (increased gastric pH) may cause decreased absorption of many compounds that require disintegration and dissolution or that need to be ionized in a more acidic environment (e.g., weak acids). Milk diets can interfere with absorption of toxic compounds by reducing gastric motility or interacting directly with the toxins. The “unstirred water layer” adjacent to the surface area of the mucosal cells is thicker in the neonate compared to the older pediatric patient, and this may limit the rate of absorption of some compounds. Absorption of fat-soluble compounds increases as biliary function develops. Both extrahepatic metabolism and enterohepatic circulation may be altered as microbial colonization of the gastrointestinal (GI) tract occurs. Absorption from the rectal mucosa is rapid in neonates.
Absorption of xenobiotics administered parenterally to pediatric animals varies from that in adults. As muscle mass develops, with its accompanying increase in blood flow and maturation of the vasomotor response, the rate of absorption after intramuscular administration of xenobiotics is altered. Subcutaneous administration of potentially toxic drugs may exhibit variable absorption rates relative to the patient’s age. Smaller amounts of body fat but greater water volume may result in quicker absorption of xenobiotics compared to that in adults.
It is suspected that environmental temperature influences subcutaneous absorption. This is especially true in neonates whose thermoregulatory mechanisms are poorly functional. If the neonate is in a cold environment, subcutaneous xenobiotic absorption tends to be reduced. The same thing would be expected for a patient that presents in a hypothermic state. Intraperitoneal exposure to xenobiotics may exhibit rapid absorption in the pediatric patient.
Percutaneous absorption of xenobiotics may be greater in pediatric patients. Percutaneous absorption is directly related to skin hydration, which is highest in neonates. Topical exposure to potentially toxic lipid-soluble compounds (e.g., hexachlorophene and organophosphates) places the pediatric patient at higher risk of significant absorption.
The two major differences between adult and pediatric patients relative to xenobiotic distribution are in body fluid compartments and toxin or drug binding to serum proteins. Body fluid compartments undergo tremendous alterations as the neonate grows. As the neonate matures, significant changes occur in both the percentage of total body water and the ratio of compartmental volumes. Although both the percentage of total body water and the volume of the extracellular vs. the intracellular compartment decrease as the animal ages, the change in the ratio of extracellular to intracellular volume is significantly greater. Daily fluid requirements are greater in neonatal and pediatric patients because a larger proportion of their body weight is represented by body water. The net effect on xenobiotic distribution depends on these differences in body compartments. Most water-soluble compounds are distributed into extracellular fluids. Plasma concentrations of these compounds are lower in pediatric patients compared to 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 total body water. Changes in xenobiotic distribution directly alter the half-life of the xenobiotic. Increases in distribution directly decrease the plasma concentration, a fact that may potentially protect the pediatric patient from toxic xenobiotic concentrations.
Distribution of lipid-soluble compounds that accumulate in the fat (e.g., some organophosphates and chlorinated hydrocarbons) may be decreased as the result of a smaller proportion of body fat in the pediatric patient. Xenobiotic plasma concentrations may be higher, but the half-life is shorter. The movement of many fat-soluble compounds may be facilitated by their high tendency to bind to plasma proteins. This binding decreases their ability to be distributed to target tissues.
Predicting the distribution of highly protein bound compounds is complicated in the pediatric patient. Most compounds are bound to serum albumin, and basic toxins have a high affinity for alpha-1-glycoproteins. Both of these proteins are available in lower concentrations in pediatric patients. Additionally, differences in albumin structure and competition with endogenous substrates (e.g., bilirubin) for binding sites may decrease protein binding. If bound toxins are displaced, the risk of toxicity increases as the concentration of free pharmacologically active compound rises. When a compound has a narrow therapeutic index and is highly protein bound, these age-related changes are significant. Xenobiotic half-life may rise because of increased amounts of compound that are unbound, allowing free distribution to the tissues and decreasing the plasma concentration. Despite the increased volume of distribution, the half-life of a compound may be “normalized” by the increased clearance of free toxin.
Pediatric patients also have differences in regional organ blood flow that may alter toxin disposition. Significant differences in renal blood flow can result in alterations in toxin excretion. Proportionally greater blood flow to the heart and brain in pediatric patients increases the risk of adverse effects that may result from lower exposures to cardiac and central nervous system (CNS) toxins. Neonatal patients have an increased permeability of the blood-brain barrier. This protects the brain from deficiencies in nutritional fuels in stressful states because oxidizable substrates, such as lactate, can pass from the blood into the CNS. However, this mechanism also increases the potential for CNS exposure to toxins. Brain cells that are normally protected in adults are at higher risk of exposure to toxins in the neonate.
Pediatric metabolism is significantly different than the adult. Hepatic and renal excretion is limited in neonatal and pediatric animals, thus decreasing toxin elimination. Absorption of xenobiotics by young animals may be manifested by decreased clearance. Near-term and neonatal puppies have incomplete hepatic metabolism. Both phase I (e.g., oxidative) and II (e.g., glucuronidation) reactions are reduced. Maturation of various metabolic pathways occurs at different rates. Neonatal puppies may not manifest phase I activity until the ninth day of life; this activity steadily increases after day 25 until it reaches adult levels at day 135. Because hepatic xenobiotic metabolism is decreased, plasma clearance of toxins is decreased, plasma half-life is increased, and toxic plasma compound concentrations may result. Until biliary function matures, the absorption of fat-soluble compounds may be impaired.
The oral bioavailability of compounds with a significant first-pass metabolism is probably greater in pediatric patients. Xenobiotics whose toxicity is generated from toxic metabolites may be less hazardous because there is decreased formation of active components. For example, children younger than 9 to 12 years of age have a lower incidence of hepatotoxicity after overdose of acetaminophen than adults. Pediatric hepatic metabolizing enzymes (e.g., cytochrome P-450) do appear to be inducible by phenobarbital and other drugs.
Alterations in toxin excretion manifest in several ways. Pups have reduced renal excretion, which decreases the clearance of renally excreted parent compounds and the products of hepatic phase II metabolism. As pups age, glomerular filtration rate (GFR) and renal tubular function steadily increase. The total number of glomeruli remains constant. Adult levels of GFR and tubular function are attained by months of age. If normal levels of body fluids and electrolytes are maintained, pediatric renal tubular resorption is equivalent to that in adults. In this pediatric renal environment, water-soluble toxins have decreased clearance and extended half-lives. An example of this phenomenon is the recommendation that pediatric patients require higher doses (as a result of the increased volume of distribution) and longer dosing intervals (as a result of increased distribution and decreased clearance) of gentamicin. One can anticipate alterations in excretion in sick or dehydrated pediatric patients.
Almost all xenobiotics cross the placenta and reach pharmacologic concentrations in the fetus after exposure of the mother. Drugs administered to the mother may cross the placenta by passive diffusion, facilitated transport, and active transport. Protein-bound xenobiotics do not cross the placenta. Factors affecting the pharmacokinetic and xenobiotic effects on mother and fetus are (1) altered maternal absorption, (2) increased maternal unbound xenobiotic fraction, (3) increased maternal plasma volume, (4) altered hepatic clearance, (5) increased maternal renal blood flow and GFR, (6) placental transfer, (7) placental metabolism, (8) placental blood flow, (9) maternal-fetal blood pH, (10) preferential fetal circulation to the heart and brain, (11) undeveloped fetal blood-brain barrier, (12) immature fetal liver enzyme activity, and (13) increased fetal unbound xenobiotic fraction.
Passive diffusion is the most common route in which xenobiotics enter milk. Xenobiotics pass through the mammary epithelium by passive diffusion down a concentration gradient on each side of the membrane. The higher the dose received by the mother, the more xenobiotic will pass into the milk. Generally, milk proteins do not bind xenobiotics well. Since milk (pH 7.2) is slightly more acidic than plasma (pH 7.4), compounds that are weak bases are more likely to pass into milk than weak acids. The more lipid soluble the xenobiotic, the greater the quantity and the faster the transfer into milk.
There is an art to acquiring a good toxicologic history. If the history is to provide any type of working diagnosis, the veterinarian’s interview must be meticulous, caring, and thorough in scope. The veterinarian must be a calming influence if a reliable account of events is to be obtained. Specific criteria characteristic of a toxicologic history include what poison or poisons are involved, when the exposure occurred, how much poison the animal was exposed to, and the route of the exposure It is particularly relevant to inquire about the entire litter, particularly if they are still together. Additionally, what is the mother’s condition and is there a possibility that she has been exposed to a compound that could be a problem for her offspring (regardless of whether she is exhibiting clinical signs of toxicosis)? Obtaining packaging containers for known exposures is significant in identifying the compounds involved and quality available to be ingested. Some aids in obtaining an organized history are outlined in Boxes 28-1 and 28-2.