Medicating neonates puppies and kittens (Proceedings)

Objectives

• To review the physiologic differences affecting pharmacokinetics in neonates.

• To review basic concepts in making drug choices for the neonatal canine and feline.

• To familiarize practitioners with the most commonly used drugs in neonates.

• To review specific drugs commonly used and avoided in the neonate.

General Key Points

• Neonates are not small dogs or cats, there are major physiologic differences affecting drug use.

• Most published drug dosages have been empirically chosen. Few scientific studies exist.

• Risk/Benefit analysis must be applied to choices.

• Whenever possible, avoid drug use in neonates.

Pharmacokinetics

• The neonate's physiologic differences from the adult can greatly alter how drugs are handled by the body.

• The cardiac output is rate dependant in the neonate. The resting output is very near the maximum potential output. Cardiac reserve is minimal.

• High metabolic rate leads to high oxygen consumption.

• Neonates poorly regulate their body temperature.

• The blood-brain barrier is more highly permeable.

• Neonates have low protein binding of drugs due to reduced albumin.

• High body water content, low body fat. Extracellular fluid volume higher than adult.

• Decreased renal function, reduced renal clearance.

• Immature hepatic enzyme function leads to reduced hepatic clearance.

Absorption

• Absorption of drugs administered by both oral and parenteral routes may differ from the adult.

• Small muscle mass and reduced vascularity affect the absorption of intramuscularly injected drugs.

• Subcutaneous absorption will vary with age, reduced subcutaneous fat stores leads to more rapid absorption of most substances. Avoid administering hypertonic solutions subcutaneously. Hypothermia slows absorption.

• Oral absorption is affected by increased intestinal permeability in the early neonatal period. Delayed GIT transit times will also delay absorption.

• Intraosseous or intraperitoneal administration of drugs may speed absorption. The intratracheal and rectal routes may also be utilized in emergency situations.

Distribution

• Neonates have higher percent body water and more fluid in the ECF space. Highly water soluble drugs may have reduced plasma concentrations. Highly fat soluble drugs may have increased plasma concentrations.

• Plasma protein levels are lower than adult levels and neonatal albumin displays less affinity for binding to drugs. Drugs which are usually highly protein bound may have increased plasma levels.

• The blood-brain barrier is much more highly permeable in the neonate increasing the risk of toxicity with certain drugs.

Biotransformation

• Metabolism of drugs by an immature hepatic enzyme system that has reduced metabolic capacity is slower than that in adults. Pro-drugs may have reduced efficiency due to delay in formation of the active metabolite.

Elimination

• Renal mechanisms of elimination are immature and rates of elimination are slower than in adults. Use caution with highly water soluble drugs that have potential for toxicity.

Types of drugs commonly used in neonates

Antibiotics

• It is generally recommended to avoid the oral route of administration for antibiotics in critically ill neonates.

• Choices should be based on bacterial species involved. If possible cultures should be obtained prior to beginning therapy.

• Every antibiotic carries some type of risk associated with its use, but none are absolutely contraindicated.

• Beta-lactams are usually considered the safest and best first choice. Chloramphenicol use is controversial due to safety issues involving blood dyscrasias associated with its use. Tetracyclines can cause not only acute toxicity, but their calcium chelating properties may lead to tooth and bone development issues. Aminoglycosides have oto- and nephro- toxicity capabilities leading to recommendations of careful therapeutic drug monitoring by Plumb and others.The fluroquinolone antibiotics are still considered controversial due to cartilage problems reported in the rapid growth phase. In neonates however, many consider their risks far outweighed by the potential benefits.

Parasiticides

• Pyrantel pamoate is considered very safe for neonates and prophylactic use is usually recommended after about 14 days of age.

• Metronidazole should be avoided in the very young neonate. The high potential for neurologic side effects may be exacerbated by the blood-brain barrier permeability in neonates. Doses for treatment of giardia in older infant (2-6 weeks) and pediatric (6-12 weeks) animals have been published.

• Fenbendozole is also considered fairly safe in neonates.

• Sulfadimethoxide is commonly used for treatment and prevention of coccidiosis in young animals without reports of toxicity.

Emergency and supportive

• Commonly used drugs include doxapram, epinephrine, atropine and naloxone.

• Administration by intratracheal, intraosseous or rectal routes may be considered in animals with reduced vascular accessibility.

Anesthesia in the Neonate

• Although no specific anesthetic is contraindicated in the neonate, caution must be taken to carefully monitor dose and administration. Body temperature must be carefully maintained and cardiopulmonary function monitored.

• Thiobarbituates require a lower dose for induction in the neonate and should probably be avoided in the first 2-3 weeks of life.

• Ketamine is poorly tolerated in the first 3 weeks of life.

• Uses of low dose inhalants, opioids, benzodiazepines, dissociatives and alpha-2 adrenergic agonists have been commonly reported as safely utilized in neonates.

Choosing Drugs

• Always assess the risk versus benefit of a drug choice.

• Make the safest choice that may reasonable be expected to treat the condition.

• Obtain informed consent of the owner in all therapeutic decisions.

• Monitor for toxicity if possible during any potentially toxic drug therapy.

• Consider the prophylactic treatment of the littermates

Drugs commonly reported to "Avoid in the Neonate"

• Doxycycline

• Chloramphenicol

• Clindamycin

• Gentamicin

• Griseofulvin

• Ivermectin

• Long acting corticosteroids

• Metronidazole

• NSAID's

• Tetracycline

Drugs reported as "Avoid in the Nursing Dam/Queen"

• Aminoglycosides

• Chloramphenicol

• Tetracyclines

• Antineoplastics

Key Drugs, Dosages and Indications

Summary

• Profound differences in neonatal physiology affect the absorption, distribution, metabolism and elimination of drugs.

• Drug choices should be made with consideration of the risks and benefits reported.

• Consideration should also be made for those risks that may logically be concluded to be associated with a drug in light of the neonate's unique physiologic parameters.

References

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Hoskins, JD(ed). Veterinary Pediatrics, Dogs and Cats from Birth to Six months, 3rd Ed. Philadelphia, W.B. Saunders, 2001.

Lee JA, Critical Care of the Neonate, in Proceedings of the Annual Conference , Society for Theriogenology, 2004: 326-333.

Pascoe PJ, Moon PF, Periparturient and Neonatal Anesthesia. Vet Clin North Am [Small Anim Pract] 2001 31:315-341.

Poffenbarger EM, Ralston AL, Chandler ML, et al. Canine neonatology. Part 1. Physiologic differences between puppies and adults. Compend Contin Ed Pract Vet 1990;12:1601-1609.

Poffenbarger EM, Olson ON, Ralston SL, et al. Canine Neonatology.Part II. Disorders of the Neonate. Comp Cont Ed Pract Vet 1991; 139: 25-37.

Plumb DC, Drugs in Neonates: Principles and Guesses, in Proceedings of the Annual Conference, Society for Theriogenology, 2004; 307-315.

Plumb DC, Veterinary Drug Handbook 5th Ed. Ames IA, Blackwell Publishing. 2005.