Acutely administered caffeine modestly increases blood pressure, plasma catecholamine levels, plasma renin activity, serum free fatty acid levels, urine production, and gastric acid secretion. It alters the electroencephalographic spectrum, mood, and sleep patterns of normal volunteers. Chronic caffeine consumption has no effect on blood pressure, plasma catecholamine levels, plasma renin activity, serum cholesterol concentration, blood glucose levels, or urine production. Caffeine does not appear to be useful for increasing the motility of hypomotile sperm in artificial insemination or in the therapy of minimal brain dysfunction, cancer, or Parkinson's syndrome, but it may be effective as a topical treatment of atopic dermatitis and as systemic therapy for neonatal apnea. Caffeine does not seem to be associated with myocardial infarction; lower urinary tract, renal, or pancreatic cancer; teratogenicity; or fibrocystic breast disease. The role of caffeine in the production of cardiac arrhythmias or gastric or duodenal ulcers remains uncertain.

The Health Consequences of Caffeine

Rational pharmacotherapy is dependent upon an understanding of the clinical pharmacokinetic and pharmacodynamic properties of the drugs employed. Although the available data on drug biodisposition and action in the neonate have increased considerably in the last few years, pharmacokinetic-pharmacodynamic interactions for many drugs remain poorly understood.

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Principles of Drug Biodisposition in the Neonate

Rational pharmacotherapy is dependent upon an understanding of the clinical pharmacokinetic and pharmacodynamic properties of the drugs employed. Although the available data on drug biodisposition and action in the neonate have increased considerably in the last few years, pharmacokinetic-pharmacodynamic interactions for many drugs remain poorly understood. The ontogeny of drug absorption, distribution, metabolism, and elimination are addressed in this review. Drug absorption from any site depends upon both the physicochemical properties of the drug and a variety of patient factors. Absorption of orally administered drugs may be affected by changes in gastric acidity and emptying time as well as by bile salt pool size, bacterial colonisation, and extraintestinal disease states such as congestive heart failure. Factors affecting drug absorption following intramuscular, percutaneous, and rectal administration are also discussed. Drug distribution in the neonate is influenced by a variety of important and predictable age-dependent factors. The developmental aspects of protein binding and body water compartments are described. Additionally, hepatic drug metabolism assumes an important role in understanding the pharmacokinetic and pharmacodynamic properties of many compounds. Certain biotransformation pathways, including hydroxylation by the P450 mono-oxygenase system and glucuronidation, demonstrate only limited activity at birth, while other pathways, such as sulphate or glycine conjugation, appear very efficient at birth. Elimination of drugs excreted unchanged in the urine is dramatically reduced in the newborn, compared with older infants and children, due to immaturity of both glomerular filtration and tubular secretory processes. The glomerular filtration rate remains markedly reduced prior to 34 weeks gestational age, increasing as a function of post-conceptual age until adult values are achieved by approximately 2.5 to 5 months of age. Tubular secretory capacity is also limited at birth, approaching adult values by approximately 7 months of age. Published reports describing the pharmacokinetics and pharmacodynamics of commonly used drugs in the neonatal period, as well as differences in drug biodisposition among premature infants, full term neonates, and older infants and children, are reviewed. Our recommendations for neonatal drug therapy are based upon a critical interpretation of these data, an understanding of fetal development and maturational processes, and an understanding of how disease states may affect drug biodisposition in the neonate.

Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (Part II)

Very few studies have been carried out looking at how the effects of drugs and their toxicity in humans change during their lifespan (developing and ageing). The purpose of this study is to review the literature on the changes in probe-drug metabolism, classified by cytochrome P450 (P450 or CYP) at five stages in life: neonates 65 years. The main probe drugs include caffeine and theophylline, whose metabolism is catalysed by CYP1A2, tolbutamide, phenytoin and ibuprofen, catalysed by CYP2C9, amitriptyline and nortriptyline, catalysed by CYP2C19, acetaminophen, catalysed by CYP2E1 and lidocaine, midazolam and terfenadine, catalysed by 3A3/4. From the published in vivo studies two different patterns of drug metabolism can be identified: (i) activity is low immediately after birth, increases, then peaks at the young/mature adult level and, finally, decreases in old age (drugs catalysed by CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A3/4) and (ii) activity increases rapidly after birth to reach a level equivalent to that in the young/mature adult, then gradually decreases and finally decreasing faster in old age (drugs catalysed by CYP2E1). Further study of the changes in P450 with age is warranted to help prevent adverse reactions and to guide us in tailoring therapy better for the individual patient.

Hubert Renaud

Papers

Plasma xanthine levels inlowbirthweight infants treated ornottreated withtheophylline