PHARMACOKINETICS OF CARDIOVASCULAR DRUGS IN CHILDREN - INOTROPES AND VASOPRESSORS

Infants and children with congenital or acquired heart disease and chi ldren with systemic disease often require pharmacological support of t heir failing circulation. Catecholamines may serve as inotropic (enhan ce myocardial contractility) or vasopressor (elevate systemic vascular resistance) agents. Noncatecholamine inotropic agents, such as the ca rdiac glycosides or the bipyridines, may be used in place of, or in ad dition to, catecholamines. Developmental changes in neonates, infants and children will affect the response to inotropic or presser therapy. Maturation of the gastrointestinal tract, liver and kidneys alters ab sorption, metabolism and elimination of drugs, although there are few clear examples of this among the vasoactive drugs considered in this r eview. Changes in body composition affect the volume of distribution ( Vd) and clearance (CL) of drugs. Developmentally based pharmacodynamic differences also affect the responses to bath therapeutic and toxic e ffects of inotropes. These pharmacodynamic differences are based in pa rt upon developmental changes in myocardial structure, cardiac innerva tion and adrenergic receptor function. For example, the immature myoca rdium has fewer contractile elements and therefore a decreased ability to increase contractility; it also responds poorly to standard techni ques of manipulating preload. Available data suggest that dopamine and dobutamine pharmacokinetics are similar to those in adults. Wide inte rindividual variability has been noted. A consistent relationship betw een CL and age has not been demonstrated, although one investigator de monstrated an almost 2-fold increase in the CL of dopamine in children under the age of 2 years. The CL of dopamine appears to be reduced in children with renal and hepatic failure. Fewer data are available reg arding the pharmacokinetics of epinephrine (adrenaline), norepinephrin e (noradrenaline) and isoprenaline (isoproterenol). Digoxin pharmacoki netics have been extensively evaluated in infants and children. The Vd for digoxin is increased in infants and children. Children beyond the neonatal period display increased CL of digoxin, approaching adult va lues during puberty. Although it was previously thought that children both needed and tolerated higher serum concentrations of digoxin than adults, more recent studies indicate that adequate clinical response c an be achieved with serum concentrations similar to those aimed for in adults, with decreased toxicity. Evaluation of studies of digoxin pha rmacokinetics is complicated by the presence of an endogenous substanc e with digoxin-like activity on radioimmunoassay. Limited studies of a mrinone pharmacokinetics in infants and children indicate a dramatical ly larger Vd, and a decreased elimination half-life in older infants a nd children, compared with values observed in adults.