Pharmacokinetics of cardiovascular drugs in children. Inotropes and vasopressors.

Abstract

Infants and children with congenital or acquired heart disease and children with systemic disease often require pharmacological support of their failing circulation. Catecholamines may serve as inotropic (enhance myocardial contractility) or vasopressor (elevate systemic vascular resistance) agents. Noncatecholamine inotropic agents, such as the cardiac glycosides or the bipyridines, may be used in place of, or in addition to, catecholamines. Developmental changes in neonates, infants and children will affect the response to inotropic or pressor therapy. Maturation of the gastrointestinal tract, liver and kidneys alters absorption, metabolism and elimination of drugs, although there are few clear examples of this among the vasoactive drugs considered in this review. Changes in body composition affect the volume of distribution (Vd) and clearance (CL) of drugs. Developmentally based pharmacodynamic differences also affect the responses to both therapeutic and toxic effects of inotropes. These pharmacodynamic differences are based in part upon developmental changes in myocardial structure, cardiac innervation and adrenergic receptor function. For example, the immature myocardium has fewer contractile elements and therefore a decreased ability to increase contractility; it also responds poorly to standard techniques of manipulating preload. Available data suggest that dopamine and dobutamine pharmacokinetics are similar to those in adults. Wide interindividual variability has been noted. A consistent relationship between CL and age has not been demonstrated, although one investigator demonstrated 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 regarding the pharmacokinetics of epinephrine (adrenaline), norepinephrine (noradrenaline) and isoprenaline (isoproterenol). Digoxin pharmacokinetics 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 values 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 can be achieved with serum concentrations similar to those aimed for in adults, with decreased toxicity. Evaluation of studies of digoxin pharmacokinetics is complicated by the presence of an endogenous substance with digoxin-like activity on radioimmunoassay. Limited studies of amrinone pharmacokinetics in infants and children indicate a dramatically larger Vd, and a decreased elimination half-life in older infants and children, compared with values observed in adults.