Mechanism of Action

Caffeine is structurally related to other methylxanthines, theophylline and theobromine. It is a bronchial smooth muscle relaxant, a CNS stimulant, a cardiac muscle stimulant and a diuretic.

Although the mechanism of action of caffeine in apnea of prematurity is not known, several mechanisms have been hypothesized. These include: (1) stimulation of the respiratory center, (2) increased minute ventilation, (3) decreased threshold to hypercapnia, (4) increased response to hypercapnia, (5) increased skeletal muscle tone, (6) decreased diaphragmatic fatigue, (7) increased metabolic rate, and (8) increased oxygen consumption.

Most of these effects have been attributed to antagonism of adenosine receptors, both A₁ and A₂ subtypes, by caffeine, which has been demonstrated in receptor binding assays and observed at concentrations approximating those achieved therapeutically.

Pharmacokinetics

Absorption: After oral administration of 10 mg caffeine base/kg to preterm neonates, the peak plasma level (C_max) for caffeine ranged from 6-10 mg/L and the mean time to reach peak concentration (T_max) ranged from 30 minutes to 2 hours. The T_max was not affected by formula feeding. The absolute bioavailability, however, was not fully examined in preterm neonates.

Distribution: Caffeine is rapidly distributed into the brain. Caffeine levels in the cerebrospinal fluid of preterm neonates approximate their plasma levels. The mean volume of distribution of caffeine in infants (0.8-0.9 L/kg) is slightly higher than that in adults (0.6 L/kg). Plasma protein binding data are not available for neonates or infants. In adults, the mean plasma protein binding in vitro is reported to be approximately 36%.

Metabolism: Hepatic cytochrome P₄₅₀ 1A₂ (CYP 1A₂) is involved in caffeine biotransformation. Caffeine metabolism in preterm neonates is limited due to their immature hepatic enzyme systems.

Interconversion between caffeine and theophylline has been reported in preterm neonates; caffeine levels are approximately 25% of theophylline levels after theophylline administration and approximately 3-8% of caffeine administered would be expected to convert to theophylline.

Elimination: In young infants, the elimination of caffeine is much slower than that in adults due to immature hepatic and/or renal function. Mean half-life (T_1/2) and fraction excreted unchanged in urine (A_e) of caffeine in infants have been shown to be inversely related to gestational/postconceptual age. In neonates, the T_1/2 is approximately 3-4 days and the A_e is approximately 86% (within 6 days). By 9 months of age, the metabolism of caffeine approximates that seen in adults (T_1/2 = 5 hours and A_e = 1%).

Special Populations: Studies examining the pharmacokinetics of caffeine in neonates with hepatic or renal insufficiency have not been conducted. CAFCIT® (caffeine citrate) should be administered with caution in preterm neonates with impaired renal or hepatic function. Serum concentrations of caffeine should be monitored and dose administration of CAFCIT should be adjusted to avoid toxicity in this population.

Bookmark this page: