Theophylline apnea

Adverse reactions to drugs differ in both type and incidence in the pediatric population. Because of immature metabolic pathways, infants and children may have different metabolic patterns than adults. This at least partially explains why neonates require lower theophylline serum concentrations for the treatment of neonatal apnea and why the incidence of hepatotoxi-city following acetaminophen overdose is much lower in young children than in adults [44,45]. Antibiotic adverse effects unique to the pediatric population may... 

M. Boutroy, P. Vert, R. Royer, P. Monin, and M. Royer-Morrot, Caffeine, a metabolite of theophylline during treatment of apnea in the premature infant, J. Pediatr., 94, 996 (1979). 

Caffeine and theophylline are more active on the central nervous system, while theobromine is much less active. Caffeine and theophylline also appear to stimulate the respiratory centers, making them useful in the treatment of infants who stop breathing for extended periods of time (sleep apnea), which can lead to sudden infant death. 

Most drugs are administered to infants and children for the same therapeutic indications as for adults. However, a few drugs have found unique uses in children. Among these are theophylline and caffeine, which are used to treat apnea of prematurity indomethacin, which closes a patent ductus arteriosus and prostaglandin Ej, which maintains the patency of the ductus arteriosus. Paradoxically, drugs such as phenobarbital, which have a sedating action on adults, may produce hyperactivity in children, and some adult stimulant drugs, such as methyl-phenidate, are used to treat children with hyperactivity. 

The xanthines are readily absorbed by the oral and rectal routes. Although these agents can be administered by injection (aminophylline is a soluble salt of theophylline), intravascular administration is indicated only in status asthmaticus and apnea in premature infants. Intramuscular injection generally produces considerable pain at the injection site. 

Theophylline is frequently used as a bronchodilator in the treatment of asthma. The importance of the methylxanthines in the management of bronchial asthma is discussed more fully in Chapter 39. Caffeine as the citrate salt (Cafcit) is used for the short-term management of apnea in premature infants (28-33 weeks of gestational age). 

Caffeine continues to be used therapeutically in analgesic combination preparations. It has superseded theophylline as the preferred drag for treatment of neonatal apnea because of its ease of administration and more predictable plasma concentrations. 

Theophylline is an example of a drug that is readily metabolized in neonates by N-methylation to caffeine (process not relevant clinically in older infants, children, and adults). It is also a compound that has pharmacologic activity versus apnea (like theophylline), but which may have toxicity when it is not readily metabolized by the liver, and its elimination is slowed by immature kidneys. ... 

Xanthines have been given to infants at the risk of sudden infant death sjmdrome or idiopathic apnea of prematurity (see monograph on Theophylline). About 50% of 30 infants treated with caffeine (and 12 of 18 infants treated with theophylline) had significant increases in episodes of gastroesophageal reflux (36). The authors stressed that screening for reflux should precede the administration of caffeine (and theophylline) to infants at the risk of sudden infant death syndrome. As expected, the frequency of adverse effects such as tachycardia and gastroesophageal reflux is lower with lower doses of caffeine for example 2.5 mg/kg qds (SEDA-17,1). 

Ten preterm infants receiving regular theophylline for apnea of prematurity, who subsequently received vancomycin and furosemide, have been studied (52). When vancomycin was introduced in the infants who were established on furosemide and theophylline, there was a consistent failure to achieve therapeutic concentrations. Starting furosemide in infants who were already receiving vancomycin resulted in falls in serum vancomycin to subtherapeutic concentrations in all but one case. Serum concentrations fell by a mean of 24% (range 12-43%), in the 24 hours after the start of furosemide treatment. Two of the 10 infants had persistence... 

Theophylline is used as a bronchodilator in the treatment of asthma and reversible bronchospasm associated with chronic bronchitis and emphysema. Unlabeled use includes treatment of sleep apnea in neonates. 

A minor metabolite of theophylline in adults, caffeine has been shown to accumulate to significant concentrations in neonates. Caffeine itself is an effective inhibitor of apnea, which may explain the lower therapeutic concentration required for control of neonatal apnea. Therapy with caffeine alone has also been demonstrated as effective in the treatment of neonatal apnea it is gaining popularity because of caffeine s long half-life in neonates (>30 hours). Caffeine is metabolized by CyP 1A2 this enzyme is not active in neonates. The optimal therapeutic concentration of caffeine in this situation ranges from 8 to 14pg/mL. Caffeine is measured by HPLC or immunoassay. 

With completion of the time course and covariate components of the model, focus turned to determining a model to describe the influence of theophylline on apnea frequency. For this analysis the exposure metric was an approximate average steady-state concentration (C vg). The general form of the exposure-response model was... 

C. Godfrey, The Population Pharmacokinetics and Pharmacodynamics of Theophylline in Neonates with Apnea of Prematurity. PhD Dissertation, University of Connecticut, 2001. 

Percutaneous absorption may be increased substantially in newborns because of an underdeveloped epidermal barrier (stratum comeum) and increased skin hydration. The increased permeability can produce toxic effects after the topical use of hexachlorophene soaps and powders, salicyhc acid ointment, and rubbing alcohol. Interestingly, a study has shown that a therapeutic serum concentration of theophylline can be achieved to control apnea in premature infants of less than 30 weeks gestation after a topical apphcation of gel containing a standard dose of theophylline. " The use of this route of administration may minimize the unpredictability of oral and intramuscular absorption and complications of intravenous drug administration for certain drugs. 

Methylxanthines have a few valid therapeutic uses, including treatment of asthma and relief of dyspnea (see Antiasthmatic agents). The CNS stimulatory effects are also utilized for the treatment of the prolonged apnea that may be observed in premature infants. Theophylline may be combined with doxapram (13) for this use (20). The methylxanthine most widely used therapeutically is theophylline, although caffeine may also be used. For parenteral administration, a salt of theophylline is employed. There are several salts available, including theophylline ethylenediamine (aminophylline [317-34-0]) and oxtriphylline (choline theophyllinate). Other synthetic xanthines that are used include dyphylline [479-18-5] and enprofylline [410784)2-8] (21). Caffeine is obtained in pure form from tea waste, from the manufacture of caffeine coffee, and by total synthesis (22,23). 

Theophylline is a methylated xanthine which exemplifies a clinically useful drug with a narrow margin of safety. Theophylline is used to treat bronchial asthma as well as apnea and bradycardia in premature infants. Serum concentrations must be maintained between 10 and 20 lg/ ml because it is ineffective at lower concentrations and it produces undesirable effects at higher concentrations. 

Theophylline Cellular mech like caffeine. More CNS stimulation than caffeine. Increased cardiac stimulation and diuresis. More effective bronchodilator. Bronchial asthma. Apnea and bradycardia in premature infants (unlabeled use). II M... 

More importantly, the effects of theophylline are not limited to bronchodila-tion, bnt also include immunomodulatory, anti-inflammatory, and bronchoprotec-tive activity that substantially contribute to its usefulness as a prophylactic drug in asthma and other respiratory diseases. Additional effects include an increase in mucociliary clearance, a decrease of microvascular leakage into the airways, and an improvement of respiratory mnscle fatigue, especially that of the diaphragm. Theophylline fnrthermore acts centrally, blocking the decrease in ventilation that occurs with sustained hypoxia. While some of these effects are the rationale for its use in asthma, others form the basis for its effectiveness in chronic obstructive pulmonary disease (COPD) or in the treatment of apnea in premature newborns. 

Theophylline has also been nsed for the treatment of preterm neonatal apnea, but recent evaluations of the available data suggest that caffeine is therapeutically advantageous compared with theophylline in this indication ... 

For the treatment of preterm neonatal apnea, theophylline serum concentrations of 5 to 10 pg/ml are being considered as effective in decreasing the number of apnea episodes. The pharmacodynamics of theophylline in this situation, however, have not well been studied, and theophylhne in neonates is converted to caffeine to varying degrees, which also is effective in suppressing apnea and thus confounds the concentration-effect relationship. 

Theophylline is a methyixanthine used for the treatment of asthma. Intravenous infusions of aminophylline, the ethylenediamine salt of theophylline, are used to treat bronchospasm, congestive heart failure, and neonatal apnea. Theophylline is most commonly used orally in sustained-release preparations (eg, Theo-Dur , Slo-Phyllin, Theo-24 , and many others). 

Henderson-Smart DJ, Steer PA. Caffeine versus theophylline for apnea in preterm infants. Cochrane Database Syst Rev 2010 (1) CD000273. 

Caffeine and theophylline are methylxanthine derivatives that are widely distributed in plant products and beverages. Theophylline and caffeine have been widely used for the treatment of asthmatic manifestations, neonatal apnea and bronchial spasms. However, these compounds produce the biological effect of dieresis, and excessive intake leads to many undesired side effects, with symptoms including tremors, excessively fast heartbeat and gastrointestinal difficulties [35]. Therefore, it is very important to determine accurately the content of these alkaloids in foods and pharmaceutical preparations. 

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