Theophylline pharmacodynamics

FIGURE 18.16 Theophylline pharmacodynamics in patients with asthma. Effect, which was measured as improvement in forced expiratory volume in 1 second (FEVI), is related to the serum drug level in six patients, who were studied after placebo and tliree incremental doses of theophylline. An Emax model is fit to the concentration-effect data. Based on this analysis, a therapeutic range of 10-20 pg/mL was proposed (shaded area). (Adapted from data published by Mitenko PA, Ogilvie RI. N Engl J Med 1973 289 600-3.)... 

More recently Brochot et al. [89] reported an extension of the isobolographic approach to interaction studies for convulsant interaction among pelloxacin, norfloxacin, and theophylline in rats. Their contribution is unique in that they started out by explaining pharmacodynamic interactions for two drugs, but then extended the approach to derive an isobol for three drug interaction. In addition they included Bayesian analysis and developed a population model with Markov chain Monte Carlo methods. 

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

B. Toxicodynamics Toxicodynamics is a term used to denote the injurious effects of toxins, ie, their pharmacodynamics. A knowledge of toxicodynamics can be useful in the diagnosis and management of poisoning. For example, hypertension and tachycardia are typically seen in overdoses with amphetamines, cocaine, and antimuscarinic drugs. Hypotension with bradycardia occurs with overdoses of calcium channel blockers, beta-blockers, and sedative-hypnotics. Hypotension with tachycardia occurs with tricyclic antidepressants, phenothiazines, and theophylline. Hyperthermia is most frequently a result of overdose of drugs with antimuscarinic actions, the salicylates, or sympathomimetics. Hypothermia is more likely to occur with toxic doses of ethanol and other CNS depressants. Increased respiratory rate is often a feature of... 

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. 

In addition to pharmacokinetic drug-drug interactions, pharmacodynamic effects have been reported as well. Halothane increases the susceptibility to ventricular arrhythmias under theophylline therapy as a result of increased sensitivity of the myocardium to endogenous catecholamine release by theophylUne. Ketamine lowers the theophyUine seizure threshold. Benzodiazepines Uke midazolam, diazepam, lorazepam, and Uurazepam increase the central nervous system concentration of adenosine, a potent central nervous system depressant. As theophyUine also blocks adenosine receptors, it counteracts benzodiazepine-induced sedation, resulting in increased dosage requirements for these compounds. ... 

In recent years drug research in the respiratory area has been at an all-time high. Much of this work has stemmed from the discovery of cromolyn sodium as a truly new therapeutic modality as well as from a better appreciation of the pharmacodynamics of theophylline. Newer agents such as prostaglandin bronchodilators are now being studied extensively. One must feel that these extensive efforts will culminate in the development of better therapy for the patient suffering from respiratory disease. 

Minton NA Henry JA. Pharmacodynamic interactions between infused adenosine and oral theophylline. Hum Exp Toxicol ( 99 ) 10,411-18. 

Gardner MJ, Ashton HM, Willavize SA, Vincent J. The effects of concomitant dofetilide therapy on the pharmacokinetics and pharmacodynamics of theophylline. Clin Pharmacol Ther... 

Auteri A, Blardi P, Bruni F, Domini L, Pasqui AL, Saletti M, Verzuri MS, Scaricabarozzi I, Vargui G, Di Perri T. Pharmacokinetics and pharmacodynamics of slow-release theophylline during treatment with nimesulide. IntJ Clin Pharmacol Res (1991) 11, 211-7. 

Minton NA, Turner J, Henry JA Pharmacodynamic and pharmacokinetic interactions between theophylline and propranolol during namic exercise BrJ Clin Pharmacol (1995) 40, 521P... 

Dockens RC, Rapoport D, Roberts D, Greene DS, Barbhaiya RH. Lack of an effect of nefazodone on the pharmacokinetics and pharmacodynamics of theophylline during concurrent administration inpatients with chronic obstructive airways disease. BrJ Clin Pharmacol (1995) 40, 598-601,... 

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