Theophylline respiratory effects

The researches of van Heerswynghels (198) on the analeptic respiratory action of theophylline-ethylenediamine follow the clinical observations of amelioration of respiratory conditions under the influence of this substance. The intravenous injection of theophylline-ethylenediamine (48 mg./kg.) provokes a prolonged and intense respiratory stimulation. It also abolishes the depression caused by morphine or Evipan by acting on the respiratory center in the medulla. This respiratory stimulation is seen in dogs whose carotid sinuses have been denervated. Theophylline alone provokes a respiratory stimulation ethylenediamine acts similarly, but its effects are very transitory. There is a synergistic activity of the respiratory effects of these two substances. 

Experimental studies in healthy subjects, on the way xanthine drugs possibly interact with adenosine, have shown that caffeine and theophylline (but not enprofylline) reduced the increased heart rate and the changes in blood pressure caused by infusions of adenosine, and attenuated adenosine-induced vasodilatation. Theophylline also attenuated adenosine-induced respiratory effects and chest pain. Similarly, an adenosine infusion antagonised the haemodynamic effects of a single dose of theophylline in healthy subjects, but did not reduce the metabolic effects (reductions in plasma potassium and magnesium). ... 

Chronic theophylline use in COPD has been shown to produce improvements in lung function, including vital capacity and FEVj. Subjectively, theophylline has been shown to reduce dyspnea, increase exercise tolerance, and improve respiratory drive. Nonpulmonary effects that may contribute to better functional capacity include improved cardiac function and decreased pulmonary artery pressure. 

CNS stimulants can be classified as Psychomotor stimulants compounds that display a stimulatory effect primarily on brain functions and which activate mental and physical activity of the organism. They are made up of methylxanthines (caffeine, theophylline, pentoxifyllin), amphetamines (dextroamphetamine, methamphetamine), and also methylphenidate and pemoline. Respiratory stimulants or analeptics compounds, which cause certain activations of mental and physical activity of the organism, and primarily excite the vasomotor and respiratory centers of the medulla (doxapram, almitrine).Drwgi that suppress appetite or anorectics drags that activate mental and physical activity of the organism, but primarily accentuate the excitatory center of satiation in the hypothalamus (phentermine, diethylpropion).In order to increase mental capability, nootropics — drugs that increase the functional state of the brain — are sometimes used, the effect of which is associated with blood flow and metabolism of the brain. 

Theophylline and other methylxanthines also display a pharmacological effect on a number of other organ systems. Of course the most pronounced effect is relaxation of smooth musculature in the respiratory tract. However, theophylline is a CNS stimulant, and it lowers arterial blood pressure, increases diuresis, displays cardiotonic activity, and has a specific effect on the gastrointestinal tract. The effects listed are the most frequently encountered side effects upon taking theophylline as a broncholytic. 

Pharmacology The methyixanthines (theophylline, its soluble salts and derivatives) directly relax the smooth muscle of the bronchi and pulmonary blood vessels, stimulate the CNS, induce diuresis, increase gastric acid secretion, reduce lower esophageal sphincter pressure, and inhibit uterine contractions. Theophylline is also a central respiratory stimulant. Aminophylline has a potent effect on diaphragmatic contractility in healthy people and may then be capable of reducing fatigability and thereby improve contractility in patients with chronic obstructive airways disease. Pharmacokinetics ... 

This xanthine derivative is an only a modest bron-chodilator in COPD, and because of its narrow therapeutic range, frequently seen adverse effect and drug interactions, it is becoming less frequently used, some patients experience side effects even within the therapeutic range. The non-bronchodilator effects of theophylline such as systemic and pulmonary vascular dilatation, central nervous system stimulation, improvement of the strength and effectiveness of respiratory muscles and possibly anti-inflammatory effects are of disputed clinical significance at usual therapeutic levels. 

Smooth muscle relaxation, central nervous system (CNS) excitation, and cardiac stimulation are the principal pharmacological effects observed in patients treated with theophylline. The action of theophylline on the respiratory system is easily seen in the asthmatic by the resolution of obstruction and improvement in pulmonary function. Other mechanisms that may contribute to the action of theophylline in asthma include antagonism of adenosine, inhibition of mediator release, increased sympathetic activity, alteration in immune cell function, and reduction in respiratory muscle fatigue. Theophylline also may exert an antiinflammatory effect through its ability to modulate inflammatory mediator release and immune cell function. 

Theophylline has a narrow therapeutic index and produces side effects that can be severe, even life threatening. Importantly, the plasma concentration of theophylline cannot be predicted reliably from the dose. In one study, the oral dosage of theophylline required to produce therapeutic plasma levels (i.e., between 10 and 20 pg/mL) varied between 400 and 3,200 mg/day. Heterogeneity among individuals in the rate at which they metabolize theophylline appears to be the principal factor responsible for the variability in plasma levels. Such conditions as heart failure, liver disease, and severe respiratory obstruction will slow the metabolism of theophylline. 

The respiratory actions of the methylxanthines may not be confined to the airways, for they also strengthen the contractions of isolated skeletal muscle in vitro and improve contractility and reverse fatigue of the diaphragm in patients with COPD. This effect on diaphragmatic performance—rather than an effect on the respiratory center—may account for theophylline s ability to improve the ventilatory response to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction. 

INHALATIONAL- HALOTHANE TERBUTALINE, THEOPHYLLINE Cases of arrhythmias when these bronchodilators are co-administered with halothane Possibly due to sensitization of the myocardium to circulating catecholamines by the volatile anaesthetics to varying degrees Risk of cardiac events is higher with halothane. Desflurane is irritant to the upper respiratory tract, and t secretions can occur and are best avoided in patients with bronchial asthma. Sevoflurane is non-irritant and unlikely to cause serious adverse effects... 

These experiments were resumed by Hazard and Jequier (199) on the dog and rabbit, but the intense effects of theophylline seen in the dog are inconstant in the rabbit whose respiration is not depressed. After a depression of the respiratory center by central depressive compounds (Somnifbne, chloralose, Evipan, morphine), theophylline, even in small doses, combats the decreased respiratory rate and volume. 

The analeptic action of theophylline-diethanolamine is much less effective in the rabbit than that of theophylline-ethylenediamine. Diethanolamine scarcely modifies the respiratory rate and amplitude but it slightly increases the total respiratory volume. This phenomenon is seen equally with or without denervation of the chemoceptors of the carotid sinuses (200). 

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... 

BZDs BRONCHODILATORS- THEOPHYLLINE i therapeutic effect of BZDs BZDs t CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors Larger doses of diazepam are required to produce the desired therapeutic effects such as sedation. Discontinuation of theophylline without i dose of BZD t risk of sedation and of respiratory depression... 

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. 

Although theophylline has extensive pharmacological actions in the respiratory system, it has also central nervous system, cardiovascular, hepatic, digestive, and metabolic activity. Some of these activities contribnte to the profile of adverse effects that might be enconntered dnring its use in clinical pharmacotherapy (Table 10.1). 

Maxwell DL, Fuller RW, Conradson T-B, Dixon CMS, Aber V, Hughes JMB, Barnes PJ. Contrasting effects of two xanthines, theophylline and enprofylline, on the cardio-respiratory stimulation of infused adenosine in man. Acta Pl siol Scand( 9S1) 131,459-65. 

No clinically significant changes in serum theophylline levels were seen in 5 studies in patients (both adults and children) " or healthy subjects given josamycin, but a modest rise in theophylline levels was described in one study in children. Another study reported a23% reduction in the levels of theophylline (given as intravenous aminophylline) in 5 patients with particularly severe respiratory impairment, but no significant effect in 5 other patients with less severe disease. However, an isolated report describes theophylline toxicity in a 80-year-old man who was given josamycin. 

Yamaki K, Miyatake H, Taki F, Suzuki R, Takagi K, Satake T. Studies on sparfloxacin (SPFX) against respiratory tract infections and its effect on theophylline pharmacokinetics. Chemotherapy (1991) 39 (Suppl 4), 280-5. 

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