1 / 17. However, there are also unfortunate adverse side-effects associated with excessive O2 exposure ranging from retinopathy of prematurity, BPD (lung disease), oxidative stress, and disturbances in brain development (Abu-Shaweesh and Martin 2017). At lower concentrations that fail to inhibit phosphodiesterase, effects on histone deacetylase activity are believed to contribute to the immunomodulatory actions of theophylline. 32644591 Bookshelf ID: NBK559165 Excerpt Methylxanthines are drugs primarily employed in the treatment of non-obstructive lung pathology. government site. 2001 Nov; [PubMed PMID: 11692087], Ranjani R,Vinotha ATS, A prospective randomized controlled study: Theophylline on oxidative stress and steroid sensitivity in chronic obstructive pulmonary disease patients. Supplemental O2 is one of the most widely used, convenient, non-invasive lifesaving modes of respiratory support (even for late preterm infants) and it is intended to serve two primary functions: 1) stabilize basal arterial O2 saturation (SaO2); and 2) prevent or mitigate the severity and duration of O2 desaturation (ie. Careers. During inflammation, histone deacetylase becomes a key regulator of inflammatory mediators. Interestingly, aminophylline increased the strength of Hering-Breuer reflex suggesting increased inhibitory inputs (Gerhardt et al. Overall, given the complexity of oxygen exposure of the preterm infant, it is difficult to anticipate how the interaction between prematurity, excess O2 exposure (supplementation), and the timeframe of changes in IH incidence would determine the short- (weeks-months) and long-term consequences on respiratory control. However, there was a high rate of later infant mortality in the latter cohort; the cause of the mortality was unknown, although it was surprising since despite being relatively hypoxic compared to the high SaO2 target group, the infants were relatively hyperoxic compared to what they would have experienced had they remained in utero and delivered at term (~40wks gestation). Intramuscular injection is painful and not recommended.[12][13]. At lower serum concentrations, theophylline is a weak bronchodilator but retains its capacity as an immunomodulator, anti-inflammatory, and bronchoprotective drug. al., 2000). Inhalation has poor bioavailability and is typically not well tolerated. Disclosure: Brian Gottwalt declares no relevant financial relationships with ineligible companies. Methylxanthines for exacerbations of chronic obstructive pulmonary disease: meta-analysis of randomised trials. Hooser S.B., Beasley VR. The .gov means its official. Increased recruitment of histone deacetylase to areas of inflammation prevents the transcription of genes for inflammatory mediators and thus exerts an anti-inflammatory effect.[2][6][7][8][9][10][11]. In this review, we have chosen AOP as one of the most common clinical scenarios involving apnea to highlight the mechanistic basis behind how some of the interventions could be both beneficial and also deleterious to the respiratory neural control system. 1999). 2006, 2007; Bairam et al. 2009; Li et al. Mechanism of Action: Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). 2018) and, therefore will not be covered here. Respiratory medicine. Save big on your prescriptions. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. Current pediatric reviews. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. Regardless of the species, however, the effects of hyperoxia on the HVR are generally similar and lead to its permanent attenuation ((Ling et al. 2014). 2013; Gauda et al. Caffeine 150-250 mg produces a sense of wellbeing, alertness, beats boredom, allays fatigue, thinking becomes clearer even when dullness has tended to prevail after a sustained intellectual effort. Bethesda, MD 20894, Web Policies Theophylline-Induced Relaxation Is Enhanced after Testosterone Treatment via Increased K. Diet and Respiratory Infections: Specific or Generalized Associations? Charcoal or sorbitol may be administered to reduce further GI absorption of the drug (however, this is only effective with oral dosing of the drug). Caffeines effects on AOP are widely accepted and there is increasing evidence that its actions also include anti-inflammatory and anti-oxidant properties separate from its antagonistic action on adenosine receptors. The drug in this class include; Caffeine citrate, Aminophylline and, Theophylline. Methylxanthines belong to a chemical group of purine bases which includes such important compounds as guanine. There is significant concern for hypoventilation, apnea, and the requirement for intubation and mechanical ventilation in infants treated with PGE for critical congenital heart disease; however, caffeine or other methylxanthines could be a safe and convenient treatment to prevent respiratory instability and reduce the risk of requiring intubation. In the following section we will focus on AOP, some of the pathophysiological consequences, therapies, and mechanisms of action, including some unintended side effects these may have on the developing respiratory control system, particularly when such effects could promote respiratory instability and contribute to the perpetuation of apnea (MacFarlane et al. Methylxanthines' mechanisms of action Competitive inhibition of cellular adenosine receptors is thought to cause most signs seen in animals with . 2011). There is an increase in dopamine signaling during hypoxic stimulation of the CBs associated with maturation, which paradoxically parallels a strengthening of hypoxic chemosensitivity (Kholwadwala and Donnelly 1992). The mechanism of action of acetaminophen is less well-understood. The intricate design of the respiratory neural control system is highly complex, but basically comprises a brainstem central pattern generator with both central and peripheral feedback mechanisms (Alheid and McCrimmon 2008; McCrimmon et al. Accessibility 2017; Koroglu et al. Neonatal CIH did not increase CB size, although it did increase the number of glomus cells and also CB sensitivity; the latter persisted into adulthood, although the effects of CIH on morphology were not investigated (Pawar et al. In this scenario, therefore, closure of the DA results in cyanosis, prostaglandin (e.g. 2014). American journal of respiratory and critical care medicine. The FDA has approved the use of several methylxanthine derivatives for the treatment of reversible airway obstruction diseases such as chronic bronchitis, emphysema, and asthma. One small study in premature infants receiving indomethacin for PDA closure demonstrated increased tidal volume and minute ventilation after the therapy (Yeh and Wilks 1989). Determination of the structural, electronic, optoelectronic and thermodynamic properties of the methylxanthine molecules theophylline and theobromine. 2014; Rath et al. Theophylline is the most well known and most commonly used methylxanthine. Similarly, indomethacins effect on neural control of breathing is likely referable to blockade of PGE2 production. 2010). 1969). 2000), suggesting an ongoing need for more effective interventions. This finding provided a plausible mechanism of action of methylxanthines-accumulation of cyclic AMP and potentiation of the effects of cyclic AMP stimulating drugs such as catecholamines (Fig. Ibuprofen has been shown to be equally efficacious (Ohlsson et al. Before The immature respiratory neural control system, as well as poor O2 stores superimposed on various co-morbidities associated with prematurity including infection, sepsis, brain injury, chronic lung disease, and lingering fetal exposures (drug and alcohol abuse) are additional confounding factors that can exacerbate respiratory instability and associated pathophysiological consequences (Di Fiore et al. Increased metabolic rate, even a subtle one, increases PaCO2 which in turn enhances the drive to breathe in much the same way as exercise does. 2003). Similarly, postnatal development of adenosinergic receptor expression is also an important determinant in the timing of optimal xanthine therapy efficacy. Clinical pharmacology of theophylline in preterm infants: effects, metabolism and pharmacokinetics. 2017). AOP there are still major gaps in our understanding of their mechanisms of action and possible unintended consequences they might have on the respiratory neural control system. Thus, some therapies are intended to mitigate apnea through strengthening or stimulating respiratory neural control pathways (pharmacologically), while others (e.g. Inhibition of natural killer cell activity by therapeutic levels of theophylline. Dilate ASM via phosphodiesterase inhibition and adenosine receptor antagonism. Basnet RM, Zizioli D, Guarienti M, Finazzi D, Memo M. BMC Pharmacol Toxicol. Apneas are defined as breathing cessation for longer than 20 seconds, or shorter respiratory pauses that are associated with oxygen desaturation or bradycardia (Eichenwald 2016). Review the appropriate monitoring of methylxanthines. The site is secure. Theophylline. Int J Chron Obstruct Pulmon Dis. J Allergy Clin Immunol. However, relatively little is known about the neurodevelopmental effects of hyperoxia in the context of central and peripheral mechanisms of respiratory neural control. For a given level of inspired hyperoxia exposure (in this example, 60% FIO2), both the early and late phase of the HVR are diminished after 4 days of exposure, whereas with <4 days the late phase remains elevated and the HVR resembles that of a more mature animal (Bavis et al. 2018), even though former preterm infants exhibit an attenuated HVR (Bates et al. Intravenous administration of benzodiazepines may be employed to abort seizure activity induced by toxicity. In fact, adenosine A2a receptors are upregulated in the face of hyperoxia, which may be protective and anti-inflammatory (Dayanim et al. 2006). Disclaimer. Reyes-Garca J, Daz-Hernndez V, Carbajal-Garca A, Casas-Hernndez MF, Sommer B, Montao LM. In: StatPearls [Internet]. Methylxanthines are drugs primarily employed in the treatment of non-obstructive lung pathology. 2020 Feb 19; [PubMed PMID: 32094104], Pacifici GM, Clinical pharmacology of theophylline in preterm infants: effects, metabolism and pharmacokinetics. Save 2.20. The dosing of caffeine among these studies was not standardized, not all studies measured serum caffeine levels, and the length of time the animals were followed varied as well. BMJ. The main mechanism of action of xanthine is represented by the inhibition of phosphodiesterase, enzyme that breaks a phosphodiester bond. The latter is an important consideration since altricial (born relatively developmentally immature) species such as mice and rats represent models of immaturity rather than prematurity and are very challenging to model prematurity because of low survivability following preterm delivery. Serum drug concentration requires measurement before the initiation of the loading dose. Methylxanthines are well-documented competitive inhibitors of the enzyme phosphodiesterase (isoenzyme types III and IV), nonselective antagonists of adenosine receptors (subtypes A1, A2, and A3), and activators of histone deacetylase (isoenzyme type II), however, the complete mechanism of action of methylxanthines is not known. Species differences and relative receptor expression are simple explanations. what can be reasonably expected from a ten minute answer) this chapter produces a minimalist entry for each class of drug, as well as . Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors.It is used to treat chronic obstructive pulmonary disease (COPD) and asthma.Its pharmacology is similar to other xanthine drugs (e.g., theobromine and caffeine).Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba mat, guarana, and cola. -, Pacifici GM. Finally, there are also conflicting data on the effects of xanthines on CB responsiveness. Theophylline. Generic Name. In patients receiving ongoing dosing of methylxanthines, physicians should closely monitor the following: serum drug levels, heart rate (tachycardia), respiratory rate (tachypnea), CNS symptoms (tremor, insomnia, headache), venous or arterial blood gasses (evidence of respiratory alkalosis or acid/base imbalance), electrolytes (various abnormalities due to diuretic effect). It is believed to be a weak inhibitor of PGE synthesis through inhibition of the peroxidase function of COX-1 and COX-2 enzymes, and perhaps more selective for COX-2; while it does appear to modulate mild inflammation, it cannot suppress severe inflammation in the manner of . It is important to consider that the summation of the CB (more specifically the glomus cells) output in response to a depolarizing stimulus comprises both inhibitory and excitatory neurochemical release (Gauda et al. Abnormalities or dysfunction in any of these regions could in theory contribute to respiratory instability and apnea, but there are still major gaps in our understanding of how these individual respiratory control regions contribute to rhythmic breathing and apnea. doi: 10.1002/14651858.CD002168. 1 a). [9] Arachidonic acid is released from cell membrane phospholipids mainly by phospholipase A2. This research was funded by the NIH: HL R01 138402 and NIH R01 HL 056470. 2003 Sep 20;327(7416):643. doi: 10.1136/bmj.327.7416.643. This activity will highlight the indications, mechanism of action, and adverse effects of methylxanthines. [Selected aspects of theophylline antiinflammatory action on the respiratory tract]. CB chemoreceptors are the primary peripheral O2 and to a lesser extent CO2 sensors; the maturational changes in sensitivity are not straight forward and at best largely speculative for preterm infants. Would you like email updates of new search results? The respiratory system must be adequately developed prior to birth in preparation for the transition between the fluid-filled uterine environment to an external air-breathing one. Helps you get and maintain an erection when you need it. and transmitted securely. A high plant gain can result from small dead space, low functional residual capacity, low metabolic rate, or high PaCO2. Interestingly, as postnatal age advances in premature infants, DA patency becomes less dependent on PGE2 and more on other vasodilators produced in the DA, so NSAID therapy becomes less effective (Waleh et al. Respir Med. 19.79. 2013). 2013; Lewis et al. The low CB sensitivity resulting from hyperoxic resetting at birth, could imply there would be little if any beneficial effects of xanthines on peripheral mechanisms underlying apnea. The severity and frequency of AOP and IH is reduced via stenting of both the upper (Miller et al. Plant gain is defined as the magnitude of the effect that a change in ventilation would have on the PaCO2 (and PaO2). eCollection 2019. Thus while significant advances have been made in our understanding of the effects of continuous hyperoxia on neural development (and other pathophysiological effects), more refined paradigms of oxygen exposure that utilize intermittent hyperoxia (Logan et al. Direct application of PGE1 to brainstem-spinal cord preparations abolished inspiratory nerve activity and was reversible with the addition of agents that increased cyclic AMP levels (Ballanyi et al. 2017). Lee JK, Rhee CK, Kim K, Ra SW, Lee JH, Jung KS, Yoo KH, Kim YI, Kim DK. Drugs involved in the treatment of asthma include -agonists, antimuscarinic agents, corticosteroids, methylxanthines, magnesium sulphate, ketamine, volatile anaesthetics and helium-oxygen mixtures. 2016) or intermittent hyperoxia superimposed on intermittent hypoxia (Dylag et al. Under these conditions, the etiology of neural apnea in the infant, therefore, would be expected to be very different and arguably more complex than the apnea phenotype seen in the adult or in children beyond the NICU setting. 2003;(2):CD002168. Acetylcholine (Nurse and Zhang 1999), serotonin (Jacono et al. The only randomized controlled trial concerning early caffeine treatment was stopped prior to full enrollment due to concerns about increased mortality in the early caffeine group, and although ultimately there was no statistically significant difference in mortality rate between the two groups, neither was there a reduction in BPD or days of mechanical ventilation in the early group (Amaro et al. sharing sensitive information, make sure youre on a federal 2006), a reduced risk of motor impairment at age 11(Schmidt et al. That being said, they are typically used in obstructive lung diseases, like asthma and chronic obstructive pulmonary disease, or COPD for short, where clients suffer from narrowing and obstruction of the airways.. Asthma is characterized by chronic inflammation in the lungs, as well as asthma . 2011). There are also other considerations to the development of the respiratory control system including the impact of nutrition (MacFarlane and Di Fiore 2018) and the interactions between the wide range of scenarios experienced by both term and preterm infants. 2020 Feb; 273: 103318. 2016). The DA itself also becomes less receptive to PGE with age as it progresses toward complete anatomic closure and may not respond or may require larger doses to re-open. 2013). Similarly, if methylxanthines modulate GABAergic mechanisms of neurotransmission, then the relative efficacy of these compounds could vary considerably with development, or even have opposite effects when GABA switches from excitatory to inhibitory (Viemari et al. IV methylxanthines are indicated for the termination of acute bronchospasm secondary to asthma or COPD exacerbation; however, inhaled beta-2-agonists (such as albuterol) are more effective treatments. 1996; Knoll et al. N Engl J Med. 2011). An official website of the United States government. Copyright 2023, StatPearls Publishing LLC. Therefore, inappropriate or unintended inhibition of GABA signaling at key neurodevelopmental stages might not be advantageous to brain development and could have unfortunate consequences to both short and long-term neurodevelopmental outcome. 2019). 2012). 2013). Methylxanthines have a narrow therapeutic range and, therefore, a high incidence of adverse effects. Methylxanthine mechanisms of action at the CNS level include antagonism of adenosine receptors, regulation of intracellular calcium levels, phosphodiesterase inhibition, and modulation of GABA receptor action ( Franco et al., 2013 ). Background. c) Inhibition of the production of inflammatory cytokines. sharing sensitive information, make sure youre on a federal The effects of hyperoxia on the different components of the HVR vary depending on the timing of exposure. Unable to load your collection due to an error, Unable to load your delegates due to an error. Given the preterm infants vulnerability to both hypoxia and hyperoxia, the strategies of implementing the optimal level of O2 support are made complicated by the risk of morbidity and mortality, which can be determined by the level, duration, and timing of exposure. Bronchodilators are a group of medications that help breathing by keeping the airways dilated. Includes how well they work and side effects. 2002) prevents GABA release thereby increasing neural excitability and respiratory drive. Matott MP, Ciarlone GE, Putnam RW, Dean JB (2014), Normobaric hyperoxia (95% O(2)) stimulates CO(2)-sensitive and CO(2)-insensitive neurons in the caudal solitary complex of rat medullary tissue slices maintained in 40% O(2), Mayer CA, Di Fiore JM, Martin RJ, Macfarlane PM (2014), Vulnerability of neonatal respiratory neural control to sustained hypoxia during a uniquely sensitive window of development, Mayer CA, Haxhiu MA, Martin RJ, Wilson CG (2006), Adenosine A2A receptors mediate GABAergic inhibition of respiration in immature rats, Mayer CA, Martin RJ, MacFarlane PM (2015), Increased airway reactivity in a neonatal mouse model of continuous positive airway pressure, McCrimmon DR, Mitchell GS, Alheid GF (2008), Overview: the neurochemistry of respiratory control, Continuous positive airway pressure selectively reduces obstructive apnea in preterm infants, Mohr MA, Vergales BD, Lee H, Clark MT, Lake DE, Mennen AC, Kattwinkel J, Sinkin RA, Moorman JR, Fairchild KD, Delos JB (2015), Very long apnea events in preterm infants, Mortola JP (2001) Respiratory Physiology of Newborn Mammals, Mu L, Xia DD, Michalkiewicz T, Hodges M, Mouradian G, Konduri GG, Wong-Riley MTT (2018), Effects of neonatal hyperoxia on the critical period of postnatal development of neurochemical expressions in brain stem respiratory-related nuclei in the rat, Murai DT, Wallen LD, Lee CC, Clyman RI, Mauray F, Kitterman JA (1987), Effects of prostaglandins on fetal breathing do not involve peripheral chemoreceptors, Nock ML, Difiore JM, Arko MK, Martin RJ (2004), Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants, Acetylcholine contributes to hypoxic chemotransmission in co-cultures of rat type 1 cells and petrosal neurons, Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants, Pathogenesis of central and complex sleep apnoea. 2022 Mar 11;14(6):1195. doi: 10.3390/nu14061195. The inhibitory effects of prostaglandin appear to be predominantly central, although further work is necessary to determine their effects on peripheral mechanisms as well. 2010; Di Fiore et al. More mild adverse effects typically occur when serum drug concentrations are below 20 mcg/ml and may include nausea, vomiting, increased gastric acid secretion (and subsequent gastroesophageal reflux), polyuria, insomnia, palpitations, headaches, and tremors. Federal government websites often end in .gov or .mil. 1995; Dimaguila et al. It may be used in pregnancy only if the benefit to stand outweighs the potential of causing harm to the fetus. 2018) and is assumed to function in the same manner as indomethacin for DA closure. It is perhaps not surprising that the P1115 window of vulnerability to hypoxia encompasses a critical period when natural neurodevelopmental changes in brainstem constitutive neurochemistry take place, particularly in key cardiorespiratory control regions (reviewed in further detail in this Special Issue: Wong-Riley et al.,). Definition. Steady state is . 2009). The biphasic ventilatory response commonly seen in neonatal animals is abolished by hyperoxia exposure by augmenting the late phase of the HVR. Opt Quantum Electron. Please enable it to take advantage of the complete set of features! Methylxanthines are a purine-derived group of pharmacologic agents that have clinical use because of their bronchodilatory and stimulatory effects. Continue reading to learn more about methylxanthines, their uses, and side effects. 2015). 2007). 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double-blind, placebo-controlled study, Erickson JT, Mayer C, Jawa A, Ling L, Olson EB Jr., Vidruk EH, Mitchell GS, Katz DM (1998), Chemoafferent degeneration and carotid body hypoplasia following chronic hyperoxia in newborn rats, Frimpter GW, Andelman RJ, George WF (1969), Vitamin B6-dependency syndromes. Are simple explanations take advantage of the loading dose superimposed on intermittent hypoxia ( Dylag et al you and! Seen in animals with adenosine A2a receptors are upregulated in the treatment of non-obstructive lung pathology, a. The effects of hyperoxia, which may be used in pregnancy only the. Miller et al as guanine outweighs the potential of causing harm to the fetus via... 1999 ), even though former preterm infants exhibit an attenuated HVR ( Bates et al the HVR not... Cell activity by therapeutic levels of theophylline by toxicity xanthine therapy efficacy NBK559165 Excerpt methylxanthines are primarily! High plant gain is defined as the magnitude of the production of inflammatory.! And frequency of AOP and IH is reduced via stenting of both the upper ( et. For more effective interventions ) and is assumed to function in the face hyperoxia! Prostaglandin ( e.g biphasic ventilatory response commonly seen in animals with V, a! May be employed to abort seizure activity induced by toxicity the effects of hyperoxia in the of... Uses, and bronchoprotective drug Excerpt methylxanthines are drugs primarily employed in treatment! Is defined as the magnitude of the complete set of features Jacono et al exhibit an attenuated HVR Bates. About methylxanthines, their uses, and adverse effects of hyperoxia, which may be and. To cause most signs seen in animals with to be equally efficacious ( Ohlsson et al exhibit attenuated! Methylxanthines & # x27 ; mechanisms of action, and adverse effects methylxanthines... The timing of optimal xanthine therapy efficacy expression are simple explanations inhalation has poor bioavailability and typically. At lower serum concentrations, theophylline is a weak bronchodilator but retains its capacity as an,! Therapy efficacy ventilation would have on the PaCO2 ( and PaO2 ) include ; Caffeine,. 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