What Are the Most Common Theophylline Side Effects?

There are more than 300 known types of theophylline drugs and their derivatives. Clinically more commonly used are theophylline, dihydroxyprophylline, choline theophylline, theophylline ethanolamine, and spiffing, etc.

There are more than 300 known types of theophylline drugs and their derivatives. Clinically more commonly used are theophylline, dihydroxypropylline, choline theophylline, theophylline ethanolamine, and spline

Chinese name

Theophylline

Use

oral

Amount

0.1 g each time, 3 times a day

Field

medicine

Characteristics of theophylline

Theophylline effects

Aminophylline is more water soluble than theophylline and is easy to dissolve and absorb. However, aminophylline has higher alkalinity and greater local irritation. It is easy to cause nausea, vomiting, decreased appetite and other gastrointestinal reactions. Intramuscular injection may have redness, swelling and pain. The systemic side effects of aminophylline include central nervous system and cardiac excitatory effects such as anxiety, tremor, irritability, headache, and palpitation. Too fast or too large an intravenous dose can also cause arrhythmias, decreased blood pressure, chest tightness, restlessness, convulsions, and even sudden death. Therefore, when using theophylline, especially for intravenous use, the theophylline concentration in plasma should be monitored. In the absence of plasma theophylline concentration monitoring, the total daily medication should be closely monitored, taking into account the individual differences in theophylline metabolism of the body, and affecting tea. Factors of alkali metabolism, and pay attention to whether there are precursor symptoms of aminophylline poisoning, such as mental symptoms or palpitations.

Theophylline medication

The usual oral dose is 0.1 g each time, 3 times a day; the extreme dose is 0.4 g each time, 1 g per day; the intravenous injection is 0.25 g each time, and then diluted by 25% to 50% glucose. Note.

New achievements of theophylline

The relationship between theophylline structure and pharmacological effects

Theophylline molecule has two effective parts. The methyl group at position 3 is related to the relaxation characteristics of smooth muscle and is also closely related to its anti-inflammatory effect. That is, it has a non-specific inhibitory effect on certain cyclic nucleotide phosphodiesterases (PDEs) in muscle and inflammatory cells. The methyl group at the first position is responsible for competing with adenosine for the receptor, and it has a beneficial effect on the neuromuscular respiratory effector, but it also has some toxic effects. In addition, at the therapeutic level, theophylline can increase plasma catecholamine levels. In the dog's trachea, theophylline moves calcium from sarcoplasm to mitochondria, thereby reducing muscle tone.

Diastolic effect of theophylline on the bronchus

Bronchodilation is mainly achieved by inhibiting PDE. It is now known that the cyclic adenosine monophosphate (cAMP) PDE family contains four PDE enzymes. Although only 5% to 10% of the total PDE activity of the entire extract of respiratory smooth muscle is PDE III (also known as "low-km cAMP PDE"), it seems to be closely related to the relaxation of smooth muscle. Therapeutic levels of theophylline can inhibit PDEIII activity by 10% to 20%, which may be very significant, especially when synergistic with endogenous and exogenous compounds that stimulate cAMP production.

Anti-inflammatory effects of theophylline

The anti-inflammatory effect of theophylline has also attracted attention, and this effect may be achieved by inhibiting the release of phosphodiesterase and neuropeptides. At the appropriate level, theophylline strongly inhibits late phase responses triggered by antigens, which are mostly the result of anti-inflammatory effects. Nielson et al believe that this is related to the inhibition of neutrophil activation and the release of mediators caused by PDE inhibition. These effects are due to the PDEIV inhibition of microsomal fragments, which is presumably the result of an increase in cAMP. In fact, it has long been discovered that patients treated with theophylline have a strong inhibition of the ability of the neutrophils to produce oxygen free radicals, and that relatively low concentrations of isoproterenol can significantly enhance this effect. This special PDE also exists in smooth muscle, and its inhibitory effect may be related to the relaxation of smooth muscle.

In the bronchi, sensory neuropeptides such as neurokinin A, P, and calcitonin gene-related peptide (CGRP) are released due to increased stimulation of C-fiber nerve endings, which are responsible for increased airway tension reactivity, inflammation, and secretion. One. However, the reported results may vary depending on the animal. However, theophylline and 2,6-oxy, 3-propylpurine (enprophylline) can significantly inhibit the release of these peptides when electrically stimulated the bronchus of guinea pigs. It is suggested that the effect of theophylline on airway may be related to anti-inflammatory mechanism. Humans and guinea pigs respond similarly.

Effects of theophylline on the diaphragm and respiration

Theophylline enhances diaphragmatic muscle strength (Pdi), enhances hypoxic respiratory drive (Edi), and the ability to resist hypoxic respiratory depression is related to adenosine antagonism. However, many opposite effects, such as central nervous system (CNS) overexcitation, supraventricular arrhythmia, and tremor are also related to the inhibitory effects of adenosine.

The clinical significance of theophylline on respiratory muscle strength is still controversial. In 1981, Aubier et al reported that when intravenous injection of aminophylline in healthy men reached an average blood concentration of 13 mg / L, the diaphragmatic muscle strength caused by bilateral phrenic nerve electrical stimulation was significantly enhanced, and fatigue caused by external resistance was reduced. Occurs and accelerates recovery from fatigue. It became clear later that these effects depended on theophylline's adenosine antagonism, because another xanthine preparation, enprophylline, lacked the adenosine antagonism and did not have the above effects. At the therapeutic level of theophylline, this effect is basically due to an increase in Pdi, and not primarily a result of an increase in Edi. At a level of 14.8 mg / L, theophylline reduced time-tension index and the degree of diaphragmatic fatigue. Some people also think that the improvement of diaphragm function in patients with COPD is related to the reduction of functional residual capacity and the improvement of diaphragm position. In conclusion, a large amount of evidence has shown that theophylline has a significant effect on diaphragm function. Theophylline also plays a role in central fatigue and conductive fatigue in neuromuscular connection.

Interaction between theophylline and theophylline

In patients with mild asthma, a small dose of 2 agonist alone is sufficient to return the expiratory flow rate to normal. However, for asthmatic patients with severe bronchospasm, increasing the dose of 2 agonist is necessary and has certain effects, but it is not satisfactory. Because at this time the functional effects of endogenous contraction agonists involved in bronchoconstriction appeared. That is, when the systolic agonist is increased to the contention level, the bronchial smooth muscle needs a stronger diastolic response to restore normal function, but the respective response of the systolic agonist to the diastolic agonist becomes weaker. This phenomenon has been confirmed by many in vitro experiments. Isoprenaline has a more significant antagonism of methacholine-induced tracheal contraction in dogs or guinea pigs than theophylline. And theophylline plus isoproterenol or salbutamol showed super-additive tracheal relaxation, that is, as long as the theophylline concentration increased to 20 mg / L, the synergistic effect of theophylline with isoproterenol and salbutamol Will be enhanced. Barnes et al. Reported that the concentration of inhaled beta agonists required for maximal bronchodilatation in normal people is lower than that in patients with stable asthma, and it is bound to increase the minimum expiratory volume in one second (FEV1) in these people. Although it is unclear whether there is a superadditive effect between theophylline and beta agonists, their effects are at least enhanced. From the pharmacological effects of theophylline, the synergistic effect of the two is also reasonable, because theophylline works by inhibiting PDE. In fact, systemic use of theophylline may also facilitate penetration of inhaled drugs.

Barclay et al. Made chronic bronchitis patients gradually increase the dose of inhaled albuterol, and found that the amount required to reach their respective maximum forced vital capacity (FVC) is 200-3000 g, which varies greatly among individuals, and most require more than 600 g. If theophylline is used alone, even if the most effective plateau concentration is reached, its lung function can only reach about half of the maximum FVC. However, if 400 g of salbutamol is inhaled, the maximum FVC is easily reached.

For patients with COPD, theophylline is sure to enhance the effects of conventional doses of inhaled beta agonists or ipratropium bromide. It can significantly increase the peak and valley levels of FEV1 formed by inhaled formulations. The airway's response to each dose of inhaled 2 agonist is transient, and its effects are mostly eliminated within 4 hours, but if used in combination with ipratropium bromide, its duration will be prolonged. With regard to the protective effects of methacholine or histamine challenge, the duration of action of inhaled 2 agonists is even shorter. When theophylline is used in combination with the new generation of long-acting 2 agonists salmeterol and formoterol, theophylline can maximize the valley of FEV1 in patients who inhale these long-acting 2 agonists. Improved symptoms.

Theophylline evaluation

The clinical status of theophylline drugs

In terms of illness, theophylline is indicated for: (1) severe COPD; (2) severe asthma to reduce oral corticosteroid use; and (3) nocturnal asthma. The optimal plasma concentration of theophylline is close to the middle of the therapeutic range, which is 12-15 mg / L, but it is generally believed that maintaining plasma concentrations of 5-10 mg / L can have anti-inflammatory and immunomodulatory effects.

Disadvantages of theophylline are metabolic instability and a narrow therapeutic index, which requires careful medication and monitoring of serum concentrations. However, no medicine is absolutely satisfactory. Theophylline is relatively simple, cheap, and effective, so it is commonly used by children with asthma. On the other hand, because the nature of asthma is a chronic non-specific inflammation of the airway, inhaled corticosteroids are undoubtedly very important and necessary for patients with moderate to severe asthma. However, the literature reports that even moderate amounts may affect the bone development of some children, and large doses can also affect the bones of the elderly. Sensitive people may experience difficulty speaking. Large doses have side effects on the pituitary-adrenal axis, so it is best to regularly measure morning cortisol or 24-hour urine free cortisol. Although inhaled corticosteroids can relieve symptoms in patients, inhaled corticosteroids do not completely eliminate airway hyperresponsiveness. The effects of nocturnal bronchospasm on sleep are common, and adjustment of theophylline levels can help alleviate this symptom. As the severity of asthma increases, it is necessary to increase the amount of bronchodilator to reduce the oral hormone dose. At this time, the value of 2 agonist and theophylline combination therapy is recognized. Patients with severe asthma cannot achieve satisfactory results even with large doses of inhaled beta agonists, because inhaled drugs do not reach the intended receptors, so some patients may require mechanical ventilation. At this time, the use of parenteral beta agonists or aminophylline may be valuable in the paralyzed state before or during mechanical ventilation.

Another reason for the widespread clinical application of theophylline in China is that it is cheap, and can greatly save expenses during the entire treatment process.

COPD Application of theophylline in theophylline drugs COPD

Broadly defined COPD includes the pathological changes of chronic bronchitis and emphysema. Patients with chronic bronchitis with typical clinical and pathological characteristics have more severe airway inflammation than patients with emphysema. Response to bronchodilators is good. Recent studies have shown that the reversibility of the airway during COPD is actually better than we think. Ipratropine (2 sprays), salbutamol (2 sprays) and theophylline combined treatment is better than ipratropine alone or theophylline and salbutamol. Although theophylline does not improve lung function significantly, theophylline has the effect of reducing lung trapped air volume (TGV), and it is dose-dependent. There was a linear correlation between theophylline blood concentration and a decrease in TGV and an increase in walking distance. When the trapped air volume decreased, COPD patients' walking distance increased by about 20% within 6 minutes, and breathing difficulties were alleviated at normal working intensity. Once stopped, the ability to exercise decreases due to difficulty breathing. Chrystyn et al. Reported that the peak expiratory flow rate (PEFR) did not increase significantly with the increase of plasma theophylline, but when the slow vital capacity (SVC) was reached, the theophylline concentration was only 8.2 mg / L. The increase in slope is equivalent to a two-fold increase in FVC, indicating that the slower emptying portions of the lung are most affected. McKay et al. Randomized 20 patients with severe COPD to placebo or theophylline (the serum theophylline levels reached 9.1 mg / L and 17.6 mg / L), and found that at high doses, the thoracic gas volume was reduced by 38% The peak expiratory flow velocity increased, the average walking distance increased by 48%, and the fatigue score decreased by 18%. However, the increase in FEV1 and FVC was not significant, and the measurement of these effects was inconsistent with the actual improvement in patient activity.

The kinetic method showed that with an average theophylline concentration of 12.3 mg / L, the total work of breathing was reduced by 16% when cycling at 1.2 miles per hour. When COPD patients changed from standing to walking, the increase in respiratory work decreased by a total of 23%. Remission of dyspnea is associated with improvement in individual FEV but not with FEV1.

Murciano et al. Reported that when theophylline-treated patients' arterial blood oxygen partial pressure (PaO2) increased from 8.3 kPa (1 mmHg = 0.133 kPa) to 8.8 kPa, the average arterial blood carbon dioxide partial pressure (PaCO2) decreased from 6.4 kPa to 5.9 kPa . Under normal workload, patients experience less difficulty breathing. COPD patients can also see that theophylline reduces the mean pulmonary arterial pressure and increases the right ventricular ejection fraction. This has the effect of protecting right heart function when COPD is exacerbated.

Theophylline treatment of severe acute asthma attacks

The indications for mild and moderate asthma as theophylline are well recognized, but whether theophylline should be used in patients with severe asthma is controversial.

1. Patients with acute exacerbations of asthma in the emergency department: The National Heart, Lung, and Blood Disease Society (NHLBI) and the International Asthma Physician Association do not promote the use of ammonia on the basis of enhanced beta agonists and corticosteroids. Theophylline.

DiGiulio et al. And Carter et al. Reported that there was no significant difference in the efficacy of theophylline with a blood concentration of 15 mg / L combined with nebulized albuterol at different doses and frequencies. However, some authors believe that theophylline's effect is "head start", that is, for the most severe asthma patients, aminophylline acts in the earliest stage, which may be the first few hours (there is Reported for 8 hours). The significance of this conclusion is to avoid adverse reactions caused by continuous intravenous infusion of theophylline.

2. Aminophylline and mechanical ventilation: In Europe, intravenous salbutamol is often used to treat persistent asthma. Unfortunately, there is a lack of persuasive data on the efficacy of parenteral application of these drugs in patients requiring mechanical ventilation.

Theophylline's effect on diaphragm and respiration facilitates the reversal of respiratory failure and detachment from the ventilator. Theophylline's ability to resist hypoxic respiratory depression is related to adenosine antagonism. As theophylline clearance and volume changes in critically ill patients cannot be predicted, patients with continuous intravenous infusion of theophylline must measure their blood concentration and should be checked daily. Recent reports indicate that theophylline clearance is wide during sepsis, and that theophylline clearance is slowed down in congestive heart failure, liver disease, and persistent fever. Therefore, some authors believe that in the intensive care unit (ICU), the use of theophylline should be limited to patients who have been identified as obstructive airway disease at the time of hospitalization, and stable in other aspects. Although there are no controlled studies, aminophylline is generally considered to be suitable for patients who evacuate the ventilator.

Some authors inject methylxanthine intravenously into patients with mechanical ventilation. Fernandez et al. Reported that 6 mg / kg aminophylline can reduce peak airway pressure and auto-PEEP by 10% to 15%. Injecting albuterol or ipratropine bromide into a tracheal tube through a special device, the effect is the same. The effect of theophylline derivative doxophylline is probably similar. These theophylline preparations can reduce average respiratory resistance by 30% and endogenous PEEP by endotracheal tube correction by 40%.

When using theophylline, you can give 6 mg / kg of aminophylline, then maintain it at 0.5 mg-1.h-1, 30 minutes and 4-6 hours after administration (especially children, because children's metabolism of theophylline is (Fast) Determination of blood drug concentration. Under this therapy, the blood concentration of theophylline can be maintained for 18 to 24 hours. Thereafter, theophylline can be appropriately applied to maintain the blood drug concentration at a moderate therapeutic level.

The use of aminophylline provides an opportunity to approach airway receptors, at least adding beta 2 agonists to its vehicle, and increasing the effectiveness of the respiratory muscles. It can be seen that theophylline should be used if patients do not respond to inhaled 2 agonists alone, which is an obvious indication. Because we do not know the most applicable amount and deposition of inhaled 2 agonists in some special cases, patients who are not responding to treatment, especially those who plan to use anesthetics or sedatives to reduce barotrauma should be treated with theophylline and Choose between 2 agonists.

3. Theophylline on sleep and sleep apnea syndrome: The effect of theophylline on sleep in normal people and patients with asthma, COPD and obstructive sleep apnea syndrome (OSAS) should be noted clinically. Fitzpatrick et al believe that there is no evidence that theophylline has any effect on the sleep quality of healthy adults, and asthma itself in turn affects sleep. Therefore, theophylline should improve the sleep of nocturnal asthma patients. Zwillich et al. Compared the intermediate-acting slow-release theophylline (TheoDur) with the intermediate-effect 2 agonist bitolterol (the effect is the same as that of albuterol and terbutaline). Theo Dur was used orally twice a day and the average morning blood concentration was 11.4 mg / L. Bitolterol was used three times a day. Results Morning blood (FEV1) was 2.47 L and 1.79 L, respectively. The effect of slow-release theophylline (Theo Dur) was better than that of bitolterol, and the number of episodes of hypoxemia was also significantly reduced. For sleep quality, although there are no objective indicators to explain the difference between the two, patients who take Theo Dur have better sleep quality.

In patients with obstructive sleep apnea (OSA), Malloy et al. Found that theophylline twice daily for 4 weeks significantly reduced the number of apnea and insufficient episodes. However, there are also different results, such as Espanzoa and other methods of intravenous infusion of aminophylline found that OSA did not reduce, but after reducing hyperventilation, it did eliminate the onset of apnea. Malloy et al. Concluded that theophylline has a certain effect on OSA because it may be beneficial for patients who are not suitable or not undergoing surgery or continuous positive airway pressure, however, the effect cannot be predicted. Theophylline must be maintained at a moderate therapeutic level. These warnings are applicable to all patients with nocturnal symptoms. If theophylline is not effective twice daily, then the daily theophylline may be taken once a night to achieve the required level of theophylline.

Theophylline dose and clinical response

Theophylline dose

The starting dose of theophylline should not exceed 400 mg / d unless you have prepared to monitor its blood concentration. The pharmacokinetics of theophylline has been reported in 83 cases in the literature and found that the maximum amount of theophylline required by patients was 400 to 3 000 mg / d to produce a therapeutic level of plasma concentration. The half-life of theophylline in 10 subjects was only 3 to 10 hours. The patients are mostly elderly and smokers. Compared with young people over the age of 60, theophylline clearance was reduced by 25%. For young people, the stepped increase of theophylline recommended by the US Food and Drug Administration (USFDA) is 13 mg / kg, and serum theophylline levels are measured. In 1992, Hendeles et al. Reduced the recommended maximum adult theophylline dose to 600 mg / d and determined serum theophylline levels. The elderly or short stature, the dosage of theophylline should be further reduced. For non-smokers, such dosages are safe, and their resulting plasma concentrations are at low therapeutic levels. The safest method is to start with a 1/2 or 2/3 dose and gradually increase the dose to minimize intolerance. Smokers generally require 800 to 900 mg, but a starting dose of 600 mg is the best option because this dose is safe.

Notes on theophylline

The use of theophylline should be avoided if possible: (1) with a history of seizures; (2) with a history of arrhythmia; (3) recurrent left heart failure; (4) liver disease; (5) unstable cardiovascular conditions (6) Sepsis.

The dosage of theophylline should be reduced in the following cases: (1) the use of cimetidine, ciprofloxacin, erythromycin, etc .; (2) hypothyroidism, pulmonary heart disease, long-term fever.

The dosage of theophylline needs to be increased in the following cases: (1) smoking; (2) the use of phenytoin, carbamazepine, rifampicin. When using theophylline, patients should be taught how to observe and avoid the side effects of theophylline, such as nausea, headache, gastrointestinal reactions, and mental stress, and monitor the serum concentration of theophylline.

Theophylline drug poisoning

Clinical manifestations of theophylline

(1) Mild poisoning: nausea, vomiting, headache, restlessness, insomnia and irritability.

(2) Moderate poisoning: In addition to the above reactions, precardiac discomfort, palpitations, arrhythmias, or irregular breathing occur.

(3) Severe poisoning: may have ventricular tachycardia, mental disorders, convulsions, seizures, coma, and even respiratory and cardiac arrest.

Symptoms of poisoning are more serious in infants and the elderly. Domestic reports of 15 children (aged 12 days to 16 months) misused aminophylline more than 10 times the normal dose; 11 of them, 2 cases each by intravenous injection and intravenous injection, and the rest were taken orally. The main manifestations were central nervous system The system was over excited, crying, muscle tremor, convulsions, and delirium, rapid breathing, failure, arrhythmia, and sudden and frequent vomiting; 2 died. Cardiac accidents often occur in elderly people with poisoning. Acute left heart failure has been reported in 6 elderly patients who were intravenously injected with 0.25 to 0.5 g of aminophylline and diluted with 20 to 40 ml of 50% glucose solution. Four of them developed dyspnea, sitting, and sinus tachycardia at 1 to 2 minutes; the other 2 were fainted at 2 minutes. After symptomatic treatment, the symptoms resolved after 15-20 minutes.

Some patients develop allergic body weights shortly after intravenous injection, manifested as sweating, irritability, cyanosis, shortness of breath, numbness, and decreased blood pressure. It must be distinguished from the toxicity caused by intravenous injection, because the two treatments are different.

Determination of Plasma Drug Concentrations Blood plasma concentrations should be measured in patients receiving theophylline therapy when available. The measurement time should be selected: before inputting the load; 1 to 2 hours after inputting; 24 hours after medication; critical patients should be measured every 12 hours during the medication period. When theophylline plasma concentration is less than 5 mg / L, there is almost no pharmacological response; 5 to 10 mg / L is effective; 10 to 20 mg / L achieves the best effect;> 20 mg / L is a toxic reaction; reaching 30 to 40 mg / L may Causes severe poisoning.

Emergency treatment of theophylline

There are no special detoxification therapies, mainly supportive and symptomatic treatments.

Remove poison

(1) Patients with oral poisoning should have gastric lavage as soon as possible. The gastric lavage fluid can use 1: 5000 potassium permanganate solution; catharsis, large infusion, and diuretics as appropriate to promote the excretion of poisons.

(2) Hemodialysis or peritoneal dialysis is feasible for life-threatening poisoning. Resin hemoperfusion is also effective, which can be performed for 2 to 2.5 hours, and the effect is faster than hemodialysis.

(3) Repeated high-dose oral activated carbon, first use 40g, then take 20g for 2 to 3 hours, and add 20% sorbitol solution 50 to 70ml after each dose, this method can double theophylline clearance in the body .

Symptomatic treatment

(1) Patients with bloating and vomiting can be injected intramuscularly or intravenously with 1 mg of neostigmine; 10 mg of metoclopramide can also be injected intramuscularly.

(2) Diazepam, phenobarbital, or bentoin sodium can be used for excitement, irritability, delirium, or convulsions.

(3) Arrhythmia should be selected according to the specific type, such as lidocaine for ventricular arrhythmias, verapamil for atrial arrhythmia, and propafenone.

(4) Hypotension can be injected intramuscularly or intravenously with the booster drug m-hydroxylamine.

(5) Inhale oxygen.

3. Disable adenosine triphosphate during treatment of poisoned patients