C. Theophylline

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C. Theophylline

Introduction

Theophylline has bronchodilator properties and is used in the treatment of asthma and COAD. Despite theophylline being widely available in a large number of proprietary preparations, little is known about its mode of action. Theophyllines are very popular in the USA and on the continent, but some respiratory physicians in this country still have reservations about its use, mainly because of the high incidence of side effects, particularly at the upper limit of its therapeutic range, and the availability of more potent and less toxic alternatives. However, it still retains an important role in the treatment of acute severe asthma.

Pharmacology

Theophylline is a naturally occurring alkaloid found in tea and is a methylxanthine similar to caffeine. It is available as a number of different salts, the most common of which are aminophylline (the ethylenediamine) and choline theophyllinate. All 3 behave similarly and will be considered together. Theophylline works as a bronchodilator by the relaxation of bronchial smooth muscle. Several mechanisms have been proposed which include the inhibition of phosphodiesterase to increase intracellular cAMP levels. However, the concentrations of theophylline required to produce measurable increases in cAMP are far outside the levels at which there is a clinical effect. Theophylline is an antagonist of adenosine at pharmacological doses, but a theophylline analogue, enprofylline, does not antagonise adenosine yet still retains potent bronchodilator activity. Recently, theophylline has also been shown to have some anti-inflammatory activity, inhibiting the activity of CD4 lymphocytes in vitro and mediator release from mast cells, and can inhibit bronchoconstriction produced by exercise and challenge testing. Theophylline has also been shown to increase the force of contraction of the diaphragm in patients with COAD although this mechanism of action, and any clinical value of this function is still disputed. Theophylline produces bronchodilatation in a concentration dependent manner and continuous therapy can reduce the symptoms of chronic asthma, reduce the dosage of oral corticosteroids in steroid dependent asthma, and reduce the requirement for symptomatic use of ß2-agonists. However, theophylline also reduces dyspnoea in patients with COAD without alteration of their lung function which could be due to a central, cardiovascular of diaphragmatic effect. Theophylline is a central nervous system stimulant and can increase minute ventilation in man by stimulation of the medullary respiratory centres. This is thought to be mediated by augmentation of hypoxic ventilatory drive and could account for its effectiveness in reducing apnoeic episodes in premature infants and reducing Cheyne-Stokes respiration. Other effects of theophylline include peripheral and coronary vasodilation, but in the central nervous system, cerebrovascular vasoconstriction and reduced cerebral blood flow. Theophylline also increases catecholamine release from the adrenal medulla, and as a consequence increases heart rate, force of contraction, cardiac output and blood pressure, and also has mild diuretic properties. Clinically, tolerance develops rapidly to the cardiac, diuretic and central stimulant effects of theophylline but not its bronchodilator properties.

Pharmacokinetics

Theophylline is well absorbed from the gastrointestinal tract with up to 90-100 per cent bioavailability. Peak levels are achieved within 1-2 hours following ingestion, but this is slowed by the presence of food. Theophylline is approximately 60 per cent plasma protein bound and has a mean volume of distribution of 0.5l/kg. Plasma protein binding is reduced in infants and in patients with liver cirrhosis. The mean plasma half-life of theophylline is about 8 hours in adults although there is large intra- and interindividual variation, and also varies greatly with age being approximately 30 hours in premature neonates, 12 hours within the first 6 months, 5 hours up to the first year of life and approximately 3.5 hours up to the age of 20 gradually increasing again thereafter. Because of the relatively short plasma half-life of theophylline, there are many sustained release preparations available commercially. These all vary as to their bioavailability and the time to peak plasma concentrations. Therefore, once stabilised on one sustained release preparation, patients should not be changed to another without monitoring of plasma levels. Theophylline is mainly metabolised in the liver by demethylation or oxidation using the cytochrome P450 system. Only small amounts are excreted by the kidney unchanged, and dosage adjustments in renal failure are unnecessary. However, caution needs to be exercised when using other drugs that are also metabolised by the cytochrome system when dosage adjustments need to be made in conjunction with the measurement of plasma levels. Many drugs may interfere with the metabolism of theophylline. Special care should be taken with certain antibiotics as patients with acute infective exacerbations of their airways obstruction may be inadvertently put on them without consideration of the effects on theophylline metabolism. These include the macrolide (e.g. erythromycin) and quinolone (e.g. ciprofloxacin) families of antibiotics which both reduce theophylline clearance to varying degrees. Other drugs that reduce theophylline clearance include cimetidine, allopurinol and propanolol (although this would be a rather unusual therapeutic combination). Drugs that increase theophylline metabolism include rifampicin, phenobarbitone and particularly phenytoin and carbamazepine but not the oral contraceptive pill. The rate of metabolism of theophylline is increased substantially in cigarette smokers (the half life can be halved), although may not be significant in those who smoke less than 10/day. Smoking marijuana has a similar effect as can eating a high protein diet. Hepatic dysfunction, heart failure and cor pulmonale all reduce the elimination of theophylline, and low albumin states reduce the amount of protein bound drug in the blood, so results of plasma levels need to be interpreted with caution. Therefore, as the clinical state of the patient with heart failure or respiratory failure with cor pulmonale improves, the clearance of theophylline alters, and dosage adjustments may be necessary.

Therapeutic Use

Theophylline is used both in the prophylaxis of chronic asthma and COAD, and as emergency treatment in acute severe asthma. Generally, theophyllines are used as third or fourth line drugs in the control of troublesome asthma. If patients are still symptomatic whilst taking high doses of inhaled corticosteroids and requiring frequent "rescue" doses of 2-agonists, especially if they have nocturnal or early morning symptoms, the addition of an oral theophylline preparation may be useful. Sustained release preparations (e.g. Theo-dur®, Phyllocontin®, Uniphyllin®) are preferred because they produce smoother plasma levels throughout a 24 hour period and have better patient compliance. Alternatively, if nocturnal and morning symptoms are the most prominent problem with good control during the day, a single bedtime dose of a sustained release preparation, tailored to give peak levels during the most troublesome hours, may be sufficient. If theophyllines are required for both day and night time control, plasma levels should be measured to ensure that the patients are within the therapeutic range. Although a rough guide to total daily dosage is 10-15mg/kg in adults (higher in children) in 2 divided doses for sustained release preparations, the inter-individual variation in metabolism of theophylline and the effect of smoking, drugs and other factors, can make the initial estimate of dosage requirements in an individual patient a hit and miss affair. It is best to start at a low end of the scale and measure levels after at least 48 hours at the same dosage and adjust accordingly. In acute severe asthma, intravenous theophylline (in the form of aminophylline) is used only when patients fail to respond to the initial treatment of repeated high doses of nebulised 2-agonists and ipratropium bromide with intravenous corticosteroids. Aminophylline should be given initially as a loading dose of 5-6mg/kg (in patients not already on oral theophylline) as an intravenous infusion over 15-30 minutes, followed by a continuous maintenance infusion (see below). In patients that are taking oral theophylline, the use of intravenous theophylline can cause problems as the plasma level will not be known. The measurement of plasma theophylline levels is seldom available as an emergency, and the patient may be uncertain as to when or if they took their last dose (the compliance with oral theophylline can be very poor because of the high incidence of side effects) or may have taken more than the prescribed dose because of their deteriorating control. Therefore, the administration of a loading dose in this situation may be dangerous as toxic levels may be achieved. In this situation, it is best not to give a loading dose, but to take blood for a theophylline level and just start a maintenance dose infusion until the result is known and give a loading dose if the result is very low. The calculation of the maintenance infusion dosage needs to take into account the age of the patient, their smoking history, any concurrent disease and medication. As a rough guide, adult non-smokers should be given 0.4-0.5mg/kg/hour, adult smokers 0.6-0.7mg/kg/hour, and patients with liver dysfunction, heart failure or cor pulmonale 0.2-0.3mg/kg/hour. Adolescents and young children may require higher dosages. Plasma levels should be measured within 24 hours of starting the maintenance infusion and the infusion rate adjusted accordingly. There are now several computer programs that can predict plasma levels given certain details of the patient and advise on adjustments in dosage.

Side effects and Overdosage

One of the factors that limits the usefulness of theophylline is the high incidence of side effects within the therapeutic range and the narrow therapeutic index. As plasma levels exceed 15mg/l (normal therapeutic range 10-20mg/l), the frequency of side effects increases, the most common being a sinus tachycardia, nausea, tremor and indigestion. Indigestion is probably due theophylline increasing gastric secretion and relaxing the gastro-oesophageal sphincter causing gastro-oesophageal reflux. Patients may also complain of central stimulatory effects such as anxiety, nervousness and insomnia. Deaths associated with theophylline toxicity have been reported. These may be due to cardiac toxicity leading to life threatening dysrhythmias, especially in association with anaesthetic agents such as pancuronium and halothane and sympathomimetics. Most deaths are associated with neurotoxicity, and the mortality from theophylline related seizures approaches 30 per cent. These seizures are often initially focal progressing to generalized tonic-clonic convulsions and an encephalopathic picture. There is no close relationship between the plasma level of theophylline and the onset of seizures as this may be also influenced by the presence of hypoxia, hypercapnia and acidosis. Other clinical features of acute theophylline overdosage include nausea, vomiting, metabolic acidosis, hypokalaemia. gastrointestinal bleeding, rhabdomyolysis. There is no specific treatment, but general measures such as gastric lavage and oral activated charcoal may help reduce plasma levels. With life threatening levels, heamoperfusion is the most effective form of clearance.

C. Theophylline

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C. Theophylline

Introduction

Pharmacology

Pharmacokinetics

Therapeutic Use

Side effects and Overdosage

Further Reading

C. Theophylline

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