Posts Tagged ‘xanthines’

Theophylline
Theophylline-type drugs are also known as xanthines or methylxanthines. These drugs are chemically similar to caffeine. They cannot be inhaled, so are taken as tablets or syrup. They start working about 30 minutes after being taken and their effects last for 6-8 hours. Slow-release preparations take 90 minutes to start working, but they last 12-24 hours, and are therefore useful for nocturnal asthma.
In Britain, doctors generally regard theophylline-type drugs as reliever drugs (see p. 152), but rather risky ones whose use is only justified for people with severe asthma. They are given, as an additional treatment, to asthmatics who are not responding well to the usual drug programme (see p. 160). Unfortunately, fairly high doses are needed for theophylline-type drugs to act as relievers, i.e. to reverse bronchospasm. There is a very narrow margin between such a dose and one that causes major (and sometimes dangerous) side effects.
Such side effects usually occur when the doctor is still trying to work out the correct dose – this varies from one person to another, so prescribing theophylline-type drugs is no easy matter. Once you are established on a safe dose (and provided your general health and your intake of alcohol, nicotine and medicinal drugs does not vary – see p. 158) you can usually continue taking theophylline without serious side effects.
In the United States, many doctors also give theophyllinetype drugs, at much lower doses, to people with mild asthma. At these low doses they do not act as relievers, but they have a slight anti-inflammatory effect and therefore act as preventers. The risk of toxicity is much less. Taking low doses of theophylline allows people with mild asthma to reduce their use of beta-2 relievers. However, inhaled steroids are usually more effective in this role, and are the preferred treatment outside the United States.
Side effects
Typical side effects include nausea, vomiting, stomach pains, diarrhoea (sometimes with blood), headache, anxiety, restlessness, insomnia, dizziness, and a pounding heart or irregular heartbeat.
Any side effect of these drugs should be taken seriously and reported to your doctor as soon as possible. If you cannot get an appointment quickly, it may be best to stop taking the drug before seeing the doctor, as long as you have other drugs to control your asthma. Call your doctor for advice.
It is remarkably easy to overdose when taking these drugs at higher doses (see p. 157). Such overdoses can be fatal. The symptoms include repeated vomiting, shaking, feeling unusually hot, needing to urinate frequently, severe thirst, maniacal behaviour, and irregular heartbeat (palpitations). Delirium and convulsions may occur shortly afterwards, so get hospital treatment urgently if you have any of these symptoms.
Unfortunately, a serious overdose can sometimes occur in people who have taken theophylline-type drugs without trouble for many years. There may be no advance warning that anything is wrong - no mild side effects preceding the serious ones. To protect yourself against this, you need regular blood tests from your doctor.
One fundamental problem with theophylline-type drugs is that many different factors - including diet, illnesses other than asthma, and taking other drugs - can alter the way your body deals with the drug. If your liver is breaking down the drug more slowly than usual, the amount in your blood will rapidly increase, and can reach toxic levels.
These are steps that can help prevent an overdose with theophylline-type drugs:
• If you start taking a new drug of any kind, or stop taking a drug (especially the contraceptive pill), or if you change your intake of nicotine or alcohol, ask your doctor - preferably in advance - if your dose of theophylline-type drug needs to be changed.
• A great many drugs interact with theophylline-type drugs, including the new anti - leukotriene drugs. You should always be cautious with any new drug, but take particular care with two antibiotics - ciprofloxacin (brand name Ciproxin) and erythromycin (various brand names) - and with cimetidine (various brand names), used for stomach ulcers and heartburn.
• If you have flu vaccinations, or develop certain illnesses, especially viral infections, heart disease or liver disease, watch for the typical side effects of theophylline-type drugs (see above) and consult your doctor immediately if any occur. These conditions all change the effects of theophylline-type drugs.
• Don’t eat meals that are very high in fats or oils. A lot of fatty food causes too much of the drug to be released at once from the slow-release preparations and increases the risk of side effects. Avoid sudden, major, changes to your diet.
• See your doctor regularly for check-ups. Simply getting older changes your reaction to these drugs: your dose may need to change over the years.
• If you are at all forgetful about tablets, keep a careful record of when you have taken your theophylline-type drugs. Be very careful never to take a second dose by mistake.
• Talk to your doctor if you are not taking a slow-release form of theophylline (see box below for brand names). There are usually fewer side effects from these than from the ordinary forms of the drug.
• Wear a Medic Alert bracelet (see box on p. 95) saying that you are taking theophylline-type drugs. If you have a severe asthma attack and are taken to hospital, it is important that medical staff know this, so that they do not give you more drugs of this type.
While pregnant or breast-feeding, it may be advisable to stop taking theophylline-type drugs: discuss this with your doctor. Although the drugs do not affect most unborn or newborn babies, there are occasional reports of toxicity. Less seriously, theophylline-type drugs go through into breast milk, and may make babies irritable and restless. This problem can be solved by always taking the drug just after a feed - this reduces the amount in the milk.
Theophylline-type drugs might produce behavioural problems and learning difficulties in young children although this is unproven. Research shows that there are no problems for children over six.
Anti-IgE drugs
For asthmatics with strong allergic reactions, who are not doing well on ordinary treatment, the new anti-IgE drugs, such as omalizumab may be very valuable (see p. 149). They are given as a depot injection under the skin.
Some common brand names
Common brand names of theophylline-type drugs include: slow-release preparations — Lasma, Nuelin SA, Phyllocontin Continus, Slo-Phyllin, Theo-Dur, Uniphyllin Continus
ordinary preparations - Aminophylline, Nuelin Ketotifen
Ketotifen (brand name Zaditen) is an antihistamine (see p. 138), although it has other effects in addition to those of ordinary antihistamines. Most significantly, it stabilises mast cells in a similar way to cromoglycate.
One advantage of ketotifen to many people is that it is taken by mouth, in capsule, tablet or syrup form. When it was first introduced, doctors hoped that it would be of particular help in asthma, but it has not lived up to expectations. However, some asthmatics do find it effective. It is worth trying because, it it works, it could permit you to reduce your dose of steroids.
Ketotifen requires up to six weeks to take effect, so continue taking your previous drugs (e.g. steroids) for at least six weeks, or you will risk losing control of your asthma.
Side effects
Minor side effects from ketotifen include nausea, headache, increased appetite and weight gain, drowsiness, dry mouth and slight dizziness. Do not drive until you are sure that ketotifen does not make you drowsy. Alcohol may pack a more powerful punch than usual, so drink very moderately at first. If drowsiness is a problem, take the drug in the late evening. The sleepy feeling may wear off after a few weeks of taking the drug.
There are no serious side effects from ketotifen, except if taken with drugs for diabetes.
Anti-leukotriene drugs
Leukotrienes are among the messenger chemicals that are produced by mast cells during an allergic reaction (see box on p. 12). They help to perpetuate the inflammatory process begun by histamine, and they amplify the reaction by attracting more immune cells into the area.
The anti - leukotriene drugs fall into two distinct groups:
• those that bind to the receptors for leukotrienes, called leu kotriene- receptor antagonists. Currently, there are two drugs in this group, montelukast (brand name Singulair) and zafirlukast (brand name Accolate). A third drug, pranlukast, is in the pipeline and currently going through its safety trials.
• those that block the production of the leukotrienes altogether, called 5-lipoxygenase inhibitors. There is only one drug in this group at present, zileuton (brand names Leutrol, Zyflo); it is not yet available in Britain.
As regards tackling inflammation, the anti - leukotriene drugs work in a completely different way from either steroids or cromoglycate. This makes them useful as an add-on treatment, supplementing the effects of existing anti-allergy drugs.
For asthmatics, anti-leukotriene drugs may be particularly good in combination with antihistamines – whereas antihistamines alone are singularly unsuccessful in asthma (see p. 138). Recent research suggests that taking antihistamines together with antileukotriene drugs is an effective way to control airway inflammation. However, there have been no large-scale trials of this treatment option yet, and it may be a while before it comes into general use.
In the airways of people with asthma, leukotrienes can directly trigger bronchospasm (contraction of the airway muscles) as well as fostering inflammation and increasing mucus production. This multiple action of leukotrienes makes anti-leukotriene drugs very valuable for asthmatics because they act as both relievers (reversing bronchospasm) and preventers (tackling inflammation). They are especially useful for exercise-induced asthma.
All the anti-leukotriene drugs are taken in tablet form. If you are trying an anti - leu kotriene drug for the first time, don’t expect any noticeable effects to occur for about three days. Once you are taking the drug regularly, each dose requires 2-4 hours to have its full effect, but goes on working for 12-24 hours in total.
Although anti - leu kotriene drugs have a reliever effect, they cannot give you immediate relief from bronchospasm. Asthmatics must therefore carry a short-acting beta-2 reliever (see pp. 152-3) as well, in case of an asthma attack.
For those who dislike inhalers, or tend to forget to use them, the fact that these drugs are taken once a day in tablet form makes them an attractive option. However, they are expensive, and at present doctors prescribe them mainly for young children who have difficulty inhaling their usual drugs.
Side effects
The side effects noted in safety trials of these drugs were all minor ones:
• zafirlukast – headache, nausea, diarrhoea, pain
• montelukast – headache, diarrhoea, abdominal pain, cough, and flu-like symptoms
• zileuton – upset stomach
As with all new drugs, you should report any unusual symptoms to your doctor, just in case these represent a rare or longterm side effect of the drug (see p. 137).
Very occasionally montelukast provokes allergic reactions, with symptoms such as itchiness, widespread nettle rash (urticaria) or swelling (angioedema).
Zafirlukast and zileuton can both cause liver damage, but this is rare. Your liver function should be closely monitored by the doctor, by means of regular blood tests, and the drug withdrawn at the first sign of trouble. Montelukast can also affect the liver, but this is extremely rare.
The most worrying development noticed to date is the appearance, in a very few people taking zafirlukast or montelukast, of a disorder called Churg-Strauss Syndrome. The symptoms may include a blotchy purplish rash (due to vasculitis – see lower box on p. 73), a flu-like illness, worsening asthma, and numbness or tingling in the limbs. The heart, lungs and nerves are all affected, because eosinophils (see p. 19) are present in large numbers and cause damaging inflammation.
A study of the cases reported so far suggests that this syndrome may not be due to the anti-leukotriene drugs themselves but to other causes – usually (though not always) a reduction in the dose of steroids. Other patients who are not taking antileukotriene drugs, but are reducing or stopping steroids, may also (again, very rarely) develop Churg-Strauss Syndrome. Doctors now suspect that all these patients were already suffering from an underlying eosinophilic disease, which first showed itself simply as asthma, and was quelled by the steroid treatment prescribed for the asthma. The disease was thoroughly masked as long as the patient was using steroids, but when steroids were withdrawn, the underlying disease flared up, producing a wide range of symptoms. In most cases, reintroducing steroids brings these symptoms under control again.
Putting it all together
What is the ideal combination of all these asthma drugs? That is something your doctor can only work out slowly, because it varies from one individual to another.
The conventional approach to asthma treatment is to start patients on a short-acting beta-2 reliever and then, if the symptoms are not controlled, to add other drugs. This approach is called ’stepping up’. The standard steps, or stages, are as follows:
1. Use a short-acting beta-2 reliever only.
2. Add cromoglycate or low-dose inhaled steroids.
3. Try a higher dose of inhaled steroid or a long-acting beta-2 reliever.
4. Try out each of the following in turn: theophylline, anticholinergic drugs, cromoglycate and higher doses of beta-2 relievers (either inhaled or as tablets/syrup).
5. If there is still no success in controlling symptoms, add regular steroid tablets.
Short courses of steroid tablets may be used at any stage, for the control of sudden, severe, attacks.
Over the last ten years, there has been a change of strategy, and very few people are now kept on Stage 1. Inhaled steroids are now given to most asthmatics, even those with relatively mild asthma. Research from Sweden, where widespread use of
inhaled steroids first became general policy, shows considerable benefits to this approach.
If you have gone beyond Stage 2, ’stepping up’ is usually followed by ’stepping down’. In other words, when the symptoms have been well controlled for 3-6 months, doses of some drugs are reduced, or certain drugs stopped altogether. If the asthma flares up again, the dose is increased or the drug reinstated. If there are no problems, and symptoms remain stable for a month or two, another reduction is tried.
An entirely different approach to asthma management is now being tried with some patients – starting off with moderate to high doses of inhaled steroids (equivalent to Stage 3) and then ’stepping down’. The idea is to get the inflammation under control promptly and fully at the outset. This often seems to be the best strategy.
A few asthmatics don’t get much benefit from steroids. If your dose of steroid needs to be raised repeatedly, or you still need to use your reliever daily in spite of taking steroids, you may have steroid-resistant asthma. There are other drugs that can help, including anti-leukotriene drugs and the more powerful anti-allergy drugs (see p. 149).
Alcohol, caffeine and asthma
Some asthmatics experience bronchodilation (opening up of the airways) when they drink alcohol, while others experience
bronchospasm (tightening of the airways). For those whose airways open up, there is probably no harm in sometimes having a drink to relieve your asthma symptoms, assuming these are fairly mild. Clearly, it would not be a good idea to make a daily habit of this.
If your airways tighten up with alcohol, you will probably be pleased to hear that it may not be the alcohol itself. Alcoholic drinks contain a great variety of other ingredients, either derived from the original ingredients or generated during the fermentation process. Called ‘congeners’, these vary from one type of alcoholic drink to another, and they are often the culprits in asthma. So you may well find that, while one kind of alcoholic drink has a bad effect, another is fine.
Caffeine has a far more uniform effect — for most asthmatics it opens up the airways. However, the amount needed to relieve an asthma attack will also produce unpleasant side effects, such as a pounding heart or shaky hands. There are also long-term problems with such high doses of caffeine, including insomnia, headaches, nervousness and ‘restless legs’. It is much better to use your reliever inhaler to control an attack: the drug in the inhaler has been chemically tailored to give the maximum therapeutic benefit with the minimum of side effects. Anyone who consumes tea or coffee excessively can make themselves seriously ill, either physically or mentally, and it is not always obvious that caffeine is the cause (see p. 235).