Drugs for Asthma
Drugs for Asthma
The drug treatment of asthma is far more complex than for any other allergic disease. Drugs prescribed for asthma fall into two basic categories: those that open up the airways by relaxing the airway muscles, called relievers, and those that treat the inflammation in the lining of the airways, called preventers. The former offer a ‘quick fix’ - like taking an aspirin when you have a headache. Just as the actual cause of the headache is not treated by an aspirin, so the actual cause of the asthma attack is not addressed by relievers. Preventers, on the other hand, tackle the basic problem - the inflammation that triggers the contraction of the airway muscles (see p. 36).
In the past ten years, there has been a quiet revolution in asthma treatment, with far more people being given preventer inhalers, usually low-dose steroids. The aim is to get the airways in better condition, with the inflammation thoroughly damped down, so that the airway muscles don’t go into spasm. The ultimate objective is to make people far less reliant on reliever inhalers, because the potential hazards of over-using them are now realised.
The details of modern asthma management, and the different approaches used, are described on p. 160, following the discussion of the main types of drug used for asthma treatment.
Beta-2 relievers (beta-agonists)
Our airways open up when we produce adrenaline. This is the body’s natural response to feeling angry or frightened. The adrenaline widens the airways so that we can run faster or fight more vigorously.
Adrenaline (epinephrine), given as a drug, was among the earliest treatments for asthma. However, it also stimulates the heart to beat faster and raises
the blood pressure. While it is useful for emergency treatment (see p. 155) the side effects make it too hazardous for routine use.
The beta-2 relievers work by mimicking adrenaline – they bind to the same receptors in the airways, the beta-2 receptors. Binding to these receptors stimulates the airway muscles to relax, so that the airways open up.
In other respects, the beta-2 relievers are not like adrenaline. Clever chemical manipulation has made them sufficiently different from adrenaline to have little effect on the heart and other organs, when taken at normal doses.
Beta-2 relievers are best taken by inhalation. Although tablets and syrup are available these are far more likely to bring on side effects, because the dose needed is so much bigger.
Inhaled beta-2 relievers target the drug directly on the airways, so the dose can be smaller. They also have the great advantage of taking effect soon after being inhaled, and giving full relief from airway narrowing within 10-15 minutes.
There are two different kinds of beta-2 relievers:
• the traditional short-acting beta-2 relievers whose effects last for 3-6 hours (usually about four). The modern consensus is that these should be used only when needed, not taken routinely.
• the newer long-acting beta-2 relievers, which last up to 12 hours. These drugs are prescribed for more severe forms of asthma (see p. 154), and are generally used routinely, twice a day.
A key question for asthma sufferers is: How often can short-acting beta-2 relievers be used? Ideas about this have changed considerably over the last 20 years, and no doctor would now want to have patients using a Ventolin inhaler five, six or more times a day - something that was quite common in the past. This level of need for beta-2 relievers indicates that the asthma is poorly controlled and requires treatment with a preventer, to quell the inflammation in the airways.
Detailed policy on beta-2 relievers still varies from one part of the world to another. British guidelines state that anyone who needs to use a short-acting beta-2 reliever more than once a day, or who suffers from nocturnal asthma, should be given a preventer as well. The international guideline is more stringent: if a short-acting beta-2 reliever is needed more than three times a week, a preventer should also be prescribed.
How safe are these drugs in the long term? The cause of the big re-think on beta-2 relievers was an epidemic of asthma-related deaths in New Zealand between 1976 and 1988. The death rate from severe asthma attacks was 2-4 times its previous level for a while, and over a thousand New Zealanders died in the epidemic.
There has been a huge controversy over what exactly caused these deaths. Most researchers now agree that the main cause was a new brand of inhaler that delivered a double dose of the drug fenoterol, a short-acting beta-2 reliever with a very powerful effect on the airways and quite high levels of side effects involving the heart. The same brand of inhaler may have been linked to increased death rates in Canada and Germany.
Research suggests that the problem was greatest in New Zealand because sales of the new inhaler were highest there, and because many patients got their inhalers through repeat prescriptions. As a result, people whose asthma was deteriorating badly were not seen by a doctor and were using large amounts of beta-2 reliever, rather than taking preventer drugs. This is now believed to be a major cause of asthma deaths. There are three separate factors involved:
• The beta-2 reliever covers up the effects of the severe inflammation of the airways. People feel reasonably well, because the reliever is opening up their airways, and don’t realise just how bad their asthma really is. The untreated inflammation in the airways can eventually lead to a very serious, and potentially fatal, asthma attack.
• The short-acting beta-2 reliever, used regularly, makes the airways more sensitive to exercise, and to allergens such as dust mite or pollen. This means that an asthmatic who is already allergic to these allergens reacts to them at much lower levels in the air.
• The airways become less and less responsive to the beta-2 reliever itself, so that when a serious attack occurs, requiring hospital treatment, huge doses of beta-2 reliever are needed to open up the airways. These massive doses carry a risk of serious side effects involving the heart.
The details of the New Zealand epidemic still evoke controversy. Was fenoterol itself, which is stronger than other beta-2 relievers, the cause of the deaths? Or was it just that the inhaler delivered a double dose - would any short-acting beta-2 reliever be dangerous at twice the normal dose? Or was it over-use of all beta-2 relievers and lack of preventer drugs?
Some common brand names
Common brand names include:
short-acting beta-2 relievers in inhalers - Aerolin, Airomir, Bricanyl, Ventolin short-acting beta-2 relievers in tablets - Bambec, Bricanyl, Volmax short-acting beta-2 relievers in syrup - Monovent, Ventolin
long-acting beta-2 relievers in inhalers - Bambec, Foradil, Oxis, Serevent
Until this is resolved, safety-conscious asthmatics may want to assume that any of these possibilities could be correct. An ultra-cautious approach would include:
• Avoiding fenoterol (it is no longer available in Britain, except in the Duovent inhaler, combined with an anti -choli nerg ic drug)
• Not using double-dose inhalers of any beta-2 reliever (i.e. inhalers that deliver 200mcg/ micrograms per puff)
• Not routinely taking two puffs of a single-dose inhaler (check with your doctor if you have been told to take two puffs)
• Using any short-acting beta-2 reliever only I as needed’ – which should be once a day or less according to British guidelines. Note that, with this level of use, there is absolutely no risk from these drugs: it is only regular over-use that is damaging and dangerous.
• Using a peak-flow meter and ensuring that you are assessed regularly by your doctor
• Always taking your preventer medication as prescribed.
Since about 1990, the death rate from asthma has been falling, particularly in countries with a policy of reducing use of beta-2 relievers, and increasing inhaled steroids. The death rate in New Zealand is now the lowest it has been for 50 years, and at the same level as in other Western countries.
Unnecessary alarm
While investigating the causes of the New Zealand epidemic, medical researchers discovered that patients inhaling a short-acting beta-2 reliever four times a day had more irritable airways after just two weeks. Their airways were also less responsive to the drug, even after this brief period of use.
Some researchers began to ask if the asthma epidemic itself – the increasing number of cases of asthma – could actually be due to these drugs. Maybe children with mild wheezing, which might have cleared up if left untreated (and which would have gone untreated in the past) were becoming full-blown asthmatics because they were now using beta-2 inhalers?
Many doctors became very concerned about these questions, and a leading medical journal
published an article with the provocative title: ‘Worldwide worsening wheezing – is the cure the cause?’ That was in 1992. Since then, much more research has been done, and it is clear that this particular fear about beta-2 relievers was unfounded.
Unfortunately, there are a few books and other publications around that are spreading unnecessary alarm about these drugs by reporting the debate as it was in 1992. They have taken up that question ‘Is the cure the cause?’, assumed that the answer is ‘yes’, and ignored all the subsequent research, which shows the opposite.
Beta-2 relievers in severe asthma
A few patients with severe asthma remain breathless and wheezy, even though they are inhaling moderate doses of a steroid preventer every day. Increasing the dose of inhaled steroids does not make a huge difference to their symptoms, and it substantially raises the risk of steroid side effects.
Taking a long-acting beta-2 reliever often works wonders for such patients. These relatively new drugs relax the airway muscles, and go on working for 12 hours or more.
There has obviously been concern about long-acting beta-2 relievers having the same sort of insidious side effects as their short-acting colleagues (see p. 153), and so increasing the likelihood of deaths from asthma. However, studies of people taking these drugs suggest that the risks are minimal. Certainly, long-acting drugs taken twice a day are very much safer than short-acting drugs taken four times a day.
Other studies show that the chemical differences of the long-acting drugs, as well as prolonging their effects, also give them a more complex set of actions in the body. For example, they improve the effect of steroids in calming inflammation, and may even have some small anti-inflammatory effect of their own.
Doctors believe that, for patients with troublesome asthma, the benefits of long-acting beta-2 relievers greatly outweigh the risks. But they should only be used in combination with inhaled steroids. Various other options, such as allergen avoidance and the new anti - leukotriene drugs (see p. 159), should probably be investigated as well.
If you are taking long-acting beta-2 relievers, do use them regularly, once every 12 hours – the good effect gradually builds up with consistent use.
Generally speaking, you should not take additional doses in between. These are not intended for use if you have a sudden asthma attack – your doctor will prescribe a short-acting beta-2 reliever for this. This limitation on the use of long-acting beta-2 relievers is certainly appropriate for salmeterol (which was the first of the long-acting beta-2 relievers to be developed) because it is very slow to take effect on the airways. However, one of the newer long-acting beta-2 relievers, called formoterol, begins to work just as quickly as a short-acting beta-2 reliever. Formoterol could, in theory, be used on an ‘as-needed’ basis to combat asthma attacks. You may want to discuss this possibility with your doctor.
Finally, don’t stop taking your preventer drug (e.g. inhaled steroid or cromoglycate), even if you feel a lot better. Long-acting beta-2 relievers are not a substitute for preventers.
Some patients with very severe asthma need to take regular doses of short-acting beta-2 relievers as well as long-acting beta-2 relievers. You should obviously follow the advice of your asthma specialist closely if you are on this kind of drug regime, and not change anything without approval. However, it might be worth discussing other options, such as anti -leukotriene drugs. In addition, do all you can to combat your asthma in other ways – by reducing allergen exposure, avoiding asthma triggers (see p. 39), and employing various other self-help measures (see p. 41).
Immediate side effects of beta-2 relievers
Minor immediate side effects of these drugs include:
• headache
• nervousness, trembling, restlessness, anxiety; children may become more excitable, and some are badly behaved or even aggressive.
• flushing
• dry mouth
• muscle cramps.
These side effects – all of which are due to the resemblance of beta-2 relievers to adrenaline – usually wear off relatively quickly. Some long-acting beta-2 relievers may cause nausea and vomiting.
A pounding heart is usually a relatively minor side effect, but it can be more serious, and should be reported to your doctor.
A few asthmatics find that their airways tighten up when these drugs are inhaled, rather than opening. This is called paradoxical bronchoconstriction. If this happens, stop using the inhaler and see your doctor as soon as you can.
Even more rarely, asthmatics can develop allergic reactions to the drugs, or suffer hallucinations or seizures. Obviously you should stop using the inhaler immediately if you experience side effects of this kind, and should see your doctor.
There can be an interaction between beta-2 relievers and other drugs or medical conditions. Should you need a diuretic, tell the doctor or pharmacist that you are also taking a beta-2 reliever, and ask which diuretics are safe. If you have high blood pressure, a heart problem, or a thyroid condition, make sure the doctor remembers this when prescribing beta-2 relievers.
Adrenaline inhalers
Adrenaline inhalers are for use in emergencies. Technically, they are not available in Britain, but they can be imported under special licence, and your doctor may be persuaded to obtain one for you if he or she thinks it might be useful. They are given to people who have asthma and have sometimes had attacks of anaphylaxis (see p. 58), for example in reaction to food, latex or an insect sting. The inhaler provides prompt emergency treatment for the kind of severe asthma attack that you may experience during anaphylaxis.
You should probably be carrying an adrenaline auto-injector as well, as you may need to use both (see p. 98). Those who usually have fairly mild reactions to their allergen can use the inhaler first, to treat symptoms in the mouth, throat and airways. If other symptoms develop, such as faintness or widespread nettle rash,
Asthma alert
If you ever find that your short-acting beta-2 reliever has no effect within ten minutes, or is needed more than once every four hours, this indicates a serious asthma attack and you need urgent medical help (see p. 100).
During a severe asthma attack, while getting to hospital or waiting for a doctor to arrive, up to 30 puffs of a short-acting beta-2 reliever should be taken as an emergency treatment, to get the airways open. There is a risk of death if you don’t use the reliever fully in this situation. (This emergency dose is safe for almost everyone, but there may be risks if you have a heart condition – get detailed advice from your doctor in advance.)
then the adrenaline injector can be used. Those with a history of more severe reactions should start with the adrenaline injector and then use the inhaler if there are still symptoms in the mouth or airways.
Don’t exceed the maximum number of puffs stated on the canister, as the propellant can cause problems. If you have a heart condition, your doctor will advise you about using this kind of treatment safely - adrenaline can affect the heart.
Ephedrine
Ephedrine and orciprenaline (brand name Alupent) belong to the previous generation of reliever drugs. They are chemically very similar to adrenaline and therefore cause a lot of side effects, especially involving the heart.
These drugs are no longer recommended, and will soon be phased out completely. Some older asthmatics may still be using them, just because they have been on them for years and no one has reviewed their treatment.
If you are taking such drugs, ask your doctor about switching to a newer form of reliever - it will be more effective in treating your asthma, as well as having fewer side effects.
Anti -cho linerg ics
These drugs, also known as anti-muscarinics, are relievers. However, they work in a completely different way from the beta-2 relievers. They block the action of the parasympathetic nervous system, a set of nerves that are the biological equivalent of auto-pilot - working without the intervention of conscious thought. The parasympathetic nervous system has many effects on the body, including keeping the airway muscles nicely toned (see box on p. 235). By blocking the parasympathetic, anticholinergics help the airway muscles to relax.
Anti-cholinergics are taken by inhaler, and require 30-90 minutes to achieve their full effects. They should continue working for 3-6 hours.
Some common brand names
Common brand names of anti-cholinergics include: inhalers – Atrovent, Oxivent
nasal spray - Rinatec
For most asthmatics, especially those with a strong allergic component to their asthma, anti-cholinergics are generally less effective than beta-2 relievers. But they are useful to children under one year, who may not respond to beta-2 relievers. They also have a role where asthma is combined with chronic bronchitis -here the anti -choli nerg ics can sometimes be more effective than beta-2 relievers - and they are particularly useful for asthma with a lot of mucus, because blocking the parasympathetic tends to reduce mucus production. For severe asthmatics, anticholinergics may be combined with beta-2 relievers.
Anti -choli nerg ics should be taken only when needed, not regularly several times a day. If used regularly, they can make the airways more sensitive, just as short-acting beta-2 relievers can (see p. 153).
Side effects
Minor side effects of anti-cholinergics may include a dry mouth, blurred vision, constipation, and irritation of the mouth and throat. A few people suffer nausea or difficulty in passing urine.
Serious side effects are rare. Any increase in the stickiness of the sputum coughed up may be a cause for concern, especially in children. If there is an increase in wheezing or coughing, stop taking the drug and see your doctor.
If you already have glaucoma or prostate problems you should be monitored carefully by your doctor, as these conditions can get worse with anti -choli nerg ic drugs.
When anti -choli nerg ics are used in a nebuliser, it is vital that the mask fits well (see p. 163).
Anti-cholinergics for the nose
Another use for anti-cholinergics is in nasal sprays, for the treatment of vasomotor rhinitis, a non-allergic condition that is frequently mistaken for allergic rhinitis (see p. 29). In this disorder, the constant flow of mucus is caused by a malfunction of the parasympathetic nervous system, which is why anti-cholinergics work well.