Inhaled Therapy For Cystic Fibrosis

Introduction

Cystic fibrosis is a genetic condition which predominantly affects the airways (along with other organs). There are different types of medicines that can be inhaled directly into the lungs for the treatment of cystic fibrosis. This article aims to give an overview of these drugs. 

What is cystic fibrosis?

Cystic fibrosis (CF) is a genetically inherited condition. It is a recessive genetic condition, meaning a child must inherit the faulty gene from both parents to have CF. 

The main symptom associated with CF is difficulty breathing, including shortness of breath. CF can also cause digestive issues, excess salt in sweat, and infertility in those assigned males at birth- however, this article will focus on respiratory symptoms.

Mucus ( commonly known as phlegm) is a normal substance in the body and can be found in areas such as the lungs, nose and digestive tract. In normal lung function, mucus acts like a lubricant and traps inhaled bacteria so that it can be coughed up or swallowed (allowing the bacteria to be destroyed in the stomach). Tiny hairs called cilia, which line the walls of the airways, beat back and forth to move the mucus up towards the throat.^2,3 There is a protein (present in everyone) called CFTR (cystic fibrosis transmembrane regulator) protein, which is involved in mucus production. Its function is to allow chloride ions into the mucus. Water then follows the ions into the mucus to make it looser and smooth. In CF, this protein is faulty. 

As water is unable to enter the mucus, the mucus in those with CF is very thick and sticky. It is unable to act as a lubricant, and the cilia are unable to beat it out of the lungs. Instead, it blocks up the airways, reducing lung function (ultimately reducing the amount of oxygen that is taken in by the body) and causing difficulty breathing.⁵ The diagram on the right illustrates this. Another cause of reduced lung function in people with CF is their higher susceptibility to respiratory tract infections (also known as chest infections).³  Difficulty breathing and repeated infections are what make CF a life-limiting condition. According to NHS UK, only around 50% of those diagnosed with CF will live past the age of 40. However, children born more recently are likely to have a longer life expectancy.²

There is currently no cure for CF, although there are some drugs called CFTR modulators, which are very promising. These work to help alter the faulty CFTR protein and allow for normal mucus production. However, CFTR modulators will not be covered in this article as they are tablets to be taken orally (i.e. swallowed) and this article will be on inhaled drugs. 

What is inhaled therapy?

Inhaled therapy is when drugs are breathed in. It can be used for many different lung conditions, such as asthma and COPD; however, this article will focus on cystic fibrosis. The advantages of inhaled therapy are that it allows for a high concentration of the drug to enter the airways, as well as being a targeted therapy. It does so by limiting the amount of the drug that enters other parts of the body, causing unwanted side effects.⁴

Drugs for inhalation can be given in a number of ways:

• Metered dose inhaler: Where the drug is in a liquid form and each puff gives a specific amount of the drug (for example, the blue and brown inhalers given to those with asthma are generally metered dose inhalers).
• Dry powder inhaler: As the name suggests, the drug is in the form of a dry powder, and a spray of this powder can be breathed in.¹⁰
• Nebuliser: A machine that turns liquid medicine into a mist. Capsules are usually inserted in the machine to give a specified dose of the medicine. The patient wears a mask that connects to the machine and the patient can inhale the mist.

Different types of drugs that can be inhaled for CF 

Bronchodilators 

Bronchodilators act on the muscles that line the walls of bronchioles (small branches of air tubes in the lungs). If there is something that goes inside the lungs as an irritant, like dust or pollen, it can cause the muscles in the bronchioles to constrict. This makes the lumen (hole in the middle, where the air can go) of the airway smaller, resulting in less air entering and exiting the lungs. This can be seen in the image above, which shows the airway with CF being narrower than the normal airway, leading to shortness of breath and wheezing. 

Bronchodilators are prescribed to almost 80% of those with CF to help manage these symptoms. These are given in one of two ways: metered-dose inhalers or nebulisers.

There are two main types of bronchodilators: SABA (short-acting beta agonists) and LABA (long-acting beta agonists). The function of SABA is to act as a ‘reliever’ in times when something triggers the bronchioles to constrict (in the UK, these are generally blue inhalers). Their effect is almost immediate (within 1-2 puffs) and will last for around 4-8 hours, depending on the specific drug that is taken as a SABA. Usually, SABA should only be reserved for emergencies and should not be over-relied upon, as this can cause worsening of symptoms long term. LABAs also help to relax the smooth muscle, but their effect lasts for around 12 hours and they are not as fast-acting as SABAs.⁵ (Note that SABAs and LABAs are not steroid inhalers).

Steroid inhalers are the ‘preventer’ inhalers, and they are often given to those with asthma. They act to reduce inflammation in the airways and prevent the bronchiole muscle from constricting and narrowing the airways. Evidence for CF, however, does not show that inhaled steroids are an effective mode of treatment. A review found low-quality evidence on this and was unable to conclude with any certainty that long-term steroid inhaler use reduces inflammation in the lungs.⁸

Antibiotics 

Antibiotics can be inhaled for those with CF. With age, individuals become more prone to infection caused by a bacteria called Pseudomonas aeruginosa, which can cause pneumonia. Repeated infections with P. aeruginosa have been shown to cause an accelerated deterioration in lung function. One Cochrane Review found that long-term use of inhaled antibiotics was beneficial for up to 6 months, but the evidence was limited for their benefit on survival rate or quality of life for any longer than this.¹ The inhaled antibiotics are usually given via a nebuliser.⁶

Mucolytics

Mucolytic drugs are another commonly used drug for CF. They work by reducing the viscosity of  

the sticky, thick mucus to make it more fluid (‘muco’ referring to mucus, ‘lytic’ referring to lysis, meaning to break up), allowing it to easily move along the airways and not cause blockages. There are different molecules and bonds within the mucus, and different types of mucolytic drugs work on different bonds within the mucus to make it more fluid. These drugs are usually given via a nebuliser, which is the preferred route of delivery as it will reach the mucus directly. Alternatively, they can be taken orally as a tablet. Some types have an anti-inflammatory effect too.⁹ 

Inhaled mRNA drugs

Inhaled mRNA therapy is an upcoming form of inhaled treatment for those with CF. CF is the result of faulty DNA, which codes for the CFTR protein. In order for the protein to be made, several intermediary molecules/substances are involved in the process. One of these intermediary molecules is mRNA (messenger ribonucleic acid), which codes for the normal CFTR protein. This form of treatment involves inhaling mRNA. The idea of this is to “skip the step” of “reading” the faulty DNA and go straight to the step of allowing further intermediary molecules to “read” the inhaled mRNA and produce a normal CFTR protein. Inhaled mRNA treatment is still in the research stages but has proven to be effective for some patients in the study.⁷

Summary

Giving drugs by inhalation allows for them to directly reach the target area. The types of inhaled drugs commonly given to those with CF are bronchodilators (for opening up the airways), antibiotics (to reduce infection), and mucolytics (to reduce the viscosity of the thick, sticky mucus). These are all for managing symptoms and improving quality of life. A fourth type of inhaled treatment (mRNA therapy) is still in the research stages.