Continuing Education Activity

Mucolytics are drugs used to manage mucus hypersecretion and its sequelae like recurrent infections in patients of COPD, cystic fibrosis, and bronchiectasis. They belong to a group of agents called mucoactive agents. This activity describes the different options and their respective mechanisms of action, indications, and contraindications pertinent for the healthcare team members as these are valuable agents in the management and treatment of productive cough and related muco-obstructive respiratory disorders.

Objectives:

• Identify the mechanisms of action of the various classes of mucolytic agents.

• Describe the adverse effects of mucolytic agents.

• Review the appropriate monitoring for patients receiving mucolytic agents.

• Outline the importance of improving interprofessional team strategies for enhancing communication and coordination to boost the outcomes in patients suffering from muco-obstructive disorders who are receiving mucolytic drugs.

Indications

Mucolytics are drugs belonging to the class of mucoactive agents. They exert their effect on the mucus layer lining the respiratory tract with the motive of enhancing its clearance. Mucus is the first line of defense for the various epithelia inside our body against harmful pathogens. Its job also entails the protection of the epithelium from the excoriating irritants found in the gastrointestinal tract. It houses an assemblage of proteins such as immunoglobulins, various glycoproteins, and even some antimicrobial enzymes like lysozyme. The cross-bridging of polymeric gel-forming mucins chiefly determines the biophysical properties of mucus. This layer is very protective against bacteria through bacterial growth inhibition and the prevention of biofilm formation. The mucus layer also works as a physical barrier against respiratory irritants and prevents fluid loss as well. Expectorated mucus is called sputum. 

The amount of mucus in our body is regulated chiefly by two mechanisms, which are the mucus-secreting cells and the mucociliary escalator. Goblet cells of the mucous membranes and the submucosal glands of the respiratory, GI, and reproductive systems are responsible for the secretion of mucus, and the mucociliary escalator is responsible for the clearance of mucus towards the pharynx, where it is eventually expectorated out by the cough reflex. However, there are some conditions where this regulation breaks down.

In conditions like COPD and asthma, chronic irritation of the airways leads to mucus hypersecretion. Excessive mucus production overwhelms the mucociliary clearance mechanisms, thus leading to the accumulation of this excess mucus. This leads to the formation of mucus plugs, which further decrease the clearance. The airways respond by secreting an excess of inflammatory mediators in an attempt to clear the obstruction. Unfortunately, this only worsens the condition as mucus viscosity increases, leading to further decreased clearance as well as the initiation of inflammation and fibrosis. This condition is only worsened because this static mucus is invaded by bacteria like Pseudomonas aeruginosa and Staphylococcus aureus. Thus, a vicious cycle initiates, which invariably ends with an acute exacerbation of the condition. Classic mucolytics like N-acetylcysteine are indicated in such conditions because they decrease mucus viscosity and increase its flowability, thereby improving its clearance.

In conditions like cystic fibrosis, mucus secretion is impaired, and thus the airway secretions mostly include filamentous actin polymers and inflammatory-cell derived DNA. These secretions are also thick and viscous and a frequent target of bacteria. Here, another class of mucolytics is helpful that targets the DNA polymers. 

Mechanism of Action

Mucolytics divide into two subgroups:

1. Classic Mucolytics

2. Peptide Mucolytics

Classic Mucolytics:

Disulfide bonds are building blocks of many complex proteins, including mucus. N-acetyl L-cysteine (NAC), the prototype drug of this class, reserves a reducing ability and works by the thiol-disulfide interchange mechanism. The mucin polymers have cysteine residues throughout their structure. The disulfide bonds are anchored on these residues to yield crosslinking of the polymer. The free thiol group in the structure of NAC hydrolyzes the disulfide bonds attached to cysteine residues. This reaction disturbs the 3-D framework of mucus by reducing the S-S bond to an S-H (sulfhydryl) bond, rendering it incapable of anchoring the complex structure of the protein.[1] This subgroup includes

N - Acetylcysteine

Along with the above-mentioned mucolytic action, N-acetylcysteine also has anti-inflammatory and antioxidative properties. These agents help reduce the reactive oxygen species and inflammatory mediators that cause the insult in respiratory airways.

Carbocysteine

Carbocysteine also increases the volume of sputum, therefore producing an additional expectorative effect. It is very safe and effective in asthmatics as it does not irritate the respiratory tract.[2] It may be indicated for reducing AECOPD (acute exacerbation of chronic obstructive pulmonary disease) due to its property of significantly reducing bacterial load in the airways of such patients.[3] Pulmonary infections have been implicated in up to 70% of all AECOPD. 

Erdosteine and Fudosteine

These are newer drugs that are thiol derivatives and have additional anti-oxidant and anti-tussive actions. They have a sulfhydryl group in their active metabolite, called Met-1, which acts during the respiratory burst of the neutrophils.[4] Erdosteine has also shown a significant antibiotic-potentiating effect. Reports have also indicated that it is protective for alpha-1 antitrypsin.[5]

Peptide Mucolytics

In contrast to classic mucolytics, peptide mucolytics preserve the protective mucins. Peptide mucolytics target DNA polymers and F-actin links that tend to increase in purulent secretions. Therefore, peptide mucolytics, which are meant to reduce mucus viscosity by depolymerizing the DNA polymers or F-actin network that often present in purulent secretions, are very useful in conditions such as cystic fibrosis.

Dornase Alfa

Dornase alfa produces a mucolytic effect by depolymerizing DNA polymers. It produces a mild increase in FEV1(forced expiratory volume after 1 second) in patients with cystic fibrosis.[6]

Thymosin β4

The mucolytic effect of thymosin β4 is produced through its effect on F-actin. F-actin is produced in a large quantity in purulent secretions and increases viscosity due to its filamentous nature. Thymosin may, therefore, be of value in breaking down airway pus through the depolymerization of these filaments.[7]

Administration

N-acetylcysteine can be administered orally, intravenously, and topically in a nebulized form. Though the topical route offered the advantage of activating the mucociliary clearance mechanism along with inducing a cough reflex, the oral route offers much better tolerability.[8] This is discussed further under adverse reactions. An oral dose of 200 to 600 mg daily is recommended for the management of muco-obstructive disorders.[9] The safety in pregnant females and children has been well established.[10]

The recommended dose for dornase alfa is 2.5 mg administered in nebulized form 1 to 2 times a day for patients with cystic fibrosis.[6] Evidence suggests an improvement in FVC and FEV1 as soon as three days after initiating therapy. The standard therapies for cystic fibrosis, like antibiotics and chest physiotherapy, should be continued along with the drug. A similar dose and route of administration have been recommended for children of all age groups and adolescents. Early administration in infants and young children diagnosed with cystic fibrosis, even when no clinical signs or symptoms of the disease are present, has shown benefit.[11] Although there is limited data regarding the safety of Dornase alfa in pregnancy, no effect on fetal outcome was reported in animal models receiving dosages much higher than the maximum recommended human dose.  

Carbocisteine is administered as an oral preparation, with dosages ranging from 750 mg twice a day to 4.5 g once a day. Evidence suggests that a higher concentration of active compounds was achieved via nocturnal administration of the drug.[2]

Erdosteine is administered orally, and the doses can range from 600 to 900 mg. However, the dose should be titrated carefully in elderly patients with chronic liver disease as an increased plasma concentration, and elimination half-life have been reported in these cases.[5]

Adverse Effects

• The most frequently reported adverse effects of oral N-acetylcysteine are vomiting and diarrhea. After 16 to 18 days of N-acetylcysteine use, the incidence of vomiting and diarrhea increased by 50% and 43.5%, respectively.[9][12] Increased blood pressure, respiratory distress, chest pain, fever, rectal bleeding, headache, hypotension, lethargy, and skin allergy reportedly occur in less than 5% of cases. Aerosolized N-acetylcysteine is poorly tolerated due to its irritant effect and a very foul odor that can induce vomiting. A high incidence of anaphylactic reactions is observed in patients given intravenous N-acetylcysteine.[13]
• The most commonly reported adverse reactions with Dornase alfa are laryngitis, voice alteration, and rash compared to placebo. Other less significant adverse were pharyngitis, chest pain, and conjunctivitis. These adverse effects were mostly transient and not reported to be severe enough to cause treatment withdrawal or require alterations in dosing. There have been no reports of an anaphylactic reaction to dornase alfa to date. Within all the studies, about 2 to 4% of patients treated with dornase alfa developed serum antibodies to the drug, the clinical significance of which is yet to be discerned.[6]
• Mild gastric discomfort, gastric ulceration, and fixed drug eruptions have been reported with carbocisteine.[2]
• Epigastralgia, headache, erythema, and nausea have been reported in patients receiving erdosteine, the latter two of which led to treatment discontinuation.[5]

Contraindications

• Due to its propensity to cause emesis, N-acetylcysteine is contraindicated in patients with peptic ulcers. It is also contraindicated in patients with esophageal varices and Mallory-Weiss tears due to similar reasons. It must be strictly avoided in patients who have had an anaphylactic reaction to the drug in the past.
• The only contraindication for dornase alfa is known hypersensitivity to the drug in the past or if the patient is hypersensitive to Chinese hamster ovary (CHO) cell products.[14]
• Carbocysteine is contraindicated in patients with active gastric ulceration.[2]

Monitoring

After a 400 mg oral dose of N-acetylcysteine, the maximum plasma concentration was calculated to be 3.47 mg/L, taking 30 minutes to achieve it. The volume of distribution for N-acetylcysteine varies from 0.33 to 0.47 L/kg. 4 hours after an intravenous dose, 50% of the drug was found to be bound to plasma proteins. N-acetylcysteine undergoes extensive first-pass metabolism in the gut wall and liver when administered orally, leading to about 6 to 10% bioavailability. A majority of the elimination of this drug is non-renal, and the kidneys eliminated only 30%.[9]

Animal studies have shown a minimal systemic absorption after aerosol inhalation of dornase alfa. Inhalation of even very high doses (10mg three times a day) did not significantly increase the serum DNase concentration.[15] Whatever little systemic absorption that does occur is believed to be protein-bound and is cleared from the body with no significant accumulation in the tissues.[16][17] This implies that minimal to no monitoring is necessary for the patients receiving this drug. Following inhalation of a 2.5 mg dose of dornase alfa, a mean sputum concentration of 2 μg/mL was detected within the first 15 minutes, and 2 hours later, the concentration fell to 0.6 μg/mL. The disappearance half-life from the lungs in animal models was calculated to be about 11 hours. In primates, the bioavailability was less than 2%.[17]

Carbocisteine shows one-compartment open model kinetics after absorption and achieves its peak plasma concentration in 1 to 1.7 hours. The drug undergoes partial metabolism in the liver, and up to 60% of the drug is excreted by the kidneys unchanged.[2]

Following oral administration, Erdosteine reaches its peak plasma concentration in 1.4 hours and has a similar elimination half-life. It contains two sulfhydryl groups that are blocked. These are released only after its hepatic metabolism, which confers the valuable property of not affecting the mucus lining the stomach. No significant drug accumulation has been reported.[5]

Drug Interactions

• Oral N-acetylcysteine must not be given with activated charcoal, as a 3 g preparation will adsorb 54.6% of the drug, and a 6 g preparation will adsorb 96.2% of the drug, markedly reducing its efficacy.[9]
• N-Acetylcysteine provides local protection from the toxic metabolites of intravenous cyclophosphamide to the urethra, bladder, ureters, and kidneys when administered orally along with it.[18]
• Evidence suggests that N-Acetylcysteine can prevent doxorubicin-induced cardiomyopathy in animal models when co-administered.
• Dornase alfa has been shown to greatly potentiate the antibiotic effect of tobramycin and amikacin against multiple strains of Pseudomonas aeruginosa and Staphylococcus aureus.[6]
• Administration of erdosteine with amoxicillin in patients with an acute infective exacerbation of chronic bronchitis resulted in higher concentrations of the antibiotic in the sputum, leading to earlier and more pronounced amelioration of clinical symptoms compared with placebo.
• A higher concentration of amoxicillin in the sputum of patients suffering from an acute infective exacerbation of chronic bronchitis was reported when it was co-administered with erdosteine.[5]

Toxicity

N-acetylcysteine has a wide therapeutic index. Dosing errors, however, have led to instances of toxicity. These are more common with intravenous administration of the drug. There is a reported instance where ten times the recommended loading dose was administered to a 23-year old female.[13] This dose led to thrombocytopenia, hemolysis, acute renal failure, and ultimately death. Another study, however, showed that oral administration of N-acetylcysteine, as commonly used in patients with muco-obstructive disorders, is safer than intravenous route and dosing errors are much less likely.[19] Research has shown that oral doses as high as 30g/day for three days were very well tolerated, with minor adverse effects like vomiting and diarrhea.[12]

Owing to its short half-life and poor systemic absorption, dornase alfa is a relatively well-tolerated drug. Toxicity to dornase alfa has not resulted in animal models exposed to doses as high as 180 times the maximum recommended human dose in single-dose inhalational studies.[14]

Animal models have not shown any clinically significant toxicity to erdosteine even after administering very large doses of the drug.[5]

Enhancing Healthcare Team Outcomes

WHO projects the global prevalence of COPD to be about 250 million, with about 3 million deaths each year. Unfortunately, this figure is expected to rise in the coming years, equating to a substantial socio-economic impact. Therefore, while research for the definitive treatment of COPD continues, it is imperative to divert attention to therapies that could improve the lifestyle and reduce acute exacerbations, hospital stay, and mortality in such patients. This area is where mucolytics show immense potential.

A well-coordinated interprofessional team of pulmonologists, physiotherapists, family clinicians (MDs, DOs, NPs, PAs), nurses, and pharmacists is required to work together to manage a case of COPD. First of all, the patient must be counseled regarding the importance of lifestyle modifications. The physician must instruct the patient thoroughly regarding the benefit of the prescribed drugs, the correct dose, the expected adverse reactions, and teaching them the proper procedure for using a nebulizer. This approach will help maximize patient compliance. Patients must also receive education about the importance of regular follow-up visits. A crucial role is also played by clinical psychologists, support groups, and de-addiction centers, as this will help delay the disease progression in patients who smoke. This interprofessional approach to care with mucolytics in patients where appropriate can drive improved outcomes with fewer adverse events. [Level 5]

In the last 30 years, great strides have occurred in the management of cystic fibrosis. Today, the median survival age of a patient is almost 40 years. This can, in part, be credited to the advancement in therapies like mucolytics. This effort can be furthered by utilizing a well-organized interprofessional team in its management. Although mucolytics prescribed by a physician are an important part of this, the role of nurses, chest physiotherapists, dieticians, and child psychiatrists is also important.[20] 

Although the effectiveness of mucolytics has been challenged in recent times, the evidence presented by large-scale studies conducted for N-acetylcysteine [Level 2], dornase alfa [Level 1], carbocisteine [Level 1], and erdosteine [Level 2] cannot be ignored.[21][22][23][24]