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 becomes increased, leading to further decreased clearance as well as the initiation of inflammation and fibrosis. This condition is only worsened by the fact that 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 the viscosity of mucus and increases 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.
Mucolytics divide into two subgroups:
1. Classic Mucolytics
2. Peptide 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 its 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 S-S bond to S-H (sulfhydryl) bond, rendering it incapable of anchoring the complex structure of the protein. This subgroup includes
N - Acetylcysteine
Along with the above mentioned mucolytic action, N-acetylcysteine also has anti-inflammatory and antioxidative properties. These help to reduce the reactive oxygen species and inflammatory mediators that are the cause of the insult in respiratory airways.
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. 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. 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. Erdosteine has also shown a significant antibiotic-potentiating effect. Reports have also indicated that it is protective for alpha-1 antitrypsin.
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 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.
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 the viscosity due to its filamentous nature. Thymosin may, therefore, be of value in breaking down airway pus through the depolymerization of these filaments.
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. 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. The safety in pregnant females and children has been well established.
The recommended dose for dornase alfa is 2.5 mg administered in nebulized form 1 to 2 times a day for the patients of cystic fibrosis. 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 as well. 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. 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.
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 has been reported in these cases.
Maximum plasma concentration after a 400mg oral dose of N-acetylcysteine 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 the bioavailability of about 6 to 10%. A majority of the elimination of this drug is non-renal, and the kidneys eliminated only 30%.
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 lead to a significant increase in the serum DNase concentration. 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. 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. Disappearance half-life from the lungs in animal models was calculated to be about 11 hours. In primates, the bioavailability was less than 2%.
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.
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, and these are released only after its hepatic metabolism, which confers it the valuable property of not affecting the mucus lining the stomach. No significant drug accumulation has been reported.
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. 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. 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.
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 who were exposed to doses as high as 180 times the maximum recommended human dose in single-dose inhalational studies.
Animal models have not shown any clinically significant toxicity to erdosteine even after the administration of very large doses of the drug.
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 team of pulmonologists, physiotherapists, 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, and the expected adverse reactions, along with 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 to delay the disease progression in patients who smoke.
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.
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.
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