Clinical Challenges in Corticosteroids Use

#### **Chapter 1**

## Corticosteroids in Emergency Pathologies

*Miroslav Radenković and Ivana Milićević*

#### **Abstract**

Ever since their discovery in the fifties of the last century, as an anti-inflammatory drugs for the treatment of rheumatoid arthritis, corticosteroids have found a significant place and wide application in various fields of medicine. Their effects are known to be diverse. The most significant ones are the anti-inflammatory, anti-allergic, and immunosuppressive effects. Furthermore, they affect the hematopoietic system. Corticosteroids produce complex metabolic effects by stimulating glyconeogenesis, increasing the uptake of amino acids in the liver and kidneys, and enhancing lipolysis. Given that natural adrenocortical hormones are synthesized under the influence of stress, it is expected that in the emergency situations, where we face vitally endangered patients whose body is under the stress due to respiratory insufficiency or impaired hemodynamics, corticosteroids do have significant place in the treatment. Thus, these drugs are used in the treatment of acute exacerbation of chronic obstructive pulmonary disease and asthma, in anaphylactic reactions, spinal shock, Addisonian crisis, and sepsis. During the COVID-19 pandemic, corticosteroids found their place in certain stages of treatment, as well as in many national protocols for the treatment of COVID-19 patients. Hence, the use of corticosteroids in the emergency pathologies will be reviewed in this chapter.

**Keywords:** corticosteroids, COPD, asthma, Addisonian crisis, anaphylaxis, sepsis, COVID-19

#### **1. Introduction**

From their first discovery, in the fifties of the last century, as anti-inflammatory drugs for the treatment of rheumatoid arthritis, corticosteroids have found a significant place and wide application in various fields of medicine. Natural adrenocortical hormones are steroid molecules that are released from the cortex of the adrenal gland and have numerous physiological functions. These include: (1) glucocorticoids (cortisol), (2) mineralcorticoids (aldosterone), and (3) androgens (dehydroepi-androsterone). Today, numerous synthetic derivatives of natural corticosteroids have been developed, with some enhanced or oppositely reduced pharmacological properties. Glucocorticoids show significant metabolic, anti-inflammatory, immunosuppressive, and vasoconstrictor effects. On the other hand, mineralcorticoids regulate the level of water and salt in the body, help the reabsorption of Na+ from the kidney tubules, and increase the excretion of K+ . Nevertheless, when we consider the practical application of corticosteroids in various pathological conditions, we usually think of glucocorticoids.

The circadian rhythm of glucocorticoids is influenced by the negative feedback loop of the hypothalamus-pituitary-adrenal cortex. These steroid hormones are synthesized from cholesterol. They achieve their physiological and pharmacological effects through the intracellular glucocorticoid receptor [1]. Initially, they diffuse through the cell membrane and bind to a receptor located on a specific protein. Afterward, this entire complex enters the nucleus and causes the expression of certain genes, responsible for the synthesis of specific proteins. This represents a gene-related and time-consuming mechanism of action. There is also another, faster way of producing the effect, where the glucocorticoid binds to the receptor in the cytoplasm, where protein synthesis is not required, and the effect is achieved after a few minutes of binding to the receptor.

The physiological and pharmacological effects of glucocorticoids are diverse. The most significant ones are related to anti-inflammatory, anti-allergic, and immunosuppressive effects. Consequently, they affect the hematopoietic system, increasing the number of neutrophils while simultaneously decreasing the number of lymphocytes, monocytes, eosinophils, and basophils. They antagonize the effect of vitamin D on the absorption of calcium from the digestive tract. To continue, they stimulate the secretion of hydrochloric acid. These drugs have complex metabolic effects as well, thus stimulating gluconeogenesis, increasing the uptake of amino acids in the liver and kidneys, and enhancing the lipolysis. They also cause catabolic effects in lymphoid and connective tissue and muscles, as well.

Due to the wide range of described effects, a large number of different pathological conditions can be identified where these drugs may be used, including various methods of administration (oral, intravenous, and inhalation). Given that natural adrenocortical hormones are usually synthesized under the influence of stress, in cases where the hypothalamus was stimulated, this endocrine structure releases corticotropin-releasing factor (CRF). Consequently, the pituitary gland releases corticotropin (ACTH) and leads to the release of cortisol, which finally starts a cascade of metabolic processes to overcome the stress. It is expected that in the emergency situations with vitally endangered patients, whose body is under the stress due to the respiratory insufficiency or impaired hemodynamics, the corticosteroids will certainly have an important place in the treatment.

These drugs are used in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD) and asthma, in anaphylactic reactions, in spinal shock, and in Addison's disease and related crisis. According to the guidelines for the treatment of sepsis and septic shock from 2017, as well as the revised recommendations from 2021, the corticosteroids are included in the treatment of this serious and urgent condition [2]. During the COVID-19 pandemic, corticosteroids have found their place in certain stages of treatment and were accordingly included in many national protocols for the treatment of COVID-19-positive patients.

In the further segments of this chapter, the most important indications for using glucocorticoids in the emergency pathologies will be addressed.

#### **2. Acute exacerbations of chronic obstructive lung disease**

Chronic obstructive pulmonary disease (COPD) is characterized by limited (reduced) airflow in the airways. The obstruction is progressive and related to the inflammatory process caused by harmful particles and gases from the external environment. Smokers and mostly people over 40 years of age were linked to the COPD.

#### *Corticosteroids in Emergency Pathologies DOI: http://dx.doi.org/10.5772/intechopen.112317*

It is the third most common cause of death in the world and the seventh cause of reduced overall health ability [3]. According to data from the World Health Organization (WHO) from 2011, only in the USA, there were about 13 million adults being treated from the COPD [4]. The main symptoms of COPD include choking, coughing, and expectoration of the purulent contents. Acute exacerbation of the disease obligatory implies the need for the additional therapy and in some cases hospitalization, and it clearly affects the progression of the disease and mortality. Exacerbations of COPD are most often associated with infection, inhalation of air pollution, and the influence of other chronic diseases that the patient is suffering from. Given the heterogeneity of the disease exacerbation causes, the basic form of COPD treatment is related to the causal therapy against the causative agent, modulation of the overall body's response, and the maintenance of the patient's respiratory and hemodynamic status.

Corticosteroids are present in all protocols for the treatment of acute COPD, but determining the most effective dose and duration of therapy is still a subject of research. They are used as intravenous, oral, and inhalation therapy. They improve ventilation and gas exchange, as shown by pulmonary function tests; also reduce dyspnea; and, finally, speed up the recovery and duration of hospital treatment.

Systemic corticosteroids have been the standard therapy in COPD exacerbations for many years. Of course, long-term use of glucocorticoids is an independent risk factor for increased mortality in patients with COPD. This is mainly due to a number of possible side effects and the impact of therapy on associated diseases. The *Reduce* study showed that the therapy with 40 mg of prednisone intravenously for 5 days was as effective as 14-day therapy in terms of repeated exacerbations [5]. The latest guidelines of the European Respiratory and American Chest Association favor a shorter treatment period (less than 14 days) and emphasize the use of oral preparations over the systemic ones. Even for patients who are hospitalized for the treatment of exacerbations, a short-term oral therapy is recommended [6]. Several studies have shown better efficacy of short-term therapy, as well as favorable pharmacokinetics of this type of treatment, which enables adequate drug bioavailability. In addition to systemic and oral therapy, inhalation therapy with corticosteroids, in combination with long-acting bronchodilators, was shown to be effective, too [7].

Today, clinicians are turning to the latest guidelines from the *GOLD* study, which represents the Global Strategy for the Diagnosis, Treatment, and Prevention of COPD, revised in 2019 [8]. The *GOLD* study emphasizes an individual approach, based on the severity of symptoms, risk of exacerbation, comorbidities, adverse effects, response to therapy, and availability of medication. This is precisely why the number of eosinophils is determined for each patient, because the anti-inflammatory effect of corticosteroids depends on how much inflammation plays a role in the pathogenesis of the disease. Recent studies have shown that the number of eosinophils is a direct predictor of the effectiveness of corticosteroids in preventing future exacerbations. Therefore, an individual pharmacological treatment plan must be applied for each patient, both for the disease and for an emergency, such as an exacerbation, still based on comorbidities, severity of symptoms, risk of side effects, hemodynamic, and respiratory status.

#### **3. Acute asthma exacerbations**

Asthma is a chronic inflammation of the airways that causes their hypersensitivity to various factors from the external environment. In fact, they provoke a narrowing of the airways, which in turn causes discomfort in the form of a feeling of shortness

of breath, coughing, and wheezing in the chest. The disease can occur in young children, and it can also develop in the elderly. There are numerous causes, recognized as external and internal ones. The external ones include air pollution, allergens in the air, pollen, industrialization, internal genetic predisposition, a diet with use of additives, maternal smoking during pregnancy, and so on. All these factors lead to airway inflammation, further increased mucus production, airway wall remodeling, and bronchial hypersensitivity. Given that inflammation has a key role in the pathogenesis of the disease, the main goal in the treatment of asthma is to control the symptoms and signs of inflammation in order to avoid future exacerbations.

An acute asthma attack is an episode of progressive suffocation, shortness of breath, coughing, and wheezing in the chest. According to some authors, an acute asthma attack is one specific condition that requires the use of systemic corticosteroids [9].

It has been established that corticosteroids reduce inflammation in the airways. They are most commonly used in the form of inhalation preparations in the chronic therapy of asthma as well as systemically when needed in severe exacerbation episodes. The recommendation in all guidelines for the treatment of acute asthma attack is to repeat the inhaled dose of a drug and if there is no improvement, to introduce systemic therapy. As with COPD, the preference is given to oral preparations, 50 mg of prednisolone for 5–7 days [10]. As previously confirmed, a short-term treatment is considered to be more effective [11]. It is recommended to introduce the oral preparation in the first hour of the attack. Oral preparations are recommended in exacerbations, as well as maintenance therapy in patients with a severe form of the disease, which accounts for about 10% of patients. Of course, the use of oral and systemic corticosteroids can be associated with a number of side effects. This is why the recommendations direct us to use systemic corticosteroids only for 5–7 days during acute exacerbation. In a large cohort study, Vorham et al. [12] showed that the use of oral corticosteroids in Great Britain is far higher than recommended, in terms of doses (more than 7.5 mg/dL) and duration of administration, wherein the excessive administration was explained by the low price of these drugs.

A special form of exacerbation of the disease is the status asthmaticus, a vitally threatening condition with hypoxia, hypercapnia, and a high risk of developing acute respiratory insufficiency. The recommendation for the treatment of this condition is, in addition to oxygen support, bronchodilators and 125 mg methylprednisolone intravenously [13].

Finally, it has to be underlined that in addition to unwanted effects of corticosteroids, there is also a problem of effectiveness in some patients, in the sense that not all patients have a good therapeutic response, which means that an individual approach is needed. Therefore, the balance between the efficacy and safety of therapy must be established for each and every patient.

#### **4. Anaphylaxis**

Anaphylaxis is a severe allergic reaction, which has a rapid onset and development of symptoms and can cause an anaphylactic shock with a possible fatal outcome. Allergic reactions can be induced by medicines, food ingredients, insect bites, and so on. Visual changes rapidly occur at the point of an allergen entry, followed by itching, urticaria of the skin, angioedema, bronchospasm, rhinorrhea, gastrointestinal disorders, a drop in arterial tension, and, if not responded to in time, an overall shock. The first step in treatment would be to administer epinephrine.

#### *Corticosteroids in Emergency Pathologies DOI: http://dx.doi.org/10.5772/intechopen.112317*

Glucocorticoids are often given in anaphylaxis, but there is a little evidence of their effectiveness. Due to the specific mechanism of action, which includes intracellular position of the respective receptors, their effect may take several hours to be fully developed. So, these drugs would not be able to act on the initial signs and symptoms of anaphylaxis. However, one of the reasons for their widespread use in this disorder is to prevent the second (so-called protracted) phase of an anaphylactic reaction, which sometimes may exist or occur even after several hours. Nonetheless, in the recent literature, there are several studies that did not confirm the previous notion. Hence, the use of glucocorticoids can be possibly justified in patients who are hospitalized for anaphylaxis, in order to further prevent bronchospasm, or who are already being treated from COPD and asthma.

In 2021, the Resuscitation Council of Great Britain published the new guidelines for the care and treatment of anaphylaxis that support the complete exclusion of the use of glucocorticoids. There was reportedly little evidence to support that glucocorticoids prevent the delayed response. In some studies, it has even been shown that the use of these drugs was associated with greater mobility, or increased hospitalization, in the case of prehospital administration. The explanations suggested that perhaps the administration of glucocorticoids actually delayed the administration of epinephrine, which should be the first drug of choice in this case [14, 15].

#### **5. Spinal shock**

Spinal shock, occurring after spinal cord injury, is a special pathological condition characterized by the loss of all neurological activity below the level of injury. These would include the loss of motor, sensory, reflex, and autonomic functions. It starts 30–60 minutes after the spinal cord injury and can last up to 6 weeks after the injury. It can lead to permanent disability.

Until recently, methylprednisolone was widely used in the early stages of treatment after the spinal cord injury, namely, in the first 8 hours. In recent years, more and more studies have shown that there is no difference between patients that received methylprednisolone and the placebo group, especially in terms of the motor response. The side effects are unfortunately numerous [16]. In animal models, the follow-up studies provided specific evidence at the molecular level, as well. Thus, Nelson et al. [17] showed in their research using a fish model that glucocorticoids inhibited neuron regeneration by directly acting on ependymal glial cells, independently of microglia.

Considering the severity of the clinical presentation that exists in a spinal cord injury, as well as a series of side effects related to corticosteroids, more studies are needed to examine the exact relationship between the risks and benefits of using these drugs in this specific condition.

#### **6. Addisonian crisis**

Addison's disease is a rare chronic condition that occurs when the adrenal glands are unable to provide sufficient amounts of hormones (glucocorticoids, mineralocorticoids, and androgens). Consequently, therapeutic hormone replacement is necessary. Addison's disease is also called primary adrenal insufficiency. Given that quoted hormones participate in the metabolism of water and electrolytes, and are also important for producing energy, this is a clinically difficult condition that can initially occur its most serious

form—adrenal crisis. The patient is vitally endangered with a severe clinical picture of arterial hypotension, dehydration, abdominal pain, nausea, and vomiting. Addisonian crisisis not such a common condition, but it is linked with a high mortality rate, as much as 45% [18]. The most common causes of adrenal gland insufficiency are autoimmune disease, then tumor infiltrations, and infarctions or hemorrhages within the glands, and so on. When the disease develops gradually, it is very difficult to establish the correct diagnosis, because the symptoms and signs are general and nonspecific, including malaise, weakness, muscle pain, loss of body mass, or hyperpigmentation on the skin.

Primary adrenal insufficiency occurs as a result of disturbed function of the adrenal gland itself, primarily in an autoimmune disease, severe infection, or cessation of the cortisol production in newborns due to congenital adrenal hyperplasia. Secondary adrenal insufficiency occurs due to dysfunction of the hypothalamus-pituitary-adrenal axis. Inadequate stimulation of the adrenal cortex occurs due to lack of adrenocorticotropic Hormone (ACTH). This condition frequently occurs associated with tumors of the pituitary gland, surgical interventions in that anatomical region, as well as after its radiation [19]. It is very important for clinicians to clarify whether a primary or a secondary adrenal insufficiency is present, because in the primary adrenal insufficiency, all the hormones produced by the adrenal cortex are absent while in the secondary insufficiency, only the hormones secreted under control of ACTH (cortisol and sex hormones). Substitution of aldosterone, which is controlled by the renin-angitensin system, is not required.

Addisonian crisis can also occur in people with adrenal insufficiency being on substitution therapy with glucocorticoids but experiencing specific circumstances, such as trauma, infection, increased effort, pregnancy, surgical interventions, and so on. It has to be underlined that the Addisonian crisis is an urgent endocrinological condition, where the prompt diagnosis and initiation of therapy is of crucial importance, since if the adequate therapy would not be started on time, a fatal outcome can occur.

Initial treatment in Addisonian crisis involves intravascular volume replacement with the crystalloid isotonic solutions and the correction of hypoglycemia by using 5% glucose solution. A correction of hormonal status by using glucocorticoids and mineralcorticoids is required, as well. Thus, in an adrenal crisis, it is necessary to immediately prescribe 100 mg intravenous hydrocortisone and then to continue with 50–100 mg intravenously every 6 hours during 1 day. In children, the recommended dose is 50 mg/m<sup>2</sup> , with maximum of 100 mg. Given that quoted doses of glucocorticoids have minimal mineralocorticoid effects, it is not necessary additionally to prescribe fludrocortisone (a mineralcorticoid) at this time.

There are still challenges existing in treating Addisonian crisis. First of all, there are no adequate biomarkers that would show us the exact levels of cortisol in the tissues. It is encouraging that there are some studies that may provide us with a certain precision in determination of cortisol in hair, saliva, and subcutaneous fat tissue [20]. It is very difficult to prescribe quite precise individual effective dose, because the levels of glucocorticoids in the blood are under different influences, and of course, there is also an existing receptor polymorphism, which needs to be considered. It is also challenging to establish how much it is necessary to increase the initial doses of glucocorticoids during the treatment that are given as a substitution in a different setting of stress reactions. Although there are studies that could investigate this problem in clear situations of infections, surgical interventions, and trauma, it is quite another thing to determine how much glucocorticoids we need during an emotional stress. Therefore, more studies are needed to help us in determining a precise individual therapeutic regimen for Addisonian crisis.

#### **7. Sepsis**

Sepsis is a life-threatening condition accompanied with organic dysfunction, which is caused by an inadequate response of the body to an infection. Considering the high incidence and mortality, as well as long-term treatment in intensive care units associated with high costs, the sepsis has become a global problem in the recent decades. For these reasons, the scientific community has been working for a long time to develop common guidelines for the prevention, rapid detection, and treatment of sepsis through the Surviving Sepsis Campaign guide. The last recommendations were revised in 2021. The guidelines help in faster recognition of sepsis, earlier initiation of antibiotic therapy, and maintenance of the patient's hemodynamic status, respiratory support, and additional therapy.

Patients with sepsis have an increased heart and respiratory rate, decreased systolic pressure, disturbed consciousness, and elevated body temperature. Septic shock can occur very quickly, represented by circulatory, cellular, and metabolic instability, and it arise with a mean arterial pressure (MAP) of less than 65 mmHg and a lactate level of more than 2 mmol/L [21]. For that reason, it is of crucial importance regarding the sepsis therapy to establish hemodynamic stability and a tissue perfusion as soon as possible. There are clear guidelines for the amount and type of infusion solutions, as well as for prescribing vasopressors. The recommendations for the treatment of sepsis from 2016 advised the use of hydrocortisone intravenously only in patients who cannot reach hemodynamic stability despite fluid replacement therapy and the inclusion of the recommended vasopressor drugs.

The latest recommendations from 2021 state that intravenous hydrocortisone should be included for all patients being in septic shock and required vasopressor support. Hence, hydrocortisone is to be prescribed in a dose of 200 mg intravenously daily, 50 mg every 6 hours, or in a continuous infusion. Since the previous guidelines were instituted, three large studies have been published on the use of corticosteroids in the treatment of sepsis [22, 23]. Rigard et al. [24] also showed in their meta-analysis that systemic corticosteroids accelerated recovery from shock and shortened the time of vasopressor use. However, in this analysis, it was established that corticosteroids increase neuromuscular weakness, and there is still no clear connection between their use and the impact on mortality, too. So, taking all together previous facts into account, in an attempt to balance the pros and cons, these drugs are still to be included in the recommendations for the treatment of sepsis.

Given that the pathogenesis of sepsis is based on an inadequate immune response, it is logical that clinicians have long been trying to include corticosteroids as drugs with anti-inflammatory effects in the regular therapy. Liang et al. [25] showed in their meta-analysis that corticosteroids had no effect on mortality after 28 days or on long-term mortality, but they did detect some reduction in in-hospital mortality. They also showed that corticosteroids prolong time the patient is without vasopressor and ventilatory support as well as increase the incidence of side effects, such as hyperglycemia and hypernatremia. Moreover, the use of corticosteroids was associated with a shorter duration of hospitalization in the covered randomized studies. Nevertheless, the proper timing of systemic corticosteroids use in sepsis is still under investigation. This all lead us to the conclusion that more studies are needed to help clarifying the individual steps in the pathophysiological process of sepsis so that clinicians could decide on the type of therapy and the precise timing for each individual drug.

#### **8. COVID-19**

At the end of 2019, a number of patients with pneumonia of unknown etiology appeared in the Chinese city of Wuhan. It was quickly established that the causative agent of coronavirus disease (COVID-19) is a virus from the Coronaviridae family, which was named Novel Coronavirus, that is, SARS-Cov-2 (Severe Acute Respiratory Coronavirus). The disease has been proved to be extremely contagious; it quickly took the form of an epidemic, so afterward, on March 11, 2020, the World Health Organization (WHO) announced the beginning of a pandemic. Quick diagnosis was difficult due to the non-specificity of symptoms and laboratory findings. The therapy included antiviral drugs, anticoagulants, corticosteroids, biological and multivitamin therapy, as well as oxygen support.

At the beginning of the pandemic, the use of corticosteroids in the treatment of COVID-19 had a controversial character. Given that it was discovered early that the disease leads to impairment in regulation of the immune response and excessive production of cytokines, it was logical that drugs with an anti-inflammatory and immunosuppressive effects would have a therapeutic effect. It has been later shown that corticosteroids were useful in patients who were on oxygen support, especially those on mechanical ventilation, and these drugs should be avoided in those with a milder form of the disease or with specific comorbidities, due to a series of possible drug-induced unwanted effects [26].

Many randomized studies have shown that corticosteroids reduced mortality in COVID-19 [27]. This led the WHO to include corticosteroids in the guidelines for the treatment of patients with a severe form of the disease [28]. Accordingly, corticosteroids have also been shown to reduce mortality and the duration of mechanical ventilation in affected patients [29].

The large randomized study RECOVERY [30] investigated the effectiveness of dexamethasone administration in patients with COVID-19. The results showed that mortality in those who received dexamethasone was significantly lower compared to the group that received the other proposed therapy, especially in patients who were on mechanical ventilation or had an oxygen support. The mortality in those who did not require oxygen support did not differ from patients who were without corticosteroids. Also, the study showed that in those who did not take corticosteroids and were on oxygen support, deterioration in terms of the need for mechanical ventilation occurred more often.

The WHO provided a prospective meta-analysis of existing research on the treatment of COVID-19, the so-called REACT study [31]. The analysis showed that mortality was lower in the groups of patients who received corticosteroids. Mortality did not differ between the dexamethasone and the hydrocortisone groups. There was no difference to in terms of the amount of dose, as well. This meta-analysis showed that the success of therapy depended on the severity of the clinical presentation. Namely, the efficacy of the corticosteroids use was more pronounced in the group that presented severe clinical features with the need for oxygen support or mechanical ventilation. This meta-analysis also showed the effect of corticosteroids on prolonging the elimination of the virus through the mucous membranes of the nasopharynx and oropharynx. This resulted in prolonging the time of the positive result of the PCR test and was explained by the suppression of the immune response. Based on the previous facts, the WHO made adjusted recommendations for the treatment of COVID-19 infection and included corticosteroids in standard therapy. The European Respiratory Society gave a strong recommendation for the systemic use of corticosteroids, as well [32].

#### **Acknowledgements**

This research was funded by the Ministry of Science and Technological Development of the Republic of Serbia; Grant No. 200110.

### **Author details**

Miroslav Radenković1 \* and Ivana Milićević2

1 Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia

2 Department of Emergency Medicine, Emergency Center Belgrade, University Clinical Center of Serbia, Belgrade, Serbia

\*Address all correspondence to: miroslav.radenkovic@med.bg.ac.rs

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 2**

## Usage of Corticosteroids in Musculoskletal Disorders

*Mohammad Ahmadi-Dastgerdi, Nafiseh Bavaghar and Aniseh Bavaghar*

#### **Abstract**

Corticosteroids are one of the most important anti-inflammatory substances that are used for many conditions. Although oral form of corticosteroids has many side effects, they are used to cure systemic diseases. Local injection of corticosteroids can be beneficial in many conditions such as mononeuropathies, degenerative joint diseases (DJD), tenosynovitis, and canal stenosis with fewer side effects and better efficacy in site of pathology.

**Keywords:** corticosteroid, ultrasonography, mononeuropathy, tendinitis, osteoarthritis

#### **1. Introduction**

We normally know corticosteroids as steroids that are one of the most important anti-inflammatory medications that are used to manage a broad variety of diseases.

This substance normally secrets by adrenal glands in response to different modules of stress and plays a very important role in humans daily life.

Different forms of this medicine such as prednisone, methylprednisolone, triamcinolone, hydrocortisone, and cortisone are used to manage a broad variety of musculoskeletal diseases. For example, the oral form of corticosteroids is used to cure systemic diseases like rheumatoid arthritis (RA) [1]. In chronic use of oral corticosteroids, the side effects are common and serious from time to time, like high blood pressure, edema as a reason of fluid retention, mood changes, weight gain, and facial features changes (moon face), ophthalmic problems like glaucoma and cataract, and high blood sugar that can exacerbate the existing diabetes and also cause overt diabetes and insulin-resistant patients, increased incidence of opportunistic fungal infections like *Candida albicans* and mucormycosis and serious infections like tuberculosis and also common bacterial, viral, and fungal infections and sometimes causes some skin conditions like frequent bruising and delayed wound healing [2].

Most of the patients who suffer from joint degenerative diseases like osteoarthritis (OA) and complain from severe pain and decreased quality of life are middle-aged and old people, and the side effects of corticosteroids intake are severally dangerous for them.

One of the very important side effects of prolonged oral corticosteroid intake is osteoporosis that limits the use of the medicine for old people. On account of this, patients already experience some diminished bone tissue mineralization due to

various reasons like malnutrition and systemic diseases. In these patients that include a large number of musculoskeletal patients to allocate pain and inflammatory joint conditions, the local injection of corticosteroids can be beneficial [1, 2].

In this treatment, there are no such side effects as the systemic use, and on the other hand the medicine can act on the problematic area, like injecting the injectable form of triamcinolone in the joint space. Usually to eliminate patient's pain in this treatment, corticosteroid is mixed with local anesthetic agents like lidocaine and is injected directly in the joint space either landmark-guided or sonographicguided [3–12].

Although this injection is way easier in large- and medium-sized joints for the operator to perform, it can also be used in smaller joints like metacarpophalangeal (MCP) and shows significant improvements in discomfort and swelling.

In this chapter, the types of intra-articular injections and their clinical application are discussed.

#### **2. Corticosteroids application in musculoskeletal diseases**

#### **2.1 Corticosteroids application in carpal tunnel syndrome**

The carpal tunnel syndrome (CTS) is referred to a condition in which the median nerve (that enters from forearm to the wrist) is stuck in the carpal tunnel. This nerve is responsible for innervation parts of thenar muscles and provide sensation for 3½ of the lateral fingers of the hand. After the nerve trap and pressure upon it, patient experiences symptoms like numbness in 3½ of the lateral fingers and in severe cases feeling of weakness and sometimes hand muscles atrophy; for example, the thenar prominence atrophy is initiated.

This condition is found in 5% of the population mostly in middle-aged women (F to M ratio: 3 to 1) and is related to age, weight, hypothyroidism, diabetes, repetitive wrist flexion, and pregnancy. This condition is divided to three different forms based on clinical presentation, electromyography, and nerve conduction velocity (EMG-NCV) and sonographic findings to mid, moderate, or severe [3, 4].

In mild and moderate form, the application of injectable corticosteroid can be used to decrease pain and adhesion on the nerve and tendon sheath around the nerve. This results in pressure sensation on the nerve and mends the patient's signs and symptoms. In severe form, the noninvasive treatment is used first and if it was not successful or thenar atrophy (the medial prominence of the palm) is present, the invasive treatment is recommended which is surgery to cut the transverse ligament on the nerve and suture it on a higher distance [3, 4].

#### **2.2 Joint arthritis**

Osteoarthritis is a degenerative joint problem that occurs with aging, wrong lifestyle, persistent and unsuitable use of joints, obesity, sports, and traumatic injury.

In this condition, the joint cartilage which has no nerve innervation and plays a very important role in easing movement and prohibiting the head of the bones from erosion is damaged and absorbed. After the initiation of arthritis process, patient experiences a progressive pain which gets worse by time and highly affects patient's quality of life [13]. Recently, joint replacement which is aggressive but very effective method to manage arthritis is widely used for big joints like hip and knee. In this

#### *Usage of Corticosteroids in Musculoskletal Disorders DOI: http://dx.doi.org/10.5772/intechopen.110056*

method, the joint and the heads of bones are cut and replaced with an artificial metal joint that can eliminate the pain and stiffness and other symptoms of arthritis.

This surgery like other surgical methods requires post-op care and use of other medications to avoid infection and clot accumulation due to motionlessness [14].

After the operation, strengthening of involved muscles in joint movement by routine workouts is highly recommended.

In mild and moderate and some major forms that patients cannot undergo surgery (like patients with decompensated heart failure, pulmonary edema, and other underlying conditions), arthritis in a joint that there is no proper way to replace it yet or when patient does not accept surgery, intra-articular injections can be beneficial. Various medicines can serve this purpose like hyaluronic acid gel (to improve joint surfaces to slide on each other and reduce erosion on bone ends), Botox, and plateletrich plasma (PRP).

One of the very common medications which can work alone or mixed with hyaluronic acid is corticosteroid.

Corticosteroid is very helpful in mending arthritis symptoms, and patient is pain-free for about 2–3 months.

Compared to corticosteroids, hyaluronic acid takes longer to effect but reduces the pain for about 6 months, while PRP does it for 12 months [13]. In this time, patient can strength the muscles around the joint and have normal daily activities pain-free. Side effects of this kind of injections are septic arthritis (due to bacterial infiltration from skin while performing the injection) and bleeding (in coagulopathic patients) which can be prevented with a good medical history taking before starting the procedure and proper disinfection of the injection area.

In severe and progressive cases, the injection needs to repeat every 3–6 months, and because the side effects are few and preventable, intra-articular injections with corticosteroid seem to be harmless and beneficial. This injection with corticosteroid is permitted three times a year [5].

#### **2.3 Tenosynovitis**

Tenosynovitis is referred to a group of condition that causes tendonitis and synovitis. De Quervain is one of this conditions that causes inflammation on tendons of extensor tendon of fingers (abductor pollicis longus and extensor pollicis brevis). Patients experience pain while grabbing on objects, fisting, and rotating the hand. To mend this inflammatory condition, first-line treatment is local corticosteroid injection in problematic tendon sheath. In different studies, it was proved that this injection clearly makes the symptoms better compared to placebo in short term [6].

#### **2.4 Adhesive capsulitis**

In this condition, severe stiffness in shoulder joint with pain and reduced range of motion (ROM) is present. There are three phases to this condition: first, the pain is dominant and local intra-articular corticosteroid injection can be beneficial. Then in the second phase, the pain decreases and ROM is reduced. In this step, greater volume of local intra-articular volume injection (attenuated corticosteroid with normal salin) can be useful. In third phase, there is a significant improvement in ROM. This condition is referred to as self-limited, and with physiotherapy and over the counter (OTC) analgesics the symptoms are improved to some extent.

Sometimes, patients complain from severe continuous pain; in this case, the intraarticular and sub-acromial corticosteroid injections are useful. If symptoms do not improve over the use of injectable corticosteroid, surgical methods are indicated to cut the fibrous bundles [7, 8].

#### **2.5 Medial and lateral epicondylitis**

In lateral epicondylitis (tennis elbow), the origin of wrist extensor muscles in elbow area is inflamed due to continuous use. Most of the patients recover after time pass and physiotherapy, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiinflammatory medication, and resting the muscles of the area.

In case of severe pain and limited daily activities, local injections, especially steroids, are a potent and valid anti-inflammatory agent that can help, although relapse happens in 50% of the cases after injection [9].

Medial epicondylitis (Golf elbow) is persistent pain in medial epicondyle. In this condition, like the lateral epicodylitis, the use of corticosteroid injection can help, but relapsing is common and the use of dextrose prolotherapy and PRP can benefit the patient for a longer period [10].

#### **2.6 Trigger finger**

In this condition, finger Pulley A1 that reasons smooth tendon movements in flexor digitorum superficialis and profound muscles is inflamed and holds the finger back while moving. Treatment can either involve surgery to cut pulley or local corticosteroid injection. Corticosteroid injection shows a significant improvement in patient's symptoms, so it is recommended in most of the patients suffering this condition [11].

#### **2.7 Greater trochanter bursitis**

One of the very important differential diagnoses in lateral hip discomforts is inflammation of the burse on the greater trochanter. To cure it NSAIDs, physiotherapy and corticosteroid injection is recommended, the later can benefit the patient faster and better [12].

#### **2.8 Facet joints injection**

Facet joints are on both sides of each vertebrae and connect each thoracic, cervical, and lumbar vertebrae to its upper and lower. Arthritis or inflammation in this joint causes pain in spine. Corticosteroid accompanied by anesthetic agents' injection in this joint is an easy procedure which is usually done by sonography or fluoroscopy guidance. The injection itself means no harm, and patient experiences the least convalescence period [15, 16].

Corticosteroid onset of effect in this type of injection is commonly 3–7 days and remains for couple of months. This treatment becomes so popular lately, since it is both noninvasive and effective in reducing pain and symptoms. This injection is advantageous on the other hand. If patient feels a significant improvement, the other techniques that have constant effects are recommended such as facet neurolysis injection and rhizolysis [15, 16].

#### **2.9 Epidural injection to treat disk herniation and canal constriction**

In cases like herniated disk, slipped vertebrae, listhesis, joint synovial cyst, spinal ligaments thickening due to spinal arthritis, epidural corticosteroid injection is useful.

In this method, the medication is injected by interlaminar on the fatty layer on the spine or transforaminal or caudal (with a greater volume). This method is very popular between clinicians and patients and provides a good improvement in patents' pain. Side effects include steroid flush as profuse heat sensation for couple of days, sleep disorders, anxiety, edema, and rarely an increase in pain for the few first days. From time to time, patient experiences a provisional paralysis in lower organs after the injection which goes away after the lidocaine or other anesthetic agents effects wear off. To increase the effect of injection, rehabilitation after performing the injection is very important [17]. Two days after the injection, patient needs complete rest, and 2 weeks later relative rest is recommended. After corticosteroid injection to prevent the joints pain, cryotherapy is indicated.

#### **3. Conclusions**

Corticosteroids are used in a wide range of disorders, and local injection is curative in mononeuropathies and inflammatory conditions such as de Quervain tenosynovitis and has temporary pain relief in DJDs and spinal canal stenosis.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Appendices and nomenclature**



### **Author details**

Mohammad Ahmadi-Dastgerdi1 \*, Nafiseh Bavaghar2 and Aniseh Bavaghar3

1 Shahid Beheshti University of Medical Science, Tehran, Iran

2 Iran University of Medical Science, Tehran, Iran

3 Tehran University of Medical Science, Tehran, Iran

\*Address all correspondence to: mo.ahmadi1370@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Usage of Corticosteroids in Musculoskletal Disorders DOI: http://dx.doi.org/10.5772/intechopen.110056*

#### **References**

[1] Yu KH, Chen HH, Cheng TT, Jan YJ, Weng MY, Lin YJ, et al. Consensus recommendations on managing the selected comorbidities including cardiovascular disease, osteoporosis, and interstitial lung disease in rheumatoid arthritis. Medicine (Baltimore). 2022;**101**(1):e28501. DOI: 10.1097/ MD.0000000000028501

[2] Rice JB, White AG, Scarpati LM, Wan G, Nelson WW. Long-term systemic corticosteroid exposure: A systematic literature review. Clinical Therapeutics. 2017;**39**(11):2216-2229. DOI: 10.1016/j. clinthera.2017.09.011

[3] Rayegani SM, Raeissadat SA, Ahmadi-Dastgerdi M, Bavaghar N, Rahimi-Dehgolan S. Comparing the efficacy of local triamcinolone injection in carpal tunnel syndrome using three different approaches with or without ultrasound guidance. Journal of Pain Research. 2019;**12**:2951-2958. DOI: 10.2147/JPR.S212948

[4] Salman Roghani R, Holisaz MT, Tarkashvand M. et al., Different doses of steroid injection in elderly patients with carpal tunnel syndrome: A triple-blind, randomized, controlled trial. Clinical Intervention Aging. 2018;**13**:117-124. DOI: 10.2147/CIA.S151290

[5] Phillips M, Bhandari M, Grant J, Bedi A, Trojian T, Johnson A, et al. A systematic review of current clinical practice guidelines on intra-articular hyaluronic acid, corticosteroid, and platelet-rich plasma injection for knee osteoarthritis: An international perspective. Orthopaedic Journal of Sports Medicine. 2021;**9**(8):2325. DOI: 10.1177/23259671211030272

[6] Keidan T, Saleh S, Svorai Band S, Gannot G, Oron A. Clinical presentation and treatment. Harefuah. 2022;**161**(11):706-708

[7] Brun SP. Idiopathic frozen shoulder. Australia Journal of Genetic Practice. 2019;**48**(11):757-761. DOI: 10.31128/ AJGP-07-19-4992

[8] Koh KH. Corticosteroid injection for adhesive capsulitis in primary care: A systematic review of randomised clinical trials. Singapore Medical Journal. 2016;**57**(12):646-657. DOI: 10.11622/ smedj.2016146

[9] Bayat M, Raeissadat SA, Mortazavian Babaki M, Rahimi-Dehgolan S. Is dextrose prolotherapy superior to corticosteroid injection In patients with chronic lateral epicondylitis?: A randomized clinical trial. Orthopedic Research and Reviews. 2019;**11**:167-175. DOI: 10.2147/ORR.S218698

[10] Foster ZJ, Voss TT, Hatch J, Frimodig A. Corticosteroid injections for common musculoskeletal conditions. American Family Physician. 2015;**92**(8):694-699

[11] Seigerman D, McEntee RM, Matzon J, Lutsky K, Fletcher D, Rivlin M, et al. Time to improvement after corticosteroid injection for trigger finger. Cureus. 2021;**13**(8):e16856. DOI: 10.7759/ cureus.16856

[12] Pianka MA, Serino J, DeFroda SF, Bodendorfer BM. Greater trochanteric pain syndrome: Evaluation and management of a wide spectrum of pathology. SAGE Open Medicine. 2021;**9**:2050. DOI: 10.1177/2050312 1211022582

[13] Raeissadat SA, Ghazi Hosseini P, Bahrami MH, Salman Roghani R, Fathi M, Gharooee Ahangar A, et al. The comparison effects of intra-articular injection of platelet rich plasma (PRP), plasma rich in growth factor (PRGF), hyaluronic acid (HA), and ozone in knee osteoarthritis; a one year randomized clinical trial. BMC Musculoskeletal Disorders. 2021;**22**(1):134. DOI: 10.1186/ s12891-021-04017-x

[14] Vaienti E, Scita G, Ceccarelli F, Pogliacomi F. Understanding the human knee and its relationship to total knee replacement. Acta Bio-Medica. 2017;**88**(2S):6-16. DOI: 10.23750/abm. v88i2-S.6507

[15] Wu T, Zhao WH, Dong Y, Song HX, Li JH. Effectiveness of ultrasoundguided versus fluoroscopy or computed tomography scanning guidance in lumbar facet joint injections in adults with facet joint syndrome: A metaanalysis of controlled trials. Archives of Physical Medicine and Rehabilitation. 2016;**97**(9):1558-1563. DOI: 10.1016/j. apmr.2015.11.013

[16] Bodor M, Murthy N, Uribe Y. Ultrasound-guided cervical facet joint injections. The Spine Journal. 2022;**22**(6):983-992. DOI: 10.1016/j. spinee.2022.01.011

[17] Manchikanti L, Candido KD, Kaye AD, Boswell MV, Benyamin RM, Falco FJ, et al. Randomized trial of epidural injections for spinal stenosis published in the New England Journal of Medicine: Further confusion without clarification. Pain Physician. 2014;**17**(4):E475-E488

#### **Chapter 3**

## Inhaled Corticosteroids: Benefits and Risks

*Hanaa Shafiek*

#### **Abstract**

Airway diseases, mainly asthma and chronic obstructive pulmonary diseases (COPD), are frequently treated with inhaled corticosteroids (ICS). ICS are considered as the cornerstone of asthma management, however, in COPD the picture is different and ICS are indicated in special circumstances. The benefits of ICS are well documented in controlling disease symptomatology. But, still there are side effects of using ICS, especially the risk of pneumonia and bacterial colonization of the airways. In this chapter, I will explore the change in the use of ICS in asthma and COPD, the indications of ICS, the benefits of ICS and its drawbacks, and how we could modify our practice in order to avoid the side effects of ICS.

**Keywords:** airway inflammation, asthma, chronic obstructive pulmonary disease, inhaled corticosteroids types, complications

#### **1. Introduction**

Systemic Corticosteroids (SC) are synthetic analogs of the naturally occurring steroid hormones produced by the cortex of the adrenal gland that is administrated by oral or injectable routes. The SC hormones have glucocorticoid and mineralocorticoid properties with varying degrees. The most important is the glucocorticoids which are predominantly involved in metabolism and have immunosuppressive, anti-inflammatory, and vasoconstrictive effects. SC is widely prescribed in medicine including respiratory medicine as in airway diseases, sarcoidosis, interstitial lung diseases, pulmonary eosinophilic diseases and others [1]. Since the 1950s, SC has been proven to be an effective therapy for persistent asthma [2, 3], however, they have various side effects.

The first pressurized metered-dose inhaler (pMDI) as a bronchodilator for asthma, was introduced in 1956 namely non-selective beta-2-agonists isoprenaline and adrenaline that was associated with rapid relief of asthma symptoms [4]. In the 1960s, there was an epidemic of asthma deaths in Britain thought to be caused by the high use of inhaled bronchodilators [5, 6] and so delayed in seeking medical advice, even if not proved, resulted in suspending the use of inhaled isoprenaline that was replaced later by salbutamol, the selective short-acting beta-2-agonist, and increase the use of SC [4]. By the early 1970s, inhaled beclomethasone dipropionate started to develop as 1st inhaled corticosteroid (ICS) and placebo-controlled studies confirmed the value of ICS therapy in asthma [7–9]. Afterward, ICS became the cornerstone of asthma management and various substitutes and forms were introduced in pulmonary medicine.

#### **2. Mechanisms of ICS**

ICS have glucocorticoids effects that suppress the ongoing inflammatory process through gene transcription mechanisms [10, 11]. Glucocorticoids act by binding to glucocorticoid receptors (GRs) in the cytoplasm resulting in their activation and translocation in the nucleus to produce their anti-inflammatory effects through various molecular effects.

Corticosteroids switch off various activated inflammatory genes that encode cytokines, chemokines, inflammatory enzymes and proteins as the anti-inflammatory proteins secretory leukoprotease inhibitor, and mitogen-activated protein kinase phosphatase-1 (MKP-1) which inhibits MAP kinase pathways [12, 13]. The nuclear GR interacts with coactivator molecules as CREB-binding protein resulting in the activation of proinflammatory transcription factors, nuclear factor-κB (NF-κB) and activator protein-1, in the airways and so reduces histone acetyltransferase activity [10, 14]. Also, activated GR recruits histone deacetylase-2 (HDAC2) to the activated inflammatory gene complex which reverses histone acetylation resulting in the suppression of all nuclear-activated inflammatory genes [15].

Further, ICS increase the gene transcription encoding β2-receptors, resulting in increased expression of β2-receptors on the cell surface of the airways [16, 17] which protect against the β2-receptors tolerance after long-term use. Moreover, ICS may enhance the β2-receptors coupling to G-proteins that promote β2-agonist effects and reverse its uncoupling in response to some inflammatory mediators as interleukin-1β through G-protein coupled receptor kinase stimulation [18]. β2-Agonists also increase the translocation of GR to the nucleus after its activation thus enhancing corticosteroids' anti-inflammatory effects through synchronized interactions [19, 20].

On the other hand, ICS have cellular effects by reducing the numbers of various inflammatory cells mainly eosinophils, mast cell, T-lymphocytes and dendritic cells through either inhibiting the recruitment of these cells in the airways or their survival [21]. Moreover, ICS restore the airway epithelial cell integrity thus inhibiting the transcription of inflammatory genes thus suppressing mucosal inflammation and eosinophilic recruitment into the airways that is associated with airway hyperreactivity [22, 23].

#### **3. Types of ICS**

Nowadays, there are eight different ICS molecules available. These are: beclomethasone dipropionate (BMD) which is the first known ICS, budesonide (BUD), ciclesonide (CC), flunisolide, fluticasone propionate (FP), fluticasone furoate (FF), triamcinolone acetonide (TA) and mometasone furoate (MF). The difference between these molecules is lipophilia with greater GR affinity and longer duration of action; as fluticasone furoate is the most lipophilic (i.e., high potency) and beclomethasone dipropionate the lowest [24].

#### *Inhaled Corticosteroids: Benefits and Risks DOI: http://dx.doi.org/10.5772/intechopen.110753*

The various ICS have also different pulmonary bioavailability (i.e., within the airways) and oral bioavailability (i.e., in the systemic circulation) [25]. Negligible oral bioavailability due to high first-pass metabolism is found for FF, FP, MF and CC and so fewer side effects [24]. Three factors are expected to affect the efficacy of an ICS: the potency (the lower inhaled dose occupied the same number of GRs), the delivered dose (the device efficiency) and airway residency duration. FF, FP, MF and CC have greater residency duration in the airways which allows one daily dose; however, twice daily is considered better [26, 27]. **Figure 1** shows the relationship between ICS dose and its affinity to GR, whereas FF has both the higher GR affinity with the lowest dose compared to triamcinolone acetonide and flunisolide [28].

ICS could be delivered by pressurized metered-dose (pMDI) inhaler, dry-powder (DPI) inhaler and nebulization which are expected to influence the ICS dose. The great difference between the devices is the size of respirable particles emitted that are generally <5 μm [29]. DPI and pMDI (with drugs dissolved in chlorofluorocarbon "CFC") usually emit particles between 3 and 5 μm, however, pMDI with drugs dissolved in hydrofluoroalkane (HFA) emits ultrafine particles of about 1 μm which allow high delivery of ICS in low-mid doses with high lung deposition. **Table 1** compares the low-, mid- and high-doses of ICS of different molecules and devices. Regarding fluticasone, according to the manufacturer's summary of Product Characteristics, FF 100 μg once daily is approximately equivalent to FP 250 μg twice daily [35]. The devices nowadays are many, especially those designed to deliver the DPI either pre-metered or device-metered (**Figure 2**) [36].

In addition, the GINA guidelines has published equivalent doses of different ICS molecules (**Table 2**) [37].


#### **Table 1.**

*Comparison between ICS molecules classified by doses\* [30–34].*

*Classifications of drug powder inhalers (DPI) [36].*


#### **Table 2.**

*Comparison between ICS molecules classified by doses as published in GINA guidelines.*

#### **4. Clinical uses and benefits of ICS**

#### **4.1 Asthma**

ICS are considered as the cornerstone treatment for the management of asthma in all ages. ICS are the first line of therapy for persistent asthma with a starting low-dose that to be increased according to the level of control of the disease including the addition of other types of inhalers such as long-acting- β2-agonist (LABA) and/or longacting muscarinic antagonists (LAMA) in a step-wise approach [37]. In addition, in the latest GINA guidelines [37], low-dose ICS in combination with formoterol (a LABA inhaler) was approved as a reliever instead of short-acting β2-agonist (SABA) as salbutamol that was associated with a decrease risk of severe exacerbations and is called the anti-inflammatory reliever.

Moreover, it is recommended the addition of low-dose ICS in the management of mild asthma. Juniper et al. showed that the use of low-dose ICS in mild asthma was associated with less symptoms and improvement of lung function up to being asymptomatic over several months of therapy [38]. Further, Pauwels et al. reported a reduction in asthma exacerbations among mild asthmatics treated with low-dose ICS [39]. Recent GINA guidelines recommend the use of low-dose ICS or low-dose ICS-formoterol as a reliever for mild asthma to decrease the risk of severe asthma exacerbation based on various studies [40–42]. Medium to high dose ICS are recommended for persistent asthma according to the step-wise approach of GINA guidelines [37]. ICS are also related to improvement in lung function in asthmatic children and adults [43, 44] owing to the switch-off of the chronic inflammatory process by ICS in asthma. Further, many studies showed that regular ICS use provides significant protection and reduces the risk of mortality, severe exacerbation and hospitalization of asthma population [39, 45, 46].

#### **4.2 Chronic obstructive pulmonary disease (COPD)**

The use of ICS is controversial in COPD medications. The response to ICS in COPD patients is less than asthma population [47] which reflects the resistance of airway inflammation to ICS secondary to the reduction of HDAC2 [48, 49]. According to Global Initiative Lung Disease (GOLD) guidelines of COPD [50], ICS are indicated in frequent COPD exacerbator phenotype (i.e., those who had ≥2 exacerbations/year required OCS or ≥ 1 exacerbation need hospitalization) or COPD patients with blood eosinophilia ≥300 cells/μL [51]. Also, the Spanish guidelines of COPD, recommended the use of ICS in asthma-COPD overlap (ACO) who are patients with criteria of asthma and COPD with blood eosinophil counts >300 cells/μL and/or a post-bronchodilator response of >400 mL and 15% in FEV1 [52]. A meta-analysis of important studies in COPD reported that ICS withdrawal did not result in a significant increase in COPD exacerbations risk [53]. Miravitlles et al. proposed an algorithm for the withdrawal of ICS in COPD patients based on FEV1% predicted and exacerbation history [54]. **Figure 3** summarizes this algorithm [54].

#### **5. Risks and complications of ICS**

#### **5.1 Local effects**

ICS are associated with some local side effects, despite being not serious but could be associated with discontinuation of therapy. Hoarseness of the voice or dysphonia is the most common local side effect that occurs in about 50% of ICS users. It is a reversible side effect of drug withdrawal that is attributed to myopathy of laryngeal muscles [55]. Oropharyngeal candidiasis is the second most common side effect, despite being more in the elderly population, a percentage of ICS users complaint of it

#### *Inhaled Corticosteroids: Benefits and Risks DOI: http://dx.doi.org/10.5772/intechopen.110753*

which is related to poor inhalation technique and high doses of ICS. The use of spacers is associated with decreasing these side effects [37, 56].

Importantly, ICS are associated with an increased risk of pneumonia. Patients with COPD, older patients, active smokers, low body mass index <25 kg/m<sup>2</sup> , patients with a history of exacerbations or pneumonia, and/or severe airflow limitation are associated with a higher risk of pneumonia on ICS use [57, 58]. In a meta-analysis, both inhaled fluticasone and budesonide were associated with a significant risk of pneumonia [59] that could be related to the use of a high dose of ICS alone or in-combination with bronchodilator [60]. Further, ICS use was associated with a specific bacterial infection in a subset of the severe COPD population. Shafiek et al. [61] found that ICS dose could be associated with *Pseudomonas aeruginosa* infection in the severe COPD population. This could be explained on the basis of impaired recognition of *P. aeruginosa* and activity of alveolar macrophages secondary to altered expression of Toll-like receptor 2 and various cytokine production in COPD patients receiving ICS [62]. On the other hand, O'Byrne et al. found that budesonide, as an ICS, was not associated with increased risk of pneumonia in asthmatic patients [63]. However, Qian et al. found that ICS use is associated with increased risk of pneumonia in asthma population with a risk of 1.44/1000 asthmatics/year [64].

A recent meta-analysis showed that ICS in high doses of fluticasone is associated with an increased risk of non-tuberculous mycobacteria in chronic respiratory diseases, and also may be associated with tuberculosis, especially in COPD patients [65].

#### **5.2 Systemic effects**

The use of ICS is less associated with systemic side effects compared to OCS. However, long-term ICS use is associated with an increased risk of bone fractures in patients with COPD which was reported to be up to 27% in a meta-analysis of various RCTs and observational studies with fluticasone or budesonide therapy [66]. Although bone density is less in patients taking high-dose of ICS, interpretation is confounded by the fact that these patients are also taking intermittent courses of OCS [21]. Further, osteoporosis is strongly correlated to COPD due to various lifestyle risk factors such as poor physical inactivity and smoking, vitamin D deficiency and COPD-associated inflammation [67].

Hypothalamic–pituitary–adrenal axis suppression is associated mainly with OCS for weeks even with short courses, but with ICS the results of the studies are inconsistent as often the patients have also been taking courses of OCS [68]. Increased risk of new-onset diabetes or diabetes progression has been reported in ICS users which was about 34% and is more among high doses ICS users and COPD [69]. Further, cataracts [70] and glaucoma [71] have been reported as side effects of high doses of ICS.

#### **6. Conclusions**

The introduction of ICS in respiratory medicine is crucial and modifies the management of diseases. ICS are good anti-inflammatory medication. ICS can effectively replace OCS in the control of chronic obstructive respiratory diseases, especially asthma. However, ICS has still side effects, especially in high doses; despite being less than OCS, it is associated with some morbidity that should be well controlled and managed.

### **Conflict of interest**

I declare that I have no conflicts in relation to the current work.

### **Author details**

Hanaa Shafiek Alexandria Faculty of Medicine, Alexandria University, Alexandria, Egypt

\*Address all correspondence to: whitecoat.med@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 4**

## Drug Delivery of Corticosteroids

*Mohamed S. El-Khooly*

#### **Abstract**

In this chapter, we will study how we were able to place drugs from the family of corticosteroids in the places where the drug is intended to be affected during the surgery. It was also possible to control the release of accumulated quantities of dexamethasone by coating it with some soluble polymers such as chitosan. We used samples of bioglass grafted with chitosan polymer to which different percentages of dexamethasone (Dexa) were added (5, 10, and 15%). In addition, the cumulative doses emitted from the samples were calculated by means of statistical functions and using the ultraviolet device. This was also tested on the plasma fluid of the humansimulating body fluid (SBF), and it was confirmed that the appropriate amounts of Dexa were emitted over a period of (1, 2, 4, 8, 16, 21, and 33) days. Due to its shown efficacy in simulating in liquid of the human body (SBF), we aim to put it within the human body as soon as feasible.

**Keywords:** DDS, stander curve, dexamethasone release, SBF, chitosan

#### **1. Introduction**

Corticosteroid drug delivery is a brand-new, fast-developing area in medical research. A corticosteroid-like dexamethasone is a suitable bioactive compound that may be used in bone tissue engineering applications. However, using drug delivery technology today is known to be crucial because it prevents the medications from passing through GIT. Additionally, this medication may be used in an osteogenic medium to encourage the development of stem cells that follow the osteogenic lineage [1–3].

Biodegradable polymers are thought to be the best choice for biological applications in tissue engineering and drug delivery, where the characteristics of bioactive glass can be enhanced and drug release patterns can be changed when polymers are utilized in bioactive glass/polymer composites. Accordingly, to increase patient compliance, the capacity of long-term medication administration for treating chronic illnesses would be crucial. By utilizing bioactive glass/polymer composites, various medications may be locally released and drug delivery systems already have employed a variety of medications, including anti-inflammatory, osteogenic, anticancer, and antibiotics [4, 5]. The characteristics of bioactive glass can be enhanced and drug release patterns can be changed when polymers are utilized in bioactive glass/polymer composites [6]. Due to the widespread usage of dexamethasone as anti-inflammatory medicine, we attempted to create a novel drug delivery system based on (chitosan and bioglass) [7].

This study aims to create and describe solid lipid nanoparticles (SLNs) loaded with Dexa-P and compare them to other drugs with a similar structure or lipophilicity demonstrating that utilizing Dexa-P increases medication loading in SLNs. The development of the standard operating procedure for preparation allowed for evaluation of the size, form, structure, and crystallinity of SLNs.

#### **2. Drug delivery systems (DDS)**

#### **2.1 Definition**

Technologies that release medications and bioactive chemicals are referred to regarded as "drug delivery" in general (e.g., proteins, growth factors, lipids, genes) [8] . Typically, it involves a substance that delivers the medication to the targeted area and keeps the therapeutic agent there. This substance is frequently referred to as the system's carrier or matrix. The idea of controlled release has, more often than not, been closely linked to the idea of medication delivery. A medicinal drug is delivered and released in a time-dependent way under the term "controlled release." This continuous release is necessary since it influences the dosage that a patient should take and how quickly an organism absorbs the medication [9, 10].

#### **2.2 Therapeutic window**

The boundaries between the minimum toxic concentration (MTC) and the lowest effective concentration are known as the therapeutic window (MEC). MTC serves as an upper limit since it is the lowest concentration necessary to cause a living thing to exhibit hazardous behavior. MEC, on the other hand, functions as a lower limit since the intended effect is produced at the minimal concentration. Therefore, to sustain the medicine's efficacy without causing a hazardous reaction, the drug concentration must constantly remain within the therapeutic window [11].

#### **2.3 Historical perspective**

The first implant, released in 1989, disperses goserelin acetate over a one- to threemonth period. Less than 10 clinical treatments that deliver additional peptides and proteins have since been developed, highlighting the challenges in product development. The second generation's final 10 years were devoted to the creation of medication delivery devices based on nanotechnology. The technologies indicated in **Table 1** represent the second generation of drug delivery, which has not yet been created. However, in order for the third generation of medication delivery to be successful, it must address and get over the problems that the first two generations of drug delivery systems have. The three generations of medication delivery are listed in **Table 1**. Smith Kline & French developed the first controlled release medication in 1952 for dextroamphetamine distribution over a 12-hour period (Dexedrine) [12].

#### **2.4 Future back**

It is impossible to forecast the developments in medication delivery technology that will occur over the next 30 years. No matter what new technologies are created, our existing demands for treating illnesses and overcoming obstacles to better


#### **Table 1.**

*Evolution of controlled drug delivery systems.*

medicine delivery will remain the same. The issues described will need to be resolved by more advanced medication delivery technology (**Table 1**).

As the number of people with diabetes keeps growing, there will be a greater need for designing modified insulin delivery devices. Since more than 10 years ago, targeted medicine delivery to tumors has been a major area of study. This demand will not go away overnight. To increase patient compliance, the capacity of long-term medication administration, that is, 6 months or longer, for treating chronic illnesses, would be crucial. Additionally, novel *in vitro* testing techniques will need to be created to precisely forecast the human *in vivo* pharmacokinetics of medicines and drug formulations. Scientists working on drug delivery can wait and see what new technologies are created in the future to address the current issues. But with this passive attitude, we will not be able to meet our objectives in a timely manner. Instead, medicine delivery researchers might use a daring new strategy called "future back." The future back method focuses on comprehending what is plainly achievable or impossible rather than trying to imagine the future to discover a means to accomplish a goal. Scientists will only be able to advance to the level of the norms and priorities of that period if they rely on future inventions that have not yet been created. This is particularly true when innovations are in small scale and soon become obsolete [13].

To reach the aim, scientists may specify what innovations are required and how to combine those breakthroughs to create the perfect drug delivery system. This allows them to start by describing an ideal drug delivery system with all desirable qualities.

At least four modified delivery mechanisms will be developed during the third generation. The targeted delivery of anticancer drugs or siRNA to tumors, the glucosesensitive transient insulin delivery with on-off switching capability, the long-term drug delivery ranging from 6 months to 1 year, and *in vitro* testing techniques that can predict *in vivo* pharmacokinetic profiles are among them. Technically speaking, creating a modified insulin delivery system, is the most difficult of them.

Delivering insulin is distinct from administering other medications in that it must be administered at the appropriate moment, that is, when the blood glucose level rises, and in a precise quantity that is just sufficient to lower the blood glucose level.

#### **Figure 1.**

*Therapeutic window are the limits between the minimum toxic concentration (MTC) and the minimum effective concentration (MEC). Single-dose drug concentration in the plasma (blue solid line), multiple-dose drug concentration in the plasma (dotted line), and zero-order controlled release (green solid line) in the therapeutic window. The range in which a pharmacological dose is effective without having a toxic impact is defined as the area between the minimum toxic concentration (MTC) and the minimum effective concentration (MEC).*

The insulin level in the blood should pulse rather than remain constant, as seen in **Figure 1**. Following a drop in glucose levels, the blood's insulin concentration should also drop.

Hypoglycemia will happen otherwise. Pulsatile drug release systems that are practical for clinical applications still need to be developed despite substantial advancements [14].

#### **2.5 DDS advantages and disadvantages**

#### *2.5.1 Advantages*

Increasing the drug's bioavailability and duration of effect.

Little medication loss and degradation.

Preventing harmful medicine side effects.

Lowering the dosage frequency.

Medication consumption is improved and drug concentration variations are minimized in plasma levels.

Patient compliance has improved.

#### *2.5.2 Disadvantages*

Products of harmful degradation.

Patients' pain with the use of the DDS device necessitates surgical Intervention, either for the installation or removal of systems.

High price of the finished item.

#### **2.6 Mechanisms of drug release**

There are a number of ways that a substance might release a drug; here, we will concentrate on the most common ones. The two primary categories of these

mechanisms are non-responsive and responsive. Non-responsive systems, in which the therapeutic agent is released as a result of matrix swelling or disintegration, do not require an external stimulus to deliver a medicine. The following is a list of ineffective methods [15].

#### *2.6.1 Diffusion mechanism*

It is based on how water (from bodily fluid) and the matrix where the medicine is loaded interact. Monolithic and reservoir matrices are the two types of matrices that adhere to this principle. This carrier is referred to be a monolithic matrix if the medicine is evenly distributed throughout the matrix and is able to diffuse *via* the pores when the matrix breaks down. If not, the matrix is categorized as a reservoir because the medication is disseminated through a coating layer that covers its surface. The superficial layer in reservoir matrices therefore regulates the release kinetics. Typically, both systems exhibit a burst release followed by zero-order kinetics.

#### *2.6.2 Controlled osmosis*

Osmotic pressure acts as the driving force to disperse the drug outward from the matrix when the difference in drug concentration is between the matrix and the surrounding fluid. The kinetics of this process frequently has zero order.

#### *2.6.3 Ionic exchange*

It is connected to ionic medications that replenish ions in live tissue *via* a concentration gradient or it is associated with ionic drugs that restore the ions in living tissue along a gradient of concentration.

#### *2.6.4 Erosion mechanism*

It is dependent on the matrix's degradation. It is divided into two stages:

Therapeutic compounds can then be released under zero-order kinetics after the matrix has first undergone a superficial degradation. As the matrix dissolves over time and the bulk degrades with time, drug release is also facilitated. Sensitive medications may often be supplied primarily in the target tissue and avoid their early degradation if the first stage is under control.

#### **2.7 Materials in drug delivery systems**

#### *2.7.1 Ceramics for biomedical applications*

Bioceramics have long been used as bone grafting for applications involving bone regeneration. Only the bioactive ceramics (such as hydroxyapatite, bioactive glass, and glass ceramics) and the resorbable ceramics (such as tricalcium phosphate and biocompatible glasses) are suitable for bone regeneration applications as scaffolds because they permit the adherence and proliferation of cells from the host tissue. This is true even though the class of ceramic biomaterials includes bioinert, bioactive, and resorbable ceramics [16].

#### *2.7.2 Polymers in drug delivery systems*

As previously indicated, DDS can be made utilizing synthetic or natural polymers that are either biodegradable or not (see **Figure 2**). Drugs, proteins, and cells can all be released using these polymeric systems. As mentioned in the preceding section, the polymers employed in DDS should exhibit a variety of characteristics that make them ideal materials to interact with the human body, with biodegradability being one of the most crucial characteristics.

Both swelling and osmosis can be used to manage solvent-activated systems. A hydrophilic polymeric crosslinked chain that can absorb a lot of water without dissolving is the foundation of systems that control swelling. The quantity of water that enters the polymeric matrix determines how quickly the medicine inside the system diffuses outward thanks to this water absorption (shown in **Figure 3**). Systems that are controlled by osmosis rely on a device.

Numerous dissolved or degradable polymers are appropriate for use in medication delivery systems. The timing of the medication release or release outside the prepared material is managed in terms of the rate of water absorption and disintegration. The polymer's high molecular weight and viscosity are blamed for the departure. Chitosan,

**Figure 2.** *Overview of the polymers used in drug delivery systems [44].*

#### **Figure 3.**

*Drug release resulting from swelling of a polymeric matrix containing a DDS, without or with small amount of drug flows toward a chamber in which the drug is contained [17].*

sodium alginate, and zein protein are the three most well-known polymers utilized in this field.

#### *2.7.3 Polysaccharides*

Monosaccharide-repeating units are the building blocks of polysaccharides, which are high-molecular-weight compounds. They provide a wide variety of structures and attributes. The variety of possible uses is increased by reactive lateral groups, which allows for the changing of their structure. Dextran, alginate, and chitosan are a few of the materials that are typically used to make DDS.

A polysaccharide of bacterial origin, dextran is mostly made up of 1,6-linked D-glucopyranose units. It could have side branches at the positions α-1,2-, α-1,3-, or α-1,4 (**Figure 4**) [18].

#### *2.7.3.1 Chitosan*

Chitosan, a cationic polymer created by the alkaline deacetylation of chitin, is the primary component of marine crab shells (see **Figure 5**). According to a review by Thu Ta and co-authors, chitosan-based hydrogels have been employed as DDS in the field of cancer therapy. There were many preparation techniques and crosslinking agents presented. Paclitaxel, doxorubicin, and camptothecin are a few examples of entrapped medicines [19].

#### **2.8 Bioactive glass/polymer composites**

Different material classes each have advantages and drawbacks of their own. For instance, bioactive glasses and other ceramic materials exhibit good biocompatibility, compression resistance, and corrosion resistance, but they have issues such as brittleness, low fracture strength, and high density. Polymers, on the other hand, may have a variety of forms, compositions, and physical characteristics, but they are too flexible and weak for some applications [20].

In this way, composite materials comprised of ceramic and polymers combine the benefits of each type of material while also addressing their drawbacks. In addition to

**Figure 4.** *Molecular structure of dextran.*

**Figure 5.** *Schematic representation of the alkaline deacetylation of chitin to obtain chitosan.*

#### **Figure 6.**

*Schematic diagrams of: (a) drug incorporated during sol-gel syntheses of BG; (b) drug entrapped inside porous of bioactive glass; (c) drug bonded by H bond on surface of BG; and (d) drug bonded by H bond on inner surface of mesoporous BG.*

modifying drug release patterns, polymers utilized in bioactive glass/polymer composites can enhance the mechanical and physical characteristics of bioactive glasses [6]. On the other hand, bioactive glass particles incorporated into polymers boost the material's bioactivity while also improving mechanical performance [4]. The medication can be put in either the glass or the polymeric matrix in these devices. Drug loading in polymers is accomplished by incorporating medicines into a polymer matrix [21].

There are two ways that the medicine can be put into the glass particles (**Figure 6**): bioactive glass (BG) and bioactive glass with mesopores (MBG) [22].

Different morphologies, such as the dispersion of bioactive glass particles into a polymeric matrix or polymeric fibers, the coating of a polymer on the surface of a bioactive glass scaffold, or the coating of bioactive glass particles on the surface of a polymeric scaffold, can result in the association of polymers with bioactive glass. Each system has distinct mechanical traits and capabilities and may be used for specialized tasks (**Figure 7**).

#### **2.9 Clinical applications of bioactive glass/polymer for DDS**

Utilizing bioactive glass/polymer composites, various medications may be locally released. Drug delivery systems have employed a variety of medications, including

#### **Figure 7.**

*Schematic diagrams of: (a) bioactive glass particles in a polymeric matrix; (b) bioactive glass particles in polymeric fibers; (c) coating of a bioactive glass scaffold with polymer; and (d) coating of a polymeric scaffold with bioactive glasses particles.*

#### **Figure 8.**

*Exemplifies functionalized pore wall of mesoporous.*

anti-inflammatory, osteogenic, anticancer, and antibiotics. This section will discuss various uses for these medications put into glass or polymer matrixes (seen in **Figure 8**) [23].

#### **2.10 Antibiotics in DDS**

Since the use of biomaterials like bone fillers, bone substitutes, or orthopedic implants may have unfavorable outcomes like infections, antibiotics make up the majority of the medications used in local release. Because the osteogenic response of glass and the drug release by the composite may be combined, employing glass/ polymer scaffolds is preferable to using glass and polymers separately. Additionally, substantial medication dosages can be locally released, improving the treatment's specificity. This capacity is necessary for bone infections like osteomyelitis because it enables the diffusion of high dosages of antibiotics to avascular regions that the systemic administration cannot [24]. Numerous studies have suggested various bioactive glass/polymer scaffolds for releasing antibiotics.

#### **2.11 Anti-inflammatory in DDS**

Inflammatory reactions are frequently seen following surgery or implant procedures. Anti-inflammatory medicine local release may be a solution to reduce this issue.

Anti-inflammatory responses are crucial for tissue regeneration because they aid in the removal of foreign infections, but if they are too strong, they can harm the tissue.

#### **2.12 DDS used to cancer treatment**

Bone cancer is another issue that causes a reduction in bone mass. Chemotherapy, which involves administering one or more medications systemically to cancer cells, is a common treatment for bone cancer. Chemotherapy has a drawback: Side effects can harm patients' quality of life and have an overall unfavorable impact on their bodies. For the treatment of bone cancer, local medication administration may enhance the medicine's activity against cancer cells and minimize or eliminate adverse effects. The interaction with bioactive eyewear may potentially promote the repair of damaged tissue (**Figure 9**).

Recombinant granulocyte colony-stimulating factor treatment showed a diminished impact, while recombinant granulocyte-macrophage colony-stimulating factor had no encouraging impact. Recombinant granulocyte-macrophage colonystimulating factor, on the other hand, increased acute myeloid leukemia incidence (by 75%), while colony-stimulating factor 1 and recombinant granulocyte colony stimulating factor had no effect. This was discovered when different factors were administered several months after the leukemogenic treatment. Recombinant interleukin 6 treatment, on the other hand, significantly (23%) decreased the risk of acute myeloid leukemia. The results show that radiation-induced preleukemia, a component of radiation-induced acute myeloid leukemia in mice, is a multiphase process [25].

#### **2.13 Multifunctional drug delivery systems**

In addition to coatings, in more sophisticated systems, such medication delivery systems have also been created: synthetic macro- and mesoporous silica Santa Barbara Amorphous (SBA-15) with magnetic particle-filled porous bioactive glass (magnetic

#### **Figure 9.**

*Schematic diagram showing the therapeutic fiber scaffolds incorporating nanospheres of mesoporous bioactive glass with dexamethasone (Dexa-loaded mBGn), where the drug releasing effect and bioactivity of mBGn can be synergized to regulate osteogenic responses.*

SBA-15). After being submerged in a hexane/ibuprofen solution to load the anti-inflammatory medication ibuprofen, magnetic SBA-15 was coated with polymer (lactic-co-glycolic acid). The diabetic medication metformin HCl was then added to bioactive glasses. *In vitro* testing revealed the release characteristics of both medications [26].

#### **2.14 Why glucocorticoids in DDS**

Drugs called glucocorticoids, sometimes known as corticosteroids or "steroids," are particularly efficient in reducing inflammation brought on by ailments such as asthma and arthritis. They may also be administered to replace the body's own natural steroids in cases of pituitary or adrenal illness. Prednisolone and dexamethasone are the two glucocorticoids that are most often utilized. They typically play a crucial role in the management of numerous medical problems and have the potential to save lives. However, doctors often utilize the lowest amount necessary to manage the disease and only suggest them when it is truly essential.

#### **2.15 How do they affect bone?**

One of the known adverse effects of glucocorticoid therapy is that it might weaken bones and increase the likelihood of fractures, especially when used for an extended length of time. Both direct and indirect actions of glucocorticoids on bone contribute to bone loss and decreased bone strength.

By promoting the activity of natural bone removal cells and decreasing the activity of bone-building cells, they have a detrimental effect on bone directly. They may also impact the amounts of sex hormones and the way the body processes calcium. The degree of bone loss varies from person to person, but for individuals taking 7.5 mg or more of prednisolone per day, the risk of fractures rises by more than 50% in the first year of treatment.

#### **2.16 Do all glucocorticoid treatments affect bone?**

The dosage of glucocorticoids and how they are administered both affect how they affect bones throughout treatment (as an injection, cream, inhaler). But glucocorticoid medications are the ones that have been most closely linked to bone loss. Although studies indicate that increased fracture risk can occur even with modest doses of prednisolone (2.5–7.5 mg per day) and climb further with increasing daily dosages, the precise quantity that is damaging to bone varies depending on the individual. Another important factor is how long glucocorticoid pills are taken. The majority of specialists concur that there may be an effect on bone if they are used constantly in tablet form for longer than 3 months. If extremely large dosages are utilized, this impact can be seen much sooner. The overall health advantages of glucocorticoids far outweigh any potential slight negative effect on bones when they are used in low doses to replace what the body is unable to produce (e.g., in Addison's disease or pituitary disease), so it is crucial that they are taken as prescribed by your doctor [27].

#### **2.17 Dexamethasone (Dexa)**

Additional medications may be given either before or simultaneously with the chemotherapeutic medicines to lessen or eliminate these chemotherapy resistance

**Figure 10.** *Structures of dexamethasone.*

factors. These medications may or may not have therapeutic benefits on their own, but their main function is as adjuvants, enhancing the effectiveness and/or reducing the toxicity of chemotherapeutic medicines. Dexa (**Figure 10**) is one such medication. Synthetic glucocorticoids like Dexa are well known for their ability to reduce inflammation and suppress the immune system. It has demonstrated benefit against several malignancies, including leukemia, and has been widely used as an anti-emetic in combination with chemotherapy drugs [28].

However, recent preclinical and clinical studies have concentrated on its use as a chemotherapeutic adjuvant. According to studies, pretreatment with Dexa can lessen the toxicity and, in some situations, boost the effectiveness of chemotherapy drugs. Prednisolone and Dexa, for instance, both efficiently defended progenitor cells in four strains of mice against 5-fluorouracil, a chemotherapeutic drug that is specific to the cell cycle and is antimetabolic. Blood cell counts and the number of bone marrow progenitors both returned to normal after 3–5 days and 1–2 days, respectively, of not receiving glucocorticoids. With Dexa, the same degree of effectiveness may be attained at almost 16.5 times the dosage of prednisolone.

In six xenograft models studied (2 colon, 2 breast, 1 lung, and 1 glioma tumors), Wang et al. found that pre-administration of Dexa was able to greatly boost the effectiveness of carboplatin, a DNA alkylating agent; gemcitabine, an antimetabolite; or a combination of both medicines by 2–4-fold. The same team also looked at how Dexa affected the treatment with Adriamycin, an anthracycline antibiotic that may intercalate DNA and is also known as doxorubicin, with similar outcomes. In a syngeneic model of breast cancer, pre-administration of Dexa led to an almost total suppression of tumor development. Dexa pretreatment has been shown in clinical studies to decrease hematological toxicity and speed up the recovery of absolute granulocyte count and platelet count [29].

By employing normal phase LC with quaternary mobile phase with regulated water content, UV detection at 254 nm, and cortisone as an internal standard, dexamethasone content in drug substance and elixir may be found. In bulk drug material and elixir, TLC, IR spectroscopy, and relative LC retention time ratios are used to validate identification.

#### **2.18 Dexamethasone interactions**

Dexamethasone's role in treating rats with gastrointestinal constipation brought on by morphine, verapamil, and atropine has been investigated. Dexamethasone was able to counteract the dose-related inhibition of charcoal meal transit brought on by these medications. More effectively than altering the effects of verapamil, dexamethasone

#### *Drug Delivery of Corticosteroids DOI: http://dx.doi.org/10.5772/intechopen.109085*

reversed the constipation caused by morphine and atropine. Dexamethasone's interaction with its receptor was shown to have the potential to release a greater amount of acetylcholine, which would reverse the constipation caused by atropine or morphine. Dexamethasone's little impact on verapamil-induced constipation revealed that calcium influx was not as important as previously thought. The aforementioned findings point to the significance of steroids in gastrointestinal transit and offer a potential mechanism by which dexamethasone might alleviate constipation brought on by morphine and atropine [30].

#### **2.19 Dexamethasone health hazard**

SYMPTOMS Fluid and electrolyte disturbances, pituitary-adrenal suppression, hyperglycemia, increased susceptibility to infection, including tuberculosis, myopathy, growth arrest, hypokalemic alkalosis, and Cushing's syndrome, which includes "moon-face," "buffalo-hump," striae, acne, and hirsutism, are all symptoms of exposure to this type of compound. Ecchymoses, "central obesity," and enlarged supraclavicular fat pads are some additional signs of Cushing's syndrome.

This condition can also lead to increased bruising and flushing. Behavioral abnormalities, glycosuria, anxiousness, mood or psyche changes, psychopathy's of the manic-depressive or schizophrenia type, and suicidal thoughts are further signs of exposure. Candidiasis, gluconeogenesis, heart failure (in severe cases), spontaneous fractures, increased hunger, slower wound healing, hyperhidrosis, neurological and mental problems, intracranial hypertension, and increased blood coagulability are all possible side effects of exposure. Aseptic necrosis of the bone, amenorrhea, muscle weakness, salt and water retention, hypertension, edema, increased severity of diabetes, pancreatitis, thrombotic episodes, and osteoporosis are other possible side effects. Sleeplessness, skin eruptions, depression, euphoria, decreased pain perception, weakness, deafness, convulsions, intestinal perforation in ulcerative colitis, hypokalemia, muscle deterioration, Achilles tendon rupture, pseudotumor cerebri, and cardiac conduction defect are additional signs of exposure to this type of substance.

Congestive heart failure, immune system suppression, impaired glucose tolerance, habituation, and the emergence of hidden psychological disorders are among its potential side effects. Additionally, it may result in potassium loss, muscle mass loss, vertebral compression fractures, abdominal distention, ulcerative esophagitis, thin and fragile skin, petechiae, erythema, increased sweating, suppressed skin test reactions, allergic dermatitis, urticaria, angioneurotic edema, vertigo, headache, decreased carbohydrate tolerance, exophthalmos, hypersensitivity, thromboembolism, malnutrition. Ascites may occur. Subcutaneous atrophy and skin collagen loss might result from skin exposure to this kind of substance. Burning, secondary infections, itching, irritation, pigmentation, dryness, folliculitis, and hypertrichosis are additional signs of this approach. This kind of chemical can cause cataracts, increased intraocular pressure, corneal ulcers, and impaired vision in the eyes. Glaucoma might also happen [31].

#### **2.20 Acute/chronic hazards**

Through consumption, inhalation, or skin absorption, this substance may be dangerous. It could irritate others. It could result in lacrimation. It releases deadly fumes of carbon monoxide, carbon dioxide, and hydrogen fluoride when heated to the point of disintegration [32, 33].

#### **2.21 Dexamethasone chemical dangers**

When heated over 275°C, it decomposes. This releases harmful gases. This creates a risk of fire and explosion, and reacts with carbon disulfide, copper, lead, silver, mercury, and other metals. Particularly shock-sensitive chemicals are created as a result and with acids reacts. As a result, poisonous and explosive hydrogen aside is produced, with a melting point between 504 and 507 degrees F. [25, 34].

#### **2.22 Preparation of drug-loaded SLNs**

It has been demonstrated that using Dexa-P improves medication loading in solid lipid nanoparticles (SLNs). This section's objectives were to manufacture and describe SLNs that were loaded with Dexa-P and to compare them to other medications with a comparable structure or lipophilicity. Size, form, structure, and crystallinity of SLNs will be evaluated, in addition to the previously mentioned characteristics (drug loading and encapsulation effectiveness). The free and encapsulated medication will be separated using ultrafiltration, and the amount will be measured using an HPLC-UV test. For the comparative experiments, curcumin and ascorbic palmitate (AP) will be employed. The palmitate moiety that may link with the SLN lipids is absent from curcumin, despite the fact that both medicines are lipophilic.

#### **2.23 Stability of drug-loaded SLNs**

The presence of CE activity seems to be necessary for the release of dexa from the SLNs. This section's objectives were to 1) establish the stability of SLNs and 2) demonstrate dexa-P retention with the SLNs in circumstances similar to those in human plasma (specifically the absence of CE activity). Monitoring the growth and morphology of SLNs cultured at 37°C was the main goal of the early experiments. The influence of SLN concentration on particle size growth was assessed, and SLNs returned to 4°C after incubation at 37°C were tested for size recovery to better clarify the process of particle size growth. After that, SLNs were exposed to human serum albumin (HSA), and a representative protein, and size and turbidity alterations were observed. As a backup strategy, size exclusion chromatography (SEC) was applied to validate the SLNs' intact status in the presence of HSA. A multi-step filtration procedure that involved first filtering *via* a 0.2-μm membrane and then ultrafiltration was used to ascertain the retention of Dexa-P with the SLNs in the presence of human plasma. Calculating the quantity of medication retained with the SLNs involved taking into consideration the known protein binding.

#### **2.24 Storage stability of drug-loaded SLNs**

This section's objectives were to examine the long-term stability of aqueous and lyophilized SLNs and to optimize a process for lyophilizing SLNs. The following factors were taken into account for optimizing the lyophilization protocol: lyoprotectant (LP) type and concentration, SLN concentration, freezing temperature, freezing rate, and drying time. The particle size, shape, mono dispersity, and drug loading of SLNs were evaluated. Lyophilized SLNs and SLN suspensions were kept at 4°C and 25°C/60% RH for the long-term stability testing. At days 0, 1, 3, 7, 14, and months 1, 2, and 3, samples were taken to evaluate the size of the particles and drug loading [35].

#### **2.25 Biological activity**

It is permitted to use dexamethasone to lessen immunological response and minimize inflammation. The following cancers are treated with it in combination with other medications: leukemia, lymphoma, fungus mycoides (a type of cutaneous T-cell lymphoma). The following cancer-related diseases are also prevented or treated using dexamethasone alone or in combination with other medications: anemia, cerebral edema (fluid build-up in the brain) (fluid build-up in the brain), hypersensitivity to drugs (allergic reactions), hypercalcemia (high blood levels of calcium) (high blood levels of calcium), thrombocytopenia (low platelet levels) (low platelet levels). Many different illnesses and ailments are treated with dexamethasone either on its own or in combination with other medications. The medication is still being researched for the treatment of many cancers and other illnesses [36].

#### **2.26 Therapeutic uses**

Dexamethasone is mostly utilized as an immunosuppressant or anti-inflammatory drug. The medication is insufficient by itself to treat adrenocortical insufficiency because it only possesses limited mineralocorticoid characteristics. Dexamethasone must be administered in conjunction with a mineralocorticoid to effectively treat this disease: steroidal anti-inflammatory drugs, antiemetics, hormonal antineoplastics, synthetic and topical glucocorticoids, and antihistamine [37].

In babies and children with Haemophiles influenzae meningitis, there is some evidence that short-term supplementary treatment with IV dexamethasone may reduce the incidence of audiologic and/or neurologic sequelae. Patients with *Streptococcus pneumoniae* meningitis may also benefit. The American Academy of Pediatrics (AAP) and other medical professionals advise considering adjunctive dexamethasone therapy in infants and kids older than 6 weeks with known or suspected bacterial meningitis, particularly in those with suspected or confirmed *Haemophilus influenzae* infection, during the first 2–4 days of anti-infective therapy. Dexamethasone should be started before or concurrently with the initial dosage of an anti-infective medication if it is used [38].

#### **3.** *In vitro* **bioactive analysis**

#### **3.1 Standard operating procedure for (SBF) preparation**

Kokubo's [39] Simulated body fluid (SBF) is a metastable solution made up of supersaturated calcium and phosphate ions in relation to apatite.

As a result, (SBF) is ready as follows:



#### **Table 2.**

*Reagents for preparation of simulated body fluid (SBF).*


#### **3.2 The soaking of the samples in (SBF)**

By soaking in 50 ml of Kokubo's (SBF), (**Figure 11**), the *in vitro* bioactivity of bioglass (BG), bioglass/chitosan (BG/CH), and different ratios of BG/CH dexamethasone was examined. The SBF solution has a buffered pH of (7.4) [40].

The samples in plastic containers were kept at a constant temperature of 37°C for 33 days in a thermodynamic (shaking-water bath) (see **Figure 12**).

**Figure 11.** *Test of the static SBF in a plastic container at 37°C.*

**Figure 12.** *Thermodynamic incubator (water bath).*

The specimens were taken out of the solution, cleaned with distilled water, and then allowed to dry at room temperature after 33 days of immersion.

#### **3.3 Elemental analysis: UV spectrophotometer technique**

Each test tube had a 2 ml sample of SBF removed from it 1, 2, 4, 8, 16, 21, and 33 days after the immersion started.

**Figure 13.** *UV-visible spectroscopy JASCO v-630.*

And kept frozen until they were evaluated using UV-Vis spectroscopy (JASCO v-630) (see **Figure 13**) to determine the concentration of Ca, P, and dexamethasone released when a medication concentration increased over time [41].

#### **4. Determination of drug release**

#### **4.1 Determination of the characteristic absorption peaks**

The UV-visible (VIS) absorption spectra of Dexa solution are displayed in **Figure 14**. Dexa have absorption peaks were found to be strongest at wavelengths of

**Figure 14.** *UV-visible absorption spectra of dexamethasone concentration.*

237, 240, and 242 nm, respectively. The absorption spectra for dexamethasone solution were photographed at 240 nm in wavelength [42].

#### **4.2 Calibration curve of the release drug dexamethasone**

Utilizing several drug reference solutions in descending order at the maximum wavelength (λ) at 240 nm, which corresponds to Dexa medicines, the UV-VIS absorption spectroscopy equipment was calibrated.

Stock solution was divided into aliquots (50, 25, 12.5, and 6.75 ml) and combined with (2 ml) of distilled water at a pH of 7.4 to create concentrations ranging from 25 to 200 g/ml. Using a UV-VIS spectrophotometer, the absorbance of these solutions was evaluated at 240 nm, as indicated in **Table 3** [43].

The drug calibration curve was altered to suit a straight line with a correlation coefficient (R<sup>2</sup> ) of 0.93692 Dexa, as shown in **Figure 15**.


#### **Table 3.**

*Standard absorption values of dexamethasone in distilled water pH 7.4 with different concentration.*

**Figure 15.** *Calibration curve of the release drug dexamethasone.*

#### **4.3 Determination of the amount of drug released**

The dynamic *in vitro* release is depicted in **Figure 16**. Dexamethasone absorption peaks were seen in all samples individually from zero day soaking in SBF to 33 days.

UV-visible absorption spectroscopy was used to identify the absorbance peaks intensities of the drug samples across the preset time periods. The equivalent quantity of the drug was calculated using the relevant calibration curve and is shown in **Table 4** as the percentage of dexamethasone drug release.

The dexamethasone release profile revealed a lower initial release that was initially sluggish and subsequently increased. After 96 hours (4 days), the rate of Dexa release rose briefly before returning to normal (**Figure 17**).

The drug's release profile was evaluated in three stages: an initial burst release (stage I), continuous release (stage II), and declining release (stage III) (stage III).

The quantity of medication released from BG15D, BG/CH5D, BG/CH10D, and BG/ CH15D composites reduced after 21 days. The profile is generally comparable for the three concentrations BG/CH5D, BG/CH10D, and BG/CH15D, as predicted given the bioglass/chitosan composites that support the medication.

The drug release is regulated by two factors: diffusion and polymer breakdown. According to the release profiles, the mechanism of Dexa release appears to be

**Figure 16.** *Dexamethasone absorbance (%) at 240 λ during (1–33) days of soaking.*

*Drug Delivery of Corticosteroids DOI: http://dx.doi.org/10.5772/intechopen.109085*


*Table 4 shows all the percentages of dexamethasone released from all samples BG/CH5D BG/CH10D BG/CH15D BG15D and over the different periods after 1, 2, 4, 8, 16, 21 and 33 days, and it also shows the release rate of each quantity of the used drug "Dexamethasone" for each sample over the same period as previously described.*

#### **Table 4.**

*The percentage of dexamethasone drug released from composite samples.*

**Figure 17.** *The amount of release Dexa concentration from samples for (1–33) days.*

through polymer breakdown rather than diffusion owing to chemical interaction amino groups of chitosan and carbonyl groups of Dexa [44].

#### **4.4 Accumulative release of Dexa**

The experimental findings showed that dexamethasone was released faster from bioglass (BG15D) than from bioglass/chitosan composites (BG/CH15D). This is owing to the fact that drug release from bioglass (BG15D) can only be impacted by diffusion, but drug release from BG/CH5D, BG/CH10D, and BG/CH15D may be sustained by chitosan degradation based on the chemical interaction of chitosan amino groups and dexamethasone carbonyl groups (**Figure 18**).

**Figure 18.** *Release profile of dexamethasone in terms of the percentage (%) of dexamethasone released as a function of time.*

#### **5. Conclusion**

At various dilution ratios, the controlled release was tested using "JASCO v-630" UV visible spectroscopy. A standard curve was developed to establish a link between the absorption rate, as measured by the UV device, and the drug concentration in the medium utilized (SBF). The release profile reveals that the dexamethasone release may be sustained for more than 30 days, and the drug release experimental data indicate that the release is driven by chitosan polymer breakdown. Based on the findings of this study, we can conclude that (bioglass/chitosan) is a good function material as a carrier for anti-inflammatory dexamethasone drug as a corticosteroid and that it may be successfully employed in bone tissue engineering applications.

It has been determined that the release profile showed that the dexamethasone release may be sustained for more than 30 days, and the drug release experimental data indicate that the release is driven by chitosan polymer breakdown. Based on the findings of this investigation, we therefore proposed that bioglass/chitosan is a suitable functional material as a carrier for the anti-inflammatory medication dexamethasone in this study.

#### **Acknowledgements**

I first and foremost thank the All-Powerful Allah for both my possessions and lack of possessions. He is the ruler of the universe. Salutations to Muhammad (PBUH), the finest and most excellent of all beings. Among the academics I am grateful to and indebted to are my brother Dr. Ahmed Ali Abdel-Aal Mohamed, my best friend Dr. Abd elrahmaan Al-esnawy, and my teachers Dr. Ahmed S. Abd raboh, Prof. Dr. M. Y. Hassan, and Prof. Dr. Khairy M. T. Ereiba of the Faculty of Science at Al-Azhar University.

*Drug Delivery of Corticosteroids DOI: http://dx.doi.org/10.5772/intechopen.109085*

#### **Conflict of interest**

Not applicable**.**

### **Author details**

Mohamed S. El-Khooly1,2

1 Faculty of Science, Biophysics Branch, Physics Department, Al-Azhar University, Nasr City, Cairo, Egypt

2 Faculty of Science, Physics Department, New Valley University, El Kharga, New Valley, Egypt

\*Address all correspondence to: ms.new39@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 2
