Irmak Sayın Alan and Bahadır Alan Irmak Sayın Alan and Bahadır Alan Additional information is available at the end of the chapter

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http://dx.doi.org/10.5772/intechopen.72019

### **Abstract**

[42] Amariles P, Giraldo N, Faus M. Interacciones medicamentosas: Aproximación para establecer y evaluar su relevancia clínica. Medicina Clínica (Barcelona). 2007;129(1):27-35 [43] Cano A, Amariles P. Liver toxicity caused by drugs: A structure review. Rev Colomb

[44] Cano A, Amariles PA. Structured review of hepatotoxic medicines during pregnancy.

Gastroenterol. Forthcoming in 2017;32(4)

92 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

Revista Colombiana de Gastroenterología. 2017;32(1):35-43

Glucocorticoids represent the most important and frequently used class of drugs in the management of many inflammatory and immunologic conditions. Beside these beneficial effects, glucocorticoids are also associated with serious side effects. Cushing's syndrome, adrenal suppression, hyperglycemia, dyslipidemia, cardiovascular disease, osteoporosis, psychiatric disturbances, and immunosuppression are among the most important side effects of systemic glucocorticoids. These side effects are especially noticeable at high doses for prolonged periods. Even in low-dose therapy, glucocorticoids could lead to serious side effects. The underlying molecular mechanisms of side effects of glucocorticoids are complex, distinct, and frequently only partly understood. This comprehensive article reviews the current knowledge of the most important side effects of glucocorticoids from a clinical perspective.

DOI: 10.5772/intechopen.72019

**Keywords:** glucocorticoids, systemic, mechanisms of actions, therapeutic use, side effects

## **1. Introduction**

The term "glucocorticoids" (GCs) represents both naturally secreted hormones by adrenal cortex and anti-inflammatory and immunosuppressive agents. Since the successful use of hydrocortisone (cortisol), the principal glucocorticoid of the human adrenal cortex, in the suppression of the clinical manifestations of rheumatoid arthritis, many synthetic compounds with glucocorticoid activity have been manufactured and tested [1]. The differences between pharmacologic effects of synthetic GCs (SGCs) result from structural variations of their basic steroid nucleus and its side groups. These structural variations may affect the bioavailability of SGCs. These include gastrointestinal or parenteral absorption, plasma half-life, and metabolism in the liver, fat, or target tissues—and their abilities to interact with the glucocorticoid receptor and to modulate the transcription of glucocorticoid—responsive genes [2]. Structural

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variations reduce the natural cross-reactivity of SGCs with the mineralocorticoid receptor (MR), eliminating the offending salt-retaining effect. In addition to these, some variations increase SGCs' water solubility for parenteral administration or decrease their water solubility to improve topical potency [3, 4]. The main SGCs used in clinical practice together with their relative biological potencies and their plasma and biological half-lives are listed in **Table 1**.

GCs are 21-carbon steroid hormones. The delta-4,3-keto-11-beta,17-alpha,21-trihydroxyl configuration is required for glucocorticoid activity and is present in all natural and synthetic GCs. Approximately 90% of endogenous cortisol in serum is bound to proteins, primarily corticosteroid-binding globulin (CBG) and albumin. Conversely synthetic GCs other than prednisolone either bind weakly to albumin or circulate as free steroids, because they have little or no affinity for CBG. The free form of the GCs can easily diffuse through the membrane and can bind with high affinity to intracytoplasmic glucocorticoid receptors. GCs perform most of their effects owing to specific, immanent distributed intracellular receptors. Binding of the GCs to this receptor creates a complex, which then translocates into the nucleus, where it can interact directly with specific DNA sequences (glucocorticoid-responsive elements [GREs]) and other transcription factors. GCs are metabolized in the liver. The kidney excretes 95% of the conjugated metabolites, and the remainder is lost in the gut. Exogenous GCs have the same metabolic processes as endogenous GCs. The half-lives of synthetic GCs are generally longer than that of cortisol, which is approximately 80 minutes [8–13]. The mechanisms of actions of GCs are shown in **Figure 1**.


GCs are used in nearly all medical specialties for systemic therapies. GCs represent the standard therapy for reducing inflammation and immune activation in asthma, as well as allergic, rheumatoid, collagen, vascular, hematological, neurological disorders, and inflammatory bowel diseases. Also GCs are used in renal, intestinal, liver, eye, and skin diseases and in the suppression of the host-vs.-graft or graft-vs.-host reactions following organ transplantation. SGCs administered as replacement therapy in primary or secondary adrenal insufficiency (AI), and as adrenal suppression therapy in glucocorticoid resistance and congenital adrenal hyperplasia. They are also used for some diagnostic purposes, such as in establishing Cushing's syndrome. Acute pharmacologic doses of GCs can be used in a small number of nonendocrine diseases, such as for patients suffering from acute traumatic spinal cord injury, with severe neurological deficits and bone pain even after surgery and critical illness-related cortisol insufficiency. In addition, all fetuses between 24 and 34 week gestation at risk of preterm delivery should be considered as candidates for antenatal treatment with GCs. Benefits of GCs have been showed in a number of other patients including high-risk cardiac surgery, liver failure, post-traumatic stress disorder, community acquired pneumonia, and weaning from mechanical ventilation [3, 4, 6, 7, 9, 14–18]. Common clinical

Side Effects of Glucocorticoids

95

http://dx.doi.org/10.5772/intechopen.72019

This comprehensive article aims to highlight the common side effects of systemic (oral and parenteral) GCs. First of all, the mechanisms of action of GCs will be described. Then the side effects of GCs will be discussed along with the pathophysiological mechanisms. While this

section was being written, current literature and databases have been utilized.

uses of systemic GCs are shown in **Table 2**.

**Figure 1.** The mechanisms of actions of GCs.

**Table 1.** Glucocorticoid equivalencies (adapted from [5–7]).

**Figure 1.** The mechanisms of actions of GCs.

variations reduce the natural cross-reactivity of SGCs with the mineralocorticoid receptor (MR), eliminating the offending salt-retaining effect. In addition to these, some variations increase SGCs' water solubility for parenteral administration or decrease their water solubility to improve topical potency [3, 4]. The main SGCs used in clinical practice together with their relative biological potencies and their plasma and biological half-lives are listed in **Table 1**.

94 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

GCs are 21-carbon steroid hormones. The delta-4,3-keto-11-beta,17-alpha,21-trihydroxyl configuration is required for glucocorticoid activity and is present in all natural and synthetic GCs. Approximately 90% of endogenous cortisol in serum is bound to proteins, primarily corticosteroid-binding globulin (CBG) and albumin. Conversely synthetic GCs other than prednisolone either bind weakly to albumin or circulate as free steroids, because they have little or no affinity for CBG. The free form of the GCs can easily diffuse through the membrane and can bind with high affinity to intracytoplasmic glucocorticoid receptors. GCs perform most of their effects owing to specific, immanent distributed intracellular receptors. Binding of the GCs to this receptor creates a complex, which then translocates into the nucleus, where it can interact directly with specific DNA sequences (glucocorticoid-responsive elements [GREs]) and other transcription factors. GCs are metabolized in the liver. The kidney excretes 95% of the conjugated metabolites, and the remainder is lost in the gut. Exogenous GCs have the same metabolic processes as endogenous GCs. The half-lives of synthetic GCs are generally longer than that of cortisol, which is approximately 80 minutes [8–13]. The mechanisms of

actions of GCs are shown in **Figure 1**.

**dose (mg)**

**Table 1.** Glucocorticoid equivalencies (adapted from [5–7]).

**Glucocorticoid potency**

**HPA suppression**

Cortisol 20.0 1.0 1.0 1.0 90 8–12 Cortisone 25.0 0.8 0.8 80–118 8–12

Prednisone 5.0 4.0 4.0 0.3 60 18–36 Prednisolone 5.0 5.0 0.3 115–200 18–36 Triamcinolone 4.0 5.0 4.0 0 30 18–36 Methylprednisolone 4.0 5.0 4.0 0 180 18–36

Dexamethasone 0.75 30 17 0 200 36–54 Betamethasone 0.6 25–40 0 300 36–54

Fludrocortisone 2.0 10 12.0 250 200 18–36

0 20 70

**Mineralocorticoid** 

**Plasma half-life (min)**

**Biologic half-life (h)**

**potency**

**Glucocorticoids Equivalent** 

*Short-acting*

*Long-acting*

acetate

*Mineralocorticoids*

Desoxycorticosterone

*Intermediate-acting*

GCs are used in nearly all medical specialties for systemic therapies. GCs represent the standard therapy for reducing inflammation and immune activation in asthma, as well as allergic, rheumatoid, collagen, vascular, hematological, neurological disorders, and inflammatory bowel diseases. Also GCs are used in renal, intestinal, liver, eye, and skin diseases and in the suppression of the host-vs.-graft or graft-vs.-host reactions following organ transplantation. SGCs administered as replacement therapy in primary or secondary adrenal insufficiency (AI), and as adrenal suppression therapy in glucocorticoid resistance and congenital adrenal hyperplasia. They are also used for some diagnostic purposes, such as in establishing Cushing's syndrome. Acute pharmacologic doses of GCs can be used in a small number of nonendocrine diseases, such as for patients suffering from acute traumatic spinal cord injury, with severe neurological deficits and bone pain even after surgery and critical illness-related cortisol insufficiency. In addition, all fetuses between 24 and 34 week gestation at risk of preterm delivery should be considered as candidates for antenatal treatment with GCs. Benefits of GCs have been showed in a number of other patients including high-risk cardiac surgery, liver failure, post-traumatic stress disorder, community acquired pneumonia, and weaning from mechanical ventilation [3, 4, 6, 7, 9, 14–18]. Common clinical uses of systemic GCs are shown in **Table 2**.

This comprehensive article aims to highlight the common side effects of systemic (oral and parenteral) GCs. First of all, the mechanisms of action of GCs will be described. Then the side effects of GCs will be discussed along with the pathophysiological mechanisms. While this section was being written, current literature and databases have been utilized.


**2. Mechanism of actions**

**2.1. Gene transcription**

matory cytokines [21, 22].

translational events [23].

**3.1. Neutrophils**

functions [26, 27].

**3.2. Monocytes and macrophages**

**2.2. Post-translational events**

**2.3. Effect on the distribution of blood cells**

with improvement of chronic inflammation [24, 25].

**3. Changes in cell function and survival**

GCs affect many, if not all, cells and tissues of the human body, thus awakening a wide vari-

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http://dx.doi.org/10.5772/intechopen.72019

Binding of the receptor to GREs may cause either enhancement or suppression of transcription of responsive downstream genes. GCs inhibit the synthesis of almost all known inflam-

GCs also inhibit secretion and synthesis of inflammatory molecules (IL-1, IL-2, IL-6, IL-8, tumor necrosis factor, inflammatory eicosanoids, and cyclooxygenase-2) by affecting post-

The administration of glucocorticoids predictably results in neutrophilic leukocytosis, dramatic reductions in circulating eosinophils and basophils, transient minor reductions in monocytes and total lymphocytes. Acute lymphopenia normalizes by 24–48 hours. GCs have no direct effects on erythrocyte and platelet counts. But anemia and thrombocytosis can heal

The most important effect of GCs on neutrophils is the inhibition of neutrophil adhesion to endothelial cells. This effect reduces trapping of neutrophils in the inflamed region and probably is responsible for the characteristic hematological change—neutrophilia. GCs at pharmacologic doses, only modestly impair neutrophil functions, such as lysosomal enzyme release, the respiratory burst, and chemotaxis to the inflamed region. Lower doses do not affect these

GCs antagonize macrophage differentiation and inhibit many of their functions. GCs (1) supress myelopoiesis and inhibit expression of class II major histocompatibility complex antigens induced by interferon-γ; (2) block the release of numerous cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-α; (3) suppress production and release of pro-inflammatory prostaglandins (PGs) and leukotrienes; (4) suppress phagocytic and microbicidal activities of activated macrophages; (5) reduce the clearance of opsonized bacteria by the reticuloendothelial

system; (6) reduce accumulation of monocytes and macrophages in the tissues [28–31].

ety of changes that involve several cell types concurrently [20].

**Table 2.** Common clinical uses of systemic GCs (adapted from [19]).
