Chemistry and Pharmacodynamics
Chemical structure
- Glucocorticoids are synthetic analogs of cortisol and cortisone.
- Alterations may include:
- Fluorination (dexamethasone, betamethasone)
- Methylation (methylprednisolone)
The chemical structure of cortisol
Image: “Structure of Cortisol” by NEUROtiker. License: Public Domain
The chemical structure of prednisone, which appears similar to cortisol.
Image: “Structure of Prednisone” by Bryan Derksen. License: Public Domain
Physiology
- Endogenous glucocorticoids are secreted from the zona fasciculata.
- Effects: respond to immediate stressors
- ↑ Immediate available energy through:
- Fat and protein catabolism → ↑ blood amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids and lipid levels
- Gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis
- Appetite stimulation
- ↑ RBCs
- ↑ Serum calcium from bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones resorption (leads to ↓ bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones mineral density over time)
- Antiinflammatory effects:
- ↓ Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
- ↓ Blood vessel permeability
- Long-term exposure suppresses the immune system
- ↑ Immediate available energy through:
- Regulated by the hypothalamic-pituitary-adrenal (HPA) axis
Flowchart showing the hypothalamic-pituitary-adrenal cortex axis:
Stresses may be physical (e.g., exercise), mental (e.g., fear), or biochemical (e.g., low blood glucose). Biologic rhythms include circadian rhythms as well as longer rhythms associated with growth and development.
ACTH: adrenocorticotropic hormone
CRH: corticotropin-releasing hormone
Mechanism of action
- Glucocorticoids enter cell → bind to glucocorticoid receptors
- Translocation to the nucleus → bind to specific
DNA
DNA
The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival.
DNA Types and Structure sequences (glucocorticoid response elements) → result in either:
- Activation of transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription
- Repression of transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription
- Results in metabolic effects (similar to normal physiology)
- Specific genomic immune system effects include:
- Blocking promotor sites for proinflammatory genes
- Promoting transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription of antiinflammatory gene products
- Diminish synthesis of inflammatory cytokines
- Additional effects:
- ↓ Inflammatory cytokine secretion
- ↑ ACE synthesis → bradykinin degradation
- ↓ Capillary permeability
- ↓ Vasodilation
- ↓ Synthesis of phospholipase A2 and COX-2 → ↓ prostaglandin and leukotriene synthesis
- ↓ Migration of PMNs
- ↓ Histamine release
Classification
By use
- Systemic (see below)
- Topical:
- Betamethasone
- Clobetasol
- Fluocinomide
- Fluticasone
- Hydrocortisone
- Mometasone
- Triamcinolone
- Inhaled:
- Beclomethasone
- Budesonide
- Fluticasone
- Mometasone
By duration of action
Systemic glucocorticoids can be divided into:
- Short-acting:
- Cortisone
- Hydrocortisone
- Intermediate-acting:
- Methylprednisolone
- Prednisolone
- Prednisone
- Triamcinolone
- Long-acting:
- Betamethasone
- Dexamethasone
By potency
Topical steroids are classified as classes I–VII based on their potency.
- Class I: most potent; includes:
- Clobetasol propionate
- Betamethasone dipropionate
- Diflorasone diacetate
- Fluocinonide
- Class VII: least potent; includes hydrocortisone
Pharmacokinetics
The following summarizes the pharmacokinetics for systemic glucocorticoids:
Absorption
- Oral absorption is:
- Rapid
- Complete
- Formulations/routes of administration:
- Oral
- IV
- IM
- Intraarticular
Distribution
- Protein binding:
- Natural glucocorticoids are highly protein-bound:
- Corticosteroid-binding globulin (CBG)
- Albumin
- Synthetic steroids are generally less protein-bound.
- Natural glucocorticoids are highly protein-bound:
- Cross the blood–brain barrier
Metabolism and excretion
- Metabolism:
- Hepatic
- Some by CYP3A4
- Excretion: primarily in urine
Indications
Systemic
Systemic glucocorticoids are commonly used for the short- and/or long-term management of a variety of conditions, including:
- Physiologic glucocorticoid replacement
- Inflammatory diseases
- Allergic conditions
- Autoimmune diseases
| System | Indications |
|---|---|
| Allergic conditions |
|
| Dermatologic |
|
| Endocrine |
|
| GI |
|
| Hematologic |
|
| Neurologic |
|
| Ophthalmic |
|
| Respiratory |
|
| Rheumatologic |
|
Topical
Topical glucocorticoids can be used for a number of dermatologic conditions, including (list is not exhaustive):
- Psoriasis
- Atopic dermatitis Atopic Dermatitis Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema)
- Acute radiation dermatitis
- Lichen planus Lichen planus Lichen planus (LP) is an idiopathic, cell-mediated inflammatory skin disease. It is characterized by pruritic, flat-topped, papular, purple skin lesions commonly found on the flexural surfaces of the extremities. Other areas affected include genitalia, nails, scalp, and mucous membranes. Lichen Planus
- Discoid lupus erythematosus
- Vitiligo Vitiligo Vitiligo is the most common depigmenting disorder and is caused by the destruction of melanocytes. Patients present with hypo- or depigmented macules or patches which often occur on the face, hands, knees, and/or genitalia. Vitiligo
Inhaled
- Persistent asthma (prevent exacerbations)
- Stable chronic obstructive pulmonary disease (prevent exacerbations)
- Eosinophilic esophagitis Esophagitis Esophagitis is the inflammation or irritation of the esophagus. The major types of esophagitis are medication-induced, infectious, eosinophilic, corrosive, and acid reflux. Patients typically present with odynophagia, dysphagia, and retrosternal chest pain. Esophagitis (not inhaled, but swallowed)
Adverse Effects and Contraindications
Adverse effects
- Endocrine:
- Cushingoid features
- Cushing syndrome
- Hyperglycemia and diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
- Growth suppression in children and adolescents
- Weight gain
- Immunologic/infectious:
- Thrush
- Immunosuppression → invasive infections
- Hematologic: neutrophilia from demargination
- GI:
- Ulcers
- Gastritis Gastritis Gastritis refers to inflammation of the gastric mucosa. Gastritis may occur suddenly (acute gastritis) or slowly over time (chronic gastritis). Gastritis may be asymptomatic or with symptoms, including burning abdominal pain (which either worsens or improves with eating), dyspepsia, nausea, and vomiting. Gastritis
- Neurologic:
- Psychosis
- Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
- Irritability
- Anxiety
- Mood lability
- ↑ Appetite
- Ophthalmologic:
- Glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
- Cataracts
- Musculoskeletal:
- Myopathy:
- Proximal muscle weakness
- Myalgias
- Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
- Osteonecrosis
- Myopathy:
- Dermatologic:
- Skin atrophy
- Striae
- Purpura
- Impaired wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing
- Hypertrichosis
- Withdrawal:
- Long-term therapy results in HPA-axis suppression
- Abrupt discontinuation may cause adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease
Contraindications and precautions
- Contraindications:
- Recent administration of live or live attenuated vaccines
- Systemic fungal infections
- Other uncontrolled active infections
- Use with caution with:
- Psychosis
- Uncontrolled hyperglycemia
- Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
- Diverticulitis or recent intestinal anastomoses → risk of perforation
- Severe hepatic or renal impairment
- Recent acute MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction → risk of wall rupture
Drug interactions
- ↑ Risk of ulcers and GI bleeding: NSAIDs
- ↓ Absorption of glucocorticoids:
- Proton pump inhibitors
- Antacids
- Bile acid sequestrants
- ↑ Metabolism of glucocorticoids due to induction of CYP3A4:
- Phenobarbital
- Phenytoin
- Rifampin
- ↓ Metabolism of glucocorticoids due to inhibition of CYP3A4:
- Ritonavir
- Clarithromycin
- Voriconazole
- Dosing adjustment may be necessary for antidiabetic agents.
References
- Gabros, S., Nessel, T.A., Zeto, P.M. (2020). Topical corticosteroids. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK532940/
- Yasir, M., et al. (2021). Corticosteroid adverse effects. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK531462/
- Corticosteroids: drug information. UpToDate, retrieved from https://www.uptodate.com/contents/table-of-contents/drug-information/general-drug-information
- Nieman, L.K. (2021). Pharmacologic use of glucocorticoids. UpToDate. Retrieved November 7, 2021, from https://www.uptodate.com/contents/pharmacologic-use-of-glucocorticoids
- Saag, K.G., Furst, D.E. (2021). Major side effects of systemic glucocorticoids. UpToDate. Retrieved November 7, 2021, from https://www.uptodate.com/contents/major-side-effects-of-systemic-glucocorticoids
- Chatham, W.W. (2021). Glucocorticoid effects on the immune system. UpToDate. Retrieved November 7, 2021, from https://www.uptodate.com/contents/glucocorticoid-effects-on-the-immune-system
- Hodgens, A., Sharma, T. (2021). Corticosteroids. StatPearls. Retrieved November 7, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK554612/
- Gabros, S., Nessel, T.A., Zito, P.M. (2021). Topical corticosteroids. StatPearls. Retrieved November 7, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK532940/
- Liang, T.Z., Chao, J.H. (2021). Inhaled corticosteroids. StatPearls. Retrieved November 7, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK470556/
- Chrousos, G.P. (2012). Adrenocorticosteroids & adrenocortical antagonists. In: Katzung, B.G., Masters, S.B., Trevor, A.J. (Eds.), Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, pp. 697–713). https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf
