Understand the basic concepts regarding the role of corticosteroids within the body.
Understand the different roles for clinical corticosteroid use including physiologic, anti-inflammatory, and immune suppression.
Learn about the different types of corticosteroids, route of administration, duration of action, and relative potency.
Recognize the adverse reactions and common side effects associated with corticosteroid use.
Identify common laboratory changes associated with corticosteroid use.
Definitions, Physiology, and Mechanism of Action
Introduction
Basic Definitions
Corticosteroids: Class of chemicals produced by the adrenal cortex including the steroid hormones.
Two primary types of corticosteroids:
Glucocorticoids
Mineralocorticoids
Mineralocorticoids
Such as aldosterone, control electrolyte and water balance within the body.
Glucocorticoids
Such as cortisol and cortisone are important in control of carbohydrate, fat, and protein metabolism.
Augmentation of the immune and inflammatory systems.
Have many other mechanisms within the body.
Corticosteroid Physiology
Adrenal gland produces:
Mineralocorticoids
Sex hormones
Endogenous glucocorticoids
Adrenal cortex is comprised of three zones:
Zona glomerulosa
Zona reticularis
Zona fasciculata
Zona Glomerulosa
Superficial or outermost layer.
Secretion of mineralocorticoids.
Aldosterone: important in the regulation of electrolytes (sodium and potassium) and water balance within the body.
Zona Reticularis
Sex hormones, predominately the androgens.
Zona Fasciculata
Endogenous glucocorticoids cortisol and cortisone.
Hypothalamopituitary Axis (HPA Axis)
Hypothalamus:
Corticotropin releasing hormone (CRH)
Pituitary:
Adrenocorticotropic hormone (ACTH)
Adrenal glands:
Glucocorticoids (cortisol and cortisone)
Negative Feedback by ACTH and Glucocorticoid
Normal HPA Axis
Hypothalamus releases CRH which stimulates the Pituitary to release ACTH. ACTH stimulates the Adrenal cortex to produce Cortisol. Cortisol then provides negative feedback to both the Hypothalamus and Pituitary.
HPA Axis with Exogenous Steroids
Exogenous steroids will cause a decrease in CRH and ACTH release by negative feedback.
Mechanism of Action
Complex.
Two primary types of corticosteroid receptors:
Type I mineralocorticoid receptors
Type II glucocorticoid receptors
Mineralocorticoids and glucocorticoids have varying degrees of affinity for both.
Type II Glucocorticoid Receptors
All cells in varying concentrations.
Up or down regulation.
Found within the cytoplasm.
Variety of actions:
Gene transcription
Protein induction or inhibition
Mechanism of Action Depends on Dose
Physiologic
Anti-inflammatory
Immunosuppression
Physiologic Effects in Health
Corticosteroids required for normal daily functions.
Stimulate formation of glucose by the liver.
Decrease peripheral utilization of glucose.
Promotes storage of glucose as glycogen.
Promote lipolysis:
Generates free fatty acids that serve as substrates for hepatic glycogen synthesis
Maintaining renal blood flow and glomerular filtration.
Maintaining normal vascular tone.
Glucocorticoids and mineralocorticoids are essential in maintaining water and electrolyte balance within the body.
Clinical Use of Corticosteroids
General Concepts of Mineralocorticoid and Glucocorticoid Use
Mineralocorticoids
Predominant use in treatment of Addison's disease (hypoadrenocorticism).
Addison’s Disease is a failure of the adrenal gland to produce aldosterone and/or glucocorticoids.
Two most common treatment options for mineralocorticoid replacement:
Fludrocortisone
Desoxycorticosterone pivalate (DOCP)
Fludrocortisone (Florinef)
Mineralocorticoid with some glucocorticoid activity.
Dosed in dogs initially at 0.01 to 0.02 mg per kilogram orally daily.
Monitored every 1 to 2 weeks
Dosage increased by small increments until desired effect achieved
Addition of a glucocorticoid may not be necessary.
Failure to respond or develop adverse effects of excessive glucocorticoid administration.
Rarely used anymore due to convenience and generally excellent response to DOCP.
Desoxycorticosterone Pivalate (DOCP; Percortin)
Mineralocorticoid, no glucocorticoid activity.
Initially administered as 2.2 mg per kilogram intramuscularly or subcutaneously every 25 days.
May be maintained on as low as 0.8 to 1 mg per kilogram and dosing intervals of 28 to 30 days.
Not tapered more than 10% per month.
Sodium and potassium concentration monitored at 28 to 30 days after administration.
Glucocorticoids
Several different clinical uses of glucocorticoids.
To better facilitate understanding, we are first going to focus on prednisone since it is the most common glucocorticoid used in veterinary medicine.
Physiologic glucocorticoid replacement
Prednisone range 0.25 to 0.5 mg/kg/day
Anti-inflammatory
Prednisone range 0.5 to 1 mg/kg/day
Immunosuppression
Prednisone range 2 to 4 mg/kg/day
Physiologic Glucocorticoid Replacement
Indicated when failure of adrenal gland to produce enough glucocorticoids for maintenance of routine daily functions.
Relative adrenal insufficiency occurring secondary to critical illness and sepsis
Controversial topic as to significance
Prednisone dose ranges 0.25 - 0.5 mg/kg/day
Patients may need a slightly higher dose during perceived or anticipated times of stress
Anti-inflammatory Glucocorticoid
Indicated in sterile or idiopathic inflammatory processes and certain allergic conditions.
Prednisone dose range 0.5 – 1.0 mg/kg/day
Examples in which anti-inflammatory glucocorticoid use may be helpful include:
Atopy (Skin manifestations and otitis externa)
Allergic reactions
Feline asthma
Chronic bronchitis
Certain neurologic and ophthalmological inflammatory diseases
Airway swelling (acute exacerbations of tracheal collapse or laryngeal paralysis)
Immunosuppressive Glucocorticoids
Indicated in immune mediated diseases and in some cancer treatment protocols.
Treatment is typically extended
Secondary agent may be used to reduce glucocorticoid use and potential adverse effects
Prednisone dose 2 – 4 mg/kg/day
Examples in which immunosuppressive doses of glucocorticoids are indicated:
Immune mediated hemolytic anemia
Immune mediated thrombocytopenia
Inflammatory bowel disease (patients may be weaned down to lower anti-inflammatory doses)
Immune mediated polyarthropathy
Sterile immune mediated meningitis or meningoencephalitis
Part of a lymphoma treatment protocol
Selected Drugs and Preparations
Commonly Encountered Glucocorticoids
Prednisone and Prednisolone
Glucocorticoid with some mineralocorticoid activity.
Prednisone metabolized by liver to prednisolone.
Prednisolone is the active form.
Liver disease has minimal effect on metabolism.
Species variability in prednisone metabolism
Dogs- dosing considered equivalent between prednisone and the prednisolone
Cats- evidence suggests higher doses of prednisone (2 to 3 fold higher) required to achieve equivalent activity of prednisolone
Resources suggest using prednisolone in cats
Prednisone:
Only oral form
Prednisolone:
Oral
Injectable
Topical preparations
Dexamethasone
Highly potent glucocorticoid with virtually no mineralocorticoid activity
Most common injectable glucocorticoid
Does not interfere with ACTH stimulation testing for diagnoses of Addison's disease
Glucocorticoid of choice for management of suspected Addisonian crisis prior to ACTH stimulation testing
7 to 10 times more potent than prednisone
Often used for acute management of diseases
Especially if not eating or vomiting
Available in oral, injectable, and topical forms
Methylprednisolone
Potency and mineralocorticoid activity similar to prednisone
Two most common forms:
Methylprednisolone sodium succinate
short acting form
Methylprednisolone acetate
longer acting form
Injectable preparations most common
Methylprednisolone Sodium Succinate
Solu-Medrol
Short duration, rapid onset
Indications
Acute spinal trauma (controversial)
Acute severe inflammatory or immune mediated CNS conditions
Methylprednisolone Acetate
Depo-Medrol
Longer acting repository glucocorticoid
Indications
Difficult to medicate patients
Certain allergic conditions
Dosing intervals
Depend on response and disease process
One week to several months
Used carefully or avoided in certain diseases
Feline asthma
Immune mediated processes
Refractory signs or exacerbation of disease
Too rapid withdrawal/lack of tapering
Budesonide
“Soft" glucocorticoid
Local activity
Once absorbed, rapidly metabolized by liver
Used orally in management of inflammatory bowel disease
Reduced adverse glucocorticoid effects
Some patients still develop adverse signs and HPA axis suppression
Found in oral, topical, and inhalant preparations
Corticosteroid Potency and Half-Lives
Corticosteroid
Glucocorticoid Potency
Mineral Corticoid Potency
Biological Half-Life (Hr)
Cortisol
1
1
8-12
Hydrocortisone
0.8
1
8-12
Prednisone
4
0.8
12-36
Prednisolone
4
0.8
12-36
Methylprednisolone
5
0.5
12-36
Triamcinolone
5+
0
24-48
Dexamethasone
25-50
0
36-72
Betamethasone
25-50
0
36-72
Fludrocortisone
10
125-200
12-36
Deoxycorticosterone
0
20
Length of Treatment and Tapering Glucocorticoids
Use should be minimized and length of treatment be tailored to the specific disease process
Hypoadrenocorticism
May require lifelong therapy
Iatrogenic adrenal suppression or RAI
Taper performed over days to a few weeks
Acute allergic or inflammatory diseases expected to resolve quickly
Short courses, tapered over days to a couple of weeks
Chronic disease or immune mediated processes
Slowly tapered over several months
May require chronic therapy at lowest dose to control clinical signs
Patients intolerant to glucocorticoids or requiring long-term therapy may benefit from addition of secondary immunosuppressive agent
Adverse Effects of Corticosteroids
Glucocorticoids have an effect on virtually every cell type and system in mammals
Adverse effects range from minor "nuisance" to severe clinically significant side effects
"Nuisance" Adverse Effects
Polydipsia
Polyuria
Polyphagia
Panting
Clinically Significant Adverse Effects
Adverse effects more commonly observed with chronic therapy:
Steroid hepatopathy
Skin and hair coat changes (thinning of the skin, alopecia, ect..)
Decrease muscle mass and wasting
Fat accumulation
Altered mentation, behavior, energy
Adverse effects which may be associated with acute and chronic administration:
Gastrointestinal ulceration
Insulin resistance
Hypercoagulability, thromboembolism
Sodium and water retention leading to exacerbation of cardiac disease
Myopathies
Immune suppression
Laboratory Changes Associated with Glucocorticoid Use
Laboratory Changes
Serum chemistry profile
Increased ALP +/- ALT
Hypercholesterolemia
Hyperalbuminemia
Hyperglycemia
Increased amylase and lipase
Complete blood count
Thrombocytosis
Stress leukogram
Mild anemia
Urinalysis
Isosthenuria or hyposthenuria associated with PU/PD
Proteinuria
Decrease in pH
Primary Reference and Suggested Further Reading
Boothe, D and Mealey, K. Glucocorticoids and Mineralocorticoids. In: Boothe, editor. Small Animal Clinical Pharmacology and Therapeutics, Second Edition. Elsevier; 2012; pp. 1119-1149.