Glucocorticoids Flashcards
What is the natural function of glucocorticoids?
The natural function of glucocorticoids is to protect glucose-dependent cerebral functions.
How do glucocorticoids protect glucose-dependent cerebral functions?
- Stimulating the formation of glucose by the liver
- Decreasing the peripheral utilization of glucose
- Promoting its storage as glycogen
The protective functions of glucocorticoids serve to?
These effects protect the glucose dependent tissues, the brain and heart, from starvation
If glucocorticoids do not perform their functions, what happens?
- Muscle wasting
- Delayed wound healing
- Thinning of the skin
List the Physiological roles of glucocorticoids:
- Increase gluconeogenesis
- Decrease protein synthesis
- Increase lipolysis → release of glycerol and free fatty acids
- Glucocorticoids during fasting contribute to the maintenance of glucose concentrations
- ↑ the release of glucose by the liver
- ↑ gluconeogenesis and glycogen synthase
Gluconeogenic precursors
→ amino acids and glycerol
Describe the effects of glucocorticoids on the development of pulmonary surfactant in the near-term fetus (lung maturation)
→ GCs stimulate the synthesis of surfactant proteins
→ Glucocorticoid receptor (GR) knockout mice do not survive because of lung atelectasis (partial/complete collapse of the lung)
→ prematurity with delayed development of the adrenal axis in foals has been suspected as a cause of neonatal respiratory distress syndrome
GCs have an ________ effect to that of insulin: ___ glucose production from amino acids (___________)
antagonistic, ↑, gluconeogenesis
GCs enhance lipolysis. GC excess may cause redistribution of ____ → stimulation of ____
and thus stimulating __________, which results in ___________.
fat, appetite, hyperinsulinemia, lipogenesis
➢ GCs inhibit bone formation by inhibiting _________ proliferation and the synthesis of bone _____ while stimulating _________ activity.
osteoblast, matrix, osteoclast
In adult dogs, 2 mg/kg __________ for 30 days reduced bone mineral density by 14%
Costa et al. 2010
prednisone
What are the cardiorespiratory effects of glucocorticoids?
➢ GCs have direct positive ___________ and ____________ actions on the heart
➢ They may induce __________ in animals and humans
➢ Increase the number and affinity of _____-___________ receptors
➢ They also increase the expression of ______-________ receptors in the vascular smooth muscle
➢ GCs have direct positive chronotropic and inotropic actions on the heart
➢ They may induce hypertension in animals and humans
➢ Increase the number and affinity of beta-adrenergic receptors
➢ They also increase the expression of alpha-adrenergic receptors in the vascular smooth muscle
How do glucocorticoids affect water and electrolyte balance?
GC use –> PU/PD –> Inhibition of ADH release (vasopressin, antidiuretic hormone)
GCs increase the glomerular filtration
Pharmacological doses of GCs stimulate the excessive production of _____ and _____ in the stomach and may cause _____ _____.
Consider also:
→Patients under ____ or
→receiving other drugs that contribute to GI damage (______)
acid, pepsin, peptic ulcer
stress, NSAIDs
GCs facilitate ____ absorption.
GCs ________ the effect of vitamin D on calcium absorption.
fat
antagonize
Pharmacological use of GCs can have what effect on the liver? Are these effects reversible?
Hepatomegaly and elevated liver enzyme activity.
The effects of GCs are slowly reversible
(1 to 1.5 months after therapy is discontinued)
Immune and hematological effects
➢ GCs results in alterations in the concentration, distribution and function of peripheral _________.
➢ ___________ production is generally unaffected by moderate dosages of GCs. An inhibition is caused only at _____ dosages and with _______-term therapy
➢ GCs inhibit ______-induced interferon synthesis
➢ GCs can induce _________ on normal lymphoid cells
➢ GCs inhibit monocyte differentiation into _________ and ___________ _________
➢ GCs results in alterations in the concentration, distribution and function of peripheral leukocytes
➢ AB production is generally unaffected by moderate dosages of GCs. An inhibition is caused only at high dosages and with long-term therapy
➢ GCs inhibit virus-induced interferon synthesis
➢ GCs can induce apoptosis on normal lymphoid cells
➢ GCs inhibit monocyte differentiation into macrophages and macrophage phagocytosis
What are the principles of rational glucocortioid therapy?
What is the physiological replacement therapy of glucocorticoids?
It involves use of GC in amounts like those of the naturally occurring GCs (cortisol) from the adrenal cortex
* Adrenalectomized and Addisonian dogs and cats
* It is rarely indicated in large animals
Hydrocortisone or cortisone at 0.2-1 mg/Kg day
Prednisolone or prednisone at 0.1-0.2 mg/Kg day
As a rule, animals produce approximately 1 mg/Kg of cortisol (hydrocortisone) every day
The effect of GC in all forms of shock may be controversial
➢ Evidence suggests GCs may lead to increased survival in _______ and _____ _______
➢ Therapy for shock should also include _____ therapy
➢ Suspected endotoxic shock should be treated with a (2)?
➢ Proponents of GCs therapy for shock point out → _____-term ( ͂ ___ h) therapy has few negative effects, and the positive effects outweigh the risks
➢ The __________ effects of GCs make their use contraindicated during chronic sepsis!
The effect of GC in all forms of shock may be controversial
➢ Evidence suggests GCs may lead to increased survival in hemorrhagic and septic shock
➢ Therapy for shock should also include fluid therapy
➢ Suspected endotoxic shock should be treated with a broad-spectrum antimicrobial and
fluid therapy
➢ Proponents of GCs therapy for shock point out → short-term ( ͂ 48 h) therapy has few
negative effects, and the positive effects outweigh the risks
The immunosuppressive effects of GCs make their use contraindicated during chronic sepsis!
What are the concerns with using GCs as anti-inflammatory and anti-allergenic therapy? List examples.
Concerns:
→ such diseases are difficult to definitively diagnose
→ misuse of GCs is not uncommon
Examples of these uses are:
* Symptomatic treatment of pruritic dermatoses
* Allergic pulmonary disease
* Allergic gastroenteritis
➢ Prednisolone or prednisone is most used in ______ animals
→ Induction: at 0.55 mg/Kg q 12 h given orally
→ and then maintenance: 0.55 - 2.2 mg/Kg every other (EOD)
All the dosages should be adjusted according to effect
➢ Prednisolone or prednisone is most used in small animals
→ Induction: at 0.55 mg/Kg q 12 h given orally
→ and then maintenance: 0.55 - 2.2 mg/Kg every other (EOD)
All the dosages should be adjusted according to effect
What is the disadvantage of using depot products?
Drug dosage cannot be stopped or reduced
List the long-acting injectable GC products.
Some long-acting injectable products
* Prednisolone acetate → 1 – 2 days
* Dexamethasone in propylene glycol → 1 – 7 days
* Triamcinolone → 3 – 7 days
Immune dysregulation is likely caused by?
➢ Immune dysregulation: It is likely multifactorial
* Genetic factors
* Environmental triggers
Environmental triggers:
* Infectious agents
* Drugs
* Vaccines
* Neoplasia
Immune system may be appropriately or inappropriately triggered
➢ Lymphocyte dysfunction:
→ failure of lymphocyte ________
→ generation of _______ or ___ cells toward self-antigens
The inappropriately response:
Tissue _________ and clinical __________
➢ Lymphocyte dysfunction:
→ failure of lymphocyte selection
→ generation of antibodies or T cells toward self-antigens
The inappropriately response
Tissue destruction and clinical disease
List Some of the common systemic inflammatory diseases with an immune-mediated etiology in dogs and cats
What are the treatment goals?
- Inflammatory bowel disease (IBD)
- Immune-mediated hemolytic anemia (IMHA)
- Immune-mediated thrombocytopenia (IMT)
- Immune-mediated polyarthritis (IMPA)
Treatment goals
Induce disease remission by inhibiting inflammation and modulating
lymphocyte function while minimizing adverse drugs effects
Glucocorticoids remain the mainstay of first line treatment of ________ and ________-mediated diseases in dogs and cats despite their long list of clinically ______ side effects
Glucocorticoids remain the mainstay of first line treatment of inflammatory
and immune-mediated diseases in dogs and cats despite their long list of
clinically limiting side effects
List the GCs that act as immunosuppressive drugs.
- Cyclosporine
- Azathioprine
- Chlorambucil
- Mycophenolate
It is highly recommended to use a glucocorticoid with ____-documented side effects
–> During acute illness, you should use the
_________ immunosuppressive recommended dosage until clinical signs decline
→ After that point, _________ taper the dose of GCs
well
→ Use highest immunosuppressive recommended dosage until clinical
signs decline
→ After that point, slowly tapering the dose of GCs
What is important to remember when using GCs for immunosuppressive therapy?
- The therapy should not be discontinued until the autoimmune disease is in remission
for 2- 3 months (recurrence of signs) - If GCs provide incomplete remission, other immunosuppressant agents such as the alkylating agent cyclophosphamide may be added
➢ GCs administration to dogs for longer than 2 weeks results in significant loss of __________ functional reserve
➢ Administration of greater than ____ mg/Kg/day of prednisolone or an equipotent dosage of a more potent drug for longer than ___ weeks should be considered chronic therapy
A _______ reduction of the dosage is indicated!
➢ GCs administration to dogs for longer than 2 weeks results in significant loss of adrenal functional reserve
➢ Administration of greater than 0.5 mg/Kg/day of prednisolone or an equipotent dosage of a more potent drug for longer than 2 weeks should be considered chronic therapy
A gradual reduction of the dosage is indicated!
The cellular effects of GCs are
dose-dependent
At anti-inflammatory doses, GCs inhibit
- Phospholipase A2
- Release of pro-inflammatory cytokines
At immunosuppressive doses, GCs target macrophage function by
- Downregulating Fc receptor expression
- ↓ responsiveness to antibody-sensitized cells
- ↓ antigen processing
Prednisone and prednisolone for immunosuppressive therapy
Prednisone is a _________ → Prednisolone
Cats achieve higher _______ concentrations when administered oral prednisolone
versus prednisone
Prednisone is a prodrug → Prednisolone
Cats achieve higher plasma concentrations when administered oral prednisolone
versus prednisone
➢ Dexamethasone for immunosuppressive therapy → lacks ____________ activity
mineralocorticoid
The term “mineralocorticoid” is used to describe those actions of adrenal corticosteroids producing sodium and fluid retention and potassium excretion.
➢ Budesonide for immunosuppressive therapy
Soft corticoid
Kind of drug that is supposed to be delivered in a place where they have to act.
Very commonly used in IBD in dogs.
Adverse reactions less if given via systemic circulation.
- The immune-suppressing effect of GC’s require ______ doses
- 2 mg/Kg per day of ____________ for the treatment of IMHA
- Initial (induction) dosage regimens employ daily doses of 2.2 to 6.6 mg/Kg/day
(prednisolone or prednisone) - Initial doses generally are in the range of 2 – 4 mg/Kg/day
- After induction period, if the patient responds favorably, the dose may be decreased by approximately _____%
- For immune-mediated disease, maintenance doses of 1 mg/Kg are possible
- The immune-suppressing effect of GC’s require high doses
- 2 mg/Kg per day of prednisolone for the treatment of IMHA
- Initial (induction) dosage regimens employ daily doses of 2.2 to 6.6 mg/Kg/day
(prednisolone or prednisone) - Initial doses generally are in the range of 2 – 4 mg/Kg/day
- After induction period, if the patient responds favorably, the dose may be decreased by approximately 50%
- For immune-mediated disease, maintenance doses of 1 mg/Kg are possible
When do you use GCs for immunosuppressive therapy?
Immunosuppressive therapy: Every other day therapy (EOD)
* When using an intermediate acting drug (12 – 36 hours)
* It is not supposed for GC with long duration activity
* EOD therapy will minimize, but will not prevent adrenal atrophy
What are the side effects of using GCs for immunosuppressive therapy?
MAIID GO
- Iatrogenic hyperadrenocorticism
- Adrenal gland suppression
- Gastrointestinal ulceration
- Insulin resistance
- Muscle catabolism
- Delayed wound healing
- Opportunistic infections
In healthy dogs, GC treatment with prednisone (2mg/Kg/day) for 28 days
resulted in endoscopic evidence of __________ _________ after 14 days of treatment
gastric ulceration
The importance of close monitoring and clinical vigilance during
steroid treatment
It is important to monitor GC use in patients with:
* __________ or _____-_________ GC side effects
* Lack any clinically significant response to steroids with ___ or ____ days
- ___________ immunosuppressive drugs need consideration
It is important to monitor GC use in patients with:
* Intolerable or life-threatening GC side effects
* Lack any clinically significant response to steroids with 7 or 14 days
Alternative immunosuppressive drugs need consideration
Glucocorticoid supplementation during stress
–> Animals with marginally _______ or ________ adrenal function
Situation of minor stress = 4?
Prednisolone or prednisone at 0.4 -1 mg/Kg
–> Animals with marginally adequate or deficient adrenal function
Situation of minor stress
* Minor surgery
* General anesthesia
* Minor illness
* Visit to the veterinarian
Prednisolone or prednisone at 0.4 -1 mg/Kg
In severely stressful situations → ______ surgery (including adrenalectomy)
__________ ___________ can be given IM at 0.4 – 2 mg/Kg
major, adrenalectomy, Prednisolone acetate
- The anti-inflammatory dose is __ times the physiologic dose
- The immunosuppressive doses are ________ the anti-inflammatory dose
- Shock doses of GCs have been reported at ___ to ___ times the immunosuppressive dose
- The anti-inflammatory dose is 10 times the physiologic dose
- The immunosuppressive doses are twice the anti-inflammatory dose
- Shock doses of GCs have been reported at 5 to 10 times the iimmunosuppressive dose
