Corticosteroids and Endocrine Therapy Flashcards
Adrenocorticosteroids
- Adrenal Cortex:
- Glucocorticoids
- effect on intermediary metabolism (Cortisol)
- Mineralicorticoids
- reabsorption of sodium and water
- Elimination of potassium (Aldosterone)
- Sex steroids
- Glucocorticoids
Hypothalamic-Pituitary-Adrenal Axis
Glucocorticoids:
Mechanism of Action
- Alter protein expression
- bind to intercellular receptors
- Translocated to the nucleus
- Bind to receptors on Glucocorticoid Response Element
- Effect RNA transcription and subsequent protein synthesis / expression
- Inhibition of nuclear factor Kappa-B (NF-kB)
- NF-kB is primarily a pro-inflammatory nuclear transcription factor
Glucocorticoids:
Cellular Effects
- PMN, Macrophages
- Decrease ability to engulf cells and process antigens
- immunosuppresive dosages
- Decrease adhesion, migration
- anti-inflammatory dosages
- Incease in mature circulating PMNs due to release from the marginal pool and decreased tissue migration
- Decrease ability to engulf cells and process antigens
- Lymphocytes
- T cell suppression Primary effect
- B cell antibody synthesis minimally affected at anti-inflammatory doses
- Lympholytic - higher doses
- Eosinophils / Basophils
- decreased migration and numbers
Glucocorticoids:
Cellular Effects:
Cytokine Inhibition
IL-1, IL-2, IL-6, TNF-a, histamine, bradykinin, serotonin, platelet activating factor
Glucocorticoids:
Cellular Effects:
Arachidonic Acid Pathway
- Inhibits phospholipase A2
- Prostaglandins
- Leukotrienes
- Prostacyclin
- Some inhibition of COX-2
Glucocortcoids:
Metabolic Effects:
Stimulate Gluconeogensis
Increase serum glucose
increase serum insulin
Decrease cellular uptake of glucose
Stimulation of lipogenesis and increased fat deposition
Glucocorticoids:
Metabolic Effects:
Catabolic and Antianabolic Effects
Decreased muscle mass and thinning
Decreased skin thickness
Osteoporosis
Glucocorticoids:
Other Effects
- Euphoria
- Feeling of well being
- Maturation of fetal lungs
- Low doses decrease CSF production
- High doses increase intracranial pressure
- Inhibition of arginine vasopression (ADH) release
- Phychogenic polydipsia
- Mineralocorticoid Effects:
- drug dependent
Glucocorticoid Usage
- Physiologic replacement
- prednisone
- Hydrocortisone
- Anti-inflammatory
- prednisone
- Immunosuppressive
- prednisone
- Shock Dose
- Methylprednisolone sodium succinate
- Only Solu-medrol for spinal trauma
Glucocorticoids:
Clinical Use:
Short Term Therapy
Administrated daily at anti-inflammatory doses without serious long-term adrenal adverse effects
Abrupt discontinuation can be performed
Glucocorticoids:
Clinical Uses
Long-term Therapy:
Titrate to lowest effective dose
Typically administered every other day
Recovery of adrenal function within 14 days
Corticosteroid Metabolism
Primarily hepatic metabolism
Minimal secreted in urine as unchanged drug
The pharmacologic effects persist beyond plasma concentrations
Choice of Corticosteroid:
Dogs
- Prednisone
- Pro-drug that is metabolized to prednisolone
- Prednisolone
- intermediate acting and administered EOD
- Dexamethasone - less common
- Longer duration, 2-3X per week
- Depo Medrol
- long acting repository formulation
- Not recommended systemically for dogs
Choice of Corticosteroid:
Cats
- Prednisolone is the corticosteroid of choice
- Intermediate acting and administered EOD
- Often require higher dosages than dogs to elicit similar effects
- More resistant to adverse effects
- Repository forms (Depo-Medrol) can be used in cats, but have increased adverse effects inc ats compared to prednisolone
- Dexamethasone is a reasonable alternative in cats
- 2-3X per week
Choice of Corticosteroids:
Horses
- Prednisone poorly absorbed and poorly converted
- Dexamethasone
- drug of choice
- Prednisolone
- OK, but costs more
Choice of Corticosteroid:
Cattle
- Dexamethasone
- drug of choice
- Low dose - no withdrawal time
- High dose - withdrawal time
Formulations:
Phosphate and Succinate Esters
Highly water soluble rapid onset
Methylprednisolone sodium succinate
Dexamethasone sodium phosphate
Formulations:
Solutions
Dexamethasone solution
Formulations:
Acetate and Acetonide ester suspensions
Poorly water soluble, prolonged absorption and effect
Methylprednisolone acetate
Glucocorticoids:
Adverse Effects
- PU/PD
- Polyphagia
- Increased ALP
- Hyperglycemia
- insulin resistance
- Secondary Infections
- Urinary tract infections
- Demodex
- Toxoplasmosis
- Fungal
- GI adverse effects
- Vomiting
- Diarrhea
- GI ulceration / perforation
- Atrophic Dermatopathy
- iatrogenic Cushing’s dz
- Steroid Hepatopathy
- Proteinuria, glomerular pathology
- Abortion (high doses / late gestation)
- Decrease bone / wound healing
- Adrenal atrophy
- Na+ / water retention (Mineralocorticoids)
- Peripheral Edema
- Hypertension
- Pancreatitis
- Behavioral Changes
- Cataracts
- Glaucoma
- Laminitis
Glucocorticoids:
Contraindications and Precautions
- Infectious disease
- Diabetes mellitus
- Liver disease
- Protein losing nephropathy
- Protein losing nephropathy
- Pregnancy
- Delayed wound / fracture healing
- Glaucoma
- Corneal Ulcer
- GIT ulceration / injury
Glucocorticoids:
Drug Interactions
- NSAIDs:
- increased risk of GI ulceration
- Insulin:
- Decreased efficacy of insulin
- Phenobarbital:
- Increased metabolism of corticosteroids
- Hypokalemia results in increased adverse effects of:
- Furosemide - hypokalemia
- Digoxin - Increased risk of toxicity dur to hypokalemia
Hypoadrenocorticism:
“Addison’s disease”
- Typically deficiency of glucocorticoids and mineralicorticoids
- Result:
- sodium loss
- Potassium retention
- arrhythmias, bradycardia, heart block
- Hypovolemia
- Supplement of mineralocorticoid and glucocorticoid
- fludrocortisone or desoxycorticosterone and prednisone or hydrocortisone
Hyperadrenocorticism:
Excessive production of cortisol:
In Dogs
- Pituitary adenoma resulting in excessive ACTH and subsequently excessive cortisol
- Or by a functional adrenal tumor
Hyperadernocirticism:
Excessive production of Cortisol
In horses
- Loss of dopaminergic inhibition of the pars pituitary intermedia resulting in increased release of proopiomelanocortin (ACTH Precursor) and subsequently increased release of ACTH and cortisol
Trilostane:
Mechanism of Action
- REVERSIBLE inhibition of B-hydroxysteroid dehydrogenase in the adrenal cortex primarily resulting in inhibition of glucocorticoid synthesis
- Mineralocorticoid synthesis is affected to a lesser extent
- Hepatic Metabolism
- Primarily used in dogs, rarely in horses
Trilostane:
Adverse Effects
- Vomiting, Nausea, Diarrhea, Lethargy
- Acute death rarely repoted
- Adrenal cortex necrosis - rare
Mitotane:
Mechanism of Action
- Cytotoxic effects of zona fasiculata and reticularis
Mitotane:
Pharmacokinetics
Oral absorption enhanced with food
Mitotane:
Adverse Effects
- Nausea, anorexia, vomiting
- Mild hypoglycemia
- CNS depression
- Hepatotoxicity
- Weakness, diarrhea, lethargy
- Destruction of Zona Glomerulosa resulting in addison’s disease
Pergolide:
Mechanism of Action
- Dopamine receptor agonist
- Suppresses ACTH release from pituitary
- Approved for use in horses
Pergolide:
Adverse Effects
- Inhibits release of prolactin
- Ataxia, Dyskinesia
- Anorexia, diarrhea, Colic
Feline Hyperthyroidism
- Most commonly functional thyroid adenoma
- Results in excessive secretion of thyroid hormone
- Weight loss:
- increased appetite, thirst and urination, Vomiting, diarrhea, hyperactivity, unkept hair coat, tachycardia, hypertension
- Treatment options:
- methimazole, I-131, surgery diet
Methimazole:
Mechanism of Action
- Competitive inhibitor of thyroid peroxidase
- decreases formation of T4, and T3
- Does not affect preformed thyroid hormone
- Does not inhibit conversion of T4 → T3
Methimazole:
Pharmicokenetics
- Oral, transdermal
- Good PO bioavailability
- Half-life ~ 3-4 hours
- Adjust dose based on T4 monitoring
Methimazole:
Adverse Effects
- Vomiting, anorexia most common
- Polyarthritis, alopecia, and scaling of head/face, anemia, thrombocytopenia
- Rare:
- vasculitis, bone marrow suppression
- Treatment may unmask renal dysfunction
I-131 Radioactive Iodine
- Use requires a radioisotope permit
- Singel SQ injection effective in more than 95% cases
- Rapidly absorbed and transported to thyroid gland
- Concentration in the adenoma resulting in selective toxicity
- Cats hospitalized in isolation for 3-5 days or until urine radioactivity drops to acceptable level
- Cats require restricted activity for 3 weeks as radioactivity in urine decreases
- Well tolerated, some cats have increased swallowing after initial treatment
