Glucocorticoids Flashcards
How much cortisol/day is produced?
How much is bound to circulating proteins?
How much is free and how much is bound to albumin
normally 10-20mg
most (90%) is bound to circulating proteins synthesized by the liver
5-10% is free and ~5% is loosely bound to albumin
the 1/2 life of cortisol is what?
what may increase the half life?
How is it metabolized?
How is it excreted?
~60-90 min
exogenous hydrocortisone is given, stress, hypothyroidism, liver dz
liver
urine
Cortisol’s effects
Influences the function of what?
Interacts with what?
most cells in the body
widely distributed glucocorticoid receptors & influence target genes
Cortisol’s effects - CHO, Protein & fat metabolism
Stimulates what in a fasting state?
Increased glucose levels/stimulation of insulin release results in what?
Stimulation of lipase/lipolysis & lipogenesis with what results?
gluconeogenesis & glycogen synthesis
inhibits glucose uptake by muscle
increase in fat deposition, increased fatty acid & glycerol release
Cortisol’s effects - Catabolic & anti-anabolic effects in skin, muscle fat, lymphoid, & connective tissue
Increased amounts of glucocorticoids = ?
decreased muscle mass, weakness, thin skin, osteoporosis
Cortisol stimulates RNA & protein synthesis where?
the liver
Cortisol’s effects - Anti-inflammatory
Affects activation, production, circulation, function & survival of what?
Increases neutrophils in peripheral circulation but decreases what cell counts?
Induction of apoptosis on what?
Decreases multiple inflammatory cytokines & interleukins (which ones?) and increases anti-inflammatory cytokines (which ones?)
Inhibits function of what cell type? limits the cells ability to do what?
leukocytes
monocytes, lymphocytes, (T&B cells), eosinophils, & basophils
immature & activated T cells
IL- 1, 2, 6, TNF); IL-4, 10, 13)
macrophages; phagocytose & kill microorganisms
Cortisol regulates the expansion of what?
the protein responsible for the conversion of NE to epi in adrenal medulla
Synthetic steroids are metabolized how?
however, alterations in glucocorticoid molecule alters what?
similarly as endogenous steroids
affinity for receptors & protein-binding affinity, stability, rate of elimination, & metabolic products
Synthetic steroids half lives are?
prolonged by > 50%
Synthetic steroids are sometimes administered as a prodrug ____ which is rapidly converted to active form ____)
prednisone –> prednisolone
Indications to administer synthetic steroids includes?
Adrenocortical insufficiency
Allergic rxns
Collagen-vascular d/os (arteritis, SLE, connective tissue disease, PMR, RA)
GI disease (IBS)
Hematologic disease (hemolytic anemia, leukemia, ITP, myeloma)
Infections/sepsis
Inflammation of bones/joints (arthritis, bursitis)
Pulmonary dz (asthma, COPD)
Transplantation
What is Critical Illness-Related Corticosteroid Insufficiency (CIRCI)?
Inadequate intracellular corticosteroid activity manifested by insufficient down regulation of pro-inflammatory transcription factors
How do we diagnose CIRCI?
CST: delta (change) in baseline cortisol @ 60 MIN OF < 9 ug/dL after cosyntropin (250 ug) administration & random plasma cortisol of < 10 ug/dL; not widely used in practice
use total cortisol level
What 3 major pathophysiologic events may be involved in CIRCI?
dysregulation of HPA axis
Altered cortisol metabolism
Tissue resistance to glucocorticoids
Clinical features of CIRCI - General
fever
asthenia
Clinical features of CIRCI - Neurologic
Confusion
Delirium
Coma
Clinical features of CIRCI - Cardiovascular
Hypotension refractor to fluid resuscitation
Decreased sensitivity to catecholamines
High CI
Clinical features of CIRCI - Digestive
Nausea
Vomiting
Intolerance to enteral nutrition
Clinical features of CIRCI - Respiratory
Persistent hypoxia
Clinical features of CIRCI - Laboratory
Hypoglycemia
Hyponatremia
Hyperkalemia
Metabolic Acidosis
Hypereosinophilia
Clinical features of CIRCI - Imaging
Hemorrhage or necrosis in hypothalamus, pituitary gland or adrenal gland
CIRCI occurs in severe acute conditions including?
Sepsis/septic shock
Severe CAP
ARDS
Cardiac Arrest
Head Injury
Trauma
Burns
Major Surgery
Treatment for CIRCI?
IV hydrocortisone < 400mg/day for >/= 3 days @ gfull dose in patients with septic shock not responsive to fluid & moderate- to high-dose vasopressor therapy (conditional, low quality evidence)
Results of Annane Trial?
Patients were randomly assigned to receive either hydrocortisone (50mg IV q 6 hrs) & fludrocortisone (50 nanogram qd) or placebo x 7days
7-day treatment w/ low doses of hydrocortisone & fludrocortisone significantly reduced risk of death in patients with septic shock & relative AI w/o increasing adverse events
Hydrocortisone MOA
decreases inflammation via suppression of migration of PMN leukocytes & reversal of increased cap permeability
Hydrocortisone Drug interactions
Decreased effect of what drugs?
Increased effect of what drugs?
insulin, phenytoin, phenobarb, rifampin d/t increased metabolism of drug
may increase PT with anticoagulants, increase risk of hypokalemia with diuretics, increase risk of arrhythmias or dig toxicity d/t hypokalemia
Hydrocortisone Pharmacokinetics
Can be given which routes?
onset of action?
Absorption?
1/2 life?
metabolism?
excretion?
Dose?
topical (acetate), IV (succinate), IM
acetate (slow), succinate (rapid)
rapid
8-12 hrs
hepatic
urine
varies
Prednisone MOA
decreases inflammation via suppression of migration of PMN leukocytes & reversal of increased cp permeability; reduces activity & volume of lymphatic system
Drug interactions with prednisone
Decreased effect
Increase risk of GI ulceration when used w/ what?
barbituates, phenytoin, rifampin
NSAIDs
Pharmacodynamics/kinetics of Prednisone
Form?
1/2 life?
Metabolism?
Excretion?
Dose?
PO
18-36 hrs
hepatic
urine
varies
Methylprednisolone Drug Interactions
Decrease what drugs effects?
Increases what?
insulin’s effect d/t increased glucose levels, phenytoin, phenobarb, rifampin increase metabolis of drug = decreased levels
CSA & tacrolimus levels, intraconazole increases steroid levels
Methylprednisolone Pharmacodynamics/kinetics
forms?
Onset of action?
Duration of action?
1/2 life?
Metabolism?
Excretion?
PO, Intra-articular, IM, IV
PO (1-2 hrs), Intra-articular (1 wk), IM acetate (4-8days), & IV succinate (rapid)
PO (30-36 hrs), intra-articular (1-5 wks), IM (1-4 wks)
18-36hrs
hepatic
urine
Dexamethasone MOA
Decreases inflammation via suppression of neutrophil migration, decreases production of inflammatory mediators, & reduces cap permeability
Dexamethasone drug interactions
decreased effect in what drugs?
increased effect in what drugs
isoniazid & phenytoin levels may be decreased, may see reduction in coumadin effect
‘azoles’, CCBs, CSA, estrogens may increase levels. NSAIDs & aspirin may increase risk of adverse GI effects. +/- increased weakness if receiving anticholinergics & neuromuscular blocking agents
Dexamethasone Pharmacodynamics/kinetics
Forms?
Onset of action?
1/2 life?
Duration of action?
Metabolism?
Excretion?
PO, IM, IV
prompt
36-54 hrs
72hrs
hepatic
urine & feces
Steroid Generalities - Adverse Effects
Cushing’s Syndrome presents as?
Moon faces
redistribution of fat from extremities to trunk, back of neck, supraclavicular fossae
Increased hair growth to face, thighs, turnk
acne
weight gain
thinning skin, striae, bruising
hyperglycemia
osteoporosis, DM, aseptic necrosis of hip
muscle weakness/wasting
Steroid Generalities
Other adverse effects
Infections
peptic ulcers
myopathy
hypomania, acute psychosis
depression
cataracts
Glaucoma
Na/H2O retention when cortisone, hydrocortisone given supraphysiologic doses
Adrenal suppression (usually not seen until after 2-3 weeks of therapy, qd dosing is less suppressive than divided doses)
ACTH stimulation test may be used to detect adrenal insufficiency - how is it done?
- measure baseline cortisol level
- inject 250 mcg cosyntropin IM or IV
- meausre cortisol level @ 30 & 60 min (level should be >18 mcg/dL
Use steroids w/ caution in what conditions?
PUD
Heart Disease
HTN
CHF
varicella
TB
psychosis
DM
osteoporosis
glaucoma
Avoid administering what while on steroids?
live vaccinations
In elderly what precautions should be made with steroids?
use the smallest effective dose for shortest amount of time
