Corticosteroids

Question 1

Describe the corticosteroid stress response and how it can be triggered.

Answer 1

Stressful situations can override the negative feedback of cortisol at the hypothalamus and anterior pituitary leading to elevated levels of cortisol. Increased levels of cortisol are closely associated with immune suppression.

Possible triggers include pain, fear, cold, major surgery, trauma, injury, hemorrhage, hypoglycemia, and severe infection.

Question 2

What is meant when corticosteroids are described as pleiotropic and permissive in their actions?

Answer 2

Corticosteroids have action at widespread locations including: metabolism, fluid balance, CV, skeletal, immune, renal, endocrine, and nervous systems.

The permissive action of corticosteroids means it modifies tissues responsiveness to other hormones.

Question 3

How is mineralocorticoid specificity preserved?

Answer 3

MR is localized to certain tissues, such as kidney, colon, salivary glands, sweat glands, and hippocampus. Also, these tissue express 11Beta-hydroxysteroid dehydrogenase, an enzyme which inactivates cortisol by converting it to cortisone. Aldosterone is resistant to this enzyme.

Question 4

Describe the effects of cortisol on metabolism of carbs, proteins, and lipids.

Answer 4

Corticosteroids produce an anti-insulin effect and stimulate proteinolysis, lipolysis, and gluconeogenesis.

Redistribution of fat occurs as central adipocity: decreased peripheral fat with abdominal deposition, buffalo hump, and moon face.

Question 5

Describe the effects of mineralocorticoids and glucocorticoids, individually, on electrolyte/fluid balance and the cardiovascular system.

Answer 5

Mineralocorticoids

Induce sodium retention and potassium and hydrogen secretion at the collecting duct and tubules. This can result in hypertension, hypokalemia, and alkalosis. Mineralocorticoid-induced hypertension can result in atherosclerosis, cerebral hemorrhage, CVA, or cardiomyopathy. Control HTN with monitored dietary Na intake.

Glucocorticoids

Their effect on electrolyte and fluid balance is more passive by stimulating the secretion of Ca in the kidneys and preventing absorption in the gut. Glucocorticoids also have a permissive effect on adrenergic receptors of the cardiovascular system.

Question 6

What are the effects of corticosteroids on skin and muscle?

Answer 6

Thinning of the skin and muscle wasting

Question 7

What are the effects of corticosteroids on the CNS?

Answer 7

Aside from the support provided by the indirect effects, glucocorticoids can cause elevation of mood, insomnia, restlessness, and euphoria. A small percentage may experience anxiety, depression, and overt psychosis.

Question 8

Describe how corticosteroids interact with the formed elements of the blood and the immune system. How does the immune system normally interact with the HPA axis?

Answer 8

Formed elements of blood

Corticosteroids cause the peripheral redistribution of monocytes, eosinophils, basophils, and lymphocytes. PMNs, platelets, and RBCs are increased.

Immune system

Corticosteroids inhibit the formation of many cytokines which play key roles in the immune response: PGs, LKTs, ILs, TNFalpha, Intrerferon, and GM-CSF. In the normal immune response IL-1 triggers CRH and ACTH production at the hypothalamus and anterior pituitary to prevent full blown inflammation.

Question 9

Describe the relative potency of glucocorticoids with respect to effects on metabolism, inflammation, and sodium retention.

Answer 9

Those with potency in sodium retention, have a direct correlation to their ability to sustain life in adrenalectomized patients.

Those with metabolic effects closely parallel those with anti-inflammatory effects

Question 10

What are the short-acting glucocorticoids?

Answer 10

Cortisol (hydrocortisone) and cortisone

Question 11

What are the intermediate acting glucocorticoids?

Answer 11

Prednisone, Prednisolone, and Methylprednisolone

Question 12

What are the long-acting glucocorticoids?

Answer 12

Dexamethasone

Question 13

What are the two categories of toxic effects from corticosteroid therapy?

Answer 13

Withdrawal toxicities and supraphysiologic dose toxicities

Question 14

What are the withdrawal effects?

Answer 14

The most frequent problem is flare-up.

The most severe problem is too rapid withdrawal leading to HPA suppression and acute adrenal insufficiency. Recovery from suppression takes weeks to a year.

Any individual with supraphysiologic doses for two weeks within the past year should be considered HPA suppressed in acute stress situations.

Less severe withdrawal - fever, myalgias, arthalgias, and malaise

Question 15

What are the toxic effects of corticosteroids with respect to the HPA axis, fluid/electrolyte balance, Immunity, and gastric mucosa?

Answer 15

HPA axis suppression can cause life-threatening susceptibility to stress

Fluid/electrolyte balance - hypertension, hypokalemia, alkalosis, and edema

Immunity - increased susceptibility to infections

Gastric mucosa - Pt.s taking NSAIDs are increased risk for peptic ulcers

Question 16

Describe the toxic effects of corticosteroids with respect to MSK, growth, behavior, and eyes.

Answer 16

MSK

Myopathy occurs in proximal muscles and manifests as weakness. Recovery is slow and partial. Osteoporosis occurs due to the effects on calcium secretion and absorption, as well as the inhibitory effects on osteoblasts. Low calcium activates osteoclasts leading to osteoporosis and veretebral compression fractures. Osteonecrosis can also occur, and manifests as joint pain or stiffness. Osteonecrosis ultimately requires joint replacement.

Growth is retarded in children who take repeated low doses

Behavior - changes in mood, insomnia, anxiety, and possibly overt psychosis

Eyes - cataracts, which are dose and duration dependent, will develop and may not resolve with discontinuation

Question 17

What two situations would not warrant consideration of harmful effects linked with corticosteroids?

Answer 17

1. A single dose, even very large, is without ADRs

2. A short course of therapy, up to one week and in the absence of CIs, is typically not harmful.

Question 18

When is corticosteroid therapy constituted curative and palliative?

Answer 18

The only situation in which corticosteroids are curative are replacement therapies for deficiency syndromes. All other situations are considered palliative.

Question 19

Describe a general approach to dosing corticosteroids.

Answer 19

In symptomatic situations which are mild: initial doses should be low and increased gradually until symptoms are minimally tolerable.

In situation of symptomatic life-threatening disease: Doses should be high at first to control the crisis then gradually lowered. If a high dose is not effective, consider doubling or tripling the dose.

Question 20

Describe the two available therapeutic regimens and the situations in which they are used.

Answer 20

Alternate-day regimen - used for long-term therapy

Pulse-regimen - used for fulminant disorders

Question 21

Describe the effects of corticosteroids on the immune system.

Answer 21

Peripheral redistribution of eosinophils, basophils, monocytes, and lymphocytes
Increased circulating PMNs
Inhibition of recruitment
Inhibiton of APCs
Inhibition of IL-2R expression

Question 22

What are the methods and effets of glucocorticoids in the treatment of systemic AI diseases, rheumatoid arthritis, osteoarthritis, and vasculitis?

Answer 22

Systemic AI disease - mainstay of Tx; give high doses to control disease, then gradually taper.

Rheumatoid Arthritis - used to Tx flare-ups, pt.s who failed physiotherapy and NSAIDs, and gap Tx until Au salts or methotrexate kick in.

Osteoarthritis - can be injected into joints; limit frequency to prevent painless joint destruction

Vasculitis - combined with cyclophosphamide

Question 23

Describe the glucocorticoid Tx of asthma, renal disease, allergic disease, or infectious disease.

Answer 23

Asthma - prophylaxis of asthma and inflammatory COPD; can be used for asthma requiring hospitalizations

Renal Disease - SLE and nephrotic syndrome

Allergic disease - delayed action, often combined with epinephrine

Infectious Disease - P. jirovecii in AIDS pt.s and H. influenzae type B meningitis

Question 24

Describe the role of glucocorticoids in ocular disease

Answer 24

Applied topically to reduce inflammation. May cause posterior cataracts.

CIs = glaucoma, herpes simplex (dendritic keratitis), and mechanical injury (poor wound healing)

Question 25

Describe the role of glucocorticoids in skin disease.

Answer 25

Can be used for a variety of disease. Occlusive dressing increase absorption

Question 26

Describe the role of glucocorticoids in GI and hepatic diseases

Answer 26

Used to treat ulcerative collitis, Crohn’s disease, and hepatitis

Question 27

Describe the role of glucocorticoids in malignancies and cerebral edema

Answer 27

Used for antilymphocytic effects in ALL

Reduces cerebral edema due to neoplasms and parasites