Module 24

Question 1

List 20 or more side-effects of chronic corticosteroid use. What is the danger associated with adrenal suppression, and how is it tested?

Answer 1

• In most patients corticosteroids cause an increased feeling of wellbeing, but in others it can cause depression, anxiety, and attention deficit.
  
  • It can also cause metabolic effects such as diabetes, sodium retention, hypertension, potassium loss, fluid retention, increases in LDL cholesterol resulting in atherosclerosis and cardiovascular disease, adrenal suppression and weight gain.
  • It can also cause glaucoma, cataracts, cerebral edema, osteoporosis, osteonecrosis (usually the hip), moon faces (very obvious in children treated with high doses of prednisone for various disorders), buffalo hump, truncal obesity, abdominal striae (stretch marks), muscle atrophy, thinning of the skin, immunosuppression with increased risk of infections, lymphopenia, peptic ulcers, hepatic steatosis, hirsutism, thinning of scalp hair, and acne. I have probably forgotten some of the many side effects.
  • Treatment with corticosteroids results in feedback inhibition of cortisol production in the adrenal glands. If this is sustained for a matter of weeks, the adrenal glands loose their ability to respond to ACTH, and if a patient is stressed and cannot produce cortisol they can go into shock and die. If a patient has been on systemic steroids for an extended period of time the degree of adrenal suppression can be tested with the corticotropin or ACTH stimulation test which measures the response of the adrenal gland to corticotropin.

Question 2

How does the half-life of prednisone compare with its duration of action and why? What is the time to onset of the action of prednisone. What is the best time of the day to take steroids and why? What is the rationale for using alternate day steroids, and when is it inappropriate? Compare oral with inhaled and topical in terms of toxicity profile.

Answer 2

• The pharmacokinetic half-life of prednisone is less than 4 hours; however, its pharmacological effects last from 12-36 hours. That is because it affects the expression of hundreds of corticosteroid-responsive genes and probably other things as well.
  ○ The products of these genes have a longer half-life than prednisone. It also takes time for these gene products to be synthesized; therefore, there is a delay in the onset of the effects of prednisone.
  ○ Many effects take on the order of 24 hours to be significant. That is why it is not useful for acute conditions such as an acute asthma attack.
  
  • There is a normal diurnal pattern of steroid release with the highest release in the morning. Therefore, it is best to mimic this pattern by giving steroids in the morning, which for one thing promotes wakefulness.
  • A major problem with the use of corticosteroids is that with chronic use they lead to adrenal suppression that is not readily reversible as described above.
    ○ With alternate day steroids, the steroid effects have decreased at 48 hours, and this ends the feedback inhibition of ACTH release and decreases the adrenal suppression.
    ○ However, there are some diseases such as temporal arteritis in which daily steroids are required, in this case to prevent blindness.
  • Topical and inhaled steroids are associated with much fewer side-effects; however, even they can cause serious side-effects. When potent steroids are used over a large surface area such as in psoriasis there can be significant absorption, and there are cases of aseptic necrosis of the hip associated with topical steroids. Fluorinated steroids, which are quite potent, can cause irreversible thinning of the skin when applied to the face. Even inhaled steroids may cause side-effects such as oral candidiasis, and they may decrease growth rate in children, although that is somewhat controversial.

Question 3

Why is the steroid prednisone used in preference to “natural” cortisol for most indications? When would it be inappropriate to use prednisone instead of cortisol? What is the theoretical basis for using prednisolone rather than prednisone in patients with liver disease?

Answer 3

• Prednisone is used for its antiinflammatory (glucocorticoid effects), and it has less undesirable mineralocorticoid side-effects such as edema than cortisol.
  ○ However, if a patient cannot make cortisol, e.g. Addison’s disease, prednisone would not be appropriate treatment because without the mineralocorticoid effects of cortisol the patient would go into shock and die.
  
  • Prednisone is a prodrug that is converted to the active agent, prednisolone, in the liver.
  • Therefore, in theory, prednisone might not be effective in someone with liver disease. However, it takes very little metabolic activity to convert prednisone to prednisolone, and therefore this is more of a theoretical problem than a practical issue.

Question 4

How may corticosteroids interfere with the immune response to infections? Are corticosteroids contraindicated in all infections?

Answer 4

• Corticosteroids depress most of the elements of the immune system and can make most types of infections worse. The use of corticosteroids can unmask latent infections, especially tuberculosis, amebiasis, and toxoplasmosis.
  
  • Vaccination with live vaccines is contraindicated in patients on systemic corticosteroid therapy.
    ○ Viral infections such as chickenpox and measles can be much worse and even fatal in patients on significant doses of corticosteroids.
  • Yet there are infections in which corticosteroids are used. In some types of eye infections they decrease the inflammation that could result in clouding of the cornea. Much of the brain damage that occurs with bacterial meningitis is due to inflammation and brain edema, and sometimes corticosteroids are used to decrease the inflammation and edema in patients with bacterial meningitis.

Question 5

Why did president Kennedy always look like he had a suntan?

Answer 5

• President Kennedy had Addison’s disease, which is an autoimmune disease that destroys the adrenal glands and their ability to produce cortisol.
  
  • This increases the production of ACTH to try to increase the production of cortisol. The precursor of ACTH (pro-opiomelanocortin) is the same as for melanocyte-stimulating hormone; therefore, there is also an increase in melanocyte-stimulating hormone and an increase in skin pigmentation