Pharmacology of Glucocorticosteroids Flashcards
1
Q
Glucocorticoids
A
- The adrenal cortex produces two major corticoids—glucocorticoids and mineralocorticoids.
- These hormones produce their effect by interaction with specific intracellular receptors.
- Binding of steroids to these receptors results in genomic effects.
- For glucocorticoids (GC) recent research has demonstrated that the transcriptional effects produced by the GC-receptor complex can be transactivation (increased RNA) or transrepression (decreased mRNA).
- These two different events are important in the anti-inflammatory effects produced by GC.
- For example, transactivation leads to the increased synthesis of certain anti-inflammatory proteins, while transrepression leads to decreased synthesis of inflammatory proteins.
- Transrepression appears to be a major factor in GC-anti-inflammatory activity.
- Development of drugs with greater transrepression activate and reduced transactivation may result in agents with reduced sideeffects/toxicities.
•GCs are also known to have non-genomic mechanisms of action, the effects of which occur more rapidly and are independent of protein synthesis.
2
Q
Therapeutic Uses of Corticosteroids
A
- Replacement therapy – Endocrine diseases associated with adrenal cortex insufficiency.
- Therapy in Non-endocrine Diseases - Pharmacological doses to suppress allergic, inflammatory and autoimmune disorders and as immunosuppressants to prevent acute transplant rejection.
3
Q
Adrenal Insufficiency
A
•Adrenal insufficiency can result from structural or functional lesions of the adrenal cortex (primary adrenal insufficiency or Addison’s disease) or from structural or function lesions of the anterior pituitary or hypothalamus (secondary adrenal insufficiency).
- Acute
- Chronic
4
Q
Acute Adrenal Insufficiency (AAI)
A
- Life threatening, with the lack of mineralocorticoid activity resulting in severe alterations in the homeostasis of the cardiovascular system.
- Treatment – management with iv fluids and bolus dose of corticosteroid (i.e. 100 mg hydrocortisone) followed by 50 to 100 mg every 8 hours. These doses of cortisol have sufficient mineral corticoid activity).
- (If a diagnosis of AAI is unconfirmed, 4 mg dexamethasone can be administered as it will not cross react with serum cortisol assay).
5
Q
Chronic Adrenal Insuffciency
A
•Primary – various glucocorticoid dosing options:
o Cortisol (short-acting)
o Prednisone (intermediate acting)
o Dexamethasone (long acting)
- Mineralocorticoid supplementation usually required (fludrocortisone)
- Secondary Chronic Adrenal Insufficiency – mineralocorticoid not required because zona glomerulosa is intact
6
Q
Notes about Treatment with Corticosteroids
A
- overtreatment leads to manifestations of Cushing’s
- enzyme inducers may require increased doses
- minor illness may require increased doses
- stress of surgery requires increased doses
7
Q
CAH Therapy
A
•goals are to restore physiological levels of steroid hormones and suppress ACTH.
Example: hydrocortisone 25-37.5 mg daily (can be given in 2 doses: 25 mg in a.m. and 12.5 mg in p.m. Fludrocortisone 0.05 to 0.2 mg per patient per day used for mineralocorticosteroid effect.
8
Q
GC Therapy in Non-Endocrine Diseases
A
- Cortisol and its synthetic analogs have widespread use in the treatment of a variety of diseases that appear unrelated to disturbances of adrenal function.
- These agents are useful in disorders in which host response is the major manifestation of the disease.
- These host responses are of an inflammatory and immune nature, and often serve critical protective functions for the host.
- However, these inflammatory responses may become pathological in that they can cause considerable damage as a result of a variety of exacerbated cellular responses.
- Excessive or persistent inflammation may necessitate the use of exogenous glucocorticoids in pharmacological doses i.e. doses in excess of the endogenous rate of glucocorticoid production.
- The doses can be considered quite high, particularly when applied at specific sites (i.e. eye, skin, etc.).
- Harmful properties of these useful agents must be considered at the site of application as well as the systemic effects that can be caused by systemic administration (or as a result of inadvertent systemic exposure (i.e. percutaneous exposure).
9
Q
Cellular Actions of Cortisol
A
- The cellular actions of cortisol are produced by three actions.
- Two influence genomic signaling and one nongenomic activation.
- With the former the cortisol glucocorticoid receptor complex is translocated to the nucleus where it binds to DNA sequences known as glucocorticoid response elements.
- The resulting complex recruits either coactivator or corepressor proteins that modify chromatin structure.
- The result is the facilitation or inhibition of assembly of the transcription machinery and the initiation of transcription by RNA polymerase II.
•The cortisol-glucocorticoid receptor can also interact with other genes involved in the responses to transcription factors such as nuclear factor –kB (NFkB).
-The result is repression of inflammatory protein expression.
- The third mechanism involves glucocorticoid signaling via membrane-associated receptors and second messengers.
- Inflammation is inhibited through all three mechanisms.
10
Q
Risk of GC Use
A
•Long term administration of high dose GC can produce numerous side effects, some of which can be severe and permanent. Examples are listed below.
-Many of these are analogous to those observed in Cushing’s Syndrome.
- Chronic application to the skin cause localized thinning of the skin, while application to the eye can result in development of increased intraocular pressure and early development of cataracts.
- Of special note is the adverse effect of GC on bone. Prolonged GC treatment causes:
- decreased calcium absorption from the intestine and kidney
- repressive effects on osteoblast
- stimulation of resorption activity by osteoclasts
- As a result bone resorption is enhanced and osteoporosis is a frequent and serious complication of GC therapy. It is estimated that 30-50% of patients on GC therapy will develop osteoporotic fractures.
- Bisphosphonates have been shown to be highly effective at limiting GC associated bone loss and the incidence of fracture
11
Q
Withdrawal of GC Therapy - Tapering
A
- Acute discontinuation of prolonged/high dose GC therapy will lead to symptoms of GC-insufficiency (a disrupted H-P-A axis).
- It is best to taper doses to minimize the side effects associated with withdrawal (malaise, anorexia, headache, lethargy, hypotension).
- Since the mineralocorticoid potency is very low for all drugs, it is very hard to induce an Addisonian crisis when abruptly stopping glucocorticosteroids when patients are stable.
- Procedures for tapering are determined by length and mode of therapy.
- When discontinuation of therapy has been successful (minimize or prevent apparent side effects) the HPA axis may not have recovered sufficiently to respond to severe stress for 6-12 months.
-During this time, supplemental glucocorticosteroids may be needed during a stressful event (e.g., severe infection, car crash).
12
Q
Asthma and GC
A
- In asthma, the use of an inhaled corticosteroid (ICS) is very important to control the symptoms of asthma (i.e., most effective at preventing asthma) and are used for all severities of asthma on a regular basis.
- Low doses of ICS are used in mild asthma. High doses of ICS are use in severe persistent asthma.
- These are available as aerosolized metered dose inhalers (MDI) that now contain halofluroalkane propellants (HFA) and dry power inhalers (DPI).
- HFA MDIs have different number of inhalations in each canister. The doses are different related to POTENCY only. From a therapeutic standpoint, the potency differences are less relevant.
13
Q
Adverse Effects of ICS
A
- Adverse effects of ICS include oral thrush (Candida albicans infection), dysphonia, and coughing.
- The use of a spacer device may reduce the frequency of these effects.
- It is possible in children to inhibit growth with the use if ICS.
- It may be possible to increase osteopenia and fractures when using high doses of ICS.
- There are combination inhalers with beta-agonists and anticholinergics that are marketed (e.g., Fluticasone and Salmeterol [Advair] is commonly used in severe asthma and COPD.
14
Q
Fludrocortisone
A
- Fludrocortisone is used to treat conditions in which the body does not produce enough of its own steroids, such as Addison’s disease, and salt-losing adrenogenital syndrome.
- High doses of fludrocortisone cause sodium retention, increase blood volume, and raise blood pressure in both supine and standing postures.
- High doses can also cause congestive heart failure, hypokalemia, and supine hypertension.
15
Q
Inhibitors of Adrenocortical Steroid Biosynthesis Receptors Antagonists
A
- Only a limited number of agents are available to suppress excess adrenal-cortical activity. They are not specific as they interfere with steroid synthesis and thus affect not only GC and mineralocorticoids, but other steroid hormones as well.
- aminoglutethimide
- ketoconozole
- metyrapone
- mifepristone
- spironolactone and eplerenone
