Lec 08: Corticosteroids Flashcards
The main precursor for the synthesis of the corticosteroids which include cortisol, aldosterone, and androgens.
Cholesterol
Main endogenous glucocorticoid
cortisol
Considering the diurnal pattern of circadian plasma cortisol concentration, drug prescription should entail higher doses in the:
a. morning
b. afternoon
a. morning.
* not following diurnal pattern -> very high cortisol concentration -> inhibits production of endogenous steroids -> atrophy of adrenal cortex -> (when you withdraw the drug) body is unable to produce endogenous cortisol.
True or False: Steroids trigger histone deacetylases as opposed to inflammation.
True.
Mechanism of Action of Glucocorticoids:
Pass freely through cell membrane -> bind to glucocorticoid receptor (w/c is bound to a heat shock protein at rest) -> steroid undergo conformational change which prompts the release of chaperone proteins (hsp 70&90 and inhibitor protein) -> enter nucleus to bind and dimerize with Glucocorticoid response elements (zinc fingers) -> facilitation of transcription of proteins.
The synthesis and secretion of glucocorticoids are directly controlled by what hormone?
Adrenocorticotropic Hormone (ACTH)
- a polypeptide synthesized by anterior pituitary gland.
What are the three types of corticosteroids and their corresponding functions?
GLUCOCORTICOIDS (21C)
- For modulating metabolism and immune responses
- Has permissive effects on catecholamines (dopamine, norepinephrine, and epinephrine) though they do not share similar structures
MINERALOCORTICOIDS (21C)
- Control of blood pressure, vascular volume, electrolytes
ADRENAL ANDROGENS (19C)
- Glucocorticoid and mineralocorticoids are very similar pharmacologically because of their similar structures.
Metabolic effects of Glucocorticoids?
(Basically, just imagine a person with Cushing’s syndrome)
- DECREASED CHO uptake and utilization with INCREASED GLYCOGENOLYSIS & GLUCONEOGENESIS (basta papuntang hyperglycemic state)
- INCREASED protein CATABOLISM & DECREASED protein SYNTHESIS (muscle weakness and atrophy)
- PERMISSIVE effect on LIPOLYTIC hormones and REDISTRIBUTION of fat
- DECREASED OSTEOBLAST formation & activity; INCREASED OSTEOCLAST activity (osteoporosis)
- DECREASED CONVERSION of Vit D2 to active Vit D: DECREASED calcium ABSORPTION from GIT
Glucocorticoid effect on inflammation?
OVER-ALL EFFECT: reduction in the activity of the innate & acquired immune systems, and also decreased healing and diminution in the protective aspects of the inflammatory process.
More detailed:
- Local and systemic effects:
- DECREASED production of prostaglandins, cytokines and interleukins
- DECREASED proliferation and migration of lymphocytes and macrophages (more neutrophils, less lymphocytes/macrophages) - Anti-inflammatory/ immunosuppressive/anti-allergic
- The anti-inflammatory action of corticosteroids are their most beneficial therapeutic effect.
- 3 major mechanims: interference with leukocyte migration and fxn, inhibition of arachidonic acid cascade, permissive effect on catecholamine activity: vasoconstriction to minimize swelling - Less capillary permeability to regress edema
- Reduce macrophage adhesion and antigen phagocytosis
- Inhibit chemotactic factors
- block activation of bradykinin and production of arachidonic acid, blocking prostaglandin and leukotriene synthesis.
Cellular effects of Corticosteroids?
o Eosinopenia and marked atrophy of thymus gland and other lymphatic tissues resulting to decreased anti-body formation (reduced immunity) and decreased allergic reactions. o Neutrophilia o Reduction of eosinophil count by 95% o Reduction of basophil count by 72% o Inhibition of Interleukin-1 (IL-1)
Glucocorticoids have the following clinical uses, EXCEPT:
a. replacement therapy for acute adrenal insufficiency
b. anti-inflammatory/ immunosuppressive therapy for connective tissue disease.
c. used in combination with cytotoxic drugs in the treatment of Hodgkin’s lymphoma
d. AOTA
e. NOTA
e. NOTA
Uses of Glucocorticoids in Clinical Practice:
1 Replacement glucocorticoid therapy
o Acute adrenal insufficiency
o Chronic adrenal insufficiency (Addison’s disease)
o Congenital adrenal hyperplasia
2 Anti-inflammatory and immunosuppressive therapy
o Asthma
o Topically in various inflammatory conditions of skin, eye, ear, or nose (eczema, atopic dermatitis, allergic conjunctivitis or rhinitis)
o Hypersensitivity states (severe allergic disease,
anaphylaxis)
o Connective tissue disease (RA, SLE), inflammatory
bowel diseases, some forms of hemolytic anemia or auto-immune thrombocytopenia
o To prevent graft-versus-host disease following organ or bone marrow transplantation
- Neoplastic Diseases
o In combination with cytotoxic drugs in the treatment of specific malignancies e.g. Hodgkin’s lymphoma & acute lymphocytic leukemia
o To reduce cerebral edema in patients with metastatic or primary brain tumors (dexamethasone)
Glucocorticoids are classified according to these three main characteristics:
- Relative potencies in sodium retention (mineralocorticoid effect)
- Effects on carbohydrate metabolism
- Anti-inflammatory effect
* Remember that the anti-inflammatory effect of a GC parallels its diabetogenic effect (ability to increase blood glucose levels). On the other hand, the anti-inflammatory effect is inversely related to the mineralocorticoid effect (sodium retention).
The following groups are essential for the anti-inflammatory activity of Glucocorticoids?
a. oxygen at C3 and C20
b. Double bond between C4 and C5
c. Hydroxyl group at C11
d. Methyl group at C6
d. Methyl group at C6
- Groups essential for anti-inflammatory activity
o Oxygen at C3 and C20
o Double bond between C4 and C5
o Hydroxyl group at C11 - Changes in these positions lead to a loss of biological activity
- Substitution in other sites may modify biological activity, imparting either greater anti-inflammatory or
mineralocorticoid activity. - Methylation at C6 increases anti-inflammatory activity but not necessarily essential
Hydrocortisone + double bond between C1 and C2 = ?
prednisolone
Prednisone or Prednisolone: which is the prodrug?
Prednisone
