Corticosteroids Flashcards
What are the 2 types of corticosteroids?
- Glucocorticoids (cortisol)
- Mineralocorticoids (aldosterone)
Name all the commonly used corticosteroids.
- Cortisol (prodrug: cortisone)
- Prednisolone (prodrug: prednisone)
- Methylprednisolone
- Triamcinolone
- Dexamethasone
- Betamethasone
(In order of increasing DOA, GC action & decreasing MC n dose)
List the metabolic effects of Cortisol.
- Increases glucose in circulation: via gluconeogenesis & decreased peripheral glucose uptake
- Increased glycogen deposition
-
increased NET fat deposition: via increased lipolysis & increased lipogenesis
=> results in buffalo hump, lipid redistribution - Mineralocorticoid activity (water retention)
List the catabolic effects of Cortisol.
-
Negative Nitrogen & Calcium balance
- increases nitrogen excretion in urine, from protein breakdown (lose muscle mass)
- reduces calcium reabsorption & increases calcium excretion (leads to osteoporosis) - Breaks down protein in lymphoid, muscle, skin, bone & connective tissues
Feedback inhibition of Hydrocortisone/Cortisol:
- increased cortisol => decreases ACTH secretion
- cuz ACTH triggers adrenal gland to produce cortisol mah
- reduce endogenous cortisol pdn
Structure of the steroid receptor:
- nuclear receptor that also functions like a transcription factor
- Nuclear receptor
- Gene-active receptor
Mechanism of action of Steroids:
- Highly lipophilic, cross cell membrane => bind to intracellular nuclear receptor
- Receptor forms homodimer & enters nucleus => regulate gene expression => regulate protein level
What are the ‘forms’ of Steroid receptors?
Nuclear receptor (gene-active receptor)
- GRα-form: active form of glucocorticoid receptor
- GRβ-form: dominant -ve form => inhibits signalling of alpha
What is the pro-drug of Cortisol?
Cortisone
What is the pro-drug of Prednisolone?
Prednisone
Name the 2 corticosteroid pro-drugs.
Prednisone & Cortisone
Side effects of Corticosteroids on the Musculoskeletal system.
- Osteoporosis (trabecular bone)
- due negative calcium balance
- decreased Ca reabsorption & increased Ca excretion - Aseptic necrosis of femoral head
- rarely happens but still documented
- bilateral, occurs on both sides of femoral head - Myopathy (dexamethasone/triamcinolone)
- muscle weakness, dysfunction of muscle fiber
Side effects of Corticosteroids on the Immune system.
Opportunistic infections (we often prescribe steroids post-op to suppress immune system, good to prescribe antibiotics tgt to prevent infection)
Can be:
Bacterial (TB), Viral (Herpes & CMV), Fungal (candidal, asperigilles & crytococcal), Parasitic (toxoplasmosis)
Side effects of Corticosteroids on the GIT system.
Peptic ulcers, GI bleeding (esp when combined w NSAIDs)
What is the withdrawal phenomena w corticosteroids?
Cuz adrenal cortex has been suppressed from producing endogenous cortisol due to negative feedback
Thus,
no abrupt withdrawal of steroids!, otherwise: lethargy, headache, fever, joint pain, HPA insufficiency (hypothalamic-pituitary-adrenal axis)
must taper dose gradually
Side effects of Corticosteroids on the Nervous system.
- usually occurs in medical settings at higher doses
- euphoria, depression, psychosis
Side effects of Corticosteroids on the Endocrine-Metabolic system.
- Hyperglycemia (more glucose in circulation)
- Moon face, ‘buffalo hump’ & truncal obesity (increased fat deposition & redistribution)
- Muscle wasting (-ve nitrogen + protein breakdown)
- Growth retardation (pediatric patients)
- Acne, hirsutism (abnormal hair growth) & menstrual disturbances (cuz steroid is a male hormone)
- Delayed wound healing (suppressed immune system)
- Skin thinning (protein breakdown)
- Na/fluid retention, oedema, hypertension, chronic heart failure (mineralcorticoid effects)
Anti-inflammatory actions of corticosteroids:
First line immunosuppressant in solid organ and hematopoietic stem cell transplantation.
-
decreases T cells, B cells, monocytes, eosinophils & basophils but increases circulating neutrophils
- immune cells downregulated thru increased apoptosis
- increases neutrophils in circulation via increased pdn & reduced extravasation
- reduced extravasation: neutrophils constrained within circulation, cannot reach tissues => reduces excessive tissue damage -
Decreases size & lymphoid content of lymph nodes
- due to catabolic effect (break down) on proteins in lymph nodes - Has more effects on cellular immunity than on humoral immunity
- aka more effect on t cells than on b cells & pdn of immunoglobulins -
Increases macrophage efferocytosis & promotion of resolution of inflammation
- more cleaning up & eating of dead cells - Decreased type-IV delayed hypersensitivity reaction (e.g. transplantation rejection)
How can corticosteroid drugs be administered?
Systemic: oral, IV, IM
Local: (decreased systemic adverse effects)
- topical (mouthwash, ointments)
- ophthalmic forms
- inhalation for asthma
- nasal sprays for allergic rhinitis
- intra-articular injection for joint disease
- enemas for ulcerative colitis
Clinical uses of corticosteroids:
- Allergic rxns: asthma, atopic dermatitis, rhinitis
- Collagen-vascular disorders:** Lupus erythematosus** (autoimmune, attack of own tissues, widespread inflammation), rheumatoid arthritis
- GI diseases: Crohn’s disease, ulcerative colitis (both are types of inflammatory bowel)
- Haematologic disorders: leukemia (blood cancer), lymphoma (lymph cancer), Hemolytic anemia, thrombocytopenia
- Organ transplants: tranplantation rejection
- Dental conditions: gingivitis, oral lichen planus (chronic inflammatory condition that affects mucus membranes in mouth), surgical swelling
- Eye diseases: Uveitis, Conjunctivitis
- most of these diseases involve inflammation, except leukemia & lymphoma (emphasis on these on reduction of blood cells & break down of lymph nodes)
Effects of aldosterone. + what happens in excess?
Mineralocorticoid. Binds to mineralocorticoid receptor to upregulate Na+/K+ ATPase gene expression at distal renal tubule
- Na+ reabsorption
- K+ & H+ excretion
In excess: hypernatremia, hypokalemia, metabolic alkalosis(due to loss of H+), edema
Name the glucocorticoid drugs that do not have water-retention side effects.
- Methylprednisolone
- Triamcinolone
- Betamethasone
- Dexamethasone
Which glucocorticoids still have water-retention side effects?
Cortisol/cortisone
Prednisolone/prednisone (less water retention than cortisol)
Steroids are not ________, only ________ inflammation.
Steroids are not curative, only suppress inflammation.
What are the gene targets decreased by steroids?
- Cytokines: TNF-α, IL-1β,IL-6
- Chemokines: RANTES
- Inflammatory enzymes: COX-2, 5-LOX, phospholipase A2
- Adhesion molecules: ICAM-1, VCAM-1 (prevent cell infiltration into inflammatory sites)
- Receptors: IL-2 receptor, T-cell receptor (decreased expression of pro-inflammatory genes)
-> general effect: less inflammation
What are the gene targets increased by corticosteroids?
- Annexin-A1 (phospholipase A2 inhibitor)
- β-adrenoreceptor (related to asthma)
- IKB-α (inhibitor of NF-KB) (NF-KB: pro-inflammatory TF)
Side effects of corticosteroids on the eye.
- cataracts
- glaucoma
