Corticosteroids Flashcards
What does the hypothalamus release to the anterior pituitary
Corticotropin Releasing Factor (CRF)
What does the anterior pituitary release to the adrenal cortex
Adrenocorticotropin releasing hormone (ACTH)
What 2 hormones does the adrenal gland release? what are their synthetic analogues? What do they cause?
Glucocorticoid (Cortisol)
Synthetic Analogue: Prednisolone
Effects: Metabolic, Anti-inflammatory, Immunosuppressive
Mineralocorticoid (Aldosterone)
Synthetic Analogue: Fludrocortisone
Effects: Sodium and water retention, K+ and H+ excretion
What are some pro-inflammatory cytokines?
TNF-a , IL-1, IL-6
What is the mechanism of action of aldosterone?
Binds to Mineralocorticoid receptors, causing upregulation of Basolateral Na+/K+-ATPase Gene Expression
Promotes NA+ re-absorption at distal renal tubules coupled to K+ and H+ excretion
What happens in excess of aldosterone?
Hypernatremia, Hypokalemia, Metabolic Alkalosis, Edema
What are the metabolic effects of cortisol?
- Increases gluconeogenesis and decreses peripheral glucose uptake => increases glucose level
- Increases glycogen deposition
- Increases Lipolysis (due to decrease glucose uptake into fat cells) and increases lipogenesis (due to increase glucose levels) => net increase in lipid level
- Has minerlocorticoid activity
What are the catabolic effects of cortisol
- Breaks down proteins in lymphoid, muscle, skin, bone, and connective tissues
- negative nitrogen and calcium balance
What is the negative feedback inhibition of cortisol
Decrease in adrenocorticotropin releasing hormone
What type of receptor is the steroid receptor?
Nuclear receptor which is a gene active receptor (functions like a transcription receptor)
Which 2 domains of the steroid receptor forms dimers?
- Transcription activating domain
2. DNA binding domain
What does the GRA and GRB receptors do?
GRA activates
GRB dominantly negatively inhibits
Hence, only 2 GRA receptor dimers can activate.
What is the genomic action of corticosteroids?
Transactivation/Transrepression
- Monomer Tethering Transactivation/Repression
- Monomer Transactivation/Repression - co-activator in between
- Dimer Transactivation/Repression
What are the anti-inflammatory targets of steroids
Decreased (Inflammatory cells):
- Cytokines (TnF-a, IL-1B, IL-6)
- Chemokines (Rantes)
- Inflammatory Enzymes (COX-2, 5-LOX, PLA2)
- Receptors (IL-2R, T-cell Receptor)
Increased (Protective proteins):
Annexin A1 (PLA2 inhibitor)
B2-adrenoceptor
IkB-a (Inhibitor of NF-kB)
What are the Anti-inflammatory actions of steroids
- Decrease circulating T cells, B cells, monocytes, eosinophils, basophils via increased apoptosis => immunosuppression
- Increase circulating neutrophils via increased production and reduced extravasation
- Decrease the size and lymphoid content of lymph nodes (through catabolic effect)
- More effect on cellular immunity than humoral immunity
- Increase macrophage efferocytosis and promotion of resolution of inflammation
- Decrease type 4 delayed hypersensitivity reaction (transplant rejection)
- First-line immunosuppressant in solid organ and hematopoietic stem cell transplantation
What is the difference between cortisone and hydrocortisone (cortisol)
cortisone:
ketostructure
inactive prodrug
hydrocortisone:
C11 hydroxyl group
active drug
What is the difference between prednisone and prednisolone
BOTH are equally active
C1-C2 double bond -> increases duration of action + increases potency of corticosteroid
prednisone:
ketostructure
prodrug
prednisolone:
C11 hydroxy group
What is the difference between methylprednisolone and triamcinolone
Both have C1-C2 double bond
Both have C11 hydroxy group –> active drug
Methylprednisolone:
additional C6 methyl group
Triamcinolone:
additional C9 Fluoride group
What is the difference between Dexamethasone and Betamethasone
Most potent forms
Both have C1-C2 double bond
Both have additional C9 Fluoride group
Dexamethasone:
Additional C16 methyl group in alpha position
Betamethasone:
Additional C16 methyl group in beta position
Difference in planar structure
What are the corticosteroids and what are their duration of actions?
8-12 hrs:
Cortisone
Hydrocortisone (Cortisol)
12-36 hrs: Prednisone Prednisolone Methylprednisolone Triamcinolone
24-72 hrs:
Dexamethasone
Betamethasone
Which corticosteroids are prodrugs?
Cortisone
Prednisolone
Which corticosteroids have no minerocorticoid effects (water retention side effects)
Methylprednisolone
Triamcinolone
Dexamethasone
Betamethasone
What inflammatory diseases are steroids used for?
- Allergic Reactions (Asthma, Atopic Dermatitis, Rhinitis, Urticaria, Conjunctivitis, Anaphylaxis)
- Collagen-Vascular Disorders (Lupus Erythematosus, Rheumatoid Arthritis) –> Autoimmune Diseases
- GI Diseases (Ulcerative Colitis, Crohn’s Disease)
- Hematologic Disorders (Leukemia, Lymphoma, Hemolytic Anemia, Thrombocytopenia)
- Organ Transplants (Graft-versus-Host Syndrome, Organ rejection)
- Dental Conditions (Aphthous Ulcers, Gingivitis, Oral Lichen Planus, Surgical Swelling, TMJ Arthritis, Oral Pemphigus, Nerve Trauma)
Are steroids curative?
No. They are merely antisymptomatic.
What is the standard choice of steroid?
Prednisolone: Shorter-acting steroid with little salt retaining activity.
Why is the lowest dose possible always given?
To achieve desired effect with minimal side effects
What are types of therapy that can be given?
Alternate-day Therapy and Pulse Therapy (high dose given before gradually slowing doses)
Can therapy be stopped abruptly?
No. Patient may not be able to produce their own cortisol (hormone endocrine system)
What should be checked in prolonged therapy?
Chest X-xray, TB, DM, PUD, Osteoporosis, Mental Disorder
What are the side effects of steroids?
Iatrogenic Cushing’s Syndrome
- Endocrine Metabolic Effects:
hyperglycemia
moon face, ‘buffalo hump’, truncal obesity
muscle wasting
growth retardation (pediatric patients)
acne, hirsutism and menstrual disturbances
delayed wound healing
skin thinning
Na/Fluid retention, edema, hypertension, congestive heart failure - Musculoskeletal System (decrease calcium levels)
Osteoporosis (Trabecular bone)
Aseptic Necrosis of femoral head - necrosis caused by lipid emboli
Myopathy (Dexamethasone/Triamcinolone)
3. Immune System Bacterial (TB) Viral (Herpes and CMV) Fungal (Canadidal, Asperigilles and Cryptococcal) Parasitic (Toxoplasmosis)
- Eye
Posterior Subcapsular Lens Cataract
Glaucoma - GIT
PUD/GI Bleeding (especially with NSAID) - Nervous System
Euphoria, Depression, Psychosis - Withdrawal Symptoms
Lethargy, Headache, Fever, Joint Pain, HPA Insufficiency - Glucocorticoid Resistance
What are the dosage forms of Steroids?
Systemic: Oral, IV, IM
Local (Reduced systemic side effects):
Topical: ointments, dental paste, mouthwash
Ophthalmic Forms
Enemas for Ulcerative Colitis
Inhalation for Asthma
Nasal Sprays for Allergic Rhinitis
Intra-articular Injection for Joint Disease
