Corticosteroids Flashcards
Adrenal Cortex: Background Knowledge
Zona Glomerulosa: Mineralocorticoids–> reg. water and
salt balance
Zona Fasciculata: Glucocorticoids–> reg. carbohydrate
and protein metabolism; anti inflammatory and immune
suppression. Can act on both glucocorticoid and
mineralocorticoid receptors. Synthetic can differentiate.
Zona Reticulata: Androgen
Cushings Disease (Syndrome when iatrogenic)
Symptoms
Excessive Glucocorticoids (endogenous tumor, iatrogenic)
Decrease protein synth–> decrease muscle amount/tone
Euphoria / Depression, Buffalo hump, moon face,
abdominal fat (decreased hormone sensitive lipase due
to insulin)
Hypertension (action on mineralocorticoids), oedema
Osteoporosis: increased osteoclast and decreased
osteoblast activity.
Decreased Ca absorption in GIT; decreased collagen
and osteoid synthesis
Hyperglycemia: Increased gluconeogenesis
Various Symptoms due to high amount of receptors located all over the body
Excessive Mineralocorticoids
Disorders of salt-water balance–> hypertension
Primary hyperaldosteronism: Conn’s Syndrome
Secondary hyperaldost: increased RAAS activity
Adrenal Cortex Insufficiency
Addison’s Disease: Lack of all cortical hormones
ex: AI adrenalitis, infections (TB, AIDS), metastatic
disease
Regulation of Adrenocortical Hormones
Hypothalamus–> Corticotropin Releasing H (CRH)
that stimulates Ant. Pituitary
Ant. Pituitary–> ACTH stimulating Adrenal Cortex
Negative Feedback:
ACTH on Hypothalmus
Glucocorticoids on Ant. Pit. and Hypothalamus
Which enzyme makes all the difference between Mineralo- and Glucocorticoids? Significance.
17 alpha hydroxylase for mineralo–>glucocorticoid: single
OH group differs
Significance: Action on each others R
REM: Cholesterol is starting point for mineralo- and glucocorticoids, as well as androgens
Enzymatic Process
Cholesterol–>Mineralocorticoids
1) Cholesterol desmolase
Choelsterol into Pregnenolone
2) 3 beta hydroxysteroid dehydrogenase
Pregnenolone into Progesterone
3) 21 beta hydroxylase
Progesterone into 11 Deoxycorticosterone
4) 11 beta hydroxylase
11 DOC into Corticosterone
5) Aldosterone synthase (activated by angiotensin II)
Corticosterone into Aldosterone
Effects of Glucocorticoids
General and Metabolic
Effects of Mesenchymal Tissue
CNS Effects
Decrease glucose uptake and utilisation–>
Hyperglycaemia
Increase gluconeogenesis due to increase insulin secret.
Decrease protein synth, increase protein catabolism
–> Negative N balance
Increased fat depo on abdomen and back
Permission of catecholamine action
High dose (pharma): mineralocorticoid effect, negative Ca
balance–> osteoporosis
Immune suppression and antiinflammatory
decreased IL2 prod, decreased activity lymphatic
tissues, decreased wound healing, decreased PG
synth, increased osteoclast and decreased osteoblast
activities
Inhibit early and late phase of inflammation:
Early: Gq coupled R of glucocorticoid
Late: IC R mediated
Inhibit haematopoietic SC prolif and activation
CNS: seizures, sleeping disorders, insomnia
Negative Feedback on ant. pituitary and hypothalamus
Glucocorticoids
Genomic Mechanism of Action
Intracellular Receptor: dimerisation–> nucleus–> bind to SRE (steroid responsive element) of DNA
Effect:
Upregulation of:
Lipocortin 1 (anexin 1): endog. phospholip A2 inhibitor
Antiinflammatory cytokines: IL-10
Downregulation of:
COX 2
Inflammatory Cytokines: IL2/3/4/5, TNFa
Adhesion Factors: ICAM-1
iNOS (resp for vasodilation)
TF: NFkB, TGFb
GF
Glucocorticoids
Non Genomic Mechanism of Action
Membrane Receptors: Gq: metabotropic glucocortic. R
Resp for fast effects
Location: vascular SM, endothelial cells, neurons
Effects: increase Ca–> vasoconstriction uA
Example: anti oedema effect
Categorisations of Glucocorticoids
- Mineralo- vs Glucocorticoid Action
- Systemic vs Local Effectiveness
- Genomic vs Non Genomic Effect
Mineralocorticoid vs Glucocorticoid Action
M G
Cortisol 1 1
Aldosterone 800 1
Fludrocortisone 800 4-5
DOC 40 0
Prednisolone 0.7 5
Betamethasone 0 5-100
Dexamethasone 0 10-35
Some have huge range of efficacy due to pleiotropic effect of R
Systemic vs Local Effectiveness
S L
Prednisolone 4-5 1-2
Betamethasone 30 5-10
Dexamethasone 30-120 10
Mometasone 0 Next all have 40-100
Fluticasone
Budesonide
Ciclesonide
Genomic vs Non Genomic Effect
G NG
Prednisolone 0.8 0.4
Methyprednisolone 1 5—> best for acute
Betamethasone 5 0.23
Dexamethasone 5 1.2
Glucocorticoids
Clinical Use and Indications
Drug Formulations
Indications:
Substitution Th: Addisons
Inflammation, allergies, anaphylactic shock, AI,
haematological malignancies, transplantation
Short term systemic therapy indications:
Severe asthma, allergic contact dermatitis,
rhinoconjunctivitis (allergic)
Drug Formulations
Oral, rectal, IM/IV/, ointments, creams, eye drops, nasal,
inhalation
Glucocorticoids
Pharmacokinetics
Good oral absorption
Corticosteroid- binding globulin and albumin
endogenous: 90%–> possible displacement
synthetic: bind only to albumin, act more rapidly
Lipophylic
Inactivated in Liver, excreted into urine
Glucocorticoids
Side Effects
Contraindications
Side Effects:
High risk of infection, peptic ulcers/erosions, Cushings,
osteoporosis, hypertension/oedema, atrophy of adrenal
cortex
Contraindications:
Absolute: active ulcers, severe psychosis, certain viral
infections
Relative: DM, pregnancy, Cushings, GI ulcers,
hypertension
How to minimise occurrence of Adrenal Cortex Atrophy?
Coadminister ACTH to sustain tropic activity of ACTH on Adrenal Cortex
Gradual withdrawal of therapeutic drugs
Glucocorticoids
Drug Names and Characteristics
Cortisol: endogenous. Substitution therapy
Cortisone: prodrug–>hydrocortisone, Substitution therapy
Fludrocortisone: Substitution therapy
DOC
Prednisolone, Methylpred, Betamethasone, Dexametha.
systemic for severe conditions ex severe asthma
Beclomethasone, Mometasone, Budesonide, Ciclesonide
Local admin
Prerequisites: Asthmatic Inhalation Agents
High R affinity
Extensive hepatic 1st pass (min 80%)
Local side effects:
candidiasis
dysphonia
Use of Glucocorticoids in Premies (<36 weeks)
Mg, b2 agonist, oxytocin R anta–> delay labour
GC injection–> boost surfactant
Mineralocorticoids
Localisation of Receptors
Main Actions
Receptor localisation: Tubular cells of kidney salivary and sweat glands pancreas intestinal epithelial cells
Main Actions:
Increase K and H secretion
Increase Na reabsorption
Mineralocorticoids
Effects
Genomic:
Increased # Na channels in apical membrane
Increased # Na/K ATPase in basolateral membrane
Non Genomic
Rapid Na influx via Na/H exchange mechanism apical
Both IC and membrane bound receptors
Mineralocorticoids used in Substitution Therapy
Names and Characteristics
Aldosterone: endogenous MC
Cortisol: endogenous GC with MC action
Fludrocortisones: synthetic, act on both Rs
