B.12 Flashcards
Glucocorticoids for oral use
Hydrocortisone,
Prednisolone,
Methylprednisolone,
Dexamethasone,
Triamcinolone
Glucocorticoid receptor actions
- Gene activation:
Annexin-1→PLA2↓
Enzymes of gluconeogenesis and amino acid metabolism (cAMP-dependent protein kinase)
Adrenergic receptors on vascular & bronchial smooth muscle (“permissive effect”: e.g. β2 agonist effect in bronchial asthma) - Gene repression:
COX-2
NOS
Cytokines
Interleukines
Cell adhesion molecules
note: 10-20% of all expressed genes are regulated by glucocorticoids
Metabolic actions
- Carbohydrates:
Glucose uptake & utilization ↓
Gluconeogenesis↑
Hyperglycemic tendency (→insulin↑→glycogen↑) - Proteins:
Catabolism↑
Anabolism↓ - Lipids:
Redistribution of fat (Cushing type)
TAGs↑
LDL/HDL↑
Regulatory actions
- Hypothalamus & anterior pituitary gland: negative feedback→release of endogenous glucocorticoids↓
- Cardiovascular system: Vasodilation↓, Plasma exudation↓
- Musculoskeletal: Activity of osteoblasts↓, osteoclasts↑
- Negative Ca2+ balance: Ca2+ absorption↓, Ca2+ elimination↑
- Inflammation & immunity:
Acute inflammation: influx & activity leukocytes ↓
Chronic inflammation: Activity of mononuclear cells↓, angiogenesis↓
In blood: Neutrophils↑, eosino-/basophils/monocytes/lymphocytes↓
Lymphoid tissue: clonal expansion of T/B cells↓, cytokine secreting T action↓ - Mediators:
Production and action of cytokines↓ (TNF-α, ILs, GM-CSF)
Generation of Eicosanoids↓
Generation of IgG↓
Complement components in the blood↓
Release of anti-inflammatory factors↑ (e.g. IL-10 & annexin-1)
Overall effects
activity of the innate & aquired immune system↓, healing & protective aspects of inflammation↓
Glucocorticoids
IND:
-Replacement therapy (adrenocortical insufficiency, Addison’s disease);
-Stimulation of lung maturation in fetus (delivery before week 34);
-Anti-inflammatory/immunosuppressive therapy [→asthma, topically in inflammatory conditions of skin/eye/ear/nose (e.g. eczema, allergic conjunctivitis, rhinitis), hypersensitivity states (e.g. severe allergic reactions), in diseases with autoimmune & inflammatory components (e.g. RA, IBD, some forms of hemolytic anemia, indiopathic thrombocytopenic purpura), to prevent graft-vs-host reaction (organ/BM transplantation)];
-In neoplastic diseases [in combination with cytotoxic drugs (e.g. Hodgkin’s disease, ALL), to reduce cerebral edema (metastatic/primary brain tumor)];
-Nausea & vomiting (in chemotherapy & general anesthesia);
SEs: <2 weeks therapy (→serious SEs are unusual! can be- insomnia/hypomania, peptic ulcer, Acute pancreatitis-rare), >2 weeks therapy [→Response to infection/injury↓ (wound healing↓,peptic ulceration, oral candidiasis), Ulcerogenic effect (PG↓, enhanced risk w/NSAIDs), Iatrogenic Cushing’s sy., Suppression of endogenous GC synthesis, Hypokalemia /Hyperthermia /edema, HTN (mineralocorticoid effect), Osteoporosis, Aseptic necrosis of femoral head, metabolic SEs (Hyperglycemia, insulin↑, weight gain, DM),
1. Musculoskeletal SEs (muscle wasting, myopathy, tendon breakdown), Inhibition of growth in children (if >6months treatment),
2. CNS effects (hypomania, psychosis, depression), Thromboembolic risk↑, Glaucoma (in predisposed), cataracts↑, intracranial pressure↑;
Comorbidities: →enhanced risk! HTN, hyperglycemia, peptic ulcer, psychiatric problems
supplementation while on GCs
high protein and K+ enriched diet, low Na+, vitamin D and Ca2+ supplementation
Dosage GCs
-Higher dose for initial effect,
-lower dose for maintenance;
-To suppress ACTH: small, frequent p.o doses or slowly absorbed p.e. preparations;
-Inflammatory & allergic disorders: same quantity in a few doses;
-Severe autoimmune diseases: high, divided dose, gradual reduction later on;
-If large dose required: synthetic with minimal mineralocorticoid action;
-If large dose for long period required: try alternate-day administration;
-SLOW gradual cessasion
Hydrocortisone
MOA: Cortisol (→activates GC-R);
Kinetics: DOA- 8-12h,; Receptor affinity: 1 ;
IND: Drug-of-choice for replacement therapy
Methylprednisolone
MOA: cortisol analog (→activates GC-R) ;
in acute cases-i.v adm (e.g. Anaphylaxis, Bronchial asthma, Thyrotoxic crisis, Brain edema, Hepatic coma); Receptor affinity: 11.9;
Prednisolone
MOA: Cortisol analog (→activates GC-R);
Receptor affinity: 2.2;
Dexamethasone
MOA: Cortisol analog (→activates GC-R);
IND: Diagnostic purposes (dexmethasone suppression test→ Cushings’ disease/syndrome),
in neoplastic diseases (to reduce cerebral edema →metastatic/primary brain tumors),
in acute cases-i.v adm (e.g. Anaphylaxis, Bronchial asthma, Thyrotoxic crisis, Brain edema, Hepatic coma); Receptor affinity: 7.1
Triamcinolone
MOA: Cortisol analog (→activates GC-R), has an Acetonide moiety (increased surface activity→dermatological use!);
Receptor affinity: 1.9;
IND: Allergic rhinitis (nasal spray), dermatological use (ointment, enema), IBD (suppository, enema)
Where is 11β-HSD2 found?
Distal nephron, colon, sweat glands, salivary glands, placenta
this enzyme catalyzes the cortisol→cortisone conversion, inactvating cortisol. This allows specific responses to aldosterone in the above mentioned tissues
where is 11β-HSD1 found?
Liver, fat, CNS, Placenta
this enzyme catalyzes the reverse reaction, activating cortisol, to ensure desired effects in desired tissues
In which ways can steroid stimuli operate?
Genomic or non-genomic mechanisms
The S-GR complex also interacts with other transcription factors such as NF-κB and AP1
involved in antiinflammatory and immunosuppressive effects
Pharmacokinetics of cortisol
A: good oral absorption
D: transport in blood by:
90%-corticosteroid-binding globulin (CBG)/α2 globulin
5-10% - free
~5%- albumin (large capacity, low affinity → practically considered free)
T1/2: 60-90min
M: 80% in the liver, 20% in the kidney & other MR containing tissue (e.g. colon, salivary glands), 1% unchanged in the urine
zones of the adrenal gland
- Zona glomerulosa → Aldostrone (mineralocorticoids)
- Zona Fasiculata→ Cortisol (glucocorticoids)
- Zona reticularis→ DHEA (Androgens)
hormones stimulate the conversion of Cholesterol to Pregnonelone
ACTH / Angiotensin II
hormone stimulate the conversion of Corticosterone to Aldosterone
Angiotensin II
