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
