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Systemic Corticosteroids

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shevyatiwari's version from 2015-10-17 10:03

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CS consist of 4 hexane rings and 1 pentane ringF, 3 hexane rings, 1 pentane ring. 3 HP like sauce
Cortisone aka hydrocortisoneF, cortisol aka hydrocortisone
Hydrocortisone is active to cortisoneT
Cortisone is converted to hydrocortisone by 11B hydroxysteroid dehydrogenaseT in the liver the then metabolites renally excreted
Methylprednisolone is converted to prednisoloneF, other way around
Hydrocortisone plus fluorine -> fludrocortisoneT
Fludrocortisone has increased glucocorticoid and mineralocorticoid activity cf hydrocortisoneT, particularly increased MC activity
Masking the 16 or 17 hydroxyl group with esters -> increased MC effectF, decreased
Hydrocortisone can be converted to triamcinolone, dexamethasone, betamethasoneF, fludrocortisone
Betamethasone has high MC and low GC effectsF, other way around
Absorbed in the lower duodenumF, upper jejunum
Approx 20% of prednisolone is absorbed orallyF, >50%
Food reduces the overall absorptionF, delays but doesn't reduce the amount
Peak levels in 30 minutesF, 30-100 minutes
The carrier protein is CBG aka transcortinT. CBG = ferrari - high affinity, low capacity vs. albumin night bus. 80% endogenous CS bound to CBG
Approx 50% of prednisolone is bound to CBGF, 80-90%
CBG is a high capacity low affinity binding systemF. CBG- ferrari- high affinity, low capacity
vs. Albumin -night bus - low affinity, high cacpacity
Synthetic CS bind to carrier proteins with more affinity than endogenous cortisolF, less affinity - therefore, a greater free fraction is available
Prednisolone binds with the least affinity cf other synthetic formsF, the highest
CBG is increased in hypothyroidism, liver disease, renal disease, obesityF, decreased
CBG is increased in oestrogen therapy, pregnancy, hyperthyroidismT. Thus reduces the free fraction- kate is HIGH
High dose and prolonged therapy leads to increased free fractionsT
Well distributed to most tissuesT. Side effects affect most of the body
Prednisone is distributed to fetal tissueF - it is the odd one out! other synthetics are
Reduction of the 4,5 double bond can occur only at hepatic sites and yields an inactive substanceF - occurs extrahepatic sites too
Reduction of the 3 ketone substituent to 3-hydroxyl forms tetrahydrocortisol which can occur at only hepatic sitesT
Water soluble metabolites are excreted in the kidneysT
11B hydroxysteroid dehydrogenase converts prednisone to prednisolone and cortisone to cortisolT
Prednisone and Cortisone are suitable in those with advanced liver diseaseF - are prodrugs and require 11B DHSD for conversion to active drug. Give those with liver disease prednsiolone - the active drug
Plasma half lives correlate well with duration of activityF
The best measure of duration of activity is ACTH suppressionT - duration of suppression correlates well with GC and anti inflammatory effects
There is a direct correlation between duration of action and relative MC effectF, inverse correlation
Hydrocortisone has similar effects to aldosteroneT
Long acting corticosteroids such as dexamethasone and betamethasone have extensive MC effectF, have no MC effect
There are 3 GCR receptorsF, only 1. For both endogenous and exogenous
GCR is a cytosolic receptorT
NFKB is activated on the degradation of IkBT
NFKB is activaetd -> nucleus -> transcription of cytokines including ILB, TNFa, IL2, IL8, GCSF, GMCSF, ICAM1, E-selectin, COX-2, phospholipase A2T
CS increase IKB -> increased inhibition of NFKBT
CS can bind to NKFB preventing its ability to bind and act as a transcription factorT
CS inhibit AP1 T
CS can induce apoptosis of lymphocytes and eosniophilsT
Below physiologic dose of dexamethasone at night can be useful for hirsutism and recalcitrant acne vulgarise due to elevated adrenal androgensT
Menstrual irregularities are not seen with IM CSF
Cold abscess, subcut atrophy, crystal deposition and purpura are all S/E of IM thearpyT
In IM CS, more frequent dosing of lower dose CS leads to more suppression of HPA than less frequent dosing of higher potency CST
Pulse CS is associated with sudden deathT. IV pulse ca cause electrolyte shifts, arrythmias and sudden death
AF anaphylaxis, acute electrolyte shifts, sudden death are S/E of pulse therapyT
Suppression of lymphocyte subsets is greater with pulse CS than standard oral T
Persistent decrease in NK cell activity is seen with pulse therapyT
Supraphysiologic doses for >3-4 weeks are associated with increased risk of serious complicationsT
CS post bowel anastomosis carries the risk of perforationT, as well as acute diverticulitis patients
PUD perforaton, pancreatitis, severe hyperglycaemia, opportunistic infections, carcinogenesis are S/ET
no significant increased risk of malformations in pregnancyT. Cat C . There may be increased still birth or spontaneous abortion. Metal HPA axis suppression if near time of delivery. Old studies showed cleft lip/palate risk in animals.
Osteonecrosis is seen only with pharmacologic doses for at least 2-3 months for life threatening conditiosnT
Patients can be at risk of osteoporosis after > 1 month of CST
Secondary exogenous adrenal insufficiency is the most important type for dermatologistsT
in secondary exogenous insufficiency, MC, ACTH and pituitary tropic hormones are all normalT. As caused by prolonged high doses of CS
Divided dose regimes and therapy not in the morning increases risk of HPA suppressionT
Shorter acting CS are more likely to produce HPA suppression than long lastingF, longer acting are
Alternate day therapy reduces the risk of HPA suppression and speeds recoveryF, reduces risk but does not speed recovery
Hypotension and electrolyte abnormalities are not frequent in HPA suppressionT - beceause MC aldosterone does not play a role in HPA axis stress response - therefore relatively unaffected
Current 8am cortisol assays are probably not affected by steroid, however the morning steroid should be omitted on the day of cortisol level testingT
With prolonged therapy, cortisol <10 is suggestive of impaired basal HPAT
Arthralgias, myalgias, mood swings, headache, fatigue, lethargy, anorexia, nasuea vomiting are signs of SWST
Azoles, macrolides, estrogen and OCP cause increased level of CST
Aminoglutethimide, anticonvulsants, anti TB, cholestyramine, ephedrine reduce levels of CST
Diuretics, cyclosporine, digoxin may be increased with use of CST
Isoniazid levels are reduced bY CST
Insulin, salicylate can have reduced levelsT
Anticoagulants may be increased/decreased with CST
Xanthine bronchodilators may interactT
Prednisolone doses of <10mg/day can reverse lipodystrophyT
Up to 30% on short term therapy develop hypomania and sleep disorderT
Up to 10% develop significant depressionT
Up to 40% of those on at least 10mg/day develop menstrual abnormalitiesF, on at least 20mg/day
Dexamethasone and betamethasone has the most MC activityF, along with methylprednisolone
Cortisol, cortisone have the greatest MC activityT
Prednisolone and prednisone have intermediate activityT
Hypertension is probably due to vasoconstriction and increased contractilityT
Betamethasone and dex have much lower risk of HPA suppression than prednisolone/pred/methylpredF, higher risk
RR of TB is 1 for prednisolone doses >/= 15mgF, 7.7
RR of TB is 1 for prednisolone doses < 15mg/dayF, 2.8 however not significant
Immunosuppressive therapy does not alter PPD screeningF, it reduces it
IFN assays are less reliable than PPD in the presence of immunosuppressive therapyF, more reliable however not ideal
Like other adverse effects, the risk of CS induced osteoporosis is not significant with sub physiologic dosingF - important - can be seen in doses of 2.5-5mg/day
Long term (>3 months) of CS increases the risk of osteonecrosis, except in SLE patientsF, mostly in SLE patients
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