Lecture 17: Corticosteroid drugs Flashcards by Brooke Thornburg

Therapuetic use of corticosteroids

-primary adrenal insufficiency
-allergic reactions
-inflammation/autoimmune diseases
-asthma
-anti-cancer

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Allergic reactions treated by corticosteroids

-insect stings
-angioedema

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inflammation and autoimmune diseases treated by corticosteroids

-burstitits, synovitis, tendonitis
-rheumatoid arthritis
-lupus
-IBS
-chronic hepatitis

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Cortisol

-active form
-11 hydroxyl

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Cortisone

-inactive form
-11 hydroxyl oxidized to ketone
-effective as cortisol
-do not give to patients with impaired livers

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11 B-hydroxysteroid dehydrogenase

-catalyzes oxidation of cortisol to cortisone
-reversible reaction
-in liver

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Short acting corticosteroids (8-12hr)

-hydrocortisone
-cortisone

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intermediate acting corticosteroids (12-36hr)

-prednisone
-prednisolone
-methylprednisolone
-triamcinolone

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long-acting corticosteroids (36-54hr)

-dexamethasone
-betamethasone

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Synthetic glucocorticoids

-fludrocortisone
-prednisone/prednisolone
-methylprednisone
-triamcinolone
-dexamethasone
-betamethasone

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Fludrocortisone

-a-Florine at C-9
-greater glucocorticoid activity
-strong mineralcorticoid activity
-intense Na+ retention that leads to edema
-used in MC therapy

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Prednisone/Prednisolone

-double bond between C1 and C2
-more GC activity
-reduced MC activity
-interconvertable by 11B-hydroxysteroid dehydrogenase

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11B-hydroxysteroid dehydrogenase

-converts prednisone to prednisolone and vice versa
-11B OH to =O

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Methylprednisolone

-6a-methyl group
-similar potency to prednisolone
-reduced MC activity

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Triamcinolone

-9a-F and 16a-OH
-similar to prednisone
-reduced MC activity
-inc hydroPHILIcity
-low oral bioavailability

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Dexamethasone

-16a-methyl group
-inc lipoHILIcity = inc binding = stronger effect
-inc stability in plasma
-reduced MC activity

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Betamethasone

-enantiomer of dexamethasone at C-16
-similar properties

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21-esters

-21-hydroxyl group modified to ester
-prodrugs activated by hydrolysis by esterases

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21-ester groups

-acetate or butyrate
-succinate
-phosphate

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21- acetate or butyrate

-inc lipoPHIlicity
-prolonged action upon IM or articular injection

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21- Succinate group

-soluble
-slow hydrolysis (30-45min)

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21- phosphate group

-inc solubility
-rapid hydrolysis by phosphatases (10min)
-IV or IM injection for emergency conditions

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1,2 double bond SAR

-inc GR to MR ratio by 5x

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11 B-OH SAR

-required for GR/MR activity
-more important for GR

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21-OH, F, Cl SAR

-required for activity -ester prodrug must be hydrolyzed to OH for max activity

17a-O SAR

-required for GR activity

16-O or B-CH3 SAR

-dec MR activity

9a-F or Cl SAR

-enhances GR and MR potency

6a-CH3 or F SAR

-enhances GR to MR ratio

Mech of glucocorticoid action in asthma

-will NOT stop attack while happening -inhibit airway inflammation -use prophylactically

GC effect on airway

-do not relax any muscle -mod cytokine and chemokine production -inhibit eicosanoid synthesis -inhibit accumulation of immune cells in lung -dec vascular permeability

inhaled gc

-use prophylactically -treat astma -max effects seen after weeks -compliance is concern

Desired properties of inhaled GCs

-high potency -minimal systemic affects -prolonged action

inhaled GC solutions

-high lipophilicity -low oral bioavailability (most is swallowed) -rapid clearance

high lipophilicity effect

-tighter binding -better penetration -prolonged action by forming microcrystals

inhaled GC drugs

-triamcinolone acetonide -beclomethasone dipropionate -Flunisolide -Budesonide -mometasone furoate -fluticasone propionate

Triamcinolone acetonide

-inhaled GC -resistant to hydrolysis -8x more potent than prednisolone

Beclomethasone dipropionate

-inhaled GC -converted rapidly to monopropionate by hydrolysis -14x more potent than dexamethasone

Flunisolide

-inhaled GC -rapid absorption -rapid metabolism (first-pass) -minimal adverse effect with long-term therapy

Budesonide

-inhaled GC -mixture of epimers at 16,17 butylacetal -faster topical uptake -low oral availability -extensive FP metabolism

Mometasone furoate

-inhaled GC -highly potent -more rapid onset -negligible availability (rapid metabolism and low oral bioavailability)

Fluticasone propionate

-inactivated by hydrolysis of thioester (FP metabolism) -highly lipoPHILIC -INsoluble -high potent -poor absorption from GI -rapid topical uptake

Desired properties of topical GCs

-high lipophilicity for fast absorption -minimal systemic effect -prolonged action

Topical GC metabolism

-absorbed thru skin -metabolized in liver -excreted to urine or bile

low potency topical GCs

-safest for chronic application -hydrocortisone cream

topical GCs with high potency

-risk systemic exposure -should be used only for short duration of treament

Halogenated analogues

-usually potent topical GCs

Topical GC forms

-acetonide/ester forms -21-chlorocorticoids -9a

Acetonide/ester topical GCs

-better potency bc high lipophilicity -triamcinolone acetonide -fluocinonide -betamethasone valerate

21-chlorocorticoids

-sub 21-OH with Cl -very high potency -topical anti-inflammatory

Fluticasone propionate and mometasone furoare

-topical GCs -medium potency -high lipophilicity but poor solubility -poor dissolution into inflamed tissue

Adverse effects of GCs

-crossover MC activity -metabolic effects -Cushing's-like effects -impaired glucose tolerance -immunosuppression -ulcer risk -CNS effects -cataracts -addisonian crisis

Adverse effect of GC crossover MC activity

-Na+ and water retention -HTN -correctable with selective GCs

Metabolic adverse effects of GC

-steroid myopathy -reduce bone growth in kids -osteoporosis

steroid myopathy

-high doses over time cause wasting of proximal muscles

Osteoporosis caused by GCs

-inhibit osteoblasts -can be prevented by bisphosphonate

Cushing's like effects

-redistribution of fat -moon face -buffalo hump

Impaired glucose tolerance form GCs

-HYPERglycemia from gluconeogenesis -dec insulin response (only diabetes)

Adverse effects of immunosuppression by GCs

-inc susceptibility -impaired healing

adverse effects of GCs on CNS

-linked to glucose metabolism -euphoria -depression

Addisonian crisis

-adrenal insufficiency upon GC withdrawal -delay recovery of hypothalmus and pituitary -dec ACTH release and response to ACTH -related to dose and duration of therapy

Addisonian crisis cause

-negative feedback on hypothalmus and pituitary from prolonged doses of GCs

Symptoms of Addisonian crisis

-inability to withstand stress -HYPOtension -weakness