Lecture 17: Corticosteroid drugs Flashcards
Therapuetic use of corticosteroids
-primary adrenal insufficiency
-allergic reactions
-inflammation/autoimmune diseases
-asthma
-anti-cancer
Allergic reactions treated by corticosteroids
-insect stings
-angioedema
inflammation and autoimmune diseases treated by corticosteroids
-burstitits, synovitis, tendonitis
-rheumatoid arthritis
-lupus
-IBS
-chronic hepatitis
Cortisol
-active form
-11 hydroxyl
Cortisone
-inactive form
-11 hydroxyl oxidized to ketone
-effective as cortisol
-do not give to patients with impaired livers
11 B-hydroxysteroid dehydrogenase
-catalyzes oxidation of cortisol to cortisone
-reversible reaction
-in liver
Short acting corticosteroids (8-12hr)
-hydrocortisone
-cortisone
intermediate acting corticosteroids (12-36hr)
-prednisone
-prednisolone
-methylprednisolone
-triamcinolone
long-acting corticosteroids (36-54hr)
-dexamethasone
-betamethasone
Synthetic glucocorticoids
-fludrocortisone
-prednisone/prednisolone
-methylprednisone
-triamcinolone
-dexamethasone
-betamethasone
Fludrocortisone
-a-Florine at C-9
-greater glucocorticoid activity
-strong mineralcorticoid activity
-intense Na+ retention that leads to edema
-used in MC therapy
Prednisone/Prednisolone
-double bond between C1 and C2
-more GC activity
-reduced MC activity
-interconvertable by 11B-hydroxysteroid dehydrogenase
11B-hydroxysteroid dehydrogenase
-converts prednisone to prednisolone and vice versa
-11B OH to =O
Methylprednisolone
-6a-methyl group
-similar potency to prednisolone
-reduced MC activity
Triamcinolone
-9a-F and 16a-OH
-similar to prednisone
-reduced MC activity
-inc hydroPHILIcity
-low oral bioavailability
Dexamethasone
-16a-methyl group
-inc lipoHILIcity = inc binding = stronger effect
-inc stability in plasma
-reduced MC activity
Betamethasone
-enantiomer of dexamethasone at C-16
-similar properties
21-esters
-21-hydroxyl group modified to ester
-prodrugs activated by hydrolysis by esterases
21-ester groups
-acetate or butyrate
-succinate
-phosphate
21- acetate or butyrate
-inc lipoPHIlicity
-prolonged action upon IM or articular injection
21- Succinate group
-soluble
-slow hydrolysis (30-45min)
21- phosphate group
-inc solubility
-rapid hydrolysis by phosphatases (10min)
-IV or IM injection for emergency conditions
1,2 double bond SAR
-inc GR to MR ratio by 5x
11 B-OH SAR
-required for GR/MR activity
-more important for GR
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
