Steroids 2020 PHRM30003 PDF

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PHRM30003 Steroids lecture notes, 2020...

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Glucocorticoids Alastair Stewart [email protected] Objectives Appreciate the range of indications for glucocorticoids Know the mechanism(s) of action Know the adverse effect profile Appreciate the limitations of this drug class

Ref: Rhen & Cidlowski (2005). N Engl J Med. 335: 1711-1723

Glucocorticoids

• Physiological roles • Pharmacological roles – Anti-inflammatory – Immunosuppressant – Anti-cancer

Glucocorticoids • eg cortisol – synthesised by the adrenal cortex, affects carbohydrate and protein metabolism – glucocorticoid - anti-inflammatory – mineralocorticoid

Table 59–2 Relative Potencies and Equivalent Doses of Representative Corticosteroids COMPOUND

AI POTENCY

Cortisol Cortisone* Prednisone * Prednisolone 6-Methylprednisolone Dexamethasone *S, short I, intermediate L, long

1 0.8 4 4 5 25

MR POTENCY

1 0.8 0.8 0.8 0.5 ~0

DURATION *

EQUIVALENT DOSE, MG

S S I I I L

20 25 5 5 4 0.75

(i.e., 8–12 hour biological half-life); (i.e., 12–36 hour biological half-life); (i.e., 36–72 hour biological half-life).

These dose relationships apply only to oral or intravenous administration, as glucocorticoid potencies may differ greatly following intramuscular or intra-articular administration. *these versions require activation by conversion to the 11 hydroxy metabolites

Source: adapted from – on-line: Goodman & Gilman's Pharmacology > XII. Hormones and Hormone Antagonists > Chapter 59. Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones > Adrenocortical Steroids > Physiological Functions and Pharmacological Effects > Physiological Actions >

(In)Activation

http://tmedweb.tulane.edu/pharmwiki/doku.php/glucocorticoid_pharmacology J Clin Invest. 2001;108(9):1299-1305. doi:10.1172/JCI12745.

Regulation of endogenous glucocorticoids

Cortisol levels -direct feedback CRH: corticotropin releasing hormone ACTH: adrenocorticotrophic hormone Cortisol: endogenous glucocorticoid

Adapted from: Kadmiel & Cidlowski (2013); Trends in Pharmacological Sciences, Vol.34, Issue 9, 518-530.

Indications for Glucocorticoids • Physiological replacement (Addison’s disease) • Anti-inflammatory use: – asthma (eg beclomethasone) – skin, eye, etc. (topical) – hypersensitivity states (severe allergic reactions) – rheumatoid arthritis (eg prednisolone)

Transactivation GCS

binding

dimersisation

nuclear localisation HSP90

ENaC GILZ

GRE

MKP-1

Control

Dexamethasone 100 nM

GR immunostaining – epithelial cells

control

Dexamethasone 10nm

GR Mechanisms: transactivation Transrepression IL-8 COX-2 ICAM-1 NOS2

kB RE

NFkB

GCS + GR D GR/GCS

Transactivation GRE

GR Mechanisms: transactivation Transrepression IL-8 COX-2 ICAM-1 NOS2

kB RE

Transactivation GRE

NFkB

GR GR

GCS + GR D GR/GCS D (GCS/GR)2

GR Mechanisms: transactivation Transrepression IL-8 COX-2 ICAM-1 NOS2

Transactivation

kB RE

GRE GILZ

NFkB

IkBa

GCS + GR D GR/GCS D (GCS/GR)2

GR GR

ENaC GILZ MKP1

GR Mechanisms: transrepression Transrepression IL-8 COX-2 ICAM-1 NOS2

Transactivation

kB RE

GRE GILZ

NFkB

IkBa

GR

GCS + GR D GR/GCS D (GCS/GR)2

GR GR

ENaC GILZ MKP1

GR Mechanisms: transrepression Transrepression IL-8 COX-2 ICAM-1 NOS2

Transactivation

kB RE

GRE GILZ IkBa

NFkB

GR

HDAC2

GCS + GR D GR/GCS D (GCS/GR)2

GR GR

ENaC GILZ MKP1

Mechanism of action GCs Transactivation

Transrepression

Anti-inflammatory efficacy IkBa GILZ MKP1

cytokines (IL-8) inducible enzymes (COX-2) adhesion molecules (ICAM-1) Adverse effects

Metabolic cortisol suppression gluconeogenesis osteoporosis muscle wasting

Anti-leukocyte/eicosanoid wound healing immunosuppression gastric ulcer (PGE2 )

Mechanism of action GCs Decrease inflammatory cell number and activation Decrease probability and severity of inflammation Slow onset of action and maximum benefit Some actions rapid eg, systemic hydrocortisone in shock

Annexin-1 Discovered 1979/80 as mediator of GC action 37kDa concave-shaped, 4 domains of 70 aa residues each Shows calcium-dependent, serine-phospholipid binding (enables membrane interaction) Unique N-terminus - specificity amongst the family (13) PKC and Tyrosine Kinase phosphorylation sites

John et al. Trends in Endocrinology and metabolism Vol 15 April 2005

Annexin-1 Distribution cytoplasm inner/outer plasma membrane extracellular Actions reduction in PLA2 activity (weak) (association with lipid membrane) membrane repair (after rupture) membrane fusion (secretory processes) phagocytosis reduces cytokine production

Annexin-1 FPR2 (aka FPRL-1, ALX) GPCR stimulated by Lipoxin A4 Lipoxin A4 is a trihydroxy arachidonic acid metabolite FPRL-1 expressed in endothelium and neutrophils Activation facilitates resolution of inflammation

Anxa 1 is an agonist at FPR2 receptor Full length and N-terminal peptide anti-inflammatory – reduced neutrophil recruitment

Annexin-1 Anxa1-/- mice intensification of inflammation in Septic shock Arthritis Peritonitis cells show increased IL-6 NO PGE2 Importantly GCs show lesser effects in anxa1 -/-! The role of transactivation is more significant than expected ! (see Hannon et al., 2003. FASEB Journal 17: 253-5.)

Glucocorticoids • Adverse effects: – suppress glucocorticoid synthesis

Regulation of endogenous glucocorticoids

Glucocorticoids • Adverse effects: – suppress glucocorticoid synthesis – suppress response to infection or injury

Glucocorticoids • Adverse effects: – suppress glucocorticoid synthesis – suppress response to infection or injury – behavioural disturbances

Glucocorticoids • Adverse effects: – suppress glucocorticoid synthesis – suppress response to infection or injury – behavioural disturbances – cataracts, glaucoma

Glucocorticoids • Adverse effects: – suppress glucocorticoid synthesis – suppress response to infection or injury – behavioural disturbances – cataracts, glaucoma – metabolic effects

Glucocorticoids • Metabolic effects – osteoporosis – fat deposition – muscle wasting – hyperglycaemia – inhibit growth in children

Dissociated steroid ” Concept - (incomplete) mechanistic separation of beneficial and detrimental actions

Goal of improved targetting of GCs to inhibit specific pro-inflammatory transcription factors

Mechanism of action GCs Transactivation

Transrepression

✓

Anti-inflammatory efficacy IkBa GILZ MKP1

cytokines (IL-8) inducible enzymes (COX-2) adhesion molecules (ICAM-1) Adverse effects

Metabolic cortisol suppression gluconeogenesis osteoporosis muscle wasting

Anti-leukocyte/eicosanoid wound healing immunosuppression gastric ulcer (PGE2 )

Mechanism of action GCs Transactivation

Transrepression

✓

Anti-inflammatory efficacy IkBa GILZ MKP1

cytokines (IL-8) inducible enzymes (COX-2) adhesion molecules (ICAM-1)

✖

Adverse effects Metabolic cortisol suppression gluconeogenesis osteoporosis muscle wasting

Anti-leukocyte/eicosanoid wound healing immunosuppression gastric ulcer (PGE2 )

Investigation of GR expression GR knockout mice - identification of essential functions GR-/- die hours post partum of respiratory failure lungs are atelectatic (collapsed) liver shows impaired gluconeogenesis adrenal cortex hypertrophic medulla atrophic - no adrenaline GR without dimerisation domains (Dim-/-) is non-lethal transrepression rather than transactivation linked to essential functions

Glucocorticoid Resistance Mechanisms

IL-8 COX-2 ICAM-1 NOS2

kB RE

GRE GILZ IkBa

NFkB

GR

GR GR

ENaC GILZ MKP1

HDAC2

GCS + GR D GR/GCS D (GCS/GR)2 Decreased GRa levels, nuclear localisation, DNA binding, ligand binding

Transrepression Decreased HDAC2 Increased NFkB

Transactivation Increased GRb –inactive heterodimer with GRa...