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Corticosteroids
Basal secretions
Group
Hormone
Daily
secretions
5 – 30 mg
2 – 5 mg
5 – 150 μg
• Cortisol
• Corticosterone
Mineralocorticoids • Aldosterone
• 11- deoxycorticosterone Trace
Sex Hormones
•Androgen
• DHEA
15 – 30 mg
•Progestogen
• Progesterone
0.4 – 0.8 mg
Trace
•Oestrogen
• Oestradiol
Glucocorticoids
From Essential of Pharmacotherapeutics, ed. FSK Barar. P.351
Cholesterol
ACTH
Oestriol
Pregnenolone
17-α- Hydroxy
pregnenolone
Dehydro-epi
androsterone
Progesterone
17- Hydroxy
progesterone
Androstenedione
11-Desoxycorticosterone
21,β hydroxylase
Oestrone
11- Desoxycortisol
Corticosterone
11,β hydroxylase
18-Hydroxycorticosterone
ALDOSTERONE
CORTISOL
TESTOSTERONE
OESTRADIOL
Glucocorticoid Analogues
Pharmacological Actions
• Direct (Intended) Actions
Anti-inflammatory
Anti-allergy
Anti-immunity
• Permissive Actions
• Lipolytic effects
• Effect on bp
• Effect on bronchial muscles
• (e.g.,sympathomimetic amine)
Pharmacological Actions
• Negative feedback mechanism.
• Steroids and drugs designed to mimic them are
directly gene-active.
• Glucocorticoids (e.g., prednisolone) used to suppress
inflammation, allergy and immune responses.
• Anti-inflammatory therapy is used in many illnesses
(e.g., RA, UC, BA, eye and skin inflammations).
-Useful in, say, tissue transplantation and
lymphopoiesis (leukemias and lymphomas).
• Striking improvements can be obtained, but severe
adverse, but highly predictable, effects are ensue.
Pharmacological Actions
• For most clinical purposes, synthetic
glucocorticoids are used because they have a
higher affinity for the receptor, are less
activated and have little or no salt-retaining
properties.
• Hydrocortisone used for: orally for
replacement therapy, i.v. for shock and
asthma, topically for eczema (ointment) and
enemas (ulcerative colitis).
• Prednisolone the most widely used drug given
orally in inflammation and allergic diseases.
Pharmacological Actions
• Betamethasone and dexamethasone: very
potent, w/o salt-retaining properties; thus,
very useful for high-dose therapies (e.g.,
cerebral edemas).
• Beclometasone, diproprionate, budesonide:
pass membranes poorly; more active when
applied topically (severe eczema for local antiinflammatory effects) than orally; used in
asthma, (aerosol).
• Triamcinolone: used for severe asthma and for
local joint inflammation (intra-articular inj.).
Stress and The Adrenal Glands
Actions: Carbohydrate and protein metabolism
Negative nitrogen balance and hyperglycemia
• Gluconeogenesis
– Peripheral actions (mobilize aas and
– Hepatic actions
glucose and glycogen)
• Peripheral utilization of glucose
• Glycogen deposition in liver
(activation of hepatic glycogen synthase)
Actions: Lipid
metabolism
• Redistribution of Fat
• Buffalo hump
• Moon face
• Promote adipokinetic agents activity
(glucagon, growth hormone, adrenaline, thyroxine)
Actions: Electrolyte and water balance
• Aldosterone is more important
• Act on DT and CD of kidney
– Na+ reabsorption
– Urinary excretion of K+ and H+
• Addison’s disease ??
• Na+ loss
• Shrinkage of ECF
• Cellular hydration
• Hypodynamic state of CVS
• Circulatory collapse,
renal failure, death
Actions: CNS
• Direct:
– Mood
– Behaviour
– Brain excitability
• Indirect:
– maintain glucose, circulation and electrolyte
balance
ICP (pseudotumor cerebri) - Rare
Actions: Stomach
Aggravate peptic ulcer. May be due to:
– Acid and pepsin secretion
– immune response to H.Pylori
Actions: Calcium metabolism
•
Intestinal absorption
•
Renal excretion
• Excessive loss of calcium from spongy bones
(e.g., vertebrae, ribs, etc)
Preparations
Drug
Cortisol
Anti-inflam.
Salt retaining
Topical
1
1.0
1
0.8
0.8
0
Prednisone
4
0.8
0
Prednisolone
5
0.3
4
Methylprednisolone
5
0
5
5
0
5
Paramethasone
10
0
-
Fluprednisolone
15
0
7
Cortisone
Intermediate acting
Triamcinolone
Preparations
Drug
Anti-inflam.
Salt retaining
Topical
Long acting
Betamethasone
25-40
Dexamethasone
30
Mineralocorticoids
Fludrocortisone
10
DOCA
0
0
0
10
10
250
20
10
0
Examples of
Corticosteroids available
•
•
•
•
•
•
hydrocortisone
prednisolone
dexamethasone
beclomethasone
budesonide
fluticasone
Uses
• Corticosteroids are used:
 to reduce inflammation (asthma, arthritis) and
swelling (cerebral oedema)
 to suppress the immune response (systemic
lupus erythematosis)
 to reduce nausea and vomiting (as in cancer
chemotherapy)
 to reduce terminal pain (associated with
cancer)
 as replacement therapy (in Addisons disease)
Unwanted Effects
• Metabolic:
–
–
–
–
–
–
–
–
growth suppression
diabetes mellitus
muscle wasting
osteoporosis
fat redistribution
skin atrophy
hirsutism
acne
–
–
–
–
hypertension
hypokalaemia
menstrual irregularities
adrenal suppression
Unwanted Effects
• Other:
– infection
– emotional disturbances (psychosis, depression,
mania)
– cataract, glaucoma
– GI bleeding, perforation
• Withdrawal
– Addisonian crisis
– raised intracranial pressure
– arthralgia/myalgia
– pustular rash
How corticosteroids work
• Gross (metabolic) actions:
– glucose: diabetogenic
» (glucose uptake and utilisation; gluconeogenesis)
– fat: Cushing’s syndrome
» (redistribution, lipolysis)
– protein: muscle wasting
» (catabolism, anabolism)
– minerals: hypertension (mineralocorticoid effect)
How corticosteroids work
• Cellular (nuclear)* level:
– anti-inflammatory and immunosuppressive actions:
»  number and activity of leucocytes,
» proliferation of blood vessels,
» activity of mononuclear cells,
» activity of cytokine secreting cells,
» production of cytokines,
» generation of eicosanoids and PAF,
» complement components in blood,
» histamine release
*Effect through gene transcription (lipocortin synthesis, inhibition of
COX-2 synthesis). THIS TAKES TIME!
Avoiding unwanted effects
of corticosteroids
• Modification of dose/dose regimen
 Use short courses/low doses if possible
 Use steroid sparing drugs
 Withdraw ‘chronic’ steroids slowly
 Give dose once daily and in morning
 Give on alternate days if possible
 Give prophylactics if possible
 Give product locally
 Remember contraindications
 Enrol help of patient
Avoiding unwanted effects
of corticosteroids
• Steroid Selection:
– remember, their effects
can differ with regard to
their mineralocorticoid
and anti-inflammatory
actions and duration of
effect eg as parenteral
AIA NaRet
products
Hydrocortisone
1
1
Prednisolone
5
1
Dexamethasone
35
<1
Fludrocortisone
<<1 20
or as topical products
(creams)
• hydrocortisone - mild
• clobetasone but. moderately potent
• betamethasone - potent
• clobetasol prop. - very
potent
Giving products locally can
still cause problems!
• systemic dosing can occur
• local toxicity can develop –skin: infection, thinning, bruising.
–eye: viral infection, cataract, glaucoma.
–inhalation: fungal infection, hoarseness
–joints: infection, necrosis