Corticosteroids. Basal secretions GroupHormoneDaily secretions Glucocorticoids Cortisol...
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Transcript of Corticosteroids. Basal secretions GroupHormoneDaily secretions Glucocorticoids Cortisol...
Corticosteroids
Basal secretions
Group Hormone Daily secretions
Glucocorticoids • Cortisol• Corticosterone
5 – 30 mg
2 – 5 mg
Mineralocorticoids • Aldosterone• 11- deoxycorticosterone
5 – 150 μgTrace
Sex Hormones•Androgen•Progestogen•Oestrogen
• DHEA • Progesterone• Oestradiol
15 – 30 mg
0.4 – 0.8 mgTrace
From Essential of Pharmacotherapeutics, ed. FSK Barar. P.351
Cholesterol
Pregnenolone
Progesterone
Corticosterone
11-Desoxy-corticosterone
18-Hydroxy- corticosterone
ALDOSTERONE
17-α- Hydroxy pregnenolone
11- Desoxy- cortisol
17- Hydroxy progesterone
21,β hydroxylase
CORTISOL
11,β hydroxylase
Dehydro-epi androsterone
Andro-stenedione
Oestrone
Oestriol
TESTOSTERONE OESTRADIOL
ACTH
Glucocorticoid Analogues
Pharmacological Actions• Direct (Intended) Actions
Anti-inflammatoryAnti-allergyAnti-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 anti-inflammatory 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
• Gluconeogenesis– Peripheral actions (mobilize aas and glucose and glycogen)
– Hepatic actions
• Peripheral utilization of glucose
• Glycogen deposition in liver(activation of hepatic glycogen synthase)
Negative nitrogen balance and hyperglycemia
• Redistribution of Fat• Buffalo hump• Moon face
• Promote adipokinetic agents activity(glucagon, growth hormone, adrenaline, thyroxine)
Actions: Lipid metabolism
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
• Direct: – Mood– Behaviour– Brain excitability
• Indirect: – maintain glucose, circulation and electrolyte
balance
Actions: CNS
ICP (pseudotumor cerebri) - Rare
Aggravate peptic ulcer. May be due to:
– Acid and pepsin secretion
– immune response to H.Pylori
Actions: Stomach
• Intestinal absorption
• Renal excretion
• Excessive loss of calcium from spongy bones (e.g., vertebrae, ribs, etc)
Actions: Calcium metabolism
PreparationsDrug Anti-inflam. Salt retaining Topical
Cortisol 1 1.0 1Cortisone 0.8 0.8 0Prednisone 4 0.8 0Prednisolone 5 0.3 4Methylpredni- solone
5 0 5
Intermediate actingTriamcinolone 5 0 5Paramethasone 10 0 -Fluprednisolone 15 0 7
PreparationsDrug Anti-inflam. Salt retaining Topical
Long actingBetamethasone 25-40 0 10Dexamethasone 30 0 10
MineralocorticoidsFludrocortisone 10 250 10DOCA 0 20 0
Examples ofCorticosteroids 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 effectsof 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 effectsof corticosteroids
• Steroid Selection: – remember, their effects can
differ with regard to their mineralocorticoid and anti-inflammatory actions and duration of effect eg as parenteral products
AIA NaRet
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