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