Lec 25-Clinical use of corticosteroid Flashcards
HPA axis
- Hypothalamus: release CRH corticotropin releasing hormone
- This stimulates the anterior pituitary
- Anterior Pituitary then releases ACTH (Adrenocorticotropic hormone) this then stimulates the adrenal cortex
- Adrenal cortex produces cortisol
Suppression of the HPA axis
- As cortisol levels rise in the blood this has a negative feedback effect on the HPA axis
- This inhibits hypothalamus and pituitary stop them producing CRH and ACTH
- If there are lots of stress stimulus then the negative feedback will be overcome
What happens when we administer exogenous steroids
e. g. oral or IV cortisol or prednisolone
- Exogenous steroid will act on the hypothalamus and the anterior pituitary
- This strongly inhibits CRH and ACTH and therefore adrenal cortex cortisol production will be reduced
- HPA is therefore shut off
Naturally occurring corticosteroid
1) Mineralocorticoids- aldosterone
- Salt/water balance
- Salt retaining activity
- Not often used in therapy
- Fludrocortisone
2) Glucocorticoids
- Carbo;protein metabolism
- Frequently used in drug therapy (anti-inflammatory and immunosuppression)
- Topical, oral, IV, inhalation
Glucocorticoid drugs
- Steroids used as drugs (exogenous) are related to the naturally occurring steroid, we synthesis and change the structure to allow it to do what we want dexamethasone
- Main endogenous glucocorticoids in man are cortisol/hydrocortisone, corticosterone
- Have immunosuppressive and anti-inflammatory effects in addition to their metabolic effects
- Metabolic effects (inc HPA suppression; protein metabolism; salt water balance) become side effects when used as anti-inflammatory drugs
Steroid structure (dexamethasone v hydrocortisone)
- Dexamethasone has slightly different structures to naturally occurring hydrocortisone
- e.g. fluorine atom; shorter side chain; additional double bonds
- Dexamethasone is incredibly potent
- Only use it when we have to because it suppresses the HPA so much
Clinical uses for corticosteroids
Replacement therapy:
-treatment of hypocorticolism (Addison’s disease)- we use hydrocortisone to replace cortisol that can’t be produced by adrenal glands
Anti-inflammatory therapy
-Asthma, by inhalation
-Topically in various conditions e.g. eczema, allergic conjunctivitis/rhinitis
-In hypersensitivity states e.g. anaphylaxis
-In various diseases with inflammatory components e.g. RA, SLE- a lot of the damage is done by inflammation so we need to stop the damage
Immunosuppressant therapy
NB- steroids DONT cure any of these
Replacement therapy
-Adrenal cortex normally secretes hydrocortisone
+has gluco- and weak minerals-corticoid activity
-Addisons disease or adrenalectomy cause deficiency in glucocorticoids
+Fatal if untreated
-In deficiency, physiological replacement achieved with exogenous
+hydrocortisone, if glucocorticoid activity needed
+Fludrocortisone, if additional mineralocorticoid needed as well as glucocorticoid
Cortisol replacement therapy
-Replacement therapy is normally prolonged or lifelong
-20-30mg hydrocortisone
-2-3 divided doses
-This is done to more closely mimic the natural release of corticosteroids from the body
Additional: steroid cover may be required at times of stress
-Normal person secretes >300mg cortisol/day in stressful situations
-Mimicked by 100mg hydrocortisone IM or IV, repeated every 8 hours
-To withdraw, half dose daily for 5 days
-e.g. when on replacement therapy if they undergo stress they won’t naturally be able to deal with this as they can’t produce cortisol
-If there is planned stress e.g. surgery then this can be given IV in high doses so the body has sufficient steroids
-These patients may carry additional steroid with them in case of stress
Recovery from adrenal suppression
- Following prolonged (>5days) therapy with exogenous glucocorticoids, HPA doesn’t recover immediatlely on withdrawal of drug
- The longer they have been suppressed the longer it takes to recover (it may not)
- A delayed stage process
- (c.f. instant recovery of HPT, see later)
- Pituitary ACTH recovers first
- Adrenal cortisol secretion in response to ACTH recovers later
Other effects of glucocorticoids
Reduction in chronic inflammation
-Inhibit both early and late phase of inflammation
-Reduced pain, inflammation
-Prevention/delay of loss of function
BUT
Immunosuppressive
-Decreased efficiency to clear infections
-Decreased healing
-Protective effects of immune response decreased
Corticosteroid used in therapy
- Hydrocortisone- mainly in replacement therapy; Anti-inflammatory potency= 1; Na retaining potency= 1
- Prednisolone- Systemic anti-inflammatory activity; Anti-inflammatory potency= 4; Na retaining potency= 0.8
- Dexamethasone- Anti-inflammatory where water retention undesirsble; Anti-inflammatory potency=25; Na retaining potency= 0
Pharmacokinetics (movement of drugs in the body)
-Can be given by a variety of routes
+oral, topical, IM or IV or intra-articular
-Most used are active orally
-Endogenous steroids bound to CBG (Corticosteroid binding globulin)
+CBG dose not bind synthetic steroids
-Free steroid enters cells by diffusion (endogenous steroids bound to CBG cannot pass the membrane because the protein is to hydrophillic- MUST BE FREE)
-Metabolised by the liver (drug interacts)
+Cortisone: Hydrocortisone, prednisone: prednisolone
Duration of action
-Short-acting t1/2 8-12 h: Hydrocortisone, drug of choice for replacement (fit in with natural rhythm) and emergencies
-Intermediate, t1/2 12-36h:
+Prednisolone, the drug of choice for systemic anti-inflammatory effects
+Prednisone, methylprednisolone, triamcinolone
-Long-acting t1/2 36-72 h:
+Bethamethasone, Dexamethasone, dexamethasone used when water retention undesirable and ACTH suppression
Place in anti-inflammatory therapy
-More effective than NSAID’s which have no effect on lipoxygenase pathways
-Systemic use: benefits must outweigh the risk
+Use lowest dose that controls symptoms
+Unless life threatening, do not aim to make bearable. Try and reduce dose at frequent intervals
+If life-threatening: Start HIGH for rapid effect and escalate quickly if no effect
-Try non-systemic route if appropriate
