Corticosteroids
The Adrenal Medulla : Catecholamines Cortex : Adrenal steroids or Corticosteroids 3 concentric zones: Zona glomerulosa : mineralocortocoids (ALDOSTERONE) Zona fasciculata : glucocorticoids (CORTISOL) Zona reticularis: androgensCorticosteroids Synthesis -Both cortisol and aldosterone are synthesized from cholesterol -Normal adults secrete: 10-20 mg of cortisol daily 0.125 mg of aldosterone daily -The rate of secretion of cortisol is controlled by a circadian rhythm that peaks at 8 AM Cortisol plasma concentration: 16 mcg/dl at 8AM and 4 mcg/dl at 4PM Aldosterone plasma concentrations are constant at 0.01 mcg/dl
Cholesterol
PregnenoloneProgesterone
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
The synthesis of adrenal steroid hormones by the adrenal cortex is regulated by the Hypothalamic -Pituitary-Adrenal (HPA) axis. -Corticotropin-releasing hormone (CRH) is released by the hypothalamus in response to circadian rhythms and a number of stress inducers such as acute trauma, surgery, fever, infection and pain. -CRH acts on the cells of the corticotropes of the Anterior Pituitary to induce the synthesis and release of adrenocorticotrophic hormone (ACTH). - ACTH binds to its adenyl cyclase-coupled receptor on the adrenal cortex and induces the expression of genes involved in the synthesis of all adrenal steroid hormones. -Importantly, Cortisol produced by the adrenal cortex acts in a negative feedback loop to inhibit the HPA axis by inhibiting the production of both CRH and ACTH.
CARBOHYDRATE AND PROTEIN METABOLISM:LIVER : ↑GLUCONEOGENESIS AND ↑ GLYCOGEN STORAGEPERIPHERY : ↑ PROTEIN CATABOLISM (MUSCLE) = ↑ SUBSTRATE FOR GLUCONEOGENESIS - ↓ PERIPHERAL GLUCOSE UTILIZATION - ↑ BLOOD GLUCOSELIPID METABOLISM: - ↑ LIPOLYSIS BY FACILITATING ACTION OF GH/B-ADRENERGIC AGENTS - ↑ GLYCEROL = ↑ SUBSTRATE FOR LIVER GLUCONEOGENESIS - ↑ FFA CONTRIBUTES TO ↑ INSULIN RESISTANCE- REDISTRIBUTION OF FAT: ↑ TRUNCAL OBESITY ↑ BACK OF NECK (BUFFALO HUMP)/UPPER CHEST ↑ MOON FACIES ↓ EXTREMITIES Physiological effects of glucocorticoids
Response to Stress- Cortisol levels increase in times of stress- the corresponding increase in blood glucose acts to protect glucose dependent tissues (e.g. brain/kidney/heart) from starvation Cardiovascular system - modulate vascular reactivity to vasoactive agents e.g. norepinephrineand vasopressin - Adrenal insufficiency results in HYPOTENSION - Excess glucocorticoids (i.e. Cushing’s Disease) results in HYPERTENSION Effects on immune system and effect on inflammations : - ↓ numbers of circulating T cells, B cells, macrophages, eosinophils & basophils- redistribution to lymphoid tissues - inhibition of cytokine synthesis IL‐1 to IL‐6, IL‐8, TNF‐α, cell adhesion factors and GM‐CSF, & ↓ generation of induced nitric oxide: supress CMI &also humoral immunity - inhibition of Phospholipase A2 activity- ↓ prostaglandin and leukotrienes production - inhibition of COX-2 synthesis- ↓ prostaglandin -↓ histamine release from basophils and mast cells -↓ IgG production
Skeletal muscle - permissive concentrations of glucocorticoids required for muscle function - muscle weakness is a sign of adrenocortical deficiency (Addison’s Disease) Other Systems GI tract- gluococorticoids promote synthesis of gastric acid & pepsin - ↓ GI absorption of Ca2+ and increase its renal excretionBone - glucocorticoids promote bone loss: ↓ osteoblasts & ↑ osteoclastsCNS - affect mood behavior and brain excitability glucocorticoid excess (e.g. Cushing’s Disease)- mood elevation glucocorticoid deficiency (Addison’s Disease)- apathy/depression
Mechanism of action - Adrenal steroids enter the cell & combine with the steroid receptors of the cytoplasm. The combination enters the nucleus & controls protein synthesis. -Inhibition of inflammation achieved through the formation of a protein (lipocortin) that inhibits the enzyme phospholipase A2 which is needed to synthesize mediators essential for the inflammatory process. -Corticosteroids also act on cell membranes altering ion permeability & modify production of neurohormones.
Therapeutic uses: General principles1. Analyze risk‐benefit ratio in each patient2. Determine appropriate dose by trial & error & re‐evaluate periodically in each patient3. Corticosteroids are neither specific nor curative, only palliative ,except for use in replacement4. Stopping Corticosteroids suddenly after prolonged therapy‐ adrenal insufficiency. Always taper the dose slowly .5. At times of stress supplementary Corticosteroids therapy must be given for (2‐ 10 times increased dose for 24‐72 hrs) 6- Dosage: Many factors should be considered in determining the dosage of corticosteroids: glucocorticoid versus mineralocorticoid activity duration of action type of preparationtime of day when the drug is administered. When large doses of the hormone are required for more than 2 weeks, suppression of the HPA axis occurs. Alternate-day administration of the corticosteroid may prevent this adverse effect by allowing the HPA axis to recover/function on days the hormone is not taken. 7-Several semisynthetic derivatives of corticosteroids are available. These agents vary in anti-inflammatory potency, mineralocorticoid activity, and duration of action.
Hydrocortisone: used in:- Replacement therapy, when it is given orally in a dose of 20 mg in themorning & l0 mg in the evening.- Shock & status asthmatic us, when it is given IIV up to 500 mg 6 hourly.- Topical application: e.g. 1 % cream or ointment in eczema; 100 mg doses asenemata or foam in treating ulcerative colitis.Prednisolone: used orally in:- Inflammatory disease; e.g. severe rheumatoid arthritis, ulcerative colitis,chronic active hepatitis.- Allergic diseases such as severe asthma, glomerulonephritis…..- Acute lymphoblastic leukemia & non-Hodgkin lymphoma. It would be usual to start at 20 mg 8 hourly& reduce the dose according to clinical improvement.Used in ulcerative colitis as 20 mg enema.Prednisone: this is usually metabolized to prednisolone.Beclomethasone dipropionate and Budesonide : A fluronated & therefore non-polar steroid which passes across membranes.It is used topically in:1. Asthma when it is given by metered aerosol doses each of 50 μg. Usual daily dose is. 100 μg 6-8 hourly. About 20% of this reaches the lungs; the rest is swallowed and destroyed by 1st pass metabolism. 2. Severe eczema, when it is used 0.025% cream.Betamethasone: used for:1. Cerebral edema caused by tumors & trauma, given either orally or I/M in a doses of up to 4 mg 6 hourly.2. Severe eczema given topically as 0.1 % cream.Dexamethasone: is used in cerebral edema.Triamcinalone: used in:1. Local inflammation of joints or soft tissue given by intra-articular injection in doses up to 40 mg depending on joint size.2. Severe eczema given topically as 0.1 % cream.Budesonide and Clobetasal : used topically in severe resistant eczema
PharmacokineticsOrally administered corticosteroid preparations are readily absorbed. Selected compounds can also be administered intravenously, intramuscularly, intra-articularly (for example, into arthritic joints), topically, or via inhalation or intranasal delivery . All topical and inhaled glucocorticoids are absorbed to some extent and, therefore, have the potential to cause hypothalamic–pituitary–adrenal (HPA) axis suppression. -90 to 95 % bound in plasma (primarily to corticosteroid binding globulin -CBG - some to albumin) plasma halflife - 60 to 90 minute Corticosteroids are metabolized by the liver microsomal oxidizing enzymes. The metabolites are conjugated to glucuronic acid or sulfate, and the products are excreted by the kidney. The half-life of corticosteroids may increase substantially in hepatic dysfunction. Prednisone is preferred in pregnancy because it minimizes steroid effects on the fetus. It is a prodrug that is not converted to the active compound ( prednisolone) in the fetal liver. Any prednisolone formed in the mother is biotransformed to prednisone by placental enzymes.
Pharmacological uses: Endocrine Uses of Glucocorticoids
Non-Endocrine Uses of Glucocorticoids Rheumatoid Disorders: e.g. RA, SLE, vasculitisa) Prednisone is typically the drug of choice- Acts by inhibiting the ongoing active autoimmune responseb) used for short periods (usually < 3-4 weeks) to provide symptomatic pain relief and to control disease “flare ups”(treatment does not cure the underlying disease etiology)c) used as a therapeutic bridge while waiting for effects of long acting DMARDsd) more effective than NSAIDs when used for < 1 month- ↓ Joint tenderness, ↓ pain & ↑ grip strengthf) short-term low-dose (<15 mg/day) is seldom associated with adverse effects g) drugs can be administered directly into joint (max. once every 3 months)- active form of drug e.g. Prednisolone must be usedh) In more severe cases low dose chronic treatment has also been shown to reduce bone erosions- however decreased efficacy after 6 months and increased potential for adverse effects especially OSTEOPOROSIS- patients should take daily Ca2+ and Vitamin D supplementationi) Once there is clinical improvement, the dose of glucocorticoid should be slowly tapered to avoid serious adverse effects
Treatment of Allergies a) e.g. bronchial asthma, allergic rhinitis, drug/serum/transfusion-related allergic diseases, contact dermatitis, urticaria, bee stings and insect bites b) Treatment is not curative - only treats symptoms c) Acts to inhibit the inflammatory response and cytokine production d) Bronchial asthma :inhalational steroids: beclomethasone, budesonide , flunisolide, fluticasone -Allows delivery of high concentrations of drug directly to the lung - Due to significant first pass effect -low risk of adverse effects and reducing the risk of HPA suppression -for serious acute cases of asthma short term oral glucocorticoids or IV administration can be used e.g. prednisolone
Respiratory distress syndrome- respiratory distress is common in premature infants- mothers treated with dexamethasone prior to birth- dexamethasone is not metabolized by 11ᵝ HSD2 and freely crosses theplacental barrier where it can promote lung maturation- prednisone is NOT USED as prednisolone formed in the maternal liveris converted to prednisone by placental 11ᵝ HSD2, and since the fetal liver doesnot operate during fetal life it cannot be converted to the active prednisolonein the fetus
Treatment of cerebral EdemaDexamethasone is used to decrease intracranial pressure due to vasogenic cerebral edema in the following conditions:-Primary and metastatic brain tumors-Bacterial meningitis (prevents hearing loss)-Brain radiation exposure-High altitude cerebral edema-Not to be used for traumatic brain injury, stroke or intracerebral hemorrhageMechanism of action though to involve: ↓inflammation and ↓ cytokine production↑Stabilization of blood brain barrier ↓ Endothelial permaeability ↓ CSF production ↑ reabsorption ↑ CSF-mediated fluid clearance
Toxicity: -Immune response: increased susceptibility to infections -Risk of peptic ulcers -Myopathy & muscle wasting -Osteoporosis -Hyperglycemia -Behavioral changes: hypomania or acute psychosis -Cataracts (posterior subcapsular), glaucoma - Fluid & electrolyte balance: Na ,water retention,HT, hypokalemia, - HPA Axis suppression - others: acne, thinning of skin, purple striae, Hirsutism, menstrual abnormalities, wt gain, pancreatitis.
Contraindications:All are relative1. Peptic ulcer2. DM3. Hypertension4. Osteoporosis5. TB & other infections6. Psychosis7. Epilepsy8. CHF9. Renal FailureAbsolute Contraindications:Herpes Simplex keratitis Cushing’s disease
Mineralocorticoids: (Aldosterone, desoxycorticosterone, flurocortisone) Aldosterone is the most important in humans, also small amounts of desoxycorticosterone are formed and released, its action, effects & metabolism are similar to that of aldosterone. Flurocortisone, a synthetic corticosteroid, the most commonly used salt-retaining hormone.
Aldosterone:Its secretion is influenced by many factors ACT, Angiotensin-Renin- Aldesterone system. ACTH produces a moderate stimulation of its release (the effect lasts for few days).It is 1/3 of cortisol effect is suppressing ACTH, the small amounts of it prevent itfrom taking part in any feedback relation in control of ACTH secretion.An important stimulus for aldosterone secretion is reduction in blood volume whether due to hemorrhage, dietary Na restriction or Na loss following diuretic administration- T1/2 15-20 min . – Metabolism: like cortisol.- About 50 μg/24 hours appearing in urine (conjugated).- 5 -15 μg/24 hours excreted free or glucoronoid.
Desoxycorticosterone:- Precursor for aldosterone, secreted in amounts of 200 μg/day. under control of ACTH and enhanced by dietary Na restriction - T Ѕ is 70 min. - Cone In plasma about 0.03 μg/dlFludrocortisone:- A potent glucocorticoid & mineralocorticoid & most widely usedmineralocorticoid.- Doses of 0.1 mg 2-7 times weekly have potent salt-retaining activity.- Used in treatment of adrenocortical insufficiency but are too small to have antiinflammatoryeffects.Clinical use and dose:Fludrocortisone is a fluorinated hydrocortisone with powerful mineralocorticoidactivity & very little anti-inflammatory action.It is used in:1. Replacement therapy in doses of 50-200 μg/day2. Congenital adrenal hyperplasia in doses up to 2 mg / day.3. Idiopathic postural hypertension 100-200 μg each day
Inhibitors of adrenocorticoid biosynthesis or function Several substances have proven to be useful as inhibitors of the synthesis or function of adrenal steroids: ketoconazole, spironolactone, and eplerenone. 1. Ketoconazole: Ketoconazole is an antifungal agent that strongly inhibits all gonadal and adrenal steroid hormone synthesis. It is used in the treatment of patients with Cushing syndrome. 2. Spironolactone: This antihypertensive drug competes for the mineralocorticoid receptor and, thus, inhibits sodium reabsorption in the kidney. It can also antagonize aldosterone and testosterone synthesis. It is effective for hyperaldosteronism and is used along with other standard therapies for the treatment of heart failure with reduced ejection fraction. Spironolactone is also useful in the treatment of hirsutism in women, probably due to interference at the androgen receptor of the hair follicle. Adverse effects include hyperkalemia, gynecomastia, menstrual irregularities, and skin rashes. 3. Eplerenone: Eplerenone specifically binds to the mineralocorticoid receptor, where it acts as an aldosterone antagonist. This specificity avoids the side effect of gynecomastia that is associated with the use of spironolactone. It is approved for the treatment of hypertension and also for heart failure with reduced ejection fraction.