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Pharmacology of Adrenocorticosteroids

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1 Pharmacology of Adrenocorticosteroids
2009 DCOM Pharmacology Lecture Series J. Richard Brown, Pharm.D., BCPS, FASHP Professor Colleges of Pharmacy and Medicine University of Tennessee Memphis, TN

2 Learning Objectives Discuss the physiology of adrenal gland function as it relates to corticosteroid synthesis Provide insight into use of select diagnostic drugs in adrenal pathological disorders Review feedback mechanisms in the HPA axis as it relates to drug induced adrenal suppression Offer an overview of pharmacology and review therapeutic application of available steroid preparations Provide potency comparisons of systemic steroids available for use Offer insight into regimens for steroid withdrawal and the complications associated with withdrawal Discuss Addisonian symptoms and provide insight into stress dosing of steroids to avoid this complication Review side effects associated with steroid use Provide usage pearls of wisdom for safe and effective prescribing of steroids

3 Adrenal glands Adrenal medulla Adrenal cortex Epinepherine
Norepinephrine Adrenal cortex Salt Sugar (stress hormones) Sex

4 Adrenal Cortex SALT (mineralcorticoids)
SUGAR (glucocorticoids)..aka “Steroids” SEX (gonadocorticoids)

5 Adrenal Cortex Anatomy
The adrenal cortex is composed of three zones histologically. Outer zona glomerulosa, site for aldosterone synthesis. Central zona fasciculata and inner zona reticularis produce both cortisol and androgens.


7 Zona Glomerulosa Outermost zone – just below the adrenal surface capsule Secretes mineralocorticoids. Mineralocorticoids are aptly termed as they are involved in regulation of electrolytes in ECF. The naturally synthesized mineralocorticoid of most importance is aldosterone.

8 Zona Fasciculata Middle zone – between the glomerulosa and reticularis
Primary secretion is glucocorticoids. Glucocorticoids, as the term implies, are involved the increasing of blood glucose levels. However they have additional effects in protein and fat metabolism. The naturally synthesized glucocorticoid of most importance is cortisol.

9 Zona Reticularis Innermost zone – between the fasciculata and medulla
Primarily responsible for secretion is androgens. Androgenic hormones exhibit approximately the same effects as the male sex hormone – testosterone. Overlap in the secretions of androgens and glucocorticoids exist between the fasciculata and reticularis.


11 POMC…The Origin of ACTH
Pro-OpioMelanoCortin Precursor Protein Produces biologicals that act on 5 melanocortin receptor subtypes (MCR1-5) Large precursor protein to ACTH ACTH is MCR2 specific at adrenal level but may overide to MCR1 in excess Source of other biological peptides Endorphins Liptropins Melanocyte stimulating hormones (MCR1 specific) Mutationally impaired process in synthesis may lead to adrenal insufficiency

12 Adrenocorticotrophic Hormone (ACTH or Corticotrophin)
Synthesized as part of a larger precursor protein, pro-opiomelanocortin (POMC) Acting via MCR2, ACTH stimulates the adrenal cortex to secrete glucocorticoids, mineralocorticoids, and the androgen precursor dehydroepiandrosterone (DHEA) ACTH is a melanocortin similar to MSH In excess, ACTH can signal through the MCR1 and cause hyperpigmentation Synthesis follows 24 hour diurnal pattern..high in the AM and low in late PM with some production following food ingestion

13 ACTH as a Drug Used mainly for diagnostic purposes
Limited therapeutic value in conditions responsive to corticosteroids Current and past products: Cosyntropin (Cortrosyn®), a synthetic ACTH Corticotropin Injection (Acthar Gel) Repository corticotropin injection (H.P. Acthar Gel)

14 A synthetic ACTH pharmaceutical

15 Site specific enzymatic inhibiton by metyrapone to decrease cortisol level

16 Glucocorticoid Release Follows ACTH Release
Cortisol, like ACTH, is secreted in a pulsitile manner and plasma levels closely parallel those of ACTH. Superimposed on this is a circadian rhythm that results in peak cortisol levels in the early morning and a nadir in the late evening. Physical and emotional stress (trauma, surgery, and hypoglycemia) can dramatically increase cortisol secretion by stimulating release of CRH and ACTH from hypothalamus and pituitary respectively.



19 Regulators of the HPA axis
Hypothalamic Corticotrophin Releasing Factor or Hormone (CRH) acting on CRF1 receptor in pituitary increases ACTH synthesis Cytokines (leukemia-inhibitory factor (LIF), interleukin-6 (IL-6) Stimulatory on POMC gene expression and ACTH expression Arginine vasopressin (AVP) Secretagogue for pituitary corticotropes Potentates the effects of CRH on ACTH release In contrast to CRH, does not increase ACTH synthesis Negative feedback by cortisol can down regulate HPA Stress can up regulate HPA significantly

20 Corticotrophin Releasing Hormone’s (CRH) Use as a Drug
“CRH Stimulation Test” for diagnosis only In US, ovine CRH with flushing as a side effect Corticorelin (ACTHREL®) Differentiates between pituitary source and ectopic source in ACTH dependent hypercorticism In Cushings..ACTH increases with a 5-10% failure rate, so test is not perfect In ectopic..ACTH does NOT increase in the majority of patients

21 HPA Axis and Stress Response
Acute stress Systemic and neurogenic Injury, cold, pain, fear, infection, hemorrhage, surgery Short term, enhanced secretion of ACTH and glucocorticoids over riding negative feedback Maximum production of cortisol is ≈200mg/24hours Immunological stress Stimulation by inflammatory cytokines (IL-1, IL-6, TNF- Repeated stress Chronic stress Endocr. Rev 21:55-88, 2000.

22 Negative Feed-Back Is achieved with endogenous and exogenous systemically active steroids at supraphysiological doses Mediated by glucocorticoids at the level of the pituitary and hypothalamus to reduce ACTH Occurs in two phases Rapid feedback occurs within seconds (inhibition of CRH and ACTH release) Delayed occurs within hours (down regulation of CRH and POMC gene expression) Occurs through both MR and GR but predominantly GR

23 Negative feedback sites in HPA axis

24 Receptors Response in Feedback
Glucocorticoids act on two receptors Mineralocorticoid receptors (MR) MR has a higher affinity for glucocorticoids than GR At lower concentrations in hippocampus and sensory and motor nuclei outside the hypothalamus Regulation of basal expression of CRH and AVP Glucocorticoid receptors (GR) At higher concentrations MR capacity exceeded (wash over) Hypothamic pituitary action to decrease ACTH Termination of the HPA axis response to stress

25 Major Functions of Adrenal Steroids
Glucocorticoids increases gluconeogenesis increases glycogenesis increases protein catabolism decreases antibody response antiinflammatory response antineoplastic response Mineralocorticoids increase sodium and water retention promote potassium loss


27 Site specific enzymatic inhibiton by metyrapone to decrease cortisol level

28 Endogenous Cortisol Normal daily production of cortisol is 10mg to 30mg in non stressed patients The liver is the main site of metabolism. Two major metabolites are 17-hydroxycorticosteroids and 17-ketosteroids that are excreted in the urine. Metabolism may be induced by CYP inducing drugs (rifampin, phenobarb, etc)

29 Steroid Metabolism

30 Normal Daily Production Rates and Circulating Levels of the Predominant Corticosteroids
CORTISOL ALDOSTERONE Rate of secretion under optimal conditions 20 mg/day 0.125 mg/day Concentration in peripheral plasma: 8 A.M. 16 ug/100 ml 0.01 ug/100 ml 4 P.M. 4 ug/100 ml

31 Anti-inflammatory Effects of Steroids with a Broad Application in Medicine
Reduces phagocytic action of WBC’s Decrease extravasation of leukocytes into areas of injury and thus decrease fibrosis Reduce fever Suppress transplant rejection Suppresses allergic reactions Decrease COX-II and NOS Reduce cytokine production inhibit the release of IL-1, IL-2 and IL-6 and TNF-alpha Decrease proteolytic and lipolytic enzymes Impairment of delayed-type hypersensitivity

32 Major Corticosteroid Products in Use Today
Prednisone (a pro drug that requires hepatic activation via cortisone reductase) Prednisolone (preferred in severe liver disease?) Dexamethasone (Decadron®) Methylprednisolone (Medrol®, SoluMedrol® for IV) Hydrocortisone (SoluCortef®) Triamcinolone (Aristocort®) Fludrocortisone (Florinef® for mineralocorticoid replacement)

33 Hydrocortisone is the most active natural glucocorticoid
COMMONLY USED GLUCOCORTICOIDS Hydrocortisone is the most active natural glucocorticoid Prednisolone is a delta-1 derivative with greater potency (made synthetically). It is the active form of prednisone.

34 Equivalent Oral Dose (mg)
Potency Comparisons Comparisons of natural and synthetic corticosteroids Agent Anti-Inflammatory Topical Salt-Retaining Equivalent Oral Dose (mg) Forms Available Short- to medium-acting glucocorticoids Hydrocortisone (closest to cortisol) 1 20 Oral, injectable, topical Cortisone 0.8 25 Oral Prednisone 4 0.3 5 Prednisolone Oral, injectable Methylprednisolone Potency is relative to hydrocortisone

35 Equivalent Oral Dose (mg)
Potency Comparisons Continued Agent Anti-Inflammatory Topical Salt-Retaining Equivalent Oral Dose (mg) Forms Available Intermediate-acting glucocorticoids Triamcinolone 5 4 Oral, injectable, topical Long-acting glucocorticoids Betamethasone 25-40 10 0.6 Dexamethasone 30 0.75 Mineralocorticoids Fludrocortisone 250 2 Oral Note: Potency is relative to hydrocortisone

36 Converting Steroids Establish the total daily # of physiological equivalent doses of the corticosteroid drug being administered Multiply this # by the physiologically equivalent dosage of the drug you are converting to Dose the converted drug at the appropriate interval for that drug

37 Equivalent Oral Dose (mg)
Potency Comparisons Comparisons of natural and synthetic corticosteroids Agent Anti-Inflammatory Topical Salt-Retaining Equivalent Oral Dose (mg) Forms Available Short- to medium-acting glucocorticoids Hydrocortisone (cortisol) 1 20 Oral, injectable, topical Cortisone 0.8 25 Oral Prednisone 4 0.3 5 Prednisolone Oral, injectable Methylprednisolone Note: Potency is relative to hydrocortisone

38 Challenge… Convert 80mg of methylprednisolone q6h to an equivalent daily oral prednisone dose??
80mg times 4 doses equals 320mg… 320mg divided by 4mg (1 equiv methylprednisolone dose) for a total of 80 equiv doses times 5mg (1 equiv prednisone dose) equals a total of 400mg oral daily prednisone Which, as you can see, is an industrial sized dose of prednisone to take once daily!!

39 Glucocorticoids Place in Therapy
Too many to count…

40 Some therapeutic indications for the use of glucocorticoids in nonadrenal disorders
Examples Allergic reactions Angioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticaria Collagen-vascular disorders Giant cell arteritis, lupus erythematosus, mixed connective tissue syndromes, polymyositis, polymyalgia rheumatica, rheumatoid arthritis, temporal arteritis Eye diseases Acute uveitis, allergic conjunctivitis, choroiditis, optic neuritis Gastrointestinal diseases Inflammatory bowel disease, nontropical sprue, subacute hepatic necrosis Hematologic disorders Acquired hemolytic anemia, acute allergic purpura, leukemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple myeloma Systemic inflammation Acute respiratory distress syndrome (sustained therapy with moderate dosage accelerates recovery and decreases mortality) Infections Acute respiratory distress syndrome, sepsis, systemic inflammatory syndrome Inflammatory conditions of bones and joints Arthritis, bursitis, tenosynovitis Neurologic disorders Cerebral edema (large doses of dexamethasone are given to patients following brain surgery to minimize cerebral edema in the postoperative period), multiple sclerosis Organ transplants Prevention and treatment of rejection (immunosuppression) Pulmonary diseases Aspiration pneumonia, bronchial asthma, prevention of infant respiratory distress syndrome, sarcoidosis Renal disorders Nephrotic syndrome Skin diseases Atopic dermatitis, dermatoses, lichen simplex chronicus (localized neurodermatitis), mycosis fungoides, pemphigus, seborrheic dermatitis, xerosis Thyroid diseases Malignant exophthalmos, subacute thyroiditis Miscellaneous Hypercalcemia, mountain sickness

41 Indications for Systemic Glucocorticoids
Endocrine disorders primary or secondary adrenocortical insufficiency congenital adrenal hyperplasia thyroiditis hypercalcemia associated with cancer shock unresponsive to conventional therapy pan-hypopituitarism

42 Ophthalmic Application both Topical and Systemic
Ophthalmic diseases allergic conjunctivitis keratitis allergic corneal marginal ulcers ophthalmic herpes zoster iritis and iridocyclitis optic neuritis retrobulbar neuritis


44 Indications for Systemic or Intra-articular Glucocorticoids
Spinal Trauma Rheumatological disorders rheumatoid arthritis ankylosing spondylitis acute and subacute arthritis acute nonspecific tenosynovitis osteoarthritis and bursitis acute gout Collagen diseases systemic lupus erythematosus acute rheumatic carditis systemic dermatomyositis

45 Intra articular methylprednisolone (Depo Medrol®) offers a duration of 1-5 weeks

46 Indications for Systemic Glucocorticoids
Respiratory diseases symptomatic sarcoidosis berylliosis disseminated pulmonary tuberculosis pulmonary emphysema aspiration pneumonitis diffuse interstitial pulmonary fibrosis pneumocystis carinii pneumonia with hypoxia H.flu type b meningitis in children septic shock acute Respiratory Distress Syndrome (ARDS) asthma and COPD exacerbations

47 Indications for Systemic or Topical Glucocorticoids
Dermatological diseases pemphigus bullous dermatitis herpetiformis severe erythema multiforme (Stevens-Johnson) exfoliative dermatitis mycosis fungoides severe psoriasis reduction of hypertrophic scar (keloid) formation contact dermatitis

48 Topical formulations for dermatological uses are numerous (OTC and RX)

49 Indications for Systemic or Topical Glucocorticoids
Allergic states seasonal or perennial allergic rhinitis bronchial asthma contact dermatitis atopic dermatitis serum sickness drug hypersensitivity reactions

50 Effect of Glucocorticosteroids in Asthma
Inflammatory Cells Structural Cells Eosinophil Epithelial cell Numbers (apoptosis) Cytokines mediators T-lymphocyte Endothelial cell Cytokines Leak Mast cell Glucocorticoids Numbers Airway Smooth Muscle Macrophage b2-receptors Cytokines Mucus Gland Dendritic cell Mucus secretion Numbers

51 ICS in Dry Powder and MDI Formulations for Asthma and COPD

52 The TORCH Trial 6112 pts in a 3 yr multi-institutional double blind, placebo controlled, randomized, parallel-group study to evaluated mortality impact of treatment in COPD patients Compared fluticasone (500 bid) vs salmeterol (50 bid) vs both FS(500/50 bid) vs placebo All cause mortality reduction: Primary endpoint (875 deaths) 15.2% with placebo Reduced to 13.5% with salmeterol (NS) Increased to 16.0% with fluticasone (NS) Reduced to 12.6% with combination p=0.052) FS Combination achieved a 2.6 percentage point mortality reduction vs placebo ( ) for a 17.5% reduction in risk of death (NS) NEJM 356: , 2007.

53 TORCH Trial Cause of deaths: Cardiac 27%, Cancer 21%, Respiratory 35%
Admission rates lowered in FSC and Salm groups vs placebo by 17% (NNT 32 to prevent 1 admission in 1yr) AE’s reduced by 25% with FSC (NNT 4 to prevent 1 AE) Adverse events (pneumonia) Significant increase in pneumonias in F and FSC arms vs placebo F 77% increase: FSC 81% increase (p<0.001) No increase in ocular or bone adverse events NEJM 356: , 2007.

54 ICS Linked to Pneumonia in COPD
Cohort of 175,906 COPD pts treated from 1988 thru 2003 including 23,942 hospitalized for pneumonia and 95,768 serving as controls COPD pts who used inhaled steroids had a 70% increase in risk of pneumonia hospitalization over those not given ICS. Odds ratio of 1.70 ( ), confidence interval of 95%. 48.2% of those admitted used ICS in the previous year vs 30.1% of controls Am J Respir Crit Care 2007;176:

55 Distribution of Inhaled Corticosteroids
Lung Mouth and pharynx Lung deposition (10% to 30%) Swallowed fraction (70% to 90%) Absorption from the lung (A) Liver Systemic circulation Absorption from the gut Active drug from the gut (B) GI tract Inactivation in the liver “first pass” Systemic concentration = A + B Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health, National Heart, Lung, and Blood Institute NIH Publication No

56 The TORCH Trial 6112 pts in a 3 yr multi-institutional double blind, placebo controlled, randomized, parallel-group study to evaluated mortality impact of treatment in COPD patients Compared fluticasone (500 bid) vs salmeterol (50 bid) vs both FS(500/50 bid) vs placebo All cause mortality reduction: Primary endpoint (875 deaths) 15.2% with placebo Reduced to 13.5% with salmeterol (NS) Increased to 16.0% with fluticasone (NS) Reduced to 12.6% with combination p=0.052) FS Combination achieved a 2.6 percentage point mortality reduction vs placebo ( ) for a 17.5% reduction in risk of death (NS) NEJM 356: , 2007.

57 Indications for Systemic Glucocorticoids
Neoplastic diseases leukemias and lymphomas in adults acute leukemia of childhood cerebral edema with brain mets chemotherapy induced nausea Hematological disorders idiopathic and secondary thrombocytopenia in adults acquired (autoimmune) hemolytic anemia

58 Adrenocortical Insufficiency
Drug induced from supraphysiological dosing Chronic adrenocortical insufficiency Addison’s disease weakness and anorexia nausea, vomiting and diarrhea hypotension sparce axillary hair increased skin pigmentation of creases, nipples and pressure areas (due to ACTH production) eosinophilia and lymphocytosis

59 Addisonian Symptoms Associated with Steroid Withdrawal
Weight loss, anorexia 90% Nausea, vomiting 66% Weakness, tiredness, fatigue 94% GI complaints % abdominal pain % Diarrhea % Muscle pain % Salt craving % Hypotension, dizziness, syncope 14% Lethargy, disorientation 12%

60 “Stress Dosing” of Steroids to Avoid Addisonian Crisis
Critical for patients on steroids chronically who are presumed to be suppressed For Minor stress requires doubling of base dose For Major Stress Standard dose for major stress including surgery is 100mg hydrocortisone q8h This approximates or exceeds the maximal cortisol 24 hour secretory rate of 200mg the HPA can achieve Endo Metab Clin North Amer 32: ,2004

61 Effects of Aldosterone
Renal and circulatory effects Promotes reabsorption of sodium from the ducts of sweat and salivary glands during excessive sweat/saliva loss. Enhances absorption of sodium from the intestine esp. colon – absence leads to diarrhea. Responsible for regulating Na+ reabsorption in the distal tubule and the cortical collecting duct Maintains extracellular fluid (ECF) volume and regulation of sodium and potassium. Excess seen in CHF causes myocardial fibrosis


63 Regulation of Aldosterone Release Involves the RAAS
Indirect stimulators of release decreased blood pressure decreased macula densa blood flow Direct stimulators of release increased extracellular K+ (primary) decreased osmolarity ACTH water deprivation


65 Aldosterone and Renin Renin is also stimulated by hyperkalemia and inhibited by potassium depletion. Angiotensin II, a potent vasoconstrictor, also stimulates zona glomerulosa to secrete aldosterone. Aldosterone then stimulates reabsorption of sodium in exchange for potassium and hydrogen ion secretion. End result is Na and water retention with intravascular volume expansion and potassium loss in urine

66 Indications for Systemic Mineralocorticoids
As replacement therapy for primary and secondary Adrenal insufficiency For salt wasting nephropathy For orthostatic hypotension +/- midodrine (an alpha agonist) In US, treatment is limited to one oral medication, fludrocortisone (Florinef®), with 125x MR activity relative to cortisol

67 FLUDROCORTISONE A potent steroid with both glucocorticoid and
mineralocorticoid activity. Used mainly for its mineralocorticoid activity in Addison’s disease along with hydrocorisone replacement. dose: 0.1 mg 2- 7 X weekly

68 Physical signs seen in Cushing’s Syndrome
“moon face” “buffalo hump” striae

69 Steroid Side Effects are Frequent and Serious
Alopecia Hirsutism Acne Oral Candidiasis Cataracts (esp in children) Glaucoma Pseudo-tumor cerebri Diabetes Hypertension Ulcerogenic Osteoporosis (30-40% incid) Proximal limb muscle weakness Memory impairment Atrial fibrillation Immunosuppressive Striae Femoral head necrosis Poor wound healing Thinning of skin Purpura Menstrual Irregularity Demargination of WBC’s Psychosis Euphoria Depression Weight gain Increased appetite Cushing’s symptoms Hypokalemic alkalosis Myocardial fibrosis (aldosterone) HPA suppression Growth retardation


71 Steroid Use Pearls Dexamethasone uniquely does not cross react with cortisol assay Single large doses and short courses of steroids (up to 1 week) are unlikely harmful Prolonged exposure requires tapering dose Stress may induce Addisonian symptoms for up to one year after stopping chronic use Single daily dosing should be done in AM Dexamethasone is most commonly used for CNS penetration (ie brain mets) Tapered doses are to reduce Addisonian risk AND reflaring of disease (ie COPD)

72 Steroid Use Pearls Chronic adrenal insufficiency replacement is usually done with hydrocortisone (20mg AM and 10mg PM) +/- fludrocortisone. Licorice may increase cortisol’s “washover” action on MR and increase BP (inhibits 11 beta-hydoxysteroid dehydrogenase) Some chewing tobacco brands are flavored with licorice and can cause hypokalemia (MR action) Dose of steroids may need upward adjustment when given with hepatic inducing drugs such as rifampin, phenobarbital and phenytoin

73 Steroid Use Pearls Most common oral steroid is prednisone and most common parenteral drug is methylprednisolone (SoluMedrol®) Steroid dosing is largely empiric The 125mg dose of methylprednisolone often seen is based on an attempt to use “largest size” bottle Topical and inhalational routes may cause systemic effects Steroids have a delayed onset of action Suggest a Med Alert Bracelet for steroid users

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