Pharmacology of Adrenocorticosteroids

2009 DCOM Pharmacology Lecture Series

J. Richard Brown, Pharm.D., BCPS, FASHPProfessor

Colleges of Pharmacy and MedicineUniversity of Tennessee

Memphis, TN

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

Adrenal glands

• Adrenal medulla– Epinepherine– Norepinephrine

• Adrenal cortex– Salt– Sugar (stress hormones)– Sex

Adrenal Cortex

• SALT (mineralcorticoids)

• SUGAR (glucocorticoids)..aka “Steroids”

• SEX (gonadocorticoids)

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.

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.

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.

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.

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

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

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)

A synthetic ACTH pharmaceutical

Site specific enzymatic inhibiton by metyrapone to decrease cortisol level

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.

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

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

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.

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

Negative feedback sites in HPA axis

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

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

Site specific enzymatic inhibiton by metyrapone to decrease cortisol level

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)

Steroid Metabolism

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 0.01 ug/100 ml

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

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)

O

CH3

CH3

CH2OH

OH

O

HO

H

H

H

HYDROCORTISONE

O

CH3

CH3

CH2OH

OH

O

HO

H

H

H

PREDNISOLONE

COMMONLY USED GLUCOCORTICOIDS

Hydrocortisone is the most active natural glucocorticoidPrednisolone is a delta-1 derivative with greater potency(made synthetically). It is the active form of prednisone.

Comparisons of natural and synthetic corticosteroids       

  AgentAnti-

InflammatoryTopical

Salt-Retaining

Equivalent Oral Dose

(mg)Forms Available

Short- to medium-acting glucocorticoids      

 Hydrocortisone (closest to cortisol)

1 1 1 20Oral, injectable, topical

  Cortisone 0.8 0 0.8 25 Oral

  Prednisone 4 0 0.3 5 Oral

  Prednisolone 5 4 0.3 5 Oral, injectable

  Methylprednisolone 5 5 0 4 Oral, injectable

 

Potency is relative to hydrocortisone     

     

     

Potency Comparisons

       

  AgentAnti-

InflammatoryTopical

Salt-Retaining

Equivalent Oral Dose

(mg)Forms Available

Intermediate-acting glucocorticoids      

  Triamcinolone 5 5 0 4Oral, injectable, topical

 

 

Long-acting glucocorticoids      

  Betamethasone 25-40 10 0 0.6Oral, injectable, topical

  Dexamethasone 30 10 0 0.75Oral, injectable, topical

Mineralocorticoids      

  Fludrocortisone 10 0 250 2 Oral

 

     

Note: Potency is relative to hydrocortisone      

     

Potency Comparisons Continued

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

Comparisons of natural and synthetic corticosteroids       

  AgentAnti-

InflammatoryTopical

Salt-Retaining

Equivalent Oral Dose

(mg)Forms Available

Short- to medium-acting glucocorticoids      

 Hydrocortisone (cortisol)

1 1 1 20Oral, injectable, topical

  Cortisone 0.8 0 0.8 25 Oral

  Prednisone 4 0 0.3 5 Oral

  Prednisolone 5 4 0.3 5 Oral, injectable

  Methylprednisolone 5 5 0 4 Oral, injectable

 

Note: Potency is relative to hydrocortisone     

     

     

Potency Comparisons

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!!

Glucocorticoids Place in Therapy

Too many to count…

Some therapeutic indications for the use of glucocorticoids in nonadrenal disorders

Disorder Examples

Allergic reactionsAngioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticaria

Collagen-vascular disordersGiant 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 disordersAcquired hemolytic anemia, acute allergic purpura, leukemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple myeloma

Systemic inflammationAcute 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 disordersCerebral 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 diseasesAspiration pneumonia, bronchial asthma, prevention of infant respiratory distress syndrome, sarcoidosis

Renal disorders Nephrotic syndrome

Skin diseasesAtopic dermatitis, dermatoses, lichen simplex chronicus (localized neurodermatitis), mycosis fungoides, pemphigus, seborrheic dermatitis, xerosis

Thyroid diseases Malignant exophthalmos, subacute thyroiditis

Miscellaneous Hypercalcemia, mountain sickness

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

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

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

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

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

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

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

Indications for Systemic or Topical Glucocorticoids

• Allergic states• seasonal or perennial allergic rhinitis• bronchial asthma• contact dermatitis• atopic dermatitis• serum sickness• drug hypersensitivity reactions

Effect of Glucocorticosteroids in AsthmaEffect of Glucocorticosteroids in Asthma

Glucocorticoids

Structural CellsEpithelial cell

Cytokinesmediators

Endothelial cell

Airway Smooth Muscle

Mucus Gland

Leak

2-receptors

Mucussecretion

Inflammatory CellsEosinophil

T-lymphocyte

Mast cell

Macrophage

Dendritic cell

Numbers(apoptosis)

Cytokines

Numbers

Cytokines

Numbers

ICS in Dry Powder and MDI Formulations for Asthma and COPD

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 (NS @ p=0.052) – FS Combination achieved a 2.6 percentage point mortality reduction vs

placebo (15.2-12.6) for a 17.5% reduction in risk of death (NS)

NEJM 356:775-789, 2007.

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 356:775-789, 2007.

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 (1.63-1.77), 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;176:162-166.

Mouth andpharynx

Lung deposition(10% to 30%)

Systemic circulation

Inactivation inthe liver “first pass”

Absorptionfrom the gut

Swallowedfraction

(70% to 90%)

Lung

Absorptionfrom thelung (A)

GI tract

Active drugfrom the gut (B)

Systemic concentration = A + B

Liver

Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health, National Heart, Lung, and Blood Institute. 1997. NIH Publication No. 97-4051.

Distribution of Inhaled Corticosteroids

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 (NS @ p=0.052) – FS Combination achieved a 2.6 percentage point mortality reduction vs

placebo (15.2-12.6) for a 17.5% reduction in risk of death (NS)

NEJM 356:775-789, 2007.

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

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

Addisonian Symptoms Associated with Steroid Withdrawal

• Weight loss, anorexia 90%• Nausea, vomiting 66%• Weakness, tiredness, fatigue 94%• GI complaints 61%• abdominal pain 28%• Diarrhea 18%• Muscle pain 16%• Salt craving 14%• Hypotension, dizziness, syncope 14%• Lethargy, disorientation 12%

“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 32:367-383,2004

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

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

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

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

FLUDROCORTISONE

C

HF

OH

O

H

CH2OH

O

HO

FLUDROCORTISONE (FLORINEF)

A potent steroid with both glucocorticoid andmineralocorticoid activity. Used mainly forits mineralocorticoid activity in Addison’sdisease along with hydrocorisone replacement.

dose: 0.1 mg 2- 7 X weekly

Physical signs seen in Cushing’s Syndrome

striae

“moon face”

“buffalo hump”

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

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)

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

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