pharmacology of adrenocorticosteroids 2009 dcom pharmacology lecture series j. richard brown,...
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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