Presentation on theme: "Pharmacology of Adrenocorticosteroids"— Presentation transcript:
1 Pharmacology of Adrenocorticosteroids 2009 DCOM Pharmacology Lecture SeriesJ. Richard Brown, Pharm.D., BCPS, FASHPProfessorColleges of Pharmacy and MedicineUniversity of TennesseeMemphis, TN
2 Learning ObjectivesDiscuss the physiology of adrenal gland function as it relates to corticosteroid synthesisProvide insight into use of select diagnostic drugs in adrenal pathological disordersReview feedback mechanisms in the HPA axis as it relates to drug induced adrenal suppressionOffer an overview of pharmacology and review therapeutic application of available steroid preparationsProvide potency comparisons of systemic steroids available for useOffer insight into regimens for steroid withdrawal and the complications associated with withdrawalDiscuss Addisonian symptoms and provide insight into stress dosing of steroids to avoid this complicationReview side effects associated with steroid useProvide usage pearls of wisdom for safe and effective prescribing of steroids
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 GlomerulosaOutermost zone – just below the adrenal surface capsuleSecretes 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 ProteinProduces biologicals that act on 5 melanocortin receptor subtypes (MCR1-5)Large precursor protein to ACTHACTH is MCR2 specific at adrenal level but may overide to MCR1 in excessSource of other biological peptidesEndorphinsLiptropinsMelanocyte 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 MSHIn excess, ACTH can signal through the MCR1 and cause hyperpigmentationSynthesis 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 corticosteroidsCurrent and past products:Cosyntropin (Cortrosyn®), a synthetic ACTHCorticotropin Injection (Acthar Gel)Repository corticotropin injection (H.P. Acthar Gel)
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 synthesisCytokines (leukemia-inhibitory factor (LIF), interleukin-6 (IL-6)Stimulatory on POMC gene expression and ACTH expressionArginine vasopressin (AVP)Secretagogue for pituitary corticotropesPotentates the effects of CRH on ACTH releaseIn contrast to CRH, does not increase ACTH synthesisNegative feedback by cortisol can down regulate HPAStress can up regulate HPA significantly
20 Corticotrophin Releasing Hormone’s (CRH) Use as a Drug “CRH Stimulation Test” for diagnosis onlyIn US, ovine CRH with flushing as a side effectCorticorelin (ACTHREL®)Differentiates between pituitary source and ectopic source in ACTH dependent hypercorticismIn Cushings..ACTH increases with a 5-10% failure rate, so test is not perfectIn ectopic..ACTH does NOT increase in the majority of patients
21 HPA Axis and Stress Response Acute stressSystemic and neurogenicInjury, cold, pain, fear, infection, hemorrhage, surgeryShort term, enhanced secretion of ACTH and glucocorticoids over riding negative feedbackMaximum production of cortisol is ≈200mg/24hoursImmunological stressStimulation by inflammatory cytokines (IL-1, IL-6, TNF-Repeated stressChronic stressEndocr. Rev 21:55-88, 2000.
22 Negative Feed-BackIs achieved with endogenous and exogenous systemically active steroids at supraphysiological dosesMediated by glucocorticoids at the level of the pituitary and hypothalamus to reduce ACTHOccurs in two phasesRapid 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
24 Receptors Response in Feedback Glucocorticoids act on two receptorsMineralocorticoid receptors (MR)MR has a higher affinity for glucocorticoids than GRAt lower concentrations in hippocampus and sensory and motor nuclei outside the hypothalamusRegulation of basal expression of CRH and AVPGlucocorticoid receptors (GR)At higher concentrations MR capacity exceeded (wash over)Hypothamic pituitary action to decrease ACTHTermination of the HPA axis response to stress
25 Major Functions of Adrenal Steroids Glucocorticoidsincreases gluconeogenesisincreases glycogenesisincreases protein catabolismdecreases antibody responseantiinflammatory responseantineoplastic responseMineralocorticoidsincrease sodium and water retentionpromote potassium loss
27 Site specific enzymatic inhibiton by metyrapone to decrease cortisol level
28 Endogenous CortisolNormal daily production of cortisol is 10mg to 30mg in non stressed patientsThe 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)
30 Normal Daily Production Rates and Circulating Levels of the Predominant Corticosteroids CORTISOLALDOSTERONERate of secretion under optimal conditions20 mg/day0.125 mg/dayConcentration in peripheral plasma:8 A.M.16 ug/100 ml0.01 ug/100 ml4 P.M.4 ug/100 ml
31 Anti-inflammatory Effects of Steroids with a Broad Application in Medicine Reduces phagocytic action of WBC’sDecrease extravasation of leukocytes into areas of injury and thus decrease fibrosisReduce feverSuppress transplant rejectionSuppresses allergic reactionsDecrease COX-II and NOSReduce cytokine productioninhibit the release of IL-1, IL-2 and IL-6 and TNF-alphaDecrease proteolytic and lipolytic enzymesImpairment 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 GLUCOCORTICOIDSHydrocortisone is the most active natural glucocorticoidPrednisolone is a delta-1 derivative with greater potency(made synthetically). It is the active form of prednisone.
34 Equivalent Oral Dose (mg) Potency ComparisonsComparisons of natural and synthetic corticosteroidsAgentAnti-InflammatoryTopicalSalt-RetainingEquivalent Oral Dose (mg)Forms AvailableShort- to medium-acting glucocorticoidsHydrocortisone (closest to cortisol)120Oral, injectable, topicalCortisone0.825OralPrednisone40.35PrednisoloneOral, injectableMethylprednisolonePotency is relative to hydrocortisone
36 Converting SteroidsEstablish the total daily # of physiological equivalent doses of the corticosteroid drug being administeredMultiply this # by the physiologically equivalent dosage of the drug you are converting toDose the converted drug at the appropriate interval for that drug
37 Equivalent Oral Dose (mg) Potency ComparisonsComparisons of natural and synthetic corticosteroidsAgentAnti-InflammatoryTopicalSalt-RetainingEquivalent Oral Dose (mg)Forms AvailableShort- to medium-acting glucocorticoidsHydrocortisone (cortisol)120Oral, injectable, topicalCortisone0.825OralPrednisone40.35PrednisoloneOral, injectableMethylprednisoloneNote: 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 times5mg (1 equiv prednisone dose)equals a total of 400mg oral daily prednisoneWhich, 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 ExamplesAllergic reactionsAngioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticariaCollagen-vascular disordersGiant cell arteritis, lupus erythematosus, mixed connective tissue syndromes, polymyositis, polymyalgia rheumatica, rheumatoid arthritis, temporal arteritisEye diseasesAcute uveitis, allergic conjunctivitis, choroiditis, optic neuritisGastrointestinal diseasesInflammatory bowel disease, nontropical sprue, subacute hepatic necrosisHematologic disordersAcquired hemolytic anemia, acute allergic purpura, leukemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple myelomaSystemic inflammationAcute respiratory distress syndrome (sustained therapy with moderate dosage accelerates recovery and decreases mortality)InfectionsAcute respiratory distress syndrome, sepsis, systemic inflammatory syndromeInflammatory conditions of bones and jointsArthritis, bursitis, tenosynovitisNeurologic disordersCerebral edema (large doses of dexamethasone are given to patients following brain surgery to minimize cerebral edema in the postoperative period), multiple sclerosisOrgan transplantsPrevention and treatment of rejection (immunosuppression)Pulmonary diseasesAspiration pneumonia, bronchial asthma, prevention of infant respiratory distress syndrome, sarcoidosisRenal disordersNephrotic syndromeSkin diseasesAtopic dermatitis, dermatoses, lichen simplex chronicus (localized neurodermatitis), mycosis fungoides, pemphigus, seborrheic dermatitis, xerosisThyroid diseasesMalignant exophthalmos, subacute thyroiditisMiscellaneousHypercalcemia, mountain sickness
41 Indications for Systemic Glucocorticoids Endocrine disordersprimary or secondary adrenocortical insufficiencycongenital adrenal hyperplasiathyroiditishypercalcemia associated with cancershock unresponsive to conventional therapypan-hypopituitarism
42 Ophthalmic Application both Topical and Systemic Ophthalmic diseasesallergic conjunctivitiskeratitisallergic corneal marginal ulcersophthalmic herpes zosteriritis and iridocyclitisoptic neuritisretrobulbar neuritis
44 Indications for Systemic or Intra-articular Glucocorticoids Spinal TraumaRheumatological disordersrheumatoid arthritisankylosing spondylitisacute and subacute arthritisacute nonspecific tenosynovitisosteoarthritis and bursitisacute goutCollagen diseasessystemic lupus erythematosusacute rheumatic carditissystemic dermatomyositis
45 Intra articular methylprednisolone (Depo Medrol®) offers a duration of 1-5 weeks
46 Indications for Systemic Glucocorticoids Respiratory diseasessymptomatic sarcoidosisberylliosisdisseminated pulmonary tuberculosispulmonary emphysemaaspiration pneumonitisdiffuse interstitial pulmonary fibrosispneumocystis carinii pneumonia with hypoxiaH.flu type b meningitis in childrenseptic shockacute Respiratory Distress Syndrome (ARDS)asthma and COPD exacerbations
47 Indications for Systemic or Topical Glucocorticoids Dermatological diseasespemphigusbullous dermatitis herpetiformissevere erythema multiforme (Stevens-Johnson)exfoliative dermatitismycosis fungoidessevere psoriasisreduction of hypertrophic scar (keloid) formationcontact dermatitis
48 Topical formulations for dermatological uses are numerous (OTC and RX)
49 Indications for Systemic or Topical Glucocorticoids Allergic statesseasonal or perennial allergic rhinitisbronchial asthmacontact dermatitisatopic dermatitisserum sicknessdrug hypersensitivity reactions
50 Effect of Glucocorticosteroids in Asthma Inflammatory CellsStructural CellsEosinophilEpithelial cellNumbers(apoptosis)CytokinesmediatorsT-lymphocyteEndothelial cellCytokinesLeakMast cellGlucocorticoidsNumbersAirway Smooth MuscleMacrophageb2-receptorsCytokinesMucus GlandDendritic cellMucussecretionNumbers
51 ICS in Dry Powder and MDI Formulations for Asthma and COPD
52 The TORCH Trial6112 pts in a 3 yr multi-institutional double blind, placebo controlled, randomized, parallel-group study to evaluated mortality impact of treatment in COPD patientsCompared fluticasone (500 bid) vs salmeterol (50 bid) vs both FS(500/50 bid) vs placeboAll cause mortality reduction: Primary endpoint (875 deaths)15.2% with placeboReduced 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 placeboF 77% increase: FSC 81% increase (p<0.001)No increase in ocular or bone adverse eventsNEJM 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 controlsCOPD 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 controlsAm J Respir Crit Care 2007;176:
55 Distribution of Inhaled Corticosteroids LungMouth and pharynxLung deposition (10% to 30%)Swallowed fraction (70% to 90%)Absorptionfrom thelung (A)LiverSystemic circulationAbsorption from the gutActive drugfrom the gut(B)GI tractInactivation in the liver “first pass”Systemic concentration = A + BExpert 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 Trial6112 pts in a 3 yr multi-institutional double blind, placebo controlled, randomized, parallel-group study to evaluated mortality impact of treatment in COPD patientsCompared fluticasone (500 bid) vs salmeterol (50 bid) vs both FS(500/50 bid) vs placeboAll cause mortality reduction: Primary endpoint (875 deaths)15.2% with placeboReduced 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 diseasesleukemias and lymphomas in adultsacute leukemia of childhoodcerebral edema with brain metschemotherapy induced nauseaHematological disordersidiopathic and secondary thrombocytopenia in adultsacquired (autoimmune) hemolytic anemia
58 Adrenocortical Insufficiency Drug induced from supraphysiological dosingChronic adrenocortical insufficiencyAddison’s diseaseweakness and anorexianausea, vomiting and diarrheahypotensionsparce axillary hairincreased skin pigmentation of creases, nipples and pressure areas (due to ACTH production)eosinophilia and lymphocytosis
60 “Stress Dosing” of Steroids to Avoid Addisonian Crisis Critical for patients on steroids chronically who are presumed to be suppressedFor Minor stressrequires doubling of base doseFor Major StressStandard dose for major stress including surgery is 100mg hydrocortisone q8hThis approximates or exceeds the maximal cortisol 24 hour secretory rate of 200mg the HPA can achieveEndo Metab Clin North Amer 32: ,2004
61 Effects of Aldosterone Renal and circulatory effectsPromotes 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 ductMaintains extracellular fluid (ECF) volume and regulation of sodium and potassium.Excess seen in CHF causes myocardial fibrosis
65 Aldosterone and ReninRenin 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 insufficiencyFor salt wasting nephropathyFor 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 forits mineralocorticoid activity in Addison’sdisease 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 AlopeciaHirsutismAcneOral CandidiasisCataracts (esp in children)GlaucomaPseudo-tumor cerebriDiabetesHypertensionUlcerogenicOsteoporosis (30-40% incid)Proximal limb muscle weaknessMemory impairmentAtrial fibrillationImmunosuppressiveStriaeFemoral head necrosisPoor wound healingThinning of skinPurpuraMenstrual IrregularityDemargination of WBC’sPsychosisEuphoriaDepressionWeight gainIncreased appetiteCushing’s symptomsHypokalemic alkalosisMyocardial fibrosis (aldosterone)HPA suppressionGrowth retardation
71 Steroid Use PearlsDexamethasone uniquely does not cross react with cortisol assaySingle large doses and short courses of steroids (up to 1 week) are unlikely harmfulProlonged exposure requires tapering doseStress may induce Addisonian symptoms for up to one year after stopping chronic useSingle daily dosing should be done in AMDexamethasone 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 PearlsChronic 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 PearlsMost common oral steroid is prednisone and most common parenteral drug is methylprednisolone (SoluMedrol®)Steroid dosing is largely empiricThe 125mg dose of methylprednisolone often seen is based on an attempt to use “largest size” bottleTopical and inhalational routes may cause systemic effectsSteroids have a delayed onset of actionSuggest a Med Alert Bracelet for steroid users