Anesthesia Pharmacology Chapter 22:  Adrenocorticosteroid Pharmacology

 

Adrenocorticosteroids and Adrenocortical Antagonists

• Overview

  • Natural adrenocortical hormones:

    • steroid molecules synthesized in released by the adrenal cortex

    • Clinical Uses:

      1. diagnosis of adrenal function

      2. treatment of adrenal function disorders

      3. treatment of inflammatory/immunological disorders (at higher doses)

    • Control over adrenocorticosteroid secretion:

      • pituitary corticotropin (ACTH) release

      • Angiotensin modulation of aldosterone secretion

  • Adrenocorticosteroids

    • Major categories of action:

      • Glucocorticoids: affecting intermediary metabolism

      • Mineralocorticoids: regulation of salt retention

      • Corticosteroids with:

        1. androgenic activity

        2. estrogenic activity

    • Major glucocorticoid: cortisol

    • Major mineralocorticoid: aldosterone

    • Major androgen: dehydroepiandrosterone (DHEA)

      • quantitatively -- DHEA

      • DHEA and androstenedione )very weak androgens

      • small amount of testosterone, secreted by the adrenals, maybe more important

    • Adrenal estrogens secretion?:

      • adrenal androgens: testosterone and androstenedione may be converted to estrone by non-endocrine tissue:

        • Major endogenous estrogen source in women after menopause

  Glucocorticoids (naturally occurring; cortisol -- hydrocortisone)

• Pharmacokinetics:

  • Synthesis:

    • major glucocorticoid: cortisol

    • precursor: cholesterol

    • site of adrenal cortisol synthesis:

      1. zona fasciculata

      2. zona reticularis

    • cortisol release modulated by ACTH

  • Characteristics:

    • Release rate of cortisol controlled by circadian rhythm affected by ACTH pulses

    • 75% of cortisol bound to plasma proteins

      • corticosteroid-binding globulin (CBG) -- alpha₂ globulin;

      • cortisol also bound to serum albumin

      • free cortisol plasma concentrations rise rapidly if CBG binding capacity is exceeded.

      • Factors that change plasma CBG concentration

        • pregnancy

        • estrogen administration (increased hepatic synthesis)

        • hyperthyroidism

        • hypothyroidism

        • protein deficiency

        • diminished synthetic capability (genetics)

      • cortisol half-life: about 60-90 minutes

      • Factors that increase cortisol half-life

        1. stress

        2. hypothyroidism

        3. liver disease

        4. large dosage of hydrocortisone administration

    • Cortisol metabolism:

      • 20% converted to cortisone (by renal/other tissues with mineralocorticoid receptors) -- catalyzed by 11-hydroxysteroid dehydrogenase

      • Cortisol and cortisone inactivated in the liver by conversion (3-hydroxysteroid dehydrogenase catalyzed) to:

        1. tetrahydrocortisol

        2. tetrahydrocortisone

      • Other metabolites: cortol, cortolone

      • Some metabolites ultimately excreted in the urine as 11-oxy, 17-ketosteroids

      • Some metabolites undergo hepatic conjugation to form glucuronic acid or sulfate derivatives

• Pharmacodynamics

  • Mechanism of Action:

    • Glucocorticoid action through glucocorticoid receptors

    • Receptor Properties:

      • member of receptor superfamily that includes:

        • steroid receptors

        • thyroid receptors

        • other receptors (many with unknown function -- "orphan receptors"

      • Receptors bound to heat shock proteins (Hsp/hsp90)

    • Sequence of activation:

      1. Free glucocorticoid hormone enters the cell

      2. binds to the receptor, inducing a conformational change

      3. receptor dissociates from heat shock proteins

      4. hormone-receptor complex associate to form homodimers

      5. homodimers actively transported to the nucleus

      6. homodimers mind to glucocorticoid receptor elements (GREs) of target genes

      7. Genomic effects -- protein synthesized; Indirect mediation of some genomic effects by paracrine influences of hormone-regulated cytokines on nearby cells

    • Some physiological effects occur to rapidly to be accounted for by gene transcription/ protein synthesis:

      • feedback suppression of pituitary ACTH (unknown mechanism)

• Physiological effects of glucocorticoids:

  • Major metabolic effects: due to direct cellular action

    • Some effects:secondary to homeostatic insulin and glucagon responses

  • Physiological responses modulated by glucocorticoids ("permissive" effects)

    1. catecholamine vascular/bronchial smooth muscle response:

       • diminished in the absence of cortisol

       • restored by physiological amounts of cortisol

    2. catecholamine-induced lipolytic adipocytes response:

       • reduced in the absence of glucocorticoids (unknown mechanism)

• Metabolic Effects:

  • Glucocorticoids: stimulate and are required for:

    • gluconeogenesis (fasted state, diabetes);

    • increasing hepatic and renal amino acid uptake

    • increase gluconeogenic enzyme activity

  • Hepatic effects:

    • Simulation of glycogen synthase

    • Increase glucose production from protein-- stimulating insulin release

  • Adipocytes:

    • inhibit glucose uptake promoting increased lipolysis

    • counteracted by enhanced insulin secretion which stimulates lipogenesis

    • net effect: fat deposition

  • Glucocorticoid effects most prominent in the fasting state, through:

    • stimulation:gluconeogenesis

    • stimulation: amino acid release from muscle (catabolism)

    • inhibition: peripheral glucose uptake

    • stimulation: lipolysis

• Catabolic Effects:

  • promotion of catabolism:

    • lymphoid tissue

    • connective tissue

    • muscle

    • fat

    • skin

  • High (supraphysiologic) glucocorticoid levels cause:

    • decreased muscle mass, weakness

  •  reduced growth in children (not prevented by growth hormone)

  • Catabolic effects on bone:

    •  osteoporosis in Cushing's syndrome

    •  major limitation in long-term use

   

• Anti-inflammatory/Immunosuppressive Effects:

  • Reduce inflammation --

    • Leukocyte-mediated; reduced leukocyte infiltration

    • glucocorticoid inhibition of interactions involving cell adhesion molecules (especially on endothelial cells)

    • Following glucocorticoid administration:

      • neutrophils levels are increased, but a decrease is noted in lymphocytes (T and B cells, monocytes, eosinophils, basophils-- movement from vasculature to lymphoid tissue)

    • Glucocorticoids inhibit:

      • leukocyte and tissue macrophage function

      • reduced antigenic and mitogenic responsiveness

      • Macrophage effects:

        • decreased interferon-gamma, interleukin 1, pyrogen, collagenase, elastase, tumor necrosis factor, plasminogen activator

      • Lymphocyte effects:

        • decreased interleukin 2

    • Reduction of prostaglandin and leukotriene synthesis (resulting from phospholipase A₂ activation)

    • Reduction of cyclooxygenase in inflammatory cells (reducing prostaglandin synthesis)

      • of the two isoforms of cyclooxygenase (COX1 and COX-II), glucocorticoids inhibit COX-II gene expression.

    • Glucocorticoids decrease capillary permeability by:

      1. reducing kinin activity

      2. reducing bacterial endotoxin activity

      3. reducing basophils histamine release

• Other Effects:

  • adrenal-insufficiency: EEG changes (slowing of alpha rhythms)

  • increased levels: behavioral changes;

  • decreased pituitary release of ACTH and beta-lipotropin

  • decreased  TSH and FSH secretion

  • increased excess acid/pepsin production (large doses)

  • increased fat absorption

  • in addition: effective vitamin D on calcium absorption

  • increased platelet production, erythrocyte production

  • without adequate cortisol: renal function -- impaired

  • glucocorticoids important in tissue development (structure/functional changes in the lung)

• Pharmacokinetics

  • Source:

    • Synthesized from cholic acid (from cattle sources) or

    • Synthesized from steroid sapogenins (diosgenin) -- plants

  • Disposition:

    • oral administration; complete absorption

    • metabolized similar to endogenous steroids

    • molecular alterations given rise to differences in:

      • affinity for mineralocorticoid or glucocorticoid receptors

      • extent of protein binding

      • stability

      • spectrum of metabolic products

    • prodrugs may be used (prednisone is converted to prednisolone)

• Pharmacodynamics:

  • Similar to those of cortisol (endogenous agents)

• Primary Adrenocortical insufficiency (Addison's Disease):

  • Overview:

    • Rare; may occur at any age; affects both sexes with equal frequency

  • Etiology/Pathogenesis

    • Addison's disease is caused by progressive destruction of the adrenals (> 90% must be destroyed before symptoms of adrenal insufficiency appear)

• Adrenal gland destruction:

  •  adrenal: common site for chronic granulomatous diseases, e.g.:

    • tuberculosis (mainly)

    • histoplasmosis

    • coccidiodomycosis

    • cryptococcosis

  •  Adrenoleukodystrophy: significant demyelination -- early death and children

  •  Adrenomyeloneuropathy: mixed motor/sensory neuropathy with spastic paraplegia -- (adults)

  •  AIDS patients-- Higher likelihood of adrenal-insufficiency because:

    • cytomegalovirus frequently involves the adrenal glands:

      • CMV necrotizing adrenalitis

      • involvement with Mycobacterium avium-intracellulare, Cryptococcus, and Kaposi sarcoma

      • note: in interpreting results from adrenal function test in AIDS patients that certain medications may potentiates adrenal insufficiency including:

        1. opiates

        2. rifampin

        3. phenytoin (Dilantin)

        4. ketoconazole (Nizoral)

  • in early cases, tuberculosis caused 70%-90% of cases

  •  Most frequent cause today is idiopathic atrophy.

    • autoimmune mechanism -- most likely

    • half of patients: circulating adrenal antibodies

      • adrenal antigens, e.g.: P450c21

      • some antibodies may cause adrenal destruction

      • other antibodies may cause adrenal insufficiency by inhibiting ACTH binding

      • some individuals also have antibodies to thyroid, parathyroid, and/or gonadal tissue

    • Increased likelihood of:

      1. chronic lymphocytic thyroiditis

      2. premature ovarian failure

      3. Type I diabetes mellitus

      4. hypothyroidism

      5. hyperthyroidism

    • Presence of two or more autoimmune endocrine disorders in the same patient: polyglandular autoimmune syndrome

• Presenting Clinical Signs and Symptoms

• Asthenia, "Cardinal symptom":

  • severe fatigue, impairment; bed rest may be necessary

• Hyperpigmentation:

  • diffuse brown, tan, bronze darkening at elbows, hand creases

  • may include bluish-black mucosal membrane patches

• Arterial hypotension with orthostatic component

• Gastrointestinal disturbances: frequent presenting symptom

• Primary Adrenocortical insufficiency: Laboratory Findings and Diagnostic Testing.

  •  Laboratory findings:

    • initially:steroid output normal; but adrenal reserve reduced

      • ACTH-adrenal stimulation: produces some normal cortisol increase or no increase

    • more advanced disease: (more adrenal destruction)

      •  serum sodium, bicarbonate, chloride: reduced

        1. decreased serum sodium: due to excessive urinary loss (secondary to aldosterone deficiency) and movement into intracellular compartments

        2. extravascular sodium loss -- depleting extracellular fluid; promotes hypotension; elevated plasma angiotensin II and vasopressin promote hyponatremia by reducing free water clearance

      •  serum potassium: elevated

        • Hyperkalemia due to:

          1. aldosterone deficiency

          2. acidosis

          3. impaired glomerular filtration

  •  Diagnosis:

    • Based on ACTH stimulation testing: evaluation of adrenal steroid production reserve capacity

    • Severe adrenal insufficiency: rate of cortisol secretion significantly reduced; low to absent 24 urine cortisol levelto

    • Mild adrenal insufficiency (decreased adrenal reserve)

    • Aldosterone secretion: low-- causing:

      • salt wasting

      • increased plasma renin

• Treatment of Primary Adrenocortical Deficiency (Addison's Disease)

  • Replacement Therapy

    • correction of both glucocorticoid and mineralocorticoid deficiency

    • Therapeutic Mainstay: cortisol

      • Treatment complications: rare; except for gastritis

    • Mineralocorticoid component: fludrocortisone

      • adequacy assessed by serum electrolyte and blood pressure measurements

      • blood pressure: normal; no orthostatic effects

      • serum sodium, potassium, creatinine, blood urea nitrogen levels: normal

      •  Treatment complications:

        1. hypokalemia

        2. hypertension

        3. cardiac enlargement

        4. congestive heart failure (secondary to sodium retention)

  •  Special considerations:

    • During illness (especially if fever is present): hydrocortisone dosage should be increased (doubled)

    • Supplemental glucocorticoid dosage before:

      • surgery

      • dental extraction

    • Supplemental fludrocortisone plus salt upon:

      • strenuous exercise with sweating

      • during very hot weather

      • gastrointestinal upsets

• Acute Adrenocortical Insufficiency:

  • May occur are due to:

    1.  rapid intensification of chronic adrenal insufficiency

       • precipitated by sepsis or surgical stress

    2.  acute hemorrhagic adrenal gland destruction in a previously healthy individual

       •  in children: associated with Pseudomonas septicemia or meningiococcemia

       •  in adults: associated with anticoagulant treatment/coagulation disorder

    3. Most frequent cause of acute adrenal insufficiency:

       • rapid withdrawal of steroids from patients who have adrenal atrophy following prolonged chronic steroid administration

    4. Other causes:

       • patients with congenital adrenal hyperplasia or with decreased adrenocortical reserve when:

         • they are given drugs that inhibit steroid synthesis, e.g. mitotane (Lysodren), ketoconazole (Nizoral) or

         • they are given drugs that increase steroid metabolism, e.g. phenytoin (Dilantin), rifampin (Rimactane)

  • Prognosis:

    • Long-term survival: dependent on prevention and proper treatment of adrenal crisis:

    • Prevention of crisis: infection, trauma, gastrointestinal upsets, other stresses: require immediate increase in administered hormone. Otherwise, symptoms may intensify --

      • nausea

      • vomiting

      • abdominal pain

      • lethargy, somnolence

      • hypovolemic vascular collapse

    • Treatment: based on replacing glucocorticoids and sodium/water deficits

      • intravenous 5% glucose infusion (in normal saline)

      • initiated with IV bolus of 100 mg hydrocortisone, followed by continuous hydrocortisone (Cortef, Solu-Cortef) infusion (10 mg/h)

      • Management of hypotension requires glucocorticoid replacement and correction of sodium and water deficit

      • Vasoconstrictive agents (dopamine) may be required in some extreme cases

      • Mineralocorticoid supplementation may be required (full mineralocorticoid effect will accompany the 100 mg hydrocortisone infusion)

Adrenocortical hyperfunction

"Hyperplastic adrenals and poorly developed ovaries, uterine tubes and uterus in a female child with congenital adrenal hyperplasia"; 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center;For more information concerning endocrine pathology

• Congenital adrenal hyperplasia

  • Caused by cortisol synthetic defects

    • autosomal recessive mutations

  • Most common adrenal disorder of childhood and infancy

  • Late-onset adrenal hyperplasia cause:

    • 5%-25% of hirsuitism and oligomenorrhea cases in women

    • Pregnancy at risk for congenital adrenal hyperplasia:

      • dexamethasone administration to the mother protects

  • Most common deficiency:

    •  decrease or lack of cytochrome P450c21 (21ß hydroxylase) activity (95% frequency) which results in:

      • cortisol synthesis reduction

      • compensatory increase of ACTH release

    • Other deficiencies:

      • P450c18, P450c17_a , P450c11_ß, 3ß- hydroxysteroid dehydrogenase

    • Increased compensatory ACTH can result in normal cortisol levels if sufficient P450c21 activity is present; however the gland will:

      • become hyperplastic

      • produce excessive precursors such as 17-hydroxyprogesterone -- diverted to androgen pathways-- leading to virilization.

      • Diagnosis:

        • Excessive 17-hydroxyprogesterone is metabolized in the liver to pregnanetriol, detected in large amounts in the urine.

        • Most reliable detection: increased plasma 17-hydroxyprogesterone to ACTH stimulation

    • Physiological consequences:

      • Female:

        • adrenal virilization associated with:

          1. ambiguous external genitalia (female pseudohermaphroditism)

          2. enlargement of the clitoris

          3. partial/complete labial fusion

          4. urogenital sinus (possible)

      • Male: enlarged genitalia

      • Postnatal period:

        • female virilization

        • isosexual prococity in the male

        • excessive androgen levels:

          • accelerated growth

          • early epiphyseal closure; growth stops --truncal development continues-- (short child with well-developed trunk.

      • 11-hydroxylation defects:

        •  excessive desoxycorticosterone production: hypertension

      • 17-hydroxylation defects:

        •  adrenal and gonadal defects increased 11-desoxycorticosterone levels-- mineralocorticoid excess signs/symptoms:

          1.  hypertension

          2.  hypokalemia

    • Infant with congenital adrenal hyperplasia:Presenting Symptoms --

      • Treatment

      •  If acute adrenal crisis:

        1. IV cortisol

        2. mineralocorticoid

        3. electrolyte solutions

      • After stabilization:

        •  hydrocortisone (Cortef, Solu-Cortef)-- adjusted as required

        • alternative: prednisone (Deltasone)

        • mineralocorticoids may be required (fludrocortisone (Florinef))

• Cushing's Syndrome:

  • Primary Cause: iatrogenic administration of steroids

  • Primary Non-iatrogenic Cause:

    • bilateral adrenal hyperplasia due to pituitary adenoma (basophilic tumor)

    • about 20 to 25 percent of Cushing's syndrome patients have adrenal neoplasm

    • ACTH Hypersecretion

  • Other Causes:

    • adrenal tumors

    • nodular adrenal hyperplasia-- causes:

      • familial autoimmune (children/young adults)-- pigmented multinodular cortical dysplasia

      • hypersensitivity to gastric inhibitory peptide (increased peptide receptor expression in adrenal cortex)

    • ectopic, nonendocrine tumors that produce ACTH

  • Incidence:

    • three times greater in women

    • most frequent age of onset: 30s to 40s

  • Manifestations:

    • Abnormal fat deposition:

      • truncal obesity-- mesenteric bed

      • rounded face ("moon facies")

      • interscapular area ("buffalo hump")

    • hirsuitism;

    • effects of protein loss --

      1. muscle wasting

      2. skin thinning

      3. striae-- secondary to weakening/rupture of dermal collagen fibers

      4. poor wound healing

      5. bruising

      6. osteoporosis

    • mental disorders--

      • irritability/emotional lability

      • severe depression, confusion, psychosis

    • diabetes

      • frequency < 20%

      • impaired glucose tolerance:

        1. increased hepatic gluconeogenesis

        2. insulin resistance

    • hypertension-- common

"Abdominal striae in a patient with trucal obesity in Cushing syndrome"; Ó 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center. For more information concerning endocrine pathology

• Short-termTreatment:

  • Surgical pituitary tumor removal

  • Irradiation/removal of pituitary adenomas (ACTH producing)

    • 

    • "Autopsy case. Unoperated macroadenoma of pituitary."

      • Ó 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

      • For more information concerning endocrine pathology

    •  microadenoma surgical resection is associated with recurrence rate that may be greater than 20 percent

  • About 20% -- 25% of Cushing's patients have an adrenal neoplasm.

    • usually unilateral;  about 50%, malignant

    •  Adrenal carcinoma diagnosis: approximate three-year post-diagnosis survival time

      • associated with liver and lung metastasis

      • primary chemotherapeutic agent: mitotane which suppresses cortisol production, decreasing plasma and urine steroid levels

      • Mitotane: -- relatively selective for glucocorticoid-secreting adrenal cortex zone; extra-adrenal cortisol metabolism may also be affected

        1. one-third of patients: tumor and metastasis regress

        2. in many patients:

           • steroidogenesis -- inhibited

           • no regression of tumor metastases

  • resection of hyperplastic adrenals -- if source of ACTH is apparent

    • cure rate approximates 100%

    •  adverse effects:

      • lifelong glucocorticoid and mineralocorticoid replacement

      • 10% to 20% probability of developing pituitary tumor over following ten year period (Nelson's syndrome)

  • in surgical approach not feasible, "medical" adrenalectomy may be required:

    • "Medical" adrenalectomy:

      • high-dose ketoconazole (Nizoral) (inhibit steroidogenesis)

      • mitotane (Lysodren) and/or aminoglutethimide (blocks steroid synthesis) and metyrapone

• Patient management:(surgical intevention)

  • Before surgery: large doses of cortisol

  • During and immediately after surgery: large doses of cortisol

  • Tapered cortisol to normal replacement doses (long-term maintenance)

• Diagnosis: Dexamethasone suppression testing

  • Initial Screening

    1. demonstration of increased cortisol production (8 a.m. plasma cortisol > 140 nmol/L (5 microgram/dL);

    2. cortisol > , following 1 mg dexamethasone (Decadron) at midnight

  • Definitive diagnosis:

    1. failure of urinary cortisol to fall to less than 80 nmol/d (30 microgram/d) or

    2. plasma cortisol to fall to less than 140 nmol/L (5 microgram/dL) following standard low-dose dexamethasone (Decadron) suppression testing (0.5 mg every six hours for 48 hours)

• Primary aldosteronism:

  • Overview:

    • twice as common in women as in man

    • most often presents between 30 in 50 years of age

  • Most common cause:

    • adrenal adenoma -- excessive aldosterone production

      • unilateral adenoma (usually small; either side)

    • Conn's syndrome

    • 

    • Conn's --primary aldosteronism:"Adrenal cortical adenoma There is a solitary, well-demarcated mass with the typical mottled yellow color of adrenal cortex."Ó 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.For more information concerning endocrine pathology

  • Other causes:

    • hyperplastic adrenal glands -- abnormal secretion

    • malignant tumor

      • adrenal carcinoma (rare)

  • Physiological Effects of aldosterone hypersecretion:

    • increased renal distal tubule or exchange of sodium for secreted potassium and hydrogen ions -- body potassium depletion/hypokalemia

  • Diagnosis--Criteria:

    1. diastolic hypertension (no edema)

    2. renin hyposecretion (low plasma renin activity)

       • renin secretion does not increase with volume depletion

    3. aldosterone hypersecretion that is not suppressed with volume expansion

  • Clinical Presentation:

    • diastolic hypertension (not very severe)

      • secondary to increase sodium reabsorption/volume expansion

    • headaches

    • polyuria, polydipsia

      • impairment of urinary concentrating ability

    • weakness

      • due to effects of potassium depletion

    • tetany

    • Electrocardiographic changes -- consistent with potassium depletion (hypokalemia-- which increases ectopy)

      • prominent U waves

      • cardiac arrhythmias

      • premature contractions

    • Many effects secondary to potassium loss associated with:

      • hypokalemia

        •  may be severe (< 3 mmol/L)

      • hypernatremia-- due to:

        • sodium retention

        • water loss from polyuria

      • metabolic alkalosis-- due to

        • urinary hydrogen ion loss

        • movement of hydrogen ion into potassium-depleted cells

        • alkalosis enhanced by potassium deficiency which increases proximal convoluted tubule capacity to reabsorb filtered bicarbonate.

  • Treatment:

    • Due to adenoma -- usually treated surgically

      • may be treated by:

        • sodium intake restriction

        • aldosterone antagonist (spironolactone (Aldactone))

          •  prolonged medical management (chronic therapy) may be side effect limited (males)

            1. gynecomastia

            2. decreased libido

            3. impotence

    • Due to idiopathic bilateral hyperplasia

      • symptomatic hypokalemia treated by:

        1. spironolactone (Aldactone)

        2. triamterene (Dyrenium)

        3. amiloride (Midamor)

      • surgery if pharmacological treatment fails

• Secondary aldosteronism:

  • Cause: appropriate increased aldosterone production due to renin-angiotensin system activation

  • Associated with:

    •  accelerated hypertension

    •  presence of edema disorder 

  • in pregnancy:

    • normal physiologic response to estrogen-induced increased plasma renin substrate and plasma renin activity and to antialdosterone actions of progestogens

  • in hypertension -- cause:

    • over production of renin (primary reninism)

    • renin over production secondary to reduced renal blood flow/perfusion pressure

      •  reduced renal artery lumen secondary to atherosclerosis or fiber muscular hyperplasia

    •  severe arteriolar nephrosclerosis (malignant hypertension)

    •  profound renal vasoconstriction (accelerated hypertension)

  • may be caused by rare renin-producing tumors (primary reninism)

    • juxtaglomerular cell tumor

  • Physiological characteristics:

    • increased plasma renin activity

    • moderate/marked increases in aldosterone levels

    • hypokalemic alkalosis

• Adrenocorticosteroids and Fetal Lung Maturation

  • Lung maturation is dependent on fetal cortisol

  • If delivery is expected before 34 weeks gestation, maternal glucocorticoid supplementation reduces likelihood of respiratory distress syndrome.

  • Betamethasone (Celestone) preferred due to reduced protein binding -- making more available for placental transfer to the fetal circulation.

•   Glucocorticoid Toxicity

  • Metabolic Effects

    •  iatrogenic Cushing's syndrome

      1.  moon facies

      2.  fat redistribution; e.g. truncal obesity

      3.  acne

      4.  hirsuitism

      5.   insomnia, increased appetite

      6.  weight gain

      7.  muscle wasting

      8.  skin thinning, bruising

      9.  hyperglycemia

      10.  osteoporosis, diabetes, aseptic hip necrosis

      11.  wound healing

  •  Other Effects:

    • peptic ulcer development

    • myopathy (triamcinolone)

    • nausea, dizziness, weight loss (triamcinolone, methylprednisolone)

    • psychosis (large dose corticosteroids)

    • subcapsular cataracts

    • increased intraocular pressure/glaucoma

    • benign intracranial hypertension

    • growth retardation and children

    • cortisone/hydrocortisone in greater than physiologic amounts: mineralocorticoid effects:

      1. sodium/fluid retention

      2. potassium loss-- hypokalemia

      3. hypochloremic alkalosis

      4. hypertension

  •   Adrenal Suppression

    • significant adrenal suppression observed with extended treatment

    • patient should receive supplemental steroid in cases of accidental trauma/surgery

    • the presence of adrenal suppression requires slow tapering of adrenocorticoid dosage

  •  Precautions

    • patient should be observed to detect development of:

      • hyperglycemia

      • glycosuria

      • Na retention with edema

      • hypertension

      • hypokalemia

      • peptic ulcer

      • osteoporosis

      • hidden infections

  • Contraindications:

    • peptic ulcer disease

    • heart disease/hypertension with congestive heart failure

    • psychoses

    • diabetes

    • osteoporosis

    • glaucoma

    • herpes simplex infection

• ACTH use

  • probably not appropriate as a therapeutic agent unless androgen increase is desired

•  Corticosteroid dosage forms:

  • ophthalmic -- eye disease

  • intra-articular -- joint disease

  • hydrocortisone enemas-- ulcertive colitis

  • aerosols (e.g.beclomethasone) -- asthma

  • nasal spray (beclomethasone, triamcinolone, flunisolide) -- allergic rhinitis

  • ointments, creams -- dermatological applications

• Mineralocorticoids (Aldosterone, Desoxycorticosterone, Fludrocortisone)

  • Most important mineralocorticoid: aldosterone

    • secondarily: desoxycorticosterone (DOC)

  • Most commonly prescribed salt-retaining hormone: fludrocortisone

  • Aldosterone:

    • synthesized in zona glomerulosa of the adrenal cortex

      • regulation -- ACTH, angiotensin

    • promotes sodium reabsorption by distal renal tubule (loosely coupled to potassium and hydrogen on and secretion)

    •  Excessive aldosterone-- (secondary to tumor/overdosage):

      • hypernatremia

      • hypokalemia

      • metabolic alkalosis

      • hypertension

      • increased plasma volume

    • Mechanism of Action:

      1. mineralocorticoid binding to cytoplasmic receptor (e.g.renal collecting tubule principal cells)

      2. subsequent steps similar to those described for glucocorticoids

  • Desoxycorticosterone (DOC)

    • precursor to aldosterone

    • secretion of DOC controlled by ACTH

    • DOC secretion enhanced in abnormal conditions e.g.:

      • adrenal carcinoma

      • congenital adrenal hyperplasia (with reduced P450c11or P450c17)

  • Fludrocortisone (Florinef)

    • most widely used mineralocorticoid

    • glucocorticoid and mineralocorticoid activity

    • used in management of adrenocortical insufficiency

• Adrenal Androgens

  • Large amounts of dehydroepiandrosterone (DHEA) secreted; smaller amounts of androstenedione and testosterone secreted

  • probably contribute to normal maturation processes

Antagonists of Adrenocortical Agents

• Synthesis Inhibitors and Glucocorticoid Antagonists:

  • Metyrapone:

    • selective inhibitor of steroid synthesis (inhibiting 11-hydroxylation which interferes with cortisol and corticosterone synthesis)

    •  produces dizziness and gastrointestinal disturbance

    • not widely used for Cushing's syndrome

    • reduces cortisol production to normal in some patients with:

      • adrenal tumor

      • ectopic ACTH syndromes

      • hyperplasia

    • may be useful in management of severe effects of cortisol excess on a temporary basis

    •  Major adverse effects:

      1. salt and water retention

      2. hirsuitism

    • most commonly used in adrenal function tests

  • Aminoglutethimide:

    • blocks cholesterol to pregnenolone conversion

    • reduces synthesis of all hormonally active steroids

    • used together with dexamethasone (Decadron) or hydrocortisone (Cortef, Solu-Cortef) to eliminate estrogen and androgen production in patients with breast carcinoma

    • used with ketoconazole (Nizoral) to reduce steroid secretion impatience with Cushing's syndrome (due to adrenocortical cancer -- not responding to mitotane)

  • Ketoconazole: (Nizoral)

    • antifungal imidazole derivative: potent, nonselective adrenal and gonadal steroid synthesis inhibitor

    • inhibition of P450 enzymes induces a compensatory increase in ACTH production and increases in progesterone, aldosterone and suppression of plasma renin activity

    • occasionally causes gynecomastia by increasing estradiol/testosterone plasma ratio

    • use for treating patients with Cushing's disease

  • Mifepristone (RU-486)

    • synthetic, partial agonist steroid

    • binds to glucocorticoid and progesterone receptors

    • treatment of Cushing's syndrome (experimental)

  •  Mitotane-- toxicities resulted in drug withdrawal from U.S. market

    • interferes with biosynthetic pathways in human adrenal cortex

  • Trilostane-- similar to aminoglutethimide;3ß-17 hydroxysteroid dehydrogenase inhibitor

• Mineralocorticoid Antagonists:

  • Spironolactone: (Aldactone)

    • used in treating primary aldosteronism

    • diagnostic use

    • management of symptoms while patient awaits adenoma surgical removal

    • reating hirsuitism in women

    •  Adverse effects:

      • hyperkalemia

      • menstrual abnormalities

      • gynecomastia

      • sedation

      • headache

      • gastrointestinal disturbances

      • skin rashes

  • Drospirenone-- progestin; antagonizes aldosterone effects

1. Goldfien, A.,Adrenocorticosteroids and Adrenocortical Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 635-650.

2. Williams, G. H and Dluhy, R. G. , Diseases of the Adrenal Cortex, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2035-2056