ACTH, Adrenal Steroids and Inhibitors

7/21/2019 ACTH, Adrenal Steroids and Inhibitors

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Goodman & Gilman: Pharmacologic Basis of

Therapeutics (11thedition)

Figures:

Harrisons Principles of Internal Medicine (18thEd.)

Berne & Levy Physiology (6thEd.)

Reference


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I. Review ACTH (synthesis and action)

II. Regulation of ACTH secretion

III. Synthetic Steroids

- Pharmacologic/ Physiologic effect

- General Mechanisms

- Absorption

- Transport, Metabolism and Excretion

- Therapeutic and Diagnostic Uses

- ToxicityIV. Inhibitors of biosynthesis and action of adrenocortical

steroids

Outline


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GLUCOCORTICOIDS

- as evidenced by the effects of these steroids in

carbohydrate metabolism (Reichstein and Kendall)

- associated with its anti-inflammatory effect

MINERALOCORTICOIDS

- Aldosterone was noted to potently affect fluid and

electrolyte balance (Tait et al)

History


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- Used principally in diagnostic assessment of the

adrenocortical function

- Synthetic steroid hormones are used therapeutically

instead of ACTH

- Could either have glucocorticoidOR mineralocorticoid

action or both

- Employed at physiologic doses for replacement therapy

- Suppress inflammation (glucocorticoids)

Introduction: ACTH and derivatives


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ACTH synthesis

Prohormone

convertase 1


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- Stimulates the adrenal cortex to secrete glucocorticoids,

mineralocorticoids and the androgen precursor DHEA

(acting on MC2R)

- Mediated predominantly at the level of the de novo

biosynthesis

ACTH: Action


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Zona glomerulosa- aldosterone

Zona fasciculata- cortisol

Zona reticularis- dehydroepiandrosterone (DHEA)


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2 Phases of response:

Acute Phase- seconds to minutes; reflects increased

supply of cholesterol substrate for enzymes

Chronic Phase- hours to days; results from increased

transcription of the steroidogenic enzymes

ACTH: Action


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Mineralocorticoid Glucocorticoid Androgen

Cholesterol

Pregnenolone

PROGESTERONE

11-deoxycorti-

costerone

Coticosterone

ALDOSTERONE

17-hydroxypregnenolone

17-hydroxyprogesterone

11-deoxycostisol

CORTISOL

DHEA

Androstenedione

11-hydroxy-

androstenedione

TESTOSTERONE

ESTRADIOL

CYP11A1


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Noted in adrenalectomized animals, given large doses of

ACTH:

KetosisLipolysis

Hypoglycemia (immediately after treatment)

Resistance to insulin (later after treatment)

ACTH: Extra-adrenal Effects


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Hypothalamic-Pituitary-Adrenal Axis

Negative Feedback Mechanism

Arginine Vasopressin

Regulation of ACTH Secretion


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Peak at 8am


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Negative feedback

Mineralocorticoid

receptor (MR)

Glucocorticoidreceptor (GR)


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- Acts as secretagogue for corticotropes potentiating the

effects of CRH

- Probably contributes to the full magnitude of the stress

response in vivo- Enhances the release of ACTH but does not cause

increased ACTH synthesis

Arginine Vasopressin


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- Has limited therapeutic effects

Testing the integrity of the HPA Axis

a) Standard Cosyntropin stimulation testb) Low-dose Cosyntropin stimulation test

CRH stimulation test

Diagnostic Applications of ACTH


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Androgens- not essential for survival

Corticosteroids- glucocorticoids and mineralocorticoids

cortisol (hydrocortisone)- main glucocorticoidaldosterone- main mineralocorticoid

- Endow the organism with the capacity to resist such

stressful circumstances as noxious stimuli and

environmental changes

Adrenocortical Steroids


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- Binding to specific receptor proteins in target tissues to

regulate the expression of corticosteroid responsive

geneschanges in the levels and arrays of proteins

synthesized

- Most effects of corticosteroids are not immediate

General mechanism for Corticosteroid Effects


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Corticosteroid products and synthetic derivatives


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Carbohydrate andprotein metabolism - Promotes gluconeogenesisandglycogenesis

- In the periphery: glucose utilization;

protein breakdown and synthesis of

glutamine; activate lypolysis

INCREASED BLOOD GLUCOSE LEVELS

Lipid Metabolism - Dramatic redistribution of body fat (buffalo

hump, moon facies, fat in the

supraclavicular area)

- Permissive facilitation of the lipolytic effects

of other agents free fatty acid

Electrolyte and water

balance

ALDOSTERONE

- Acts on the distal tubules and collecting

ducts

- reabsorption of Na+from tubular fluid

- urinary excretion of K+and H+

Physiologic Effects of Corticosteroids


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Cardiovascular - Direct effects of MR on the heart and bloodvessel wall

- Hypertension and cardiac fibrosis

- Enhanced vascular reactivity to vasoactive

substances

Skeletal muscle - Muscle weakness

- Skeletal muscle wasting (steroid myopathy)

CNS - apathy, depression, irritability, psychosis

(adrenal insufficiency)- Mood elevation, mania, insomnia, increased

motor activity, anxiety, depression, psychosis

(glucocorticoid administration)



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Hematologic - Minor effects in hemoglobin and RBCcontent (polycythemia)

- circulating lymphocytes, eosinophils,

monocytes and basophils

- circulating PMNs

- Lymphocytosis; anemia (AddisonsDisease)

Anti-inflammatory and

immunosuppressive

actions

- release of vasoactive and

chemoattractive factors

- secretion of lipolytic and proteolyticenzymes

- extravasation of neutrophils to areas of

injury

- fibrosis


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Absorption:orally effectivemay be given IV, IM

Absorbed systemically from local sites

When administration is prolonged, when site of

application is covered by an occlusive dressing and

large areas are involved may cause systemic effects

Changes in the chemical structure may alter the

specificity and/or potency

Pharmacokinetics


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Transport:

- at normal or low concentrations- most of the

hormone is protein-bound

- unbound fraction is active and can enter cells

corticosteroid-binding globulin (CBG; transcortin)

- high affinity, low total binding capacity

- binds cortisol > aldosterone

albumin

- low affinity, high total binding capacity

Excretedin the urine

Pharmacokinetics


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Flare up of the underlying disease- most common

Acute adrenal insufficiency- most severe

- due to suppression of the HPA axis

- recovery variable from several weeks to months

Glucocorticoid withdrawal syndrome

- fever, myalgia, arthalgia and malaise

Pseudotumor cerebri- increased ICP with papilledema

- associated with reduction or withdrawal of

corticosteroid therapy

Toxicity: Withdrawal of Therapy


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Hypokalemic alkalosis and hypertension

Hyperglycemia with glucosuria

Increased susceptibility to infection and risk for

reactivation of latent TB

Possible risk of PUDSteroid myopathy

Behavioral changes

Cataracts (duration and dose-related)

OsteoporosisOsteonecrosis

Growth retardation in children

Toxicity: Continued Use of Supraphysiological Doses


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- Use is EMPIRICAL except in replacement therapy

A single dose of glucocorticoid, even a large one, is

virtually without harmful effects, and a short courseoftherapy (up to 1 week), in the absence of contraindicationsis unlikely to be harmful.

- Beyond 1 week: increased risk of side effects

- ABRUPT withdrawal after prolonged use Adrenal

insufficiency

Therapeutic Uses


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Therapeutic Uses: Endocrine

Replacement therapy

a) Primary and secondary AI

b) Acute adrenal AIc) Chronic AI

d) Congenital adrenal hyperplasia


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Therapeutic Uses: Non-endocrine

- Rheumatic disorders- Renal diseases

- Allergic diseases

- Bronchial asthma

- COPD

- Infectious diseasesa) Pneumocystis carinii pneumonia

b) septic shock

c) H. influenzatype b meningitis

- Autoimmune hepatitis

- Spinal cord injury

- Ocular disease- Inflammatory dermatoses

- Inflammatory bowel

diseases

- Cerebral edema

- Sarcoidosis

- Thrombocytopenia (ITP)

- Autoimmune hemolytic

anemia (AIHA)

- Organ transplantation


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- life-threatening disease

- GI symptoms (nausea, vomiting, abdominal pain),

dehydration, hyponatremia, hyperkalemia, weakness,

lethargy and hypotension

- Associated with disorders in the adrenals- Follows abrupt withdrawal of glucocorticoids

Tx: Hydration therapy (D5NSS)

Correction of electrolyte imbalanceIV corticosteroids in tapered doses

Address precipitating condition

Adrenal insufficiency


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- Address HYPERCORTISOLISM caused by:

corticotroph adenomas that overproduce ACTH

(Cushings Disease)

adrenocortical tumors

bilateral hyperplasias that overproduce cortisol(Cushings Syndrome)

adrenocortical carcinomas

ectopic ACTH- or CRH-producing tumors

- ALL of these inhibitors may precipitate Acute AI

Indications for Inhibitor Use


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- Antifungal agent

- In higher doses, inhibits adrenal and gonadal

steroidogenesis due to inhibition of CYP17

(17-hydroxylase)

- At even higher doses, inhibits CYP11A1- Best tolerated and most effectiveinhibitor

600-800 mg/day (2 divided doses)

1200 mg/day (2-3 doses)

Side effect: hepatic dysfunction

Ketoconazole (Nizoral)


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- Selective inhibitor of CYP11B (11-hydroxylase)

- The biosynthesis of cortisol is markedly impaired

increased levels of precursors

Metyrapone (Metopirone)


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- Selective inhibitor of CYP11B (11-hydroxylase)

- The biosynthesis of cortisol is markedly impaired

increased levels of precursors

- The elevated levels of 11-deoxycortisol sustain

mineralocorticoid-dependent functions

Diagnostics:Metyrapone test (test for HPA integrity),

Diagnose Cushings syndrome (equivocal

Dexamethasone suppression test)



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Therapeutic Uses

- Used to treat hypercortisolism 2to adrenal neoplasm or

ACTH-secreting tumors

(dose: 4g/day)

- Adjunctive therapy for those who have received pituitaryirradiation

(dose: 500-750mg TID or QID)

Side effects: hirsutismhypertension (2to 11-deoxycortisol)

nausea, headache, sedation, rashes



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- A substituted imidazole used primarily as anesthetic and

sedative

- Inhibits CYPB1 activity at subhypnotic doses

- Off-label use

- Administered IV for patients treated for hypercortisolism

who cannot take oral medications

Dose: 0.03 mg/kg IV bolus followed by 0.1 mg/kg/hr infusion

Max: 0.3 mg/kg/hr infusion

Etomidate (Amidate)


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- An adrenocorticolytic agent used to treat inoperable

adrenocortical CA

- Used for long-term control of hypercortisolism

- Converted to a reactive acyl chloride by adrenal

mitochondrial CYPs reactivity to cellular proteins

Dose: 0.5-3g TID

- Onset of action takes weeks to months

Side effects: GI disturbances, ataxia

Mitotane (Lysodren)


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Aminoglutethimide (Cytadren)

- Primarily inhibits CYP11A1 (rate-limiting step in the

synthesis of all physiological steroids

- ALL classes of steroid hormones is impaired- No longer available commercially

Trilostane- Competitive inhibitor of the type II 3-hydroxysteroid

dehydrogenase (3-HSD)

- Both adrenal and gonadal hormones affected

- Used in humans and dogs

Others


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ACTH, Adrenal Steroids and Inhibitors