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ACTH, Adrenal Steroids

and Pharmacology of
the Adrenal Cortex
Hyacinth D. Jumalon, MD, DPCP
Cebu Doctors University- College of Medicine

Reference

Goodman & Gilman: Pharmacologic Basis of


Therapeutics (11th edition)

Figures:
Harrisons Principles of Internal Medicine (18th Ed.)
Berne & Levy Physiology (6th Ed.)

Outline
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
- Toxicity

IV. Inhibitors of biosynthesis and action of adrenocortical


steroids

History

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)

Introduction: ACTH and derivatives


- Used principally in diagnostic assessment of the
adrenocortical function
- Synthetic steroid hormones are used therapeutically
instead of ACTH
- Could either have glucocorticoid OR mineralocorticoid
action or both
- Employed at physiologic doses for replacement therapy
- Suppress inflammation (glucocorticoids)

ACTH synthesis

Prohormone
convertase 1

ACTH: Action

- 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

Zona glomerulosa- aldosterone


Zona fasciculata- cortisol
Zona reticularis- dehydroepiandrosterone (DHEA)

ACTH: Action

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

Mineralocorticoid

Glucocorticoid

Androgen

Cholesterol
CYP11A1
Pregnenolone

PROGESTERONE

17-hydroxypregnenolone

DHEA

Androstenedione
11-deoxycorticosterone

17-hydroxyprogesterone

Coticosterone

11-deoxycostisol

ALDOSTERONE

11-hydroxyandrostenedione

CORTISOL

TESTOSTERONE

ESTRADIOL

ACTH: Extra-adrenal Effects

Noted in adrenalectomized animals, given large doses of


ACTH:
Ketosis
Lipolysis
Hypoglycemia (immediately after treatment)
Resistance to insulin (later after treatment)

Regulation of ACTH Secretion

Hypothalamic-Pituitary-Adrenal Axis
Negative Feedback Mechanism
Arginine Vasopressin

Hypothalamic-Pituitary-Adrenal
(HPA) Axis

Characteristic modes of regulation:


a) Diurnal rhythm in basal
steroidogenesis
b) Negative feedback regulation
c) Marked increases in
steroidogenesis in response to
stress

Peak at 8am

Negative feedback

Mineralocorticoid
receptor (MR)
Glucocorticoid
receptor (GR)

Arginine Vasopressin

- 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

Diagnostic Applications of ACTH

- Has limited therapeutic effects


Testing the integrity of the HPA Axis
a) Standard Cosyntropin stimulation test
b) Low-dose Cosyntropin stimulation test

CRH stimulation test

Adrenocortical Steroids

Androgens- not essential for survival


Corticosteroids- glucocorticoids and mineralocorticoids
cortisol (hydrocortisone)- main glucocorticoid
aldosterone- main mineralocorticoid

- Endow the organism with the capacity to resist such


stressful circumstances as noxious stimuli and
environmental changes

General mechanism for Corticosteroid Effects

- Binding to specific receptor proteins in target tissues to


regulate the expression of corticosteroid responsive
genes
changes in the levels and arrays of proteins
synthesized
- Most effects of corticosteroids are not immediate

Corticosteroid products and synthetic derivatives

Physiologic Effects of Corticosteroids


Carbohydrate and
protein metabolism

Promotes gluconeogenesis and


glycogenesis
- In the periphery: glucose utilization;
protein breakdown and synthesis of
glutamine; activate lypolysis
INCREASED BLOOD GLUCOSE LEVELS

Lipid Metabolism

Electrolyte and water


balance

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

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


Cardiovascular

Direct effects of MR on the heart and blood


vessel 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)

Physiologic Effects of Corticosteroids


Hematologic

Anti-inflammatory and
immunosuppressive
actions

Minor effects in hemoglobin and RBC


content (polycythemia)
circulating lymphocytes, eosinophils,
monocytes and basophils
circulating PMNs
Lymphocytosis; anemia (Addisons
Disease)
release of vasoactive and
chemoattractive factors
secretion of lipolytic and proteolytic
enzymes
extravasation of neutrophils to areas of
injury
fibrosis

Pharmacokinetics
Absorption: orally effective
may 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
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

Excreted in the urine

Toxicity: Withdrawal of Therapy


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: Continued Use of Supraphysiological Doses

Hypokalemic alkalosis and hypertension


Hyperglycemia with glucosuria
Increased susceptibility to infection and risk for
reactivation of latent TB
Possible risk of PUD
Steroid myopathy
Behavioral changes
Cataracts (duration and dose-related)
Osteoporosis
Osteonecrosis
Growth retardation in children

Therapeutic Uses
- Use is EMPIRICAL except in replacement therapy
A single dose of glucocorticoid, even a large one, is
virtually without harmful effects, and a short course of
therapy (up to 1 week), in the absence of contraindications
is unlikely to be harmful.
- Beyond 1 week: increased risk of side effects
- ABRUPT withdrawal after prolonged use Adrenal
insufficiency

Therapeutic Uses: Endocrine

Replacement therapy
a) Primary and secondary AI
b) Acute adrenal AI
c) Chronic AI
d) Congenital adrenal hyperplasia

Therapeutic Uses: Non-endocrine


-

Rheumatic disorders
Renal diseases
Allergic diseases
Bronchial asthma
COPD
Infectious diseases
a) Pneumocystis carinii pneumonia
b) septic shock
c) H. influenza type 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

Adrenal insufficiency
- 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 imbalance
IV corticosteroids in tapered doses
Address precipitating condition

Indications for Inhibitor Use


- 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

Ketoconazole (Nizoral)
- 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 effective inhibitor
600-800 mg/day (2 divided doses)
1200 mg/day (2-3 doses)

Side effect: hepatic dysfunction

Metyrapone (Metopirone)

- Selective inhibitor of CYP11B (11-hydroxylase)


- The biosynthesis of cortisol is markedly impaired
increased levels of precursors

Metyrapone (Metopirone)
- 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)

Metyrapone (Metopirone)
Therapeutic Uses

- Used to treat hypercortisolism 2 to adrenal neoplasm or


ACTH-secreting tumors
(dose: 4g/day)
- Adjunctive therapy for those who have received pituitary
irradiation
(dose: 500-750mg TID or QID)
Side effects: hirsutism
hypertension (2 to 11-deoxycortisol)
nausea, headache, sedation, rashes

Etomidate (Amidate)
- 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

Mitotane (Lysodren)

- 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

Others
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

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