ACTH,

Mineralocorticoids
and Inhibitors
Burford et al., 2017
Ünvan Ad Soyad
Sinan ŞERMET, PhD, Asst. Prof. of Pharmacology
Istinye University Faculty of Medicine Anabilim Dalı
Department of Pharmacology and Clinical Pharmacology
Grade III Committee VI Urogenital – Endocrine Kurul/Staj Adı eklemek için Tıklayın
Lecture Learning Outcomes
1) The student should be able to explain biosynthesis, regulation and pharmacodynamic effects
of ACTH and mineralocorticoids.
2) List indications and warnings for ACTH and mineralocorticoids.
3) List adrenal steroid biosynthesis inhibitors, glucocorticoid and mineralocorticoid antagonists,
their mechanism of actions and indications.
4) Describe important aspects of pharmacokinetics.
5) List untoward reactions.

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Content
1. Adrenocorticosteroids
2. Mineralocorticosteroids
3. Adrenocortical Antagonists
4. Mineralocorticoid Antagonists
5. Corticotropin (ACTH)
1. Adrenocorticosteroids

Natural adrenocortical hormones are steroid molecules produced and secreted by the adrenal cortex.
Deficiency of adrenocortical hormones causes signs and symptoms of Addison's disease and overproduction causes
Cushing's syndrome.
Both natural and synthetic corticosteroids are used in the diagnosis and treatment of adrenal dysfunction. They are also
used (more frequently and in much higher doses) for the treatment of various inflammatory and immunological disorders.
The secretion of adrenocortical steroids, especially glucocorticoids, is controlled by the secretion of corticotropin (ACTH)
from the pituitary gland. Corticotropin is derived from a larger protein (pro-opiomelanocortin (POMC) synthesized in the
pituitary.
The secretion of the salt-sparing hormone aldosterone is mainly influenced by circulating angiotensin and potassium.
Corticotropin (ACTH) has some effects that are not dependent on its effect on adrenocortical secretion. However, its use as
an anti-inflammatory agent and in testing adrenal function depends on its secretory action. Synthesis inhibitors or
antagonists of adrenocortical steroids are important in the treatment of certain conditions.

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1. Adrenocorticosteroids

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1. Adrenocorticosteroids
The adrenal cortex secretes a large number of steroids into the circulation.
Hormonal steroids can be classified into those with important effects on intermediary metabolism and immune function
(glucocorticoids), those with mainly salt-retaining activity (mineralocorticoids) and those with androgenic and estrogenic
activity. In humans, the major glucocorticoid is cortisol and the most important mineralocorticoid is aldosterone.

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1. Adrenocorticosteroids
3 types of hormones are synthesized in the adrenal cortex.
Glucocorticoid ---- Cortisol
Mineralocorticoid ---- Aldosterone
Androgens ----- Precursor Hormones
Dehydroepiandrosterone (DHEA), In the periphery it is
converted to
DHEA sulphate, testosterone and
dihydrotestosterone
Androstenedione and also to estrogens.

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1. Adrenocorticosteroids

https://www.news-medical.net/health/What-is-Addisons-Disease.aspx (Access: 05.16.2024) https://drudayphadke.in/cushing.html (Access: 05.16.2024)

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2. Mineralocorticosteroids

The most important mineralocorticoid in man is aldosterone. However, small amounts of deoxycorticosterone (DOC) are also formed and
secreted.
Fludrocortisone, a synthetic corticosteroid, is the most commonly prescribed salt-retaining hormone.
Aldosterone: synthesized mainly in the zona glomerulosa of the adrenal cortex.
Moderately stimulates ACTH secretion, this effect lasting no more than a few days in normal individuals. The suppression of ACTH secretion
by aldosterone is also milder than that by cortisol (about one third) and does not provide any significant feedback on ACTH secretion.
Aldosterone and other mineralocorticoids increase the reabsorption of sodium from the kidneys (distal tubule and cortical collecting
ducts) and promote the excretion of potassium and hydrogen ions.
They exert these effects by binding to mineralocorticoid receptors in the cytoplasm of the cells of the target structures.
Activation of the aldosterone receptor increases the expression of Na+/K+-ATPase and epithelial sodium channel (ENaC).

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2. Mineralocorticosteroids

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2. Mineralocorticosteroids

Aldosteron:
Metabolism: It is secreted at a rate of 100-200 mcg per day. Trace amounts of injected aldosterone have a half-life of 15-20 minutes and are
tightly bound to plasma proteins. Aldosterone is conjugated to 50 mcg of tetrahydroaldosterone in 24 hours. Approximately 5-15 mcg is
excreted freely or as 3-oxoglucuronide.
Dihydrocorticosterone: Secreted as a precursor of aldosterone in an amount of approximately 200 mcg daily. Half-life is 70 minutes when
injected into the circulation. Unlike aldosterone, its secretion is mainly under the control of ACTH.
Fludrocortisone: A potent steroid with both glucocorticoid and mineralocorticoid activity. It is the most widely used mineralocorticoid. It
has a strong salt-sparing effect and is used in the treatment of adrenocortical insufficiency due to mineralocorticoid deficiency (0.1 mg
orally 2-7 times a week). It does not have significant anti-inflammatory or antigrowth effects at these doses.
Adrenal Androgens: The adrenal cortex secretes large amounts of Dehydroepiandrosterone (DHEA) and smaller amounts of
androstenedione and testosterone.
DHEA can convert to more potent androgens and estrogens in the periphery, stimulating androgen and estrogen receptors respectively.
There is no evidence to support the use of DHEA to increase muscle strength or improve memory.

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3. Adrenocortical Antagonists

Synthesis Inhibitors and Glucocorticoid Antagonists:

Inhibitors of steroid synthesis act in several different steps, whereas glucocorticoid antagonists act at the receptor level.
(1) Aminoglutethimide: blocks the conversion of cholesterol to pregnenolone and causes a decrease in the synthesis of all hormonally
active steroids.
It has now been replaced by tamoxifen or aromatase inhibitors in breast cancer treatment.
It can be used together with metyrapone or ketoconazole to reduce steroid secretion in Cushing's syndrome that does not respond to
mitotane. A dose of 1 g per day is well tolerated. Drowsiness and skin rash are commonly seen at high doses.
(2) Ketoconazole: is an imidazole-derived antifungal that potently and relatively non-selectively inhibits gonadal steroid synthesis. It inhibits
the cholesterol side chain cleavage enzyme P450c17, C1720-lyase, 3β-hydroxysteroid dehydrogenase and P450c11 enzymes required for
steroid synthesis. Its steroid synthesis inhibitory effect is seen at high doses.
It is used in the treatment of patients with Cushing syndrome due to various reasons. It may cause hepatotoxicity. The daily dose should
start from 200 mg and gradually increase to 1000 mg.

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3. Adrenocortical Antagonists

Xu et al., 2017

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3. Adrenocortical Antagonists

(3) Etomidate: used for induction of general anesthesia and sedation. At subhypnotic doses, it inhibits adrenal steroidogenesis at the 11β-
hydroxylase level. It is the only parenteral drug used in the treatment of severe Cushing's syndrome.
(4) Metyrapone: is a relatively selective inhibitor of cetoride 11-hydroxylation. It inhibits cortisol and corticosterone synthesis.
It was widely used in adrenal function tests. It is not commonly used in Cushing's syndrome. It is the only adrenal inhibitor that can be given
to pregnant patients with Cushing's syndrome. It may cause temporary dizziness and gastrointestinal disturbances. Water and salt retention
and hirsutism may occur.
(5) Trilostane: It is a 3β-17 hydroxysteroid dehydrogenase inhibitor similar to aminoglutethimide, which inhibits the synthesis of adrenal
and gonadal hormones.
Its adverse effects are mostly on the gastrointestinal system. Adverse effects occur in approximately 50% of patients treated with either
trilostane or aminoglutethimide.
(6) Abiraterone: It is the newest steroid synthesis inhibitor to be approved. It blocks 17α-hydroxylase (P450c17) and 17,20-lyase. It reduces
cortisol synthesis in the adrenal gland and gonadal steroid synthesis in the gonads. A compensatory increase in ACTH and aldosterone
synthesis occurs, which can be prevented by simultaneous dexamethasone administration.
Abiraterone is an orally active steroid prodrug approved for the treatment of refractory prostate cancer.

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3. Adrenocortical Antagonists

(7) Mifepristone (RU-486): a pharmacological antagonist of steroid receptors. It has potent antiprogestin activity. At high doses, it binds to
glucocorticoid receptors, inhibit glucocorticoid receptors, causing anti-glucocorticoid effects.
The average half-life is 20 hours (longer than many glucocorticoids). Less than 1% of the dose is excreted in the urine. It is highly bound to
plasma proteins and has a long half-life.
It is recommended for inoperable patients with adrenal carcinoma or ectopic ACTH secretion that does not respond to other treatments.
(8) Mitotane: a non-selective cytotoxic effect on the adrenal cortex in dogs and to a lesser extent in humans. Approximately one-third of
patients with adrenal carcinoma show a decrease in tumor mass. Toxic effects severe enough to require dose reduction are observed in
80% of patients. Diarrhea, nausea, vomiting, depression, drowsiness and skin rashes. It has been withdrawn from the market in the USA
(like metyrapone) but can be used within the scope of the humanitarian access to drugs program (compassionate use).

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4. Mineralocorticoid Antagonists
In addition to drugs that inhibit aldosterone synthesis, there are steroids that compete with aldosterone against its receptor and reduce
its effect peripherally.
Spironolactone: 7α-acetylthiospirolactone. The onset of action is slow and lasts 2-3 days after discontinuation of the drug.
It is used in the treatment of primary aldosteronism. It has been found useful in making a diagnosis in some patients and in relieving signs
and symptoms when the adenoma needs to be surgically removed.
It is an androgen antagonist. It is sometimes used to treat hirsutism and acne in women.
It is a diuretic. Hypertension treatment. The drug provides more benefits in heart failure than expected from its diuretic effects alone.
Adverse Effects: hyperkalemia, cardiac arrhythmia, menstrual abnormalities, gynecomastia, sedation, headache, gastrointestinal
disturbances, skin rash.
Eplerenone: another aldosterone antagonist. It is approved for the treatment of hypertension and heart failure. Like spironolactone, it
reduces mortality in heart failure.
It is more selective than spironolactone, with no reported effects on androgen receptors.
The most common adverse effect is hyperkalemia, but it is usually mild.
Drospirenone: a progestin, is an oral contraceptive and antagonizes the effects of aldosterone.

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5. Corticotropin (ACTH)
Corticotropin (ACTH) is a peptide hormone secreted from the anterior pituitary and regulates the endocrine function of the adrenal
cortex.
Its structure is similar to α-melanocyte stimulating hormone, so ACTH can cause «pigmentation».
Natural ACTH is obtained by extraction from the pituitary of cattle, sheep and pigs.
Tetracosactide (Tetracosactrin): Synthetic ACTH has begun to be used instead of the natural one.
ACTH Synthesis and Release:
ACTH and β-endorphin are formed and stored together in the basophil cells in the anterior pituitary lobe, as a result of the hydrolysis of
pro-opiomelanocortin, a 165-amino acid peptide that is the hormone precursor.
There are four primary mechanisms that regulate synthesis and release:
Negative feedback inhibition between the hypothalamic-pituitary axis and the adrenal cortex
Short Circuit Feedback
Neural Control
Extra-adrenal cortex endocrine control

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5. Corticotropin (ACTH)

ACTH Physiological and Pharmacological Properties:

The most important function; corticosteroid synthesis in the adrenal cortex and
This increases the release of these hormones and
It ensures that the adrenal cortex tissue remains in normal size with its trophic effect.
ACTH is the main hormone involved in the control of cortisol and the synthesis of adrenocortical adrogens. Its contribution to the control of
aldosterone synthesis is secondary.
ACTH Preparations:
Tetracosactide (Tetracosactrin): It is synthetic. Acetate form is used (i.m.) as medicine.
Corticotropin Zinc Hydroxide Suspension: Natural ACTH is complexed with zinc. It is long-acting, i.m. is applied.
Corticotropin Solution for Injection: It is the solution of natural hormone. i.m. and s.c. is given.

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5. Corticotropin (ACTH)
ACTH Use in Treatment:
As a Diagnostic Tool:
The ability of the adrenal cortex to respond to ACTH is assessed by measuring corticosteroid levels in plasma or urine before and after
administration of natural or synthetic ACTH.
In Addison's disease, the adrenals do not respond to ACTH.
Following long-term corticosteroid treatment, the sensitivity of the cortex to ACTH decreases in proportion to the dose and duration of
treatment.
Use of ACTH in Treatment:
In general, glucocorticoids are preferred to corticotropin. Because;
ACTH necessarily requires injection, glucocorticoids can be given orally (p.o.).
ACTH increases glucocorticoid activity up to a certain limit, whereas glucocorticoids can be given at any desired dose, producing stronger
anti-inflammatory activity.
ACTH treatment is planned. The risk of allergy is higher. The mineralocorticoid effect is minimized in the new glucocorticoids. This is not
possible with ACTH.

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5. Corticotropin (ACTH)

In these cases, ACTH is preferred over glucocorticoids.

When corticosteroid treatment is required in children, growth inhibition is less in long-term treatment with ACTH.
They have been suggested to be more beneficial than glucocorticoids in conditions such as colitis, myositis, multiple sclerosis and bullous
skin diseases.
Additionally, it does not atrophy the skin like glucocorticoids. However, local application is ineffective.
***«ACTH is not preferred in the treatment of adrenal cortex insufficiency.***

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