Post on 04-Feb-2018
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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)
Physiologic Effects of Corticosteroids
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Physiologic Effects of Corticosteroids
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)
Metyrapone (Metopirone)
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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
Metyrapone (Metopirone)
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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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thank you