Professional Documents
Culture Documents
and Pharmacology of
the Adrenal Cortex
Hyacinth D. Jumalon, MD, DPCP
Cebu Doctors University- College of Medicine
Reference
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
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)
ACTH synthesis
Prohormone
convertase 1
ACTH: Action
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
Hypothalamic-Pituitary-Adrenal Axis
Negative Feedback Mechanism
Arginine Vasopressin
Hypothalamic-Pituitary-Adrenal
(HPA) Axis
Peak at 8am
Negative feedback
Mineralocorticoid
receptor (MR)
Glucocorticoid
receptor (GR)
Arginine Vasopressin
Adrenocortical Steroids
Lipid Metabolism
ALDOSTERONE
- Acts on the distal tubules and collecting
ducts
- reabsorption of Na+ from tubular fluid
- urinary excretion of K+ and H+
Skeletal muscle
Muscle weakness
Skeletal muscle wasting (steroid myopathy)
CNS
Anti-inflammatory and
immunosuppressive
actions
Pharmacokinetics
Absorption: orally effective
may be given IV, IM
Absorbed systemically from local sites
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
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
Replacement therapy
a) Primary and secondary AI
b) Acute adrenal AI
c) Chronic AI
d) Congenital adrenal hyperplasia
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
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)
Metyrapone (Metopirone)
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
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)
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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