Endocrine Pharmacology Flashcards by Pauline Mendoza

Adrenal steroids are manufactured by enzymes located in the:

Mitochondria and SER

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Three primary pathways (adrenal cortex)

MGA

Mineralocorticoid
Glucocorticoid
Androgen/estrogen

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Precursor for steroid biosynthesis

Cholesterol

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Synthesis and secretion is controlled by CRH from the hypothalamus and ACTH from the pituitary

Cortisol / hydrocortisone

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Steroid binding proteins

Corticotropin binding globulin (CBG) aka transcortin
Albumin

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MOA: Glucocorticoids

● Steroids exert their effects by altering protein synthesis through a direct effect
on the cell’s nucleus
● glucocorticoids first enter the cell and bind to a receptor in the cytosol
● ”hormone-receptor“ complex (transcription factor)
● this complex travels (translocates) to the nucleus
● binds to specific DNA gene segments that control inflammation and other
processes
● transcription factor:
○ modulates the transcription of DNA mRNA units
○ inhibits other transcirption factors (nuclear factor-kappa B, activator
protei-1) that normally activate inflammatory genes
■ thus, turning off proinflammatory genes and suppressing the
production of inflammatory products
● Changes in mRNA transcription ultimately lead to a change of protein
synthesis in the cell

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MOA: Glucocorticoids

Rapid effect mediated by

Surface receptors

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MOA: Glucocorticoids

Delayed effect

more prolonged; mediated by intracellular receptor; affects
transcription at the genomic level

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MOA: Glucocorticoids

Genomic effects

takes SEVERAL HOURS OR DAYS TO OCCUR because of the time required to alter protein synthesis and create new proteins that reach meaningful concentrations in the cell

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Physiological Effects: Glucocorticoids

AEI

● Anti-inflammatory
● immunosuppresion
● Effects on Glucose, Protein, and Lipid Metabolism

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Glucocorticoid Effect on Glucose, Protein, and Lipid Metabolism

● increase blood glucose
● increase liver glycogen
● inhibits the uptake of glucose into muscle and fat
● muscle breakdown to amino acids
● lipid breakdown to free fatty acids

Effects:
● maintain blood glucose levels and liver glycogen
levels
● enables a supply of energy substrate readily
available for increased activity

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Anti-inflammatory Effects: Glucocorticoids

Attenuate the heat, swelling, and tenderness regardless of the cause

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glucocorticoids act on macrophages, lymphocytes, and endothelial cells to
inhibit inflammatory proteins (cytokines):

○ IL-1, IL-6, TNF alpha, IFN gamma,
■ Primary chemical signal for activating other inflammatory cells (T lymphocytes, fibroblasts, NK cells)

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Anti-inflammatory effects: Glucocorticoids

reduce the number of circulating lymphocytes, eosinophils, and other cells

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Anti-inflammatory effects: Glucocorticoids

inhibit the transcription and expression of adhesion molecules:

endothelial leukocyte adhesion molecule 1, intracellular adhesion
molecule 1

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responsible for attracting leukocytes in the bloodstream to
endothelial cells at the site of inflammation

endothelial leukocyte adhesion molecule 1, intracellular adhesion
molecule 1

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Anti-inflammatory Effects: Glucocorticoids

Inhibit the production of proinflammatory substances:

prostaglandins and
leukotrienes

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Anti-inflammatory Effects: Glucocorticoids

activate genes to synthesize annexins / lipocortins

inhibits phospholipase A2 enzyme

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● inhibit hypersensitivity reactions, especially delayed or cell-mediated allergic
reactions
● suppress the ability of immune cells to synthesize or respond to chemical
mediators such as cytokines that promote autoimmune responses

Immunosupression

Other effects of Glucocorticoids

● Enhances sodium and water reabsorption by impairing the ability of the
kidneys to excrete water
● Alter CNS function: changes in behavior and mood
● decreased vascular permeability

○ destruction of adrenal cortex
○ autoimmune
○ nonspecific symptoms
○ acute adrenal crisis: hypotension, hyponatremia,
hyperkalemia, hypoglycemia
○ low cortisol and aldosterone levels
○ high renin levels
○ blunt cortisol reponse with ACTH stimulation
○ life threatening; severe endocrine emergency
○ life-long treatment with hormonal replacement is needed
○ Hydrocortisone, identical to cortisol, is given to correct the
deficiency
○ Fludrocortisone, a potent synthetic mineralocorticoid may
also be necessary

Primary adrenal insufficiency / Addison
disease / autoimmune adrenalitis

Glucocorticoid use in Nonendocrine
Conditions

● Collagen diseases
● Autoimmune disorders
○ Rheumatic disorders (Rheumatic arthritis)
● musculoskeletal injuries
● tenosynovitis
● myositis
● back and neck pain
● Carpal Tunnel Syndrome
● Joint inflammation
○ rule of thumb: limit glucocorticoid injection to a specific joint to 4 or < per year
● Allergies, allergic rhinitis, asthma (fluticasone)
● Acceleration of lung maturation in preterm newborn (dexamethasone, betamethasone)
● Cerebral edema (dexamethasone) to suppress inflammation and angiogenesis

Adverse effects: Glucocorticoids

Adrenocortical suppression
Drug-induced Cushing Syndrome
Breakdown of supporting tissues
Osteoporosis

Adrenocortical suppression

○ Negative feedback to the hypothalamic-anterior pituitary (HPA) axis is
caused by the administration of exogenous hormones
■ to prevent this, alternate-day administration, to allow the HPA axis
to recover/function
○ abrupt withdrawal of therapy can also be life-threatening, it must be
withdrawn slowly by tapering the dose

Breakdown of Supporting Tissues

○ Involves muscle, bone, ligaments, tendons ○ The magnitude of wasting depends on the duration and dosage of drug therapy including the patient’s overall health ○ PTs must be careful to avoid overstressing weakened tissues

Osteoporosis

○ glucocorticoids suppress Calcium absorption in the intestines, inhibit bone formation (osteoblastic activity) ○ Patients are advised to take Bisphosphanates and Vitamin D

Topical application

skin atrophy, ecchymosis, purple striae

Other advserse effects of glucocorticoids

● Peptic ulcer ● increased susceptibility to infection ● inhibitory effect on the growth plates in developing bone ● glaucoma ● cataract formation ● mood changes ● psychoses ● hypertension ● altered glucose metabolism (hyperglycemia, insulin resistance in DM patients)

Therapeutic Uses and Diagnostic Applications: Glucocorticoids

“ A single dose of glucocorticoid, even a large on, is virtually without harmful effects, and a short course of therapy (up to 1 week), in the absence of specific contraindications, is unlikely to be harmful. As the duration of glucocorticoid therapy is increased beyond 1 week, there are time- and dose-related increases in the incidence of disabling and potentially lethal effects.”

aromatase inhibitor; estrogen synthesis inhibitor

Aminoglutethimide

selective inhibitor of CYP11B1: inhibits conversion of 11-deoxycortisol to cortisol

Metyrapone

Antifungal; in higher doses, an effective inhibitor of adrenal and gonadal steroidogenesis by inhibiting 17a-hydroxylase

Ketoconazole

antineoplastic drug; adrenocorticolytic agent used to treat inoperable adrenocortical carcinoma

Mitotane

● Aldosterone ● maintains fluid and electrolyte balance ● kidneys: increase sodium and water reabsorption and potassium excretion ● Aldosterone release is regulated by fluid and electrolyte status in the body ● can also be produced by the brain, heart, and other tissues

Mineralocorticoids

● Angiotensin II: primary stimulus for aldosterone release as part of the reninangiotensin system concerned with maintaining BP; potent vasoconstrictor ● Elevated potassium: serves as a stimulus to increase aldosterone release ● ACTH may also play a role in aldosterone release

Regulation of Secretion of Mineralocorticoids

Aldosterone MOA

Mineralocorticoids increase sodium reabsorption by affecting sodium channels and sodium pumps on the epithelial cells lining the renal tubules 1. Aldosterone enters the cell and binds to a cytosolic receptor = hormone-receptor complex 2. A-R complex travels to the cell’s nucleus, where it induces mRNA synthesis 3. mRNA units undergo translation in the cytosol 4. proteins synthesized increase membrane permeability to sodium 5. Na enters the cell from the lumen down an electrochemical gradient (passive) 6. Na is ACTIVELY reabsorbed into the body and K is actively secreted by the Na-K pump

● Excess production of aldosterone ● can initially present as mild or severe to refractory hypertension ● can often go undiagnosed

Hyperaldosteronism

○ Primary: tumor in the gland itself (Conn Syndrome) or bilateral adrenal hyperplasia, other rare tumors ○ Secondary: due to excessive activation of the RAAS which can be due to a renin-producing tumor, renal artery stenosis, or edematous d/o(Left sided heart failure, pregnancy, cor pulmonale, or cirrhosis with ascites

Hyperaldosteronism etiology

○ Surgery, adrenalectomy ○ Non-surgical: Mineralocorticoid receptor antagonists (MRAs) ○ ACEi and ARB to control BP ○ salt restriction

Hyperaldosteronism Tx/Mx

As replacement therapy when natural production of mineralocorticoid is impaired (Addison dse., post adrenalectomy)

Mineralocorticoid drugs / aldosterone agonists

○ primary aldosterone-like agent for replacement therapy ○ chemically classified as a glucocorticoid but has high levels of mineralocorticoid activity

Fludrocortisone

Mineralocorticoid drugs / aldosterone agonists adverse effects

hypertension, peripheral edema, weight gain, hypokalemia

● Spironolactone ● Eplerenone

Mineralocorticoid Antagonists

Eplerenone

○ competitive antagonists - they bind to the receptor but do not activate it; prevent aldosterone from binding with renal cells and other tissues ○ increased sodium and water excretion and decreased potasssium excretion (“potassium sparing diuretics”) ○ Administered as diuretics, in treating hypertension and heart failure ○ Spironolactone is also used to diagnose hyperaldosteronism

● Spironolactone ● Eplerenone

○ Adverse effects: hyperkalemia ○ Spironolactone may interfere with endogenous sex hormones (increased body hair, deepening of voice, decreased libido, menstrual irregularities, gynecomastia in men ○ GI disturbances ○ Spironolactone CNS effects (drowsiness, lethargy, confusion, headache