Lecture 7: Adrenocortocosteroids Flashcards
List drugs for each class:
Glucocorticoids (3):
Mineralocorticoids (1):
Anti-glucocorticoids (1):
- Glucocorticoids: Prednisone, Triamcinolone, Dexamethasone
- Mineralocorticoid: Fludrocortisone
- Anti-glucocorticoids: Ketoconazole
What were the effects of giving Dexamethasone to Covid 19 patients?
- Effective Ventilator: Severe Covid
- No Effective when no O2 was received: Mild Covid
What was the conclusion about giving corticosteroids to brain trauma patients?
DO NOT GIVE GLUCOCORTICOID
What are the risk factors for corticosteroid usage (4)?
- increase sepsis
- Increase chance of blood clots
- Increase in features
- new-onset diabetes
What 2 tissues make up the adrenal gland? What do they secrete?
Adrenal gland: cortex & medulla
– Cortex: adrenocorticosteroids & androgens
– Medulla: epinephrine (catecholamines)
What are the 3 zones of the cortex? What hormones does each secrete?
- Outer zona glomerulosa → aldosterone which regulates Na+ (H2O) kidney reabsorption
Aldosterone regulated by Renin-Angiotensin System → MINERALCORTICOIDS - Middle zona fasciculata → cortisol which involved w/ metabolism & resistance to stress → GLUCOCORTICOIDS
- Inner zona reticularis → dehydroepiandrosterone (DHEA) → ANDROGENS
With the top-down mechanism, what is happening at the highest level?
Corticotropin-releasing hormone (CRH)
- CRH is released from the hypothalamus
- CRH controls the secretion of ACTH
With the top-down mechanism, what is happening after CRH?
Adrenocorticotropic hormone (ACTH, corticotropin)
- ACTH is secreted from the anterior pituitary
- Enters the circulation and induces secretion of hormones from the adrenal cortex
- Stimulates the secretion from the two inner zones (not zona glom)
- DOES not exert significant control on hormones in the outer zone (Ang II)
Cortisol mediates feedback inhibition of what?
ACTH and CRH secretion
Synthetic glucocorticoids are used in the treatment of what?
many diseases
- Asthma, RA, allergies
Explain what is happening with CRH, ACTH and the adrenal cortex
Zona glomerulosa is under the control of what?
RAAS
What gives neg feedback on hypothalamus and decreases CRH?
Cortisol
Explain the mechanism of action of adrenocorticosteroids
- Step 1: Hormones bind to specific intracellular cytoplasmic receptor
- Step 2: Dimerization of ligand-bound receptor subunits
- Step 3: Dimerized receptor-hormone complexes translocate to the nucleus
- Step 4: Complexes attach to gene promoter elements
– “transcription factor”
– genes turned on or off (can be modified by co-adaptor proteins)
Adrenocorticosteroid:
1. Fast or slow?
2. Glucocorticoids localized?
3. Mineralocorticoid localized?
- Takes time to produce an effect
- Glucocorticoid receptors are widely distributed
- Mineralocorticoid receptor distribution is more limited - kidney, colon, salivary & sweat glands (i.e., excretory organs)-> LESS SE
Principal human glucocorticoid =
Cortisol
How do cortisol levels work in our bodies?
Diurnal production w/ early morning peak followed by decline & then smaller peak(s) in late afternoon
peak during meals
What can influence cortisol secretions?
Meals, Stress, & Cortisol Plasma Concentration
What are the general effects of glucocorticoids? (6)
- Promote normal intermediary metabolism
- Glucocorticoids increase resistance to stress
- Alter blood cell concetrations in plasma
- Anti-inflammatory action
- Endocrine sytem effect
- Additional effects
How does glucocorticoids promote intermediary metabolism?
- Promotes ↑ AA uptake by liver & kidney
- Promotes gluconeogenesis thru ↑ activity of gluconeogenic enzymes in the liver
- Promotes enzymes that increase protein catabolism (except liver-> anabolism because increasing glucose)
- Overall Objective: Provide (a) building blocks & (b) energy for glucose synthesis
breaking things down for energy
How do glucocorticoids affect Lipolysis?
Promote ↑ hormone-sensitive lipases (Lipolysis)
- Growth hormone (GH) and adrenaline induce lipolysis. Glucocorticoids augment these effects.
- Glucocorticoids primarily increase lipolysis in subcutaneous adipose tissue.
- Glucocorticoids can decrease lipolysis and increase lipogenesis in visceral adipose tissue (abdominal) (more on this later)
How might we get hypoglycemia with glucocorticoids?
During stress or fasting → if Glucocorticoid insufficiency → then hypoglycemia
How do glucocorticoids increase resistance to stress?
↑ glucose concentrations. Provides the body w/ energy to combat stress
- trauma, fright, infection, bleeding, disease
How can glucocorticoids affect BP?
Can cause a modest ↑ Blood Pressure (BP)
- Mechanism: Enhances vasoconstrictor actions of catecholamines/vasopressin
What may cause low BP?
Adrenal insufficiency
What has been shown favorable for surivival after in hospital cardiac arrest?
Vasopressin, sterioids, and epinephrine -> work synergic and increase chance of ROSC
how can glucocorticoids alter blood cell concentration in plasma? ⭐️
- ↑ plasma erythrocytes (increase O2 delivery), platelets (stop bleeding), & neutrophils (but shifts neutrophils away from sites of tissue inflammation)
- ↓ eosinophils, basophils=> decrease histamine, monocytes, lymphocytes. Also, redistribution from circulation to lymphoid tissue-> TO SAVE ENERGY
- But because they ↓ monocytes & lymphocytes, ↓ ability to fight infections, but useful in tx of leukemia
What is the anti-inflammatory action of glucocorticoids?
- Very important therapeutic property!
- Dramatically ↓ inflammatory response & suppress immunity
- ↓ plasma monocytes & lymphocytes
- ↑ lipocortin, which ↓ phospholipase A2 (indirect inhibition). Blocks production/release of arachidonic acid. => ↓ PG & LT.
- Inhibition of NFκB → ↓ IL-6, IL-8, MCP-1, COX-2 (↓ PG)
- ↓ mast cell degranulation, ↓ histamine → ↓ capillary permeability
What is the endocrine system effects of glucocorticoids?
- ↑ exogenous glucocorticoid levels cause feedback inhibition
- ↓ ACTH production w/ ↓ endogenous cortisol, can ↓ TSH, and alter GH production (In Vivo Decrease GH and In Vitro Increase GH)
Glucocorticoids affect renal blood flow how?
Physiological cortisol concentration essential for normal glomerular filtration (↑ renal blood flow)
How does glucocorticoids affect gastric acid and pepsin? What is the effect?
- Glucocorticoid high doses, ↑ gastric acid & pepsin production (breaksdown proteins).
- May exacerbate ulcers
How do glucocorticoids affect bone?
Glucocorticoid chronic therapy may cause severe bone loss
- Decreased intestinal Ca2+ absorption
- Increased renal Ca2+ excretion
LOTS OF Ca LOSS
How can glucocorticoids affect muscles
myopathy-> weaknesss
becasue breaking down amino acids from muscles
How does Glucocorticoids affect CNS?
- initially insomnia & euphoria → depression
- High doses ↑ intracranial pressure (worse after discontinuation – possible from decreased absorption of CSF)
After you stop taking them=> ICP
What is the function of mineralocorticoids
Control of plasma H2O volume & concentrations of Na+ & K+
What is the main mineralocorticoids?
aldosterone
What does aldosterone do/cause?
- ↑ reabsorption of Na+, HCO3- & H2O in kidney collecting tubules & ducts
- ↓ reabsorption of K+ and H+ in urine (i.e., ↑ excretion)
- Effects mediated by activation of mineralocorticoid receptors
What are the consequences and SE?
- Hypertension: Retention of Na+ & H2O, ↑ blood volume → ↑ BP
- Hypokalemia & Alkalosis-> can alter heart rhythm and pH
What is identical to endogenous cortisone?
hydrocortisone
What gets metabolized by liver enzymes to inactivate ?
- C3 Ketone Group
- C4-5 Double Bond
What is important for glucocorticoid activity? ⭐️
C11 hydroxyl group
Fill in
What drugs are selective for anti-inflammatory?
- Triamcinolone
- betamethasone
- Dexamethasone
- Paramethasone
What mineralocorticoids affect both anti-inflammatory and salt-retaining mechanisms?
Fludrocortisone
Semisynthetic glucocorticoids?
- Vary in anti-inflammatory potency
- Vary in Na+ retention
- Vary in the duration of action
What is the duration of action:
- Short-acting
- intermediate-acting
- long-acting
- Short Acting, 8-12 hrs (Cortisol, Cortisone)
- Intermediate Acting, 12-36 hrs (Prednisone, Triamcinolone)
- Long Acting, 36-72 hrs (Betamethasone, Dexamethasone)
What is affected by 1°,2°, and 3° adrenal insufficiency?
- 1°: adrenal gland
- 2°: pituitary gland
- 3°: hypothalamus
What disease is 1° adrenal insufficiency?
Addison disease: inadequate secretion of cortisol by adrenal glands
Addision disease
1. Symptoms?
2. Cause?
3. Dianostic test?
4. Treatment?
5. Divide dosage?
- Symptoms: weakness, no energy, low BP
- Possible Cause: Autoimmune damage to the adrenal cortex resulting in dysfunction
- Diagnostic Test: Negative response to the administration of ACTH (ACTH NEGATIVE)-> if adrenal glands dont make cortisol then the gland is not working-
- Treatment: Hydrocortisone (identical to natural cortisol)
- Divide Dosage: 2/3 in morning & 1/3 in afternoon. Approximates daily cortisol conc.
Besides Hydrocortisone for addison disease, what else you might adminster and why?
Administration of Fludrocortisone may also
be necessary to ↑ mineralcorticoid activity to normal
What conditions can be for 2° or 3° adrenal insufficiency?
- Deficit in ACTH production from the pituitary (2°)
- Deficit in CRH production from the hypothalamus (3°)
What are the possible causes of 2° or 3° Adrenal Insufficiency
- Adenoma of the Pituitary (2°)
- Brain Tumor (3°)
- Acute Brain Injury (2° or 3°)
- Withdrawal of Synthetic Glucocorticoids (2°or3°)-> because you shut down natural hormones
2° or 3° Adrenal Insufficiency:
1. Diagnostic test
2. Treatment
3. Additional characteristics
- Diagnostic Test: Adrenal cortex responds to ACTH bolus injection by syn & releasing adrenal corticosteroids (ATCH POSITIVE
- Treatment: Hydrocortisone
- Additional Characteristics: Aldosterone synthesis less impaired than cortisol
Cushing syndrome:
1. Condition?
2. Cause?
3. Presentation?
- Condition: Pathologically increased cortisol
- Possible Cause: Pituitary tumor causing excess ACTH (Cushing’s Disease)
- Presentation: ↑ cortisol → ↑ weight, ↑ hair, ↑ BP, osteoporosis
What is the diagnostic test for cushing syndrome?
- Dexamethasone suppression test
- If High Dose Dex causes ↓ cortisol release, suggestive of pituitary tumor (Cushing’s Disease)
- If High Dose Dex has no effect, suggestive of adrenal tumor or ectopic ACTH secreting tumor
Chronic high dose glucocorticoids can also cause what?
a Cushing-like syndrome
What is congenital adrenal hyperplasia
Group of diseases that produce a deficiency in the enzymes that synthesize cortisol
congenital adrenal hyperplasia:
1. Findings?
2. Symptoms?
3. Treatment?
- Diagnostic Findings: ↑ ACTH
- Virilization of ♀, overproduction of adrenal androgens
- Treat with corticosteroids
- Normalizes androgen concentrations (i.e., ↓ androgen production) by ↓ the release of CRH & ACTH though feedback inhibition
How does glucocorticoids relief inflammatory? SE?
- Glucocorticoids ↓ inflammation (redness, swelling, heat, tenderness), e.g., RA, OA, skin
- Mechanism of Action: ↓ plasma conc. of leukocytes by redistribution, ↓ lymphocytes, ↓ basophils, ↓ eosinophils, ↓ monocytes
- ↓ ability to respond to mitogens & antigens
- ↓ PG & LT, important inflammatory effect
- ↓ histamine release from mast cells & basophils
how does glucocorticoids alleviate severe allergies? What drugs? ⭐️
- Glucocorticoids alleviate symptoms of asthma, allergic
rhinitis, drug allergies, transfusion allergies - Beclomethasone, Triamcinolone
- Inhalation therapy for Asthma, ↓ systemic side effects
- What is common in premature infants?
- What is the regulator of lung maturation?
- Premature infants → respiratory distress syndrome
- Fetal cortisol → regulator of lung maturation
What is used to help respiratory distress syndrome? ⭐️
Intramuscular injection (IM) of Betamethasone or Dexamethasone to the mother 24 hrs before birth (prenatal period)
How does sterioids affect immunosuppression?
Organ transplants: Prevent/treat rejection
What is the metabolism of adrenocortcosteroid
Corticosteroids metabolized 1° by liver enzymes
- Glucuronosyltransferase (UGT)
- Sulfotransferase (SULT)
- Hepatic dysfunction with ↑ t1/2
What occurs with the Suppression of the hypothalamic-pituitary-adrenal axis (HPA)?
Suppression of hypothalamic-pituitary-adrenal axis (HPA)
- Large doses of glucocorticoids, e.g., > 2 weeks
- Limit suppression by QOD dosing (every other day). Allows HPA to recover
- Do not abruptly stop administration of corticosteroids; may cause severe withdrawal symptoms & exacerbate disease processes
- Slowly taper off the use of synthetics to alleviate HPA suppression & prevent acute adrenal insufficiency syndrome → otherwise can cause death
What are the side effects of Glucocorticoids?
- osteoporosis
- increase appetite
- cushing like syndrome
- cataracts
- Hyperglycemia => new onset diabetes
- hypokalemia
- Peptic ulcers
- Glaucoma
- Hypertension
- Edema
- Euphoria/Depression/Psychosis
- Impaired wound healing: ↑ infection risk
How do you get osteoporsis? treatment?
- ↓ intestinal Ca2+ absorption, ↓ bone formation, ↓ sex hormone syn.
- Treat these side effects with Ca2+ & Vit D (helps absorption)
side affect of steroids
What effect is on the appetite of steroids?
increase
- predinisone-> chemotherapy
What are symptoms of cushing like syndrome?
- Redistribution of fat (buffalo hump), Puffy face (moon face), ↑ hair, Acne, Insomnia
What is the antiglucocorticoids?
Ketoconazole
Ketoconazole
1. Therapeutic use?
2. MOA?
3. SE?
- Therapeutic use: Cushing Syndrome (increase cortisol) and Antifungal
- Mechanism of action: Inhibits cortisol biosynthesis by Inhibiting CYP17A1 & CYP11A1 (at higher doses)
- Side effects: Hepatoxicity and Heart Function by ↑ QTc prolongation (delayed ventricular repolarization), Tachycardia and Caused by drug inhibition of cytochrome P450 enzymes (CYP)
Where does ketoconazole block
