Lec 6 Adrenal Therapy + Cushing + Conn's Syndrome Flashcards
Mineralcorticoid Effects
(Aldosterone)
<– REABSORBS Na & Water
Secretes Potassium & Mg –>
comes from Zona Glomerulosa
Glucocorticoid INCREASES / ACTIVATES
Cortisol
Glucocorticoid Activity
-
Carb metabolism
- increased gluconeogenesis / glycogen storage
- diminished glucose utilization
-
Lipid metabolism
- redistribution of fat –> buffalo hump/moonface
- enhanced lipolysis / more FFA
- CV effects –> HT
- CNS excitabolity & mood
Glucocorticoid Decreases / Inhibits
Cortisol
Glucocorticoid Activity
-
Growth & Development
- decreased skeletal growth in pediatrics
-
Anti-Inflammatory
- supresses T lymphocytes / cytokines / inflammatory mediators
- INCREASE in erythrocytes / platelet conc
- Imunosuppresant
- Bone Effects
- Skeletal Muscle
- Would Healing
Carbohydrate Metabolism
Glucocorticoid Activity
Increased Gluconeogenesis
Increased Glycogen Synthesis / Storage in LIVER
Diminshed Glucose utilization
Growth & Development
Glucocorticoid Activity
- Decreased Skeletal Growth in Pediatrics*
- decrease in bone growth / premature epiphyseal closure*
- impairment of GH release*
Lipid Metabolism
Glucocorticoid Activity
Redistribution of Body Fat
Moon Face / Buffalo Hump
Enhanced Lipolysis –> increased FFA
Anti-inflammatory Action
Glucocorticoid Activity
- Supresses T-lymphocyte activation*
- Supresses production of Cytokines by T-helper cells*
- Prevents release of Prostaglandins / Histamines / LK’s*
VasoCONSTRICTION &** decrease **Capillary Permeability
INCREASED Erythrocyte / Platelet Conc
RBC / Platelets
Bone Effects
Glucocorticoid Activity
Increased Bone Catabolism
more OsteoCLAST
- Reduced Bone Formation*
- less Osteoblast activity*
- reduced absorption of Calcium*
Cardiovascular Effects
Glucocorticoid Activity
Increased risk for:
Hypertension
Atherosclerosis
Stroke
HT Cardiomyopathy
Skeletal Muscle
Glucocorticoid Activity
EXCESS Steroid -> Muscle Wasting (myopathy)
Steroid Deficit: –> Weakness & Fatigue
Hypothalmic - Pituitary - Adrenal Axis
HPA
-
Hypothalmus -> CRF (corticotropin releasing hormone)
-
Anterior pituitary -> ACTH
-
Adrenal Cortex - Secretes:
- Androgens
-
Corticosteroids
- -> NEGATIVE FEEDBACK
- to hypothalmus & anterior pituitary
- -> NEGATIVE FEEDBACK
-
Adrenal Cortex - Secretes:
-
Anterior pituitary -> ACTH
Cortisol Circadian Rhythm
Most predictable time = In the morning before meals
Peaks at meals (HIGHEST @ Breakfast)
very difficult to replicate the circadian rhythem with STEROIDS
Cortisol Plasma Protein Binding
- Cortisol is Highly Protein Bound (>95%)
- so it is hard to get rid of, takes a time rid of cortisol
- Albumin
- CBG (Corticosteroid Binding Globulin)
- Only Free Cortisol is active, can increase or decrease:
- HIGH STRESS (surgery / major operation)
- –> up to 4x normal levels
- HIGH STRESS (surgery / major operation)
What INCREASES Cortisol Secretion?
Exercise / Physical Stress
Surgery / Major Operation –> 4x normal cortisol
Anxiety / Depression
Anoxeria / Alcoholism
Chronic RENAL Failure
What Decreases Free Cortisol?
Increase in CBG –> *Decrease in Free Cortisol*
Estrogen Therapy
Pregnancy
Hypothyrodism / Diabetes
Hematological disorders
Congenital (from birth)
What STIMULATES Aldosterone release?
Low BP
Sodium depletion
Beta-adrenergic stimulation
What INHIBITS Aldosterone release?
HIGH BP
EXCESS Sodium
ACTH-Dependent
Cushing’s Syndrome
Etiology
-
80-85% of Cushing Syndrome cases ( HYPERcortisolism )
- 80% from Pituitary Adenoma = Cushing’s DISEASE
- tumor is at the pituitary gland
- 20% from Ectopic ACTH syndrome
- tumor is somewhere else causing more cortisol or ACTH to be secreted
- 80% from Pituitary Adenoma = Cushing’s DISEASE
ACTH - INdependent
Cushing’s Syndrome
Etiology
-
20% of all Cushing’s Syndrome cases = HYPERcortisolism
- 60% - Adrenal Cortical Adenoma
-
Benign tumor of the Adrenal Cortex
- __OVERsecreting Cortisol
-
Benign tumor of the Adrenal Cortex
- 40% - Adrenal Cortical CARcinoma
- cancerous growth of the adrenal cortex
- 60% - Adrenal Cortical Adenoma
Iatrogenic Cushing Syndrome
Etiology
Caused by the TREATMENT:
Prolonged administration of glucocorticoid
in SUPRAphysiological doses
Physical Signs/Symptoms
of Cushing’s Syndrome
(HYPERcortisolism)
- Moon Faces / Buffalo Hump / Central obesity
-
Skin Hyperpigmentation
-
ONLY with ACTH-Dependent (cushing;s DISEASE)
- comes from the EXCESS ACTH
-
ONLY with ACTH-Dependent (cushing;s DISEASE)
- Thin Skin / Striation / Poor Wind Healing
-
From Excess ANDROGEN Secretion:
- Acne
- Alopecia (hair loss for men)
-
Hirsutism (hair gain for women)
- Amenorrhea (no menses)
Clinical Symptoms of
Cushing’s Syndrome
(HYPERcortisolism)
- HYPERtension
- Weakness / Fatigue / Depression
- Osteopenia (bone loss)
- Glucose Intolerance
- Central Obesity
Evaluation & Diagnosis
of ACTH INdependent Cushing’s Syndrome
(HYPERcortisolism)
- Test for Urine Cortisol –> if HIGH
- Test for ACTH –> if Undetected
- Adrenal Imaging - CT / MRI
- if abnormal –> ADRENAL TUMOR
- ACTH - Independent
- if abnormal –> ADRENAL TUMOR
- Adrenal Imaging - CT / MRI
- Test for ACTH –> if Undetected
Evaluation & Diagnosis
of ACTH-Dependent Cushing’s Syndrome
(HYPERcortisolism)
-
TEST FOR URINE CORTISOL –> if HIGH
- Test for ACTH –> if Elevated
-
Abnormal Pituitary - MRI / DST / CRH
- CUSHING’S DISEASE
-
Normal Pituitary from MRI
-
No gradient on IPSS / JVS –>
- Ectopic ACTH Syndrome
- __If gradient is shown –> Cushing Disease
-
No gradient on IPSS / JVS –>
-
Abnormal Pituitary - MRI / DST / CRH
- Test for ACTH –> if Elevated
Treatment goals
of Cushing’s Syndrome
(HYPERcortisolism)
-
UNTREATED Cushing’s Patients life expectancy is:
-
4-5 Years
- due to stroke / heart attack risk
-
4-5 Years
- Goals:
- Reduce Mortality
- Reduce Morbidity / Symptoms
- Correct lab abnormalities
Non-Pharmacologic Therapies
of Cushing’s Syndrome
(HYPERcortisolism)
- 1st line = Surgery
- recurrance rate is 10-30%
- 2nd line = Radiation
- Used for a more mild disease
- or if they failed surgery
-
Bilateral Adrenalectomy
- removal of BOTH glands
- –> REQUIRED chronic glucocorticoid / MC replacement
- very difficult to supplement this
- –> REQUIRED chronic glucocorticoid / MC replacement
- removal of BOTH glands
Pharmacologic Therapies
of Cushing’s Syndrome
(HYPERcortisolism)
Adrenal Enzyme Inhibitors
Useful for AcTH - INdependent Cushing’s Syndrome
- Most common:
- Ketaconazole
- Metyrapone
- Mitotane
- Pasireotide for ACTH-Dependent (Cushing’s Disease)
Adrenal Enzyme Inhibitors
used for AcTH -INdependent Cushing’s Syndrome
- Inhibits DIFFERENT steps of adrenal hormone productions
- –> Takes a LONG Time to work (weeks-months)
- since there is a lot of BOUND CORTISOL in body
- –> Takes a LONG Time to work (weeks-months)
-
Dose can increase over time:
- to compensate for Tumor Growth
- –> ACTH increases in secretion.
- to compensate for Tumor Growth
-
HIGH relapse rate
- using with radiation can lower the rate
Ketoconazole
Adrenal Enzyme Inhibitor
for –> ACTH-independent Cushing’s
-
INHIBITS Sterol Synthesis:
- Cortisol
-
Aldosterone / Testosterone
- cause side effects
- Monitor Free Cortisol & Liver Transaminases
- Many Drug Interactions
Metyrapone
Adrenal Enzyme Inhibitor
for –> ACTH-independent Cushing’s
-
Inhibits 11B-Hydroxylase
- the FINAL step in cortisol biosynthesis
-
Typically not monotherapy,
- used with other enzyme inhibitors
Mitotane
Adrenal Enzyme Inhibitor
for –> ACTH-independent Cushing’s
-
Inhibition of Cortisol / Androgen synthesis
- in Lower doses
- DOES NOT inhibit Aldosterone**
- HIGH DOSE –> KILLS the adrenal glond
-
Adrenalectomy
- but you can KILL BOTH GLANDS (not wanted)
-
Adrenalectomy
Pasireotide
ACTH - Secretion INHIBITOR
for Cushing’s DISEASE
(ACTH-Dependent Cushing’s Syndrome)
- Activates Somatostatin Receptors on Adenomas
- –> INHIBITS ACTH secretion
Conn’s Syndrome
Etiology
HYPERAldosteronism
Very RARE, 10-20% of resistant HT cases
often discovered when BP does not go down w/ medication
-
Primary: Excess Aldosterone from adrenal source
- 50% Adenoma 50% Ideopathic
-
Secondary: Extraadrenal hyperaldostonism
- aldosterone comes from another source (not adrenals)
Clinical Presentation / Diagnosis
of Conn’s Syndrome
HYPER-Aldosteronism
-
HYPERtension, often RESISTANT
- patients on 3+ full dose HTN meds
-
HypoKalemia
- fatigue / muscle weakness / arrythmia
- High aldosterone retains water/Na ,but K leaves
- Diagnosed with ARR
-
Aldosterone : Renin Ratio
- Aldosterone >> Renin
-
Aldosterone : Renin Ratio
Treatment Options
for Conn’s Syndrome
(HYPER-Aldosteronism)
- 1st: Adrenalectomy (surgery)
- for unilateral disease
- 2nd: Aldosterone Antagonist medical management
- preferred in BILATERAL disease
- Spiranolactone / Epelenone
- preferred in BILATERAL disease
-
Combination
- often give meds BEFORE surgery
Mineralcorticoid Antagonist
Aldosterone
Spiranolactone & Eplerenone
for Conn’s Syndrome = HYPERaldosteronism
- Mineralcorticoid Aldosterone Receptor blockers
- at VERY HIGH DOSE vs normal HT dose
-
Inhibits synthesis of Aldosterone and Testosterone
- eplerenone does not block these androgens
- does not cause gynecomastia / sex issues
