Lec 6 Adrenal Therapy + Cushing + Conn's Syndrome Flashcards by Karlo Sison

Mineralcorticoid Effects

(Aldosterone)

<– REABSORBS Na & Water

Secretes Potassium & Mg –>

comes from Zona Glomerulosa

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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

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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

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Carbohydrate Metabolism

Glucocorticoid Activity

Increased Gluconeogenesis

Increased Glycogen Synthesis / Storage in LIVER

Diminshed Glucose utilization

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Growth & Development

Glucocorticoid Activity

Decreased Skeletal Growth in Pediatrics*
decrease in bone growth / premature epiphyseal closure*
impairment of GH release*

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Lipid Metabolism

Glucocorticoid Activity

Redistribution of Body Fat

Moon Face / Buffalo Hump

Enhanced Lipolysis –> increased FFA

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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

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Bone Effects

Glucocorticoid Activity

Increased Bone Catabolism

more OsteoCLAST

Reduced Bone Formation*
less Osteoblast activity*
reduced absorption of Calcium*

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Cardiovascular Effects

Glucocorticoid Activity

Increased risk for:

Hypertension

Atherosclerosis

Stroke

HT Cardiomyopathy

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Skeletal Muscle

Glucocorticoid Activity

EXCESS Steroid -> Muscle Wasting (myopathy)

Steroid Deficit: –> Weakness & Fatigue

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Hypothalmic - Pituitary - Adrenal Axis

HPA

Hypothalmus -> CRF (corticotropin releasing hormone)
- Anterior pituitary -> ACTH
  - Adrenal Cortex - Secretes:
    - Androgens
    - Corticosteroids
      - -> NEGATIVE FEEDBACK
        to hypothalmus & anterior pituitary

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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

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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

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What INCREASES Cortisol Secretion?

Exercise / Physical Stress

Surgery / Major Operation –> 4x normal cortisol

Anxiety / Depression

Anoxeria / Alcoholism

Chronic RENAL Failure

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What Decreases Free Cortisol?

Increase in CBG –> *Decrease in Free Cortisol*

Estrogen Therapy

Pregnancy

Hypothyrodism / Diabetes

Hematological disorders

Congenital (from birth)

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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

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
- 40% - Adrenal Cortical CARcinoma
  - cancerous growth of the adrenal cortex

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
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

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

**Treatment goals** of **Cushing's Syndrome** (HYPERcortisolism)

* *UNTREATED* Cushing's Patients life expectancy is: * **4-5 Years** * due to **stroke / heart attack risk** * 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

**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 * **Dose can** **i****ncrease over time:** * to compensate for **Tumor Growth** * --\> **ACTH** increases in secretion. * *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)*

**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

**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 * **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***