Inhibits 11beta-hydroxylase: - blocks production of cortisol - ACTH secretion increases (feedback systems) - plasma deoxycortisol increases

Hyperadrenal Disorders Flashcards by Rama Jha

Clinical features of Cushing’s?

x Excess cortisol
x Centripetal obesity
x Moon face &amp; buffalo hump
x Proximal myopathy (muscle weakness)
x Hypertension
x Hypokalaemia
x Red striae
x Thin skin &amp; bruising
x Osteoporosis
x Diabetes

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Link between fat, protein & Cushing’s?

SYNTHESISE too much FAT

- Break DOWN too much PROTEIN

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Potential causes of Cushing’s?

x Taking too many steroids (glutocorticoids)
x Pituitary dependent Cushing’s Disease
x Ectopic ACTH from lung cancer
x Adrenal adenoma (secretes cortisol)

Last 3 are endogenous causes

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Difference between Cushing’s Syndrome & Disease?

If Cushing’s DISEASE - has a pituitary source!

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What are the investigations to determine the cause of Cushing’s Syndrome?

24h urine collection for urinary free cortisol
Blood diurnal cortisol levels
Low-dose dexamethasone suppression test

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How does the blood diurnal cortisol levels test work?

Varying levels depends upon time of say (highest at 9am, lowest at midnight)

Cushing’s - cortisol HIGH at ALL times

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LDDST?

Low-dose dexamethasone suppression test

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How does LDDST work?

Dexamethasone = artificial steroid

Normal - will suppress cortisol to 0 as excess cortisol
Cushing’s - will FAIL to suppress cortisol (ANY cause/type of Cushing’s)

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Can you determine type of Cushing’s after the 3 investigative tests?

Nope - need more tests to see TYPE of Cushing’s (pituitary OR ectopic OR adrenal)

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How can pharmacology be used in the treatment of Cushing’s>

Manipulate the steroids

Enzyme inhibitors
Receptor blocking drugs

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Specific drugs used in the treatment of Cushing’s?

Metyrapone

Ketoconazole

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Metyrapone MOA?

Inhibits 11beta-hydroxylase:

blocks production of cortisol
ACTH secretion increases (feedback systems)
plasma deoxycortisol increases

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Why does plasma deoxycortisol increase through the use of Metyrapone?

Steroid synthesis in zona fasciculata (and reticularis) arrested at 11-deoxycortisol stage (has NO feedback effect) so levels increase

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Clinical uses of Metyrapone?

Control of Cushing’s Syndrome prior to surgery:

dose adjusted to cortisol
improves patient’s symptoms & promotes post-op recovery

Control of Cushing’s symptoms AFTER radiotherapy (usually slow to take effect)

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What are some unwanted actions associated with Metyrapone?

x Hypertension - deoxycorticosterone accumulates in z. glomerulose which has aldosterone-like activity leading to salt retention & hypertension

x Hirsutism - increased androgen production

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History of Ketoconazole?

Main use as an antifungal work - not anymore

At HIGHER [ ], off-label use in Cushing’s Syndrome

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Ketoconazole MOA?

Inhibits steroidogenesis (gluco/mineralcorticoids & sex steroids)

As blocks main enzyme converting cholesterol to pregnenolone (first-step)

Uses of Ketoconazole?

(similar to Metyrapone)

x Treatment and control of symptoms prior to surgery
x Orally active

Ketoconazole unwanted effects?

Liver damage

Other than drugs, how else can you treat Cushing’s?

Surgery

Different types of surgery available for Cushing’s?

Depends on cause

x Pituitary surgery (transsphenoidal hypophysectomy)
x Bilateral adrenalectomy
x Unilateral adrenalectomy for adrenal mass

Conn’s Syndrome?

A benign adrenal cortical tumour (zona glomerulosa)

What does Conn’s Syndrome lead to?

Excess aldosterone so hypertension & hypokalaemia

This is due to water retention, aldosterone enhances Na+ reabsorption and K+ excretion in the kidneys

Type of diagnosis that can be reached for those with Conn’s Syndrome?

1o hyperaldosteronism

RAAS should be suppressed to exclude 2o hyperaldosteronism

Treatment available for Conn's?

x Aldosterone receptor antagonists i.e. Spironolactone & Epleronone x Surgery

Mineralcoticoid Receptor Antagonists used for Conn's?

Spironolactone Epleronone

When is Spironolactone used?

For 1o hyperaldosteronism (Conn's)

Spironolactone MOA?

Converted to several active metabolites: | x CANRENONE being one - a competitive antagonist of the MR

In Spironolactone MOA, how do the metabolites work?

Block Na+ resorption & K+ excretion in the kidney tubules (potassium sparing diuretic)

Pharmacokinetics of Spironolactone?

x Orally active x Highly protein bound x Metabolised in the liver

Spironolactone unwanted actions?

x Menstrual irregularities [women] (via. + progesterone receptors) x Gynaecomastia [men] (via. - androgen receptor)

Similarities & differences of epleronone to spironolactone?

- also a MR antagonist - similar affinity to MR BUT -LESS binding to androgen & progesterone receptors so better tolerates

Phaeochromocytomas?

Tumours of the adrenal MEDULLA which secrete catecholamines (A or NA)

What are the clinical features of phaeochromocytomas?

``` x sudden episode of hypertension (in young people as well) x sweating x headache x sudden dizziness x sudden anxiety ```

Defining clinical feature of phaeochromocytomas?

Episodic SEVERE hypertension (after abdominal palpation - squeezes more A out) More common in certain inherited conditions

Difference between phaeochromocytomas and Conn's?

Conn's hypertension is episodic in the older population not in the young

Why is the episodic severe hypertension so dangerous in phaeochromocytomas?

Can cause MI or stroke High adrenaline can cause VI & death if not treated SO is a medical emergency

How can phaeochromocytomas be managed?

Eventually need surgery BUT anaesthetic needs careful preparation as can precipitate a hypertensive crisis (causes releases of A) Remember: this is curable so important!

Before surgery, what is the first step for phaeochromocytomas treatment?

Alpha-blockade! - patients may need IV FLUID during this as will see a severe DROP in BP - beta-blockage is added to prevent tachycardia This ensures that even if there is A released, can have NO EFFECT as the receptors are blocked

Some key facts of phaeochromocytomas?

x 10% are extra-adrenal (down the SN chain) x 10% are maligant x 10% are bilateral VERY RARE