Ted - Sample Endo

Hyperadrenal Disorders 1. List and describe the clinical features of Cushing’s and Conn’s Syndromes.

Clinical Features Cushing’s: • Too much cortisol • Centripetal obesity • Moon face and buffalo hump • Proximal myopathy • Hypertension and hypokalaemia • Red striae, thin skin and bruising • osteoporosis, diabetes

Conn’s Syndrome:  The effect (described by Conn) of a benign adrenal tumour (zona glomerulosa) producing aldosterone in a patient.  Clinical features: 1. Hypertension 2. Hyperkalaemia  Diagnosis: 1. Primary Hyperaldosteronism 2. Renin-angiotensin system should be suppressed.

2. Identify the four causes of Cushing’s Syndrome.

• • • •

Taking too many steroids Pituitary dependent Cushing’s disease Ectopic ACTH from lung cancer Adrenal adenoma secreting cortisol

3. Describe the principal investigations required to determine the cause of Cushing’s Syndrome in an individual.

4. Recognise that suppression tests are useful in hyperfunction.

free cortisol • Blood diurnal cortisol levels - These •

24h urine collection for urinary

are the night and day measures of cortisol levels and required hospital admission. The levels fluctuate greatly between the day and night. Usually, the levels are highest at about 9am and lowest at midnight (but you must be asleep to achieve this very low level).

• Low dose dexamethasone suppression test • • • •

0.5 mg 6 hourly for 48 hrs Dexamethasone is a very potent artificial steroid that causes the pituitary to stop making ACTH. Normals will suppress cortisol to zero Any cause of Cushing’s will fail to suppress

• High dose dexamethasone suppression test • • • •

Give 2.0mg dexamethasone every 6 hours for 48 hours.

Used to distinguish pituitary Cushing’s from other types Only pituitary Cushing’s will suppress ACTH to 50% Ectopic ACTH and adrenal tumours will not suppress at all.

E.g.:  Basal (9am) cortisol 800 nM  End of LDDST: 680 nM  End of HDDST: 235nM Therefore Diagnosis = Pituitary Cushing’s.

5. List the drugs used to treat Cushing’s and Conn’s Syndromes.

Disorders of adrenal • •

ENZYME INHIBITORS e.g. metyrapone; trilostane; ketoconazole, aminoglutethamide.

ALDOSTERONE RECEPTOR ANTAGONISTS eg. spironolactone

Disorders of adrenal •

cortex

medulla

SNS ANTAGONISTS (refer to PT lectures) eg. propranolol, phentolamine, phenoxybenzamine

1. Enzyme Inhibitors i)

Metyrapone: actions & mechanisms of action.  Inhibition of 11β-hydroxylase  Cortisol synthesis blocked  ACTH secretion increased

 Plasma 11-deoxycortisol increased  Steroid synthesis in the zona fasciculata and reticularis is arrested at the 11-deoxycortisol stage NB. 11-deoxycortisol has no negative feedback effect on the hypothalamus and pituitary gland. Therefore, under physiological conditions, circulating ACTH levels would increase.

Uses of metyrapone: •

To treat some causes of Cushing’s syndrome. eg. bronchial tumours that are inaccessible to surgery - Doses may be tailored to corticosteroid production - Corticosteroid replacement therapy may be necessary with high doses.

•

Control of Cushing’s symptoms prior to surgery.

Unwanted effects: • • •

Nausea, vomiting, dizziness.

Sedation, hypoadrenalism caution against impaired performance of skilled tasks eg. driving, operating machinery.

Hypertension on long-term administration - deoxycorticosterone accumulates in z. glomerulosa; it has aldosterone-like (mineralocorticod) activity, leading to salt retention and hypertension.

Pharmacokinetics : administered orally. ii)

Trilostane : actions and mechanisms of action

 Blocks activity of 3β-hydroxysteroid dehydrogenase  Blocks production of glucocorticoids, mineralocorticoids & sex steroids  (i.e. aldosterone, corticosterone, cortisol etc.)

Uses: • •

•

Cushing’s syndrome Primary hyperaldosteronism  NB. Not easy to tailor dose to corticosteroid production.  Monitor circulating corticosteroids and plasma electrolytes and replace with glucocorticoids and mineralocorticoids when necessary.

Reduction of sex steroid hormone production eg. post-menopausal breast cancer which has relapsed after initial therapy with anti-estrogens.

Unwanted effects: • • • •

iii)

Nausea Vomiting Diarrhoea Flushing

Ketoconazole: actions and mechanisms of action.  Main use as an antifungal agent

 At higher concentrations, inhibits steroidogenesis due to non-specific inhibition of cytochrome P450 enzymes  Blocks production of glucocorticoids, mineralocorticoids & sex steroids.

Uses: (similar to metyrapone) Cushing’s syndrome - treatment and control of symptoms prior to surgery

Pharmacokinetics: orally active Unwanted effects: • • • • • • •

iv)

nausea, vomiting, abdominal pain alopecia gynaecomastia oligospermia ventricular tachycardias liver damage - possibly fatal - monitor liver function clinically and biochemically reduced androgen production

Aminoglutethamide: actions and mechanisms of action.  inhibits the conversion of cholesterol to pregnenolone (very toxic)  therefore, blocks the production of glucocorticoids, mineralocorticoids and sex steroid hormones

Uses: • •

Adrenocortical carcinoma (malignant) Prostatic cancer (malignant) NB. replace corticosteroids

Pharmacokinetics: orally active

2. Aldosterone Receptor Antagonists Spironolactone : Uses: •

•

Primary hyperaldosteronism (Conn’s syndrome) also used in treatment of oedema, congestive heart failure, nephrotic syndrome and cirrhosis of the liver (cross-reference to relevant parts of the course)

Mechanisms of action: • •

Spironlactone (a prodrug) is rapidly converted to canrenone, a competitive antagonist of the mineralocorticoid receptor.

Blocks Na+ resorption and K+ excretion in the kidney tubules (potassium sparing diuretic).

Pharmacokinetics: • •

Orally active Given daily in single or divided doses

•

Highly protein bound and metabolised in the liver

Unwanted actions: • • • •

Menstrual irregularities gynaecomastia (androgen receptor binding) GI tract irritation blood dyscrasias

Caution/contraindications •

Renal and hepatic disease

6. List the surgical options for treatment of Cushing’s and Conn’s Syndromes.

Treatment of Cushings: • • • •

Depends on cause Pituitary surgery (transsphenoidal hypophysectomy) Bilateral adrenalectomy Unilateral adrenalectomy for adrenal mass

Medical Treatment: • Metyrapone 250 - 750 mg tds • Ketoconazole 200 - 400 mg bd • Usually use this for 6 weeks before surgery to prevent wound infection Conn’s Syndrome: • Image and remove adenoma • If bilateral adrenal hyperplasia, can stay on spironolactone 7. Note that finding a phaeochromocytoma is a medical emergency.

8. List the clinical features and treatment of a patient with a phaeochromocytoma.

Phaeochromocytomas: • •

These are tumours of the adrenal Medulla which secrete catecholamines (adrenaline and nor-adrenaline)

Clinical features of a ‘phaeo’: • • •

Hypertension in young people Episodic severe hypertension (after abdominal palpation) More common in certain inherited conditions

• • •

Severe hypertension can cause myocardial infarction or stroke High adrenaline can cause ventricular fibrillation + death Thus this is a medical emergency

Management of a ‘phaeo’: •

Eventually need surgery, but patient needs careful preparation as anaesthetic can precipitate a hypertensive crisis 1. Alpha blockade is first therapeutic step.

2. Patients may need intravenous fluid as alpha blockade commences

3. Beta blockade added to prevent tachycardia Phaeochromocytoma key facts: • • •

10 % extra-adrenal (sympathetic chain) 10 % malignant 10 % bilateral