Cushing's syndrome

Question 1

Cushing’s syndrome results from chronic exposure to (?) cortisol

Answer 1

Excess cortisol

Question 2

Cushing’s syndrome results from chronic exposure to excess (?)

Answer 2

Cortisol

Question 3

What is the most common cause of Cushing’s syndrome?

Answer 3

Exogenous corticosteroid use

Question 4

What are the endogenous causes of Cushing’s syndrome?

Answer 4

1. ACTH-secreting pituitary tumours (Cushing’s disease)
2. Cortisol-secreting adrenal tumours
3. Ectopic ACTH-secreting tumours (rare)

Question 5

What is Cushing’s disease?

Answer 5

ACTH-secreting pituitary tumours

Question 6

How are most endogenous Cushing’s syndrome treated?

Answer 6

Surgically

Question 7

Metyrapone is a competitive inhibitor of (?) in the adrenal cortex; the resulting inhibition of cortisol (and to a lesser extent aldosterone) production leads to an increase in ACTH production which, in turn, leads to increased synthesis and release of cortisol precursors.

Answer 7

11β-hydroxylation

Question 8

Metyrapone is a competitive inhibitor of 11β-hydroxylation in the adrenal cortex; the resulting inhibition of (?) (and to a lesser extent aldosterone) production leads to an increase in ACTH production which, in turn, leads to increased synthesis and release of cortisol precursors.

Answer 8

cortisol

Question 9

Metyrapone is a competitive inhibitor of 11β-hydroxylation in the adrenal cortex; the resulting inhibition of cortisol (and to a lesser extent aldosterone) production leads to an increase in (?) production which, in turn, leads to increased synthesis and release of cortisol precursors.

Answer 9

ACTH

Question 10

What are the indications for the use of metyrapone? (3)

Answer 10

1. Differential diagnosis of ACTH-dependent Cushing’s syndrome
   - Oral: 750 mg every 4 hours for 6 doses
2. Management of Cushing’s syndrome
   - Oral: usual dose 0.25-6g daily
3. Resistant oedema to increased aldosterone secretion in cirrhosis, nephrotic syndrome, congestive heart failure (with glucocorticoid replacement therapy)
   - Oral: 3 g daily in divided doses

Question 11

What is the contraindication for the use of metyrapone?

Answer 11

Adrenal insufficiency

Question 12

What are the common side effects of the drug metyrapone? (6)

Answer 12

Dizziness
Headache
Hypotension
Nausea
Sedation
Vomiting

Question 13

Can a pregnant patient take the drug metyrapone?

Answer 13

NO

May impair biosynthesis of fetal-placental steroids

Question 14

What do you need to tell a patient about driving if they are taking metyrapone?

Answer 14

Drowsiness may affect the performance of skilled tasks (e.g. driving)

Question 15

Which two drugs are licensed for the treatment of Cushing’s syndrome?

Answer 15

Metyrapone

Ketaconazole (only endogenous Cushing’s syndrome)

Question 16

Which type of Cushing’s syndrome is the drug ketaconazole licensed to treat?

Answer 16

Endogenous Cushing’s syndrome

Ketaconazole: An imidazole derivative which acts as a potent inhibitor of cortisol and aldosterone synthesis by inhibiting the activity of 17α-hydroxylase, 11-hydroxylation steps and at higher doses the cholesterol side-chain cleavage enzyme.

It also inhibits the activity of adrenal C17-20 lyase enzymes resulting in androgen synthesis inhibition, and may have a direct effect on corticotropic tumour cells in patients with Cushing’s disease.

Question 17

Ketaconazole MOA

An imidazole derivative which acts as a potent inhibitor of (?) and (?) synthesis by inhibiting the activity of 17α-hydroxylase, 11-hydroxylation steps and at higher doses the cholesterol side-chain cleavage enzyme.

It also inhibits the activity of adrenal C17-20 lyase enzymes resulting in androgen synthesis inhibition, and may have a direct effect on corticotropic tumour cells in patients with Cushing’s disease.

Answer 17

Cortisol

Aldosterone

Question 18

Ketaconazole MOA

An imidazole derivative which acts as a potent inhibitor of cortisol and aldosterone synthesis by inhibiting the activity of 17α-hydroxylase, 11-hydroxylation steps and at higher doses the cholesterol side-chain cleavage enzyme.

It also inhibits the activity of adrenal C17-20 lyase enzymes resulting in (?) synthesis inhibition and may have a direct effect on corticotropic tumour cells in patients with Cushing’s disease.

Answer 18

androgen

Question 19

Ketaconazole MOA

An imidazole derivative which acts as a potent inhibitor of cortisol and aldosterone synthesis by inhibiting the activity of 17α-hydroxylase, 11-hydroxylation steps and at higher doses the cholesterol side-chain cleavage enzyme.

It also inhibits the activity of adrenal C17-20 lyase enzymes resulting in androgen synthesis inhibition and may have a direct effect on (?) tumour cells in patients with Cushing’s disease.

Answer 19

Corticotropic

Question 20

Ketaconazole MOA

An imidazole derivative which acts as a potent inhibitor of cortisol and aldosterone synthesis by inhibiting the activity of 17α-hydroxylase, 11-hydroxylation steps and at higher doses the cholesterol side-chain cleavage enzyme.

It also inhibits the activity of adrenal C17-20 lyase enzymes resulting in androgen synthesis inhibition and may have a direct effect on corticotropic tumour cells in patients with Cushing’s (?).

Answer 20

disease

Question 21

In addition to the treatment and management of fungal disease, what is the other indication for the use of ketoconazole?

Answer 21

Endogenous Cushing’s syndrome
- Oral: Initially 400–600 mg daily in 2–3 divided doses, increased to 800–1200 mg daily; maintenance 400–800 mg daily in 2–3 divided doses,

Question 22

What are the contraindications for the use of ketoconazole? (3)

Answer 22

1. Acute porphyrias
2. Acquired or congenital QTc prolongation
3. Concomitant use of hepatotoxic drugs

Question 23

Which drinks improve the bioavailability of ketoconazole?

Answer 23

Carbonated drinks (e.g. cola)

Question 24

What happens if you drink a carbonated drink (e.g. cola) when taking ketaconazole?

Answer 24

Improves the bioavailability of ketaconazole

Question 25

What are the common side effects of the drug ketoconazole if taken orally?

Answer 25

``` Adrenal insufficiency Diarrhoea GI discomfort Nausea Vomiting ```

Question 26

What is a rare but potentially life-threatening side effect of ketoconazole?

Answer 26

Hepatotoxicity Reduce dose if hepatic enzymes increased to less than 3 times the upper limit of normal. Discontinue permanently if hepatic enzymes at least 3 times the upper limit of normal

Question 27

What action should you take if hepatic enzymes increase to less than 3 times the upper limit of normal in a patient taking ketoconazole?

Answer 27

Reduce dose of ketoconazole

Question 28

What action should you take if hepatic enzymes increase to 3 or more times the upper limit of normal in a patient taking ketoconazole?

Answer 28

Discontinue ketoconazole permanently

Question 29

Can pregnant women take ketoconazole orally?

Answer 29

NO Teratogenic in animal studies

Question 30

Women of childbearing potential must use effective (?) is taking oral ketoconazole

Answer 30

Contraception Teratogenic in animal studies

Question 31

Should a woman breastfeed if taking oral ketoconazole?

Answer 31

No Present in breast milk

Question 32

Should a patient with hepatic impairment take oral ketoconazole?

Answer 32

No

Question 33

What monitoring is required prior to the initiation of oral ketoconazole? (2)

Answer 33

1. ECG | 2. Liver function

Question 34

What needs to be monitored one week after the initiation of oral ketaconazole?

Answer 34

1. ECG 2. Adrenal function 3. Liver function

Question 35

Once cortisol levels are normalised or close to the target, how often should you monitor adrenal function in a patient taking oral ketoconazole?

Answer 35

Every 3-6 months There is a risk of autoimmune disease development or exacerbation after normalisation of cortisol levels

Question 36

When should liver function be checked in a patient taking oral ketoconazole? (3)

Answer 36

1. Before initiation of treatment 2. Weekly for 1 months after initiation 3. Monthly for 6 months

Question 37

What advice do you need to give patients (or carers) taking oral ketoconazole?

Answer 37

1. Signs of liver disorder (anorexia, nausea, vomiting, fatigue, jaundice, abdominal pain, dark urine) 2. Signs of adrenal insufficiency (fatigue, anorexia, nausea, vomiting, hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia)

Question 38

What advice about driving do you need to give to patients taking oral ketoconazole?

Answer 38

Dizziness and somnolence may affect the performance of skilled tasks (e.g. driving)