Cushing's syndrome Flashcards
Cushing’s syndrome results from chronic exposure to (?) cortisol
Excess cortisol
Cushing’s syndrome results from chronic exposure to excess (?)
Cortisol
What is the most common cause of Cushing’s syndrome?
Exogenous corticosteroid use
What are the endogenous causes of Cushing’s syndrome?
- ACTH-secreting pituitary tumours (Cushing’s disease)
- Cortisol-secreting adrenal tumours
- Ectopic ACTH-secreting tumours (rare)
What is Cushing’s disease?
ACTH-secreting pituitary tumours
How are most endogenous Cushing’s syndrome treated?
Surgically
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.
11β-hydroxylation
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.
cortisol
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.
ACTH
What are the indications for the use of metyrapone? (3)
- Differential diagnosis of ACTH-dependent Cushing’s syndrome
- Oral: 750 mg every 4 hours for 6 doses - Management of Cushing’s syndrome
- Oral: usual dose 0.25-6g daily - Resistant oedema to increased aldosterone secretion in cirrhosis, nephrotic syndrome, congestive heart failure (with glucocorticoid replacement therapy)
- Oral: 3 g daily in divided doses
What is the contraindication for the use of metyrapone?
Adrenal insufficiency
What are the common side effects of the drug metyrapone? (6)
Dizziness Headache Hypotension Nausea Sedation Vomiting
Can a pregnant patient take the drug metyrapone?
NO
May impair biosynthesis of fetal-placental steroids
What do you need to tell a patient about driving if they are taking metyrapone?
Drowsiness may affect the performance of skilled tasks (e.g. driving)
Which two drugs are licensed for the treatment of Cushing’s syndrome?
Metyrapone
Ketaconazole (only endogenous Cushing’s syndrome)
Which type of Cushing’s syndrome is the drug ketaconazole licensed to treat?
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.
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.
Cortisol
Aldosterone
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.
androgen
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.
Corticotropic
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 (?).
disease
In addition to the treatment and management of fungal disease, what is the other indication for the use of ketoconazole?
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,
What are the contraindications for the use of ketoconazole? (3)
- Acute porphyrias
- Acquired or congenital QTc prolongation
- Concomitant use of hepatotoxic drugs
Which drinks improve the bioavailability of ketoconazole?
Carbonated drinks (e.g. cola)
What happens if you drink a carbonated drink (e.g. cola) when taking ketaconazole?
Improves the bioavailability of ketaconazole
What are the common side effects of the drug ketoconazole if taken orally?
Adrenal insufficiency Diarrhoea GI discomfort Nausea Vomiting
What is a rare but potentially life-threatening side effect of ketoconazole?
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
What action should you take if hepatic enzymes increase to less than 3 times the upper limit of normal in a patient taking ketoconazole?
Reduce dose of ketoconazole
What action should you take if hepatic enzymes increase to 3 or more times the upper limit of normal in a patient taking ketoconazole?
Discontinue ketoconazole permanently
Can pregnant women take ketoconazole orally?
NO
Teratogenic in animal studies
Women of childbearing potential must use effective (?) is taking oral ketoconazole
Contraception
Teratogenic in animal studies
Should a woman breastfeed if taking oral ketoconazole?
No
Present in breast milk
Should a patient with hepatic impairment take oral ketoconazole?
No
What monitoring is required prior to the initiation of oral ketoconazole? (2)
- ECG
2. Liver function
What needs to be monitored one week after the initiation of oral ketaconazole?
- ECG
- Adrenal function
- Liver function
Once cortisol levels are normalised or close to the target, how often should you monitor adrenal function in a patient taking oral ketoconazole?
Every 3-6 months
There is a risk of autoimmune disease development or exacerbation after normalisation of cortisol levels
When should liver function be checked in a patient taking oral ketoconazole? (3)
- Before initiation of treatment
- Weekly for 1 months after initiation
- Monthly for 6 months
What advice do you need to give patients (or carers) taking oral ketoconazole?
- Signs of liver disorder (anorexia, nausea, vomiting, fatigue, jaundice, abdominal pain, dark urine)
- Signs of adrenal insufficiency (fatigue, anorexia, nausea, vomiting, hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia)
What advice about driving do you need to give to patients taking oral ketoconazole?
Dizziness and somnolence may affect the performance of skilled tasks (e.g. driving)
