Pharmacotherapy For Endocrine And Exocrine Disorders

Front 1

Adrenal Gland Anatomy and Physiology

Back 1

Adrenal cortex (90% of gland) is divided into three regions:
•Zona glomerulosa (15%) produces mineralocorticoids such as aldosterone.
•Zona fasiculata (60%) is the middle region and is high in cholesterol. Responsible for glucocorticoid production.
•Zona reticularis (25%) inner zone is responsible for all androgen production.

Adrenal function in aging:
•Structural changes
•Decreased size of the adrenal cortex
•Functional changes
•Decreased production and secretion of androgens
•Unchanged production and secretion of glucocorticoids (i.e. cortisol) under basal conditions
•Decreased resiliency of the HPA axis during stress (blunting of negative feedback)
•Decreased production and secretion of mineralocorticoids

Front 2

Disorders of Adrenal Hormone Secretion

Back 2

Cushing’s syndrome: Abnormally high
levels of cortisol.

Addison’s disease: Abnormally low levels
of cortisol (and sometimes aldosterone).

Pheochromocytoma: Abnormally high
levels of catecholamines (NA, Adrenaline)
-rule this out if pt hv sustained high BP
-Surgical removal

Hyperaldosteronism: Abnormally high
levels of aldosterone
-diagnosis: aldosterone/renin ratio >30
-unilateral adenoma: surgical removal
-bilateral: Spiranolactone

Front 3

Onset and Incidence of Cushing’s Syndrome

Back 3

Incidence:
•Spontaneous + Pituitary + Ectopic: 5-25/1,000,000 per year.
•Ectopic: mainly from lung cancer; incidence increases with age.
•Iatrogenic: high in elderly due to corticosteroid therapy.

Onset:
•Spontaneous Cushing’s: childhood and adulthood.
•Pituitary Cushing’s: ages 25-45 years.
•Ectopic Cushing’s: adulthood.
•Iatrogenic or Factitious Cushing’s: after prolonged use of pharmacologic doses of glucocorticoid medications.

Front 4

Comparison of Corticosteroids

Back 4

Physiological dose ~5mg prednisone/day

Cushing’s syndrome can be caused by supraphysiologic doses of glucocorticoid medications.

Front 5

Presentation of Cushing’s Syndrome in the Elderly

Back 5

In Older Patients:

•Easy bruising, poor healing
•Falls, - risk of fractures
•Failure to thrive
•Refusal to eat, weight loss
•Confusion, dementia, paranoia
•Hypochondriasis, psychosis
•Compromised immune system

Front 6

Diagnosis of Cushing’s Syndrome

Back 6

?Cortisol excess
-Blood cortisol
-24hr-urine free cortisol >30-100mcg/day

?Cortisol overproduction
-Dexamathasone suppression test
-Low dose test: Dexamethasone 0.5mg qid for 4 days then 24hr-urine collection for day 0-4;
-if cortisol decrease = normal, no Cushing's;
-if cortisol no change on low dose but decrease on high dose = might be Cushing's;
-if cortisol no change on low/high dose = other causes

?ACTH dependent or independent
-Corticotropin-releasing-hormone
-petrosal sampling

Front 7

Treatment of Cushing’s Syndrome

Back 7

Surgery
-need Heparin prophylaxis
-require glucocorticoid replacement (20-30mg hydrocortisone daily)
-if bilateral: hydrocortison + Fludrocortisone 50-100mcg daily

Front 8

Drug Therapy of Cushing’s Syndrome

Back 8

Compounds acting at hypothalamic-pituitary level to decrease corticotrophin secretion (rarely effective-toxicity in elderly):
•Serotonin antagonists (cyproheptadine, metergoline, ketanserin, nitanserin)
•Dopamine agonists (bromocriptine)
•GABA agonists (sodium valproate)
•Somatostatin analogues (octreotide)


Compounds acting on adrenal glands to inhibit corticol synthesis:
•Mitotane*
•Metyrapone
•Ketoconazole
•Aminoglutethimide

Compounds acting on adrenal glands compete with cortisol at the receptor level.
•Glucocorticoid antagonists (mifepristone)
•Megestrol acetate

Front 9

Addison’s Disease

Back 9

• Primary adrenal insufficiency
– Lack of cortisol and/or aldosterone
– Increased ACTH
• Causes
– Infiltrative disorder
• Disrupted normal adrenal function
– Destructive disorder/event

Front 10

Etiology and Pathogenesis of Addison’s Disease

Back 10

Primary Adrenal insufficiency:
- Autoimmune (70%)
- TB (20%)
-Others
Secondary
-Interruption of glucocorticoid meds
-pituitary dysfxn
-removal of ACTH producing hormones

Tertiery
-Interruption of glucocortocoid meds
-Iatrogenic suppession of HPA axis
-Hypothalamic dysfxn/failure

Front 11

Drugs that Can Inhibit Adrenal Function

Back 11

• High dose steroids (e.g., > 20 mg prednisone for 3 wks) – suppresses the HPA axis
• Mitotane – destroys adrenal cortex, affecting peripheral conversion of cortisol
• Aminoglutethimide – inhibits P450scc, resulting in compensatory increase in ACTH
• Metyrapone – inhibits P450 C11 hydroxylase, affecting cortisol and aldosterone production
• Ketoconazole – inhibits P450 C11 hydroxylase
• Etomidate – inhibits P450 C11 hydroxylase
• Mifepristone – competitively inhibits receptor binding
• Megestrol Acetate – has slight glucocorticoid activity and may suppress the HPA axis
• Human Growth Hormone- a synthetic analog of a pituitary hormone that has been correlated with adrenal insufficiency
• Rifampin- enhances the hepatic metabolism of cortisol
• Warfarin- case reports of adrenal hemorrhage from hypocoagulopathy

Front 12

Common Signs and Symptoms of Addison’s Disease

Back 12

•Fatigue
•Muscle weakness
•Loss of appetite and weight loss
•Nausea & vomiting
•Diarrhea
•Orthostatic hypotension
•Hyperpigmentation of exposed and non-exposed areas
•Irritability and depression
•Craving for salty foods
•Hypoglycemia
•Disruption of menstrual periods

Front 13

Addisonian Crisis Onset caused by an illness, accident or other stressful event.
Signs and Symptoms:

Back 13

•Sudden penetrating pain in the lower back,
abdomen or legs
•Severe vomiting and diarrhea, followed by
dehydration
•Low blood pressure
•Loss of consciousness

Front 14

Diagnosis of Addison's Disease

Back 14

ACTH test
-measure blood/urine cortisol after ACTH injection
-If corticol lvls not rise -> suspect adrenal insufficiency

Insulin-induced hypoglycaemia test
-determine HPA respond to stress

X-ray- adrenal Ca deposits

CT & MRI- size & shape of pituitary

Front 15

Treatment of Addison's

Back 15

Normal Addison's
1. Hydrocortisone
-to replace cortisol
-if BD: give 2/3 of daily dose mane & 1/3 at ~4pm

2. Fludrocortisone
-to replace aldosterone (decrease K+, increase Na+, postural hypotension)
-0.1mg OD three times/week

3. Decrease salt intake

Addisonian Crisis:
•Hydrocortisone 100 mg IV immediately and every 6-8 hours for 24-48 hours
•IV NS 0.9% and dextrose supplementation to maintain hemodynamic support; then when stable
•Hydrocortisone 50 mg PO every 8 hours for 48 hours; taper to 30-50 mg/day