Adrenal Gland Pharmacology

Question 1

Metabolic effects of glucocorticoids

Answer 1

• Carbohydrates: ↑ gluconeogenesis, ↑ blood glucose, ↑ insulin
  
  • Excess = diabetes like state
• Protein: ↓ protein synthesis, ↑ AA to glucose
  
  • Excess: muscle wasting, weakness, skin- connective tissue atrophy
• Fat: ↑ lipolysis peripherally, ↑ FFA
  
  • Excess: ↑ lipogenesis (centrally via insulin) → centripetal obesity (moon facies and buffalo hump)

Question 2

Drugs that must be activated @ liver

Answer 2

• Ketone at carbon 11 means must be activated in liver
• Hydrocortisone (Solu-Cortef®) → inactive until goes through liver
• Prednisone → inactive until goes through liver where it is converted into Prednisolone

Question 3

Drugs that are physiologically active as given

Answer 3

• Drugs have Hydroxyl at Carbon 11 which means physiologically active.
• Prednisolone has C1=C2 (double bond) which ↑ anti-inflammatory effects
• Methylprednisolone (Solu-Medrol®) → has C1=C2 (double bond) + α-methyl group on C-6 which ↑ anti-inflammatory activity (5-6x stronger than cortisone)
• Fludrocortisone has a fluorine at C-9 which ↑ mineralocorticoid activity
• Dexamethasone has a fluorine at C-9 + α-methyl group on C-16: which ↑ anti-inflammatory effects 18x and essentially eliminates mineralocorticoid activity (of the fluorine group)
• Triamcinolone is active and a topical/oral/injectable.

Question 4

Tx of addison’s disease (acute and chronic)

Answer 4

• Chronic: administer hydrocortisone with increased dose during stress.
  
  • Fludrocortisone is usually required for sufficient salt-retaining effect (unless mild case).
• Acute (i.e. life threatening, immediate treatment): High IV cortisol dose until stable (correct fluid/electrolyte abnormalities).
  
  • Sometimes fludrocortisone needs after switch to lower oral cortisol dose

Question 5

Tx of Cushing’s disease

Answer 5

• Surgery is treatment of choice (pituitary/chest/abdomen).
• Pharmacotherapy is adjunctive in refractory or inoperable cases = cortisol synthesis inhibitors.

Question 6

Pharmacotherapy in Cushing’s disease/syndrome

Answer 6

• ACTH Secretion Inhibitors
  
  • Cabergoline, Pasireotide
• Cortisol Synthesis Inhibitors
  
  • Ketoconazole, Metyrapone, Etomidate
• Adrenolytic Agents
  
  • Mitotane
• Cortisol Receptor Blockers
  
  • Mifepristone

Question 7

Tx of Primary Aldosteronism

Answer 7

• Aldosterone antagonists (Spirinolactone + eplerenone)
• hypertensive medications (Thiazide, CCB, ACE-I, ARBs)

Question 8

Tx of Pheochromocytoma

Answer 8

• Surgical removal of tumor but first need preoperative α blockade:
  
  • α-blockade: phenoxybenzamine: irreversible α1 + α2 antagonist
  • β-blockade: metoprolol always after adequate α-receptor blockade.
• Then maybe Ca2+ blocker (nifedipine), then catecholamine synthesis inhibitor (metyrosine).
• Then adrenalectomy - if inoperable or metastatic.

Question 9

Tx of glucocorticoid insufficiency

Answer 9

• Hydrocortisone
• Prednisone
• Dexamethasone

Question 10

Tx of mineralcorticoid insuffiency

Answer 10

Fludrocortisone

Question 11

Tx of Sex Steriod insuffieciency

Answer 11

DHEA

Question 12

Hydrocortisone: GC v. MC vs. Anti-inflammatory actions & clinical uses

Answer 12

• GC: MC: AI = 1:1:1
• Uses
  
  • Acute (ER)
  • GC + MC replacement
  • Addison’s disease

Question 13

Prednisone: GC v. MC vs. Anti-inflammatory actions & clinical uses

Answer 13

• GC: MC: AI = 4:1:4
• Use
  
  • Steroid burst ==> GC + (less) MC

Question 14

Methylprednisolone: GC v. MC vs. Anti-inflammatory actions & clinical uses

Answer 14

• GC: MC: AI = 5:0:5
• Use
  
  • steroid burst

Question 15

Triamcinilone: GC v. MC vs. Anti-inflammatory actions & clinical uses

Answer 15

• GC: MC: AI = 5:0:5
• Use
  
  • Potent systemic agent with excellent topical activity.

Question 16

Dexamethasone: GC v. MC vs. Anti-inflammatory actions & clinical uses

Answer 16

• GC: MC: AI = 30:0:30
• Use
  
  • Most potent α-inflammatory, used in cerebral edema, chemo-induced vomiting.
  • Greatest suppression of ACTH secretion

Question 17

Hydrocortisone: administration routes

Answer 17

• Oral
• Injectable
• Topical

Question 18

Prednisone: administration routes

Answer 18

oral only

Question 19

Methylprednisolone: administration routes

Answer 19

• Oral
• Injectable
• Parenteral

Question 20

Triamcinolone: administration routes

Answer 20

• Topical (5³)
• Oral
• Injectable

Question 21

Dexamethasone: administration routes

Answer 21

• Oral
• Injectable
• Topical

Question 22

Salt-retaining activity of drug correlates to…

Answer 22

MC activity

Question 23

ACTH suppression of drug correlates to..

Answer 23

GC activity

Question 24

Corticosteroids that can be used topically

Answer 24

• hydrocortisone
• triamcinolone
• dexamethason

Question 25

General dosing consideration for use of corticosteroids for anti-inflammatory use

Answer 25

• REMEMBER: Mineralocorticoid side effects vary with agent
• Dosage often by trial and error with re-evaluation
• Consider seriousness of disease - minimal amount for desired effect - duration of therapy
• Reduce dosage as soon as therapeutic objectives are obtained

Question 26

If using large doses of corticosteroids you should…

Answer 26

• use shorter-acting agent with little MC
  
  • e.g. methylprednisolone

Question 27

Dosing consideration used to minimize adrenal suppression or adrenal insufficiency

Answer 27

• Alternate day schedule à minimize adrenal suppression
  
  • Anti-inflammatory actions outlast HPA suppression
• Terminate administration gradually (duration > 7-28 d)
  
  • Minimizes disease rebound and potential for symptoms of adrenal insufficiency (adrenal crisis)

Question 28

Potential toxicity of acute, short course, high dose

Answer 28

• Mineralocorticoid effects: Salt and water retention ==> edema ==> increased blood pressure, hypokalemia
• Glucocorticoid effects: Glucose intolerance in diabetics, mood changes (up or down), insomnia, GI upset

Question 29

Glucocorticoid effects of high dose sustained corticosteroid therapy

Answer 29

• Iatrogenic Cushing’s syndrome
• Hypothalamic-pituitary-adrenal axis suppression
• Mood disturbance
• impaired wound healing
• increased susceptibility to infection

Question 30

Characteristics of iatrogenic cushing’s syndrome

Answer 30

• hyperglycemia
• protein wasting (muscle)
• lipid deposition (weight gain)
• ==> diabetes-like state

Question 31

Characteristics of HPA axis suppression

Answer 31

• Can result in insufficient response to stress
• More suppression with dexamethasone and betamethasone
• Also may cause decrease in ACTH, GH, TSH, LH, sex steroids

Question 32

Possible consequences of large, chronic doses of corticosteroids

Answer 32

• osteoporosis
• posterior capsular cataracts
• skin atrophy, loss of collagen support
• growth retardation in children
• peptic ulceration

Question 33

Short-medium acting corticosteroids

Answer 33

• hydrocortisone
• prednisone
• methylprednisolone

Question 34

Intermediate-acting corticosteroids

Answer 34

• tramicinolone
• fluprednisolone

Question 35

Long-acting corticosteroids

Answer 35

dexamethasone

Question 36

Most common mineralcorticoid agent

Answer 36

fludrocortisone