STEROID THERAPY AND DRUGS USED IN ADRENAL DYSFUNCTION

Question 1

ADRENOCORTICAL STEROIDS

Answer 1

1)Corticosteroids (glucocorticoids and mineralocorticoids)

2)
androgens

Question 2

Main glucocorticoid and main mineralocorticoid ?

Answer 2

is cortisol

is aldosterone.

Question 3

Synthetic glucocorticoids include

Answer 3

bethamethasone, triamcinolone, prednisolone, dexamethasone, paramethasone, methylprednisolone, decorticosterone acetate.

Question 4

Cortisol (hydrocortisone). pharmacokinetics

Answer 4

Major glucocorticoid
Synthesised in the zona fasciculata.
C-21 steroid.
Secretion follows a diurnal rhythm being maximal around 8am.
Secretion is regulated by ACTH and also influenced by stress.
10-20mg secreted daily.
More than 90% protein bound mainly to CBG and albumin.
T1/2 is 60-90 minutes.
Metabolism is in the liver by glucoronidation or sulfation to form water soluble metabolites which are excreted in the urine.

Question 5

Cortisol
Mechanism of action

Answer 5

Binding of cortisol to receptor.
Dissociation of receptor from associated proteins.
Interaction with coactivators to induce trasncription of GRE in the regulatory region of the gene.
New protein synthesis.
Glucocorticois can also interact with GRE to inhibit transcription of some genes like POMC, COX-2, NOS2 genes.
Second mechanism of action is by direct interaction to cell membrane receptors to produce quicker responses.

Question 6

Effects on carbohydrate and protein metabolism.

Answer 6

Increased production of glucose from amino acids and glycerol.
Increased storage of glucose as glycogen.
Diminished glucose utilization in the peripheral tissues.
Increased lipolysis to provide amino acids and glycerol for gluconeogenesis.
Increased protein breakdown.
Net effect is increased blood glucose levels

Question 6

Effects on lipid metabolism:

Answer 6

Fat redistribution.
Lipolytic effects of agents like growth hormone, beta antagonists are facilitated.
Net effect is increased free fatty acids.

Question 7

Effects on electrolyte and water balance (mineralocorticoids):

Answer 7

Enhancement of distal tubular reabsorption of Na+.
Increased urinary excretion of K+ and H+.
ECF volume expansion.

Question 8

Effects on blood

Answer 8

Polycythemia in cushing’s syndrome and anemia in adrenal insufficiency.
Lymphocytopenia and leukocytosis.
Decreased number of eosinophils, monocytes and basophils.

Question 9

CVS effects

Answer 9

Hypertension can be consequent upon primary hyperaldosteronism.
Enhancement of vascular reactivity to other vasoactive agents.

Question 10

Antiinflammatory and immunosuppressive effects

Answer 10

Decreased release of vasoactive and chemoattractive factors.
Decreased migration of leucocytes to areas of injury.
Reduced number of circulating lymphocytes, monocytes, eosinophils, basophils and increased neutrophils.
Inhibition of the functions of tissue macrophages and other antigen-presenting cells
Decresaed production of IL-1, IL-6, TNF-alpha, GM-CSF, IFN-γ.
Reduced synthesis of PGs, leukotriene, PAF
Reduced expression of COX2
Reduced antibody production but only by very large doses

Question 11

CNS effects

Answer 11

High doses cause:
Elevated mood.
Euphoria.
Insomnia.
Restlessness.
Increased motor activity.
Psychosis.
Increased intracranial pressure (pseudotumor cerebri)

Question 12

Catabolic and antianabolic effects

Answer 12

Decreased muscle mass
Weakness and thinning of the skin
Osteoporosis
Reduced growth in children

Question 13

Other effects:

Answer 13

Suppression of TSH, LH, ACTH release.
Important effects on fetal lung development.
Normal functioning of skeletal muscles

Question 14

CBG which has a higher affinity for ? than for ?.

Answer 14

glucorticosteroids than for mineralocorticoids

Question 15

Principles of therapeutic use of glucocorticoids (5)

Answer 15

The advantage of use must outweigh the risks.
Appropriate dose to achieve a predetermined effect and should be adjusted periodically based on response or development of toxicities.
A single dose even if large is usually safe.
Administration for a short period (up to one week) is usually safe.
The agents are only palliative except in specific replacement settings. (The agents primarily manage symptoms except when used as hormone replacements in specific conditions.)

Question 16

Uses of glucocorticoids

Answer 16

Replacement therapy in adrenal insufficiency which may be primary or secondary.
Rheumatic disorders.
Diseases of the kidneys.
Allergic disorders.
Skin disorders.
Bronchial asthma.
GIT diseases.
Eye problems.
Malignancies.
Cerebral edema.
Organ transplantation.

Question 17

Toxicities/ADRs

Answer 17

Iatrogenic Cushing’s syndrome
Peptic ulcer
Masking of bacterial and mycotic infections
Myopathy
Hypomania and acute psychosis
development of posterior subcapsular cataracts
Increased IOP and glaucoma
Benign intracranial hypertension
Growth retardation in children
Sodium and fluid retention leading to elevated bp
Adrenal suppession

Question 18

Caution

Answer 18

Monitor patients for the development of peptic ulcer, hyperglycemia, glycosuria, osteoporosis, infections, sodium retention, edema, hypertension
Great caution in patients with peptic ulcer, HT, TB, psychosis, DM, osteoporosis, glaucoma.

Question 19

Preparations

Answer 19

Topical
Opthalmic
Inta-articular injections
Inhaled forms e.g. dipropionate, furoate for asthma and allergic rhinitis

Question 20

Adrenal insufficiency

Answer 20

can be acute, chronic or a result of congenital adrenal hyperplasia.
Result from inadequate secretion of cortisol and or aldosterone.
Potentially fatal.
Commonly due to abrupt withdrawal of chronic glucocorticoid therapy.
Primary adrenocortical failure is called Addison’s disease.
Causes of Addison’s disease include autoimmune, TB, HIV/AIDS, metastatic carcinomas, bilateral adrenalectomy, lymphoma, intraadrenal hemorrhage, amyloidosis, haemochromatosis, CAH, drugs.

Question 21

Clinical presentation of adrenal insufficiency
Symptoms due to mineralocorticoid insufficiency include:

Answer 21

Hypotension
Shock
Hyponatremia
Hyperkalemia.

Question 22

Symptoms due to glucocorticoid insufficiency include:

Answer 22

Weight loss
Malaise
Weakness
Anorexia
Hypoglycemia

Question 23

Treatment of acute adrenal insufficiency

Answer 23

Administration of normal saline.
Administration of cortisol, 100mg bolus followed by continous infusion at a rate of 50-100mg 8 hrly.
Treatment of precipitating cause.

Question 24

Treatment of chronic adrenal insufficiency

Answer 24

require daily corticosteroid supplementation usually administered as 2/3 of the total dose in the morning and 1/3 in the evening.

Question 25

CAH (congenital adrenal hyperplasia )

Answer 25

Genetic disorder characterized by absence of enzymes in the steroid biosynthetic pathway.
90% of cases are due to deficiency of CYP21 (21-hydroxylase).
Classified as classical and non-classical.
Female patients with classical not treated in utero develop pseudohermaphroditism.
“Salt wasters” have aldosterone deficiency and are unable to conserve sodium.

Question 26

Treatment of CAH

Answer 26

is administration of glucocorticoids and mineralocorticoids(fludrocortisone acetate) for salt wasters.

Question 27

Inhibitors of adrenal steroids’ synthesis and actions

Answer 27

Mitotane is used for treatment of adrenal neoplasms.
Metyrapone inhibits CYP11B1(11β-hydroxylase).
Aminoglutethimide inhibits CYP11A1.
Ketaconazole inhibits CYP17(17α-hydroxylase.
Trilostane inhibits 3β-HSD (hydroxysteroid dehydrogenase)
Mifepristone has glucocorticoid receptor antagonism effects.
Most common side effect is precipitation of adrenal insufficiency.

Question 28

Mineralocorticoids
Aldosterone PK

Answer 28

Secretion is under influence of angiotensin II and extracellular K+
Major urinary metabolite is conjugated tetrahydroaldosterone.

Question 29

Mineralocorticoids
Aldosterone
MOA

Answer 29

It stimulate sodium reabsorption from the renal tubules in exchange for Na+ and H+ ions.
Also increase sodium reabsorption from sweat, salivary glands and the intestinal mucosa.

Question 30

Hyperaldosteronism present with

Answer 30

hypokalemia, metabolic alkalosis, increased plasma volume, HT.

Question 31

Deoxycorticosterone (DOC) pharmacology

Answer 31

Precusor for aldosterone.
Secretion is mainly controlled by ACTH.
Marked elevation of secretion in CAH and adrenocortical Ca.

Question 32

Fludrocortisone pharmacology

Answer 32

Has glucocorticoid and mineralocorticoid activities.
Used in adrenocortical insufficiency associated with mineralocorticoid deficiency.

Question 33

Metyrapone pharmacology

Answer 33

Inhibitor of 11-hydroxylation
It interferes with cortisol and corticosterone synthesis
Causes an increase in ACTH synthesis in the presence of normal pituitary fxn
Diagnostic test
Safe in pregnancy
Used in cushing’s syndrome
Toxicities: salt and water retention, hirsutism, dizziness, GI disturbances

Question 34

Aminogluthetimide pharmacology

Answer 34

Blocks first step in steroid synthesis
Used in breast cancer
Also used in Cushing’s sx due to adrenocortical Cancer

Question 35

Ketoconazole pharmacology

Answer 35

Commonly used as an antifungal agent
Non-selective inhibitor of adrenal and gonadal steroid synthesis.
Only effective for steroid inhibition at high doses
Used in tx of Cushing’s syndrome
Causes hepatotoxicity

Question 36

Mifepristone pharmacology

Answer 36

Antiglucocorticoid effect at high doses
Blocks glucocorticoid receptor
Used for tx of patients with inoperable ectopic ACTH secretion or adrenal Ca who have failed other drugs

Question 37

Mitotane

Answer 37

Used in tx of adrenal Ca
Causes diarrhoea, nausea, vomiting, depression, somnolence, skin rashes.

Question 38

Mineralocorticoid antagonists

Answer 38

Spironolactone
Eplerenone
Drospirenone

Question 39

Spironolactone

Answer 39

Competitive antagonist of the aldosterone receptor

Uses
-Treatment of primary aldosteronism
-Diagnosis of aldosteronism.
-Treatment of hirsutism in women.
-Diuretic.
-Mgt of hrt failure

Side effects
-Cardiac arrythmias
-Gynecomastia
-Sedation
-Headache
-Skin rashes
-Menstrual disturbances
-Hyperkalemia.

Question 40

Eplerenone

Answer 40

-No effect on androgen receptors
-Used in mgt of hypertension.
-Causes hyperkalemia.