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PoD - E4 > Corticosteroids > Flashcards

Corticosteroids Flashcards

1
Q

Time of day when glucocorticoid level at highest and lowest

A
  • Highest: morning

- Lowest: late afternoon

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2
Q

Glucocorticoids - Calcium

A

Negative calcium balance

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3
Q

Glucocorticoids - Cardiovascular

A
  • Hypertension

- Polycythemia

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4
Q

Glucocorticoids - Bone

A

Reabsorption

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5
Q

Glucocorticoids - Inflammation

A

Increases lipocortin levels:
- Inhibits phospholipase A2 activity

Reduces NF-kappa B levels, leads to reduced levels of:

  • Proteolytic enzymes
  • Vasoactive cytokines
  • Chemoattractant cytokines
  • COX2
  • NOS
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6
Q

Time of day when mineralocorticoid level at highest and lowest

A

Contant throughout the day

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7
Q

Diseases associated with glucocorticoid excess

A

Cushing’s syndrome

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8
Q

Diseases associated with glucocorticoid insufficiency

A
  • Addison’s disease

- Congenital Adrenal Hyperplasia

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9
Q

Cushing’s syndrome

A
  • Excessive cortisol levels
  • Leads to fat redisposition, moon face, hyperglycemia, etc
  • Treat with cortisol synthesis inhibitors - can precipitate adrenal insufficiency so should be used with care
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10
Q

Cushing’s syndrome - Major causes

A
  • Corticosteroid therapy (most common)
  • Adrenocortical adenoma/carcinoma
  • Pituitary hypersecretion - ACTH
  • Hypothalamic hypersecretion - CRH
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11
Q

Dexamethasone test

A
  • Dexamethasone is a high potency glucocorticoid that will promote feedback inhibition of the HPA leading to a decrease in ACTH production and then cortisol
  • If cortisol levels are reduced by dexamethasone then the feedback system is operative
  • Dexamethasone does not interfere with the lab test for cortisol
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12
Q

Treatment options for excess cortisol

A

If due to high exogenous glucocorticoids
- Reduce dose

Tumors

  • Surgery
  • Pharmacological options: inhibitors of cortisol production (aminoglutethimide, ketoconazole, metyrapone), inhibitors of cortisol action (mifepristone)
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13
Q

Aminoglutethimide - Mechanism of Action

A
  • Inhibits CYP11A1 and to a lesser extent CYP11B1

- Reduces the synthesis of all corticosteroids

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14
Q

Aminoglutethimide - Uses

A

Controlling hypercortisolism in patients with Cushing’s syndrome caused by:

  • Adrenal tumor secreting cortisol
  • ACTH dependent causes
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15
Q

Aminoglutethimide - Pharmacokinetics

A

Orally available

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16
Q

Aminoglutethimide - Side effects

A
  • Over time can induce adrenal INSUFFICIENCY
  • May need to supplement corticosteroids and fludrocortisones to REPLACE MINERALOCORTICOIDS
  • Drowsiness, morbilliform skin rash, nausea/vomiting, anorexia, adrenal insufficiency, hypothyroidism, masculinization, hirsutism, dizziness, hypotension, pruritis, myalgia, fever, acute generalized exanthematous pustulosis
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17
Q

Aminoglutethimide - Drug interactions

A

Induces hepatic microsomal enzymes leading to increased metabolism of other drugs such as warfarin, theophylline, digitoxin
- Major reason for withdrawal from market

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18
Q

Ketoconazole - Mechanism of Action

A
  • Antifungal agent
  • At higher doses than those employed in anti fungal therapy inhibits CYP17 (inhibits glucocorticoid and androgen synthesis)
  • Even higher doses inhibits CYP11A1 thus inhibiting all steroidogenesis
  • Inhibits CORTICOTROPH ADENYLATE CYCLASE activation (reduces ACTH secretion at therapeutic doses)
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19
Q

Ketoconazole - Uses

A

Cushing’s disease

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20
Q

Ketoconazole - Side effects

A

Adrenal insufficiency

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21
Q

Ketoconazole - Drug interactions

A
  • Strong inhibitor of CYP1A2, CYP2C9 and CYP3A4 so considerable potential for drug-drug interactions
  • Inhibits P-GLYCOPROTEIN so may increase levels of P-GP substrates
  • Co-administration with ergot derivatives, cisapride or triazolam is contraindicated due to risk of potentially fatal cardiac arrhythmias
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22
Q

Metyrapone - Mechanism of Action

A

Selective inhibitor of CYP11B1 reducing the biosynthesis of cortisol

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23
Q

Metyrapone - Uses

A

Hypercorticism resulting from either adrenal neoplasms or tumors producing ACTH ectopically

Diagnostic test for Cushing’s syndrome:

  • Cushing’s disease indicated when cortisol reduces and ACTH increases
  • If non-pituitary based Cushing’s no change in ACTH
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24
Q

Metyrapone - Pharmacokinetics

A

Oral administration

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25
Q

Metyrapone - Side effects

A
  • HIRSUITISM (due to increased synthesis of adrenal androgens upstream from enzymatic block)
  • Nausea, headache, sedation and rash
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26
Q

Mifepristone - Mechanism of Action

A
  • Blocks release of glucocorticoid receptors from chaperone proteins
  • Also progesterone antagonist (abortion pill)
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27
Q

Mifepristone - Uses

A
  • Patients with inoperable ectopic ACTH tumors

- Adrenal carcinomas unresponsive to other treatments

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28
Q

Mifepristone - Side effects

A

VAGINAL BLEEDING, GI upset, abdominal pain, diarrhea, headache

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29
Q

Primary adrenal insufficiency

A
  • Structural/functional lesion of the adrenal cortex (Addison’s disease)
  • High ACTH levels (lack normal negative feedback of corticosteroids)
  • Decrease in glucocorticoids and mineralocorticoids
30
Q

Secondary adrenal insufficiency

A
  • Pituitary or hypothalamic deficiency
  • Decrease ACTH
  • Decrease glucocorticoids and adrenal androgens
31
Q

Primary adrenal insufficiency diagnostic with cosyntropin (synthetic ACTH)

A
  • Administer consyntropin
  • Measure plasma cortisol prior and after
  • ACTH - HIGH, CORTISOL - LOW
  • Symptoms: weakness, weight loss, anorexia, hypotension, dark skin pigmentation (from POMC), hyponatremia
32
Q

Secondary adrenal insufficiency diagnostic with cosyntropin (synthetic ACTH)

A
  • Baseline levels of ACTH and cortisol low

- Symptoms: malaise, anorexia, NO HYPERPIGMENTATION

33
Q

Primary insufficiency - Treatment

A
  • Treat with glucocorticoids and mineralocorticoids
  • HYDROCORTISONE and CORTISONE preferred
  • Supplement with FLUDROCORTISONE to give higher mineralocorticoid effect
  • ACUTE INSUFFICIENCY is life threatening, should also consider ISOTONIC NaCl and GLUCOSE therapy in conduction with STEROIDS
34
Q

Secondary insufficiency - Treatment

A
  • Treat with HYDROCORTISONE, CORTISONE, or PREDNISONE

- MINERALOCORTICOIDS ARE NOT NEEDED

35
Q

Congenital Adrenal Hyperplasia - Major Causes

A
  • Mutation in enzymes involved in corticosteroid synthesis
  • Deficiency in CYP21 (most common): reduced levels of corticosteroids, increased 17-HYDROXYPROGESTEROINE (clinical test), increased DHEA and ANDROGENS due to lack of feedback inhibition and excess ACTH
36
Q

Congenital Adrenal Hyperplasia - Presentation

A
  • Females: pseudohermaphroditism
  • Males normal at birth, precocious puberty
  • Non-classic POST puberty presentation (mild androgen excess hirsuitism, amenorrhea, etc)
37
Q

Congenital Adrenal Hyperplasia - Treatment

A
  • Corticosteroid replacement therapy (hydrocortisone) females with classic treatment in utero
  • Mineralocorticoids once daily
  • Goal to provide sufficient hormone to maintain normal function
  • Stimulate normal circadian rhythm
38
Q

Diseases associated with mineralocorticoids

A
  • Hypertension and hypokalemia

Most common forms:

  • Aldosterone producing adenomas
  • Bilateral idiopathic hyperaldosteronism

Less common forms:

  • Unilateral hyperplasia or primary adrenal hyperplasia
  • Familial hyperaldosteronism
  • Pure-aldosterone producing adrenocortical carcinomas and ectopic aldosterone secreting tumors
39
Q

Diseases associated with mineralocorticoids - Treatment

A

Surgery:

  • Aldosterone producing adenomas (if unilateral)
  • Unilateral hyperplasia

Treatment with aldosterone antagonist:

  • SPIRONOLACTONE (also a progesterone agonist and androgen antagonist) : breast tenderness and menstrual irregularities in women; impotence, decreased libido and gynecomastia in men
  • EPLERENONE: fewer side effects, more expensive
40
Q

Therapeutic use of glucocorticoids

A
  • Excellent anti-inflammatory activity
  • UNDERLYING CAUSE IS STILL PRESENT
  • Corticosteroids are palliative not curative
  • Use for steroid responsive conditions
  • USE ONLY WHEN LESS TOXIC SUBSTANCES ARE INEFFECTIVE
  • USE THE MINIMUM EFFECTIVE DOSE (though in general a single large dose will have minimal side effects)
  • Administer locally if possible
  • Topical administration will lessen systemic effects
  • AVOID RAPID WITHDRAWAL
  • GLUCOCORTICOIDS MAY SUPPRESS SIGNS AND SYMPTOMS OF DISEASES OR INTERFERE WTIH DIAGNOSTIC TESTS
  • Once in remission, use every other day therapy (reduces suppression of HPA axis, better compliance, fewer side effects)
41
Q

Steroids and Rheumatic Disorders

A
  • Start with HIGH dose and taper to minimal effective dose based on clinical outcome
  • Used in conduction with other immunosuppressants
  • Caution should be used if VIRUS may be a contributing factor to disorder
42
Q

Steroids and Rheumatoid Arthritis

A
  • Typically used as temporizing agent when non-responsive to non-steroidals
  • Major symptoms confined to a few joints can be treated with intra-articular injections
  • Intra-articular can be used in non-inflammatory degenerative disease (osteoarthritis) and localized pain (tendinitis)
  • Minimize frequency, potential of painless joint destruction 3 month intervals
43
Q

Steroids and Respiratory Disease

A

Asthma and COPD

  • Low systemic side effects in inhalation
  • Most common side effect is oral candidiasis
44
Q

Steroids and Allergies

A
  • NOT USED FOR SEVERE ALLERGIC REACTIONS LIKE ANAPHYLAXIS - use epinephrine
  • Useful for control of short duration allergic disorders in conjunction with other agents such as anti-histamines
45
Q

Steroids and GI

A
  • Inflammatory bowel disease (chronic ulcerative colitis/ Crohn’s disease etc.)
  • Used when other therapies FAIL - care required as glucocorticoids may MASK SYMPTOMS of complications such as intestinal perforations and peritonitis
46
Q

Steroids and Transplant

A
  • Low doses useful in acute rejection
  • Higher dose required in established rejection
  • ALWAYS GIVE IN CONJUNCTION WITH OTHER AGENTS
47
Q

Steroids and Respiratory Distress Syndrome

A
  • Problem in premature infants - cortisol is a regulator of lung maturation
  • Candidates are babies likely to be born 24-24 weeks
  • BECLAMETHASONE - 2 doses IM to mother 48, then 24 hours prior to delivery
  • DEXAMETHASONE - 4 doses IM starting 48 hours pre-delivery then ever 12 hours
48
Q

Glucocorticoid used as a standard by which all others are compared

A

Hydrocortisone

49
Q

Corticosteroids used in mild disease

A
  • Cortisol
  • Hydrocortisone
  • Cortisone
50
Q

Corticosteroids used in moderate disease

A
  • Prednisone
  • Prednisolone
  • Methyprednisolone
  • Triamcinolone
  • FLUDROCORTISONE (go-to drug)
51
Q

Corticosteroids used in severe disease

A
  • Betamethasone

- Dexamethasone

52
Q

Absorption of corticosteroids

A
  • Many orally active
  • Water soluble esters given via IV to give rapid high concentration
  • More prolonged effects when give IM
  • Absorption from local sites possible (on prolonged therapy can suppress HPA)
53
Q

Transport of corticosteroids

A

90% cortisol in plasma is protein bound:

  • Corticosteroid binding globulin (CBG) and albumin
  • Binding affinity varies - HIGH for cortisol, LOW for aldosterone and glucoronide-steroid conjugates
  • CBG LEVELS RAISED IN PREGNANCY
54
Q

Activation of corticosteroids

A

HSD1, 11-beta-hydroxysteroid dehydrogenase type 1 isoenzyme activates (cortisone to cortisol)
- Found in most glucocorticoid target tissues

55
Q

Deactivation of corticosteroids

A

HSD1, 11-beta-hydroxysteroid dehydrogenase type 2 isoenzyme deactivates (cortisol to cortisone)

  • Found in mineralocorticoid target tissues
  • Kidney, colon, salivary glands and also placenta
56
Q

Metabolism of corticosteroids

A
  • Hepatic conjugation with glucoronides/sulfate (first pass effect varies by steroid)
  • Renal excretion
57
Q

Corticosteroid - oral administration

A

All

58
Q

Corticosteroid - aerosol administration

A
  • Beclomethasone
  • Flunisolide
  • Flutacisone
  • Triamcinolone
59
Q

Corticosteroid - topical administration

A
  • Beclomethansone
  • Dexamethasone
  • Hydrocortisone
  • Triamcinolone
60
Q

Corticosteroid - IV and IM administration

A
  • Dexamethasone
  • Hydrocortisone
  • Methylprednisone
  • Prednisone
61
Q

Corticosteroid - IM administration

A
  • Cortisone
  • Deoxycortisone
  • Triamcinolone
62
Q

Withdrawal effects from corticosteroids

A
  • HPA suppression
  • Suppress HPA axis due to feedback loops that inhibits ACTH release
  • Results in decreased ACTH induced cortisol secretion - leads to SECONDARY adrenocortical insufficiency (severity depends on individual/dose/duration of therapy, can last up to 12 months)
  • To prevent, have gradual reduction of steroid following prolonged therapy
  • Potential flare up of underlying disease process
63
Q

Adverse effects of corticosteroids

A
  • Prolonged administration of replacement doses generally do not lead to adverse effects
  • Adverse effects are associated with both the dose and prolongation of therapy
  • Short term and/or highly localized administration reduce the probability of adverse effects
64
Q

Adverse effects of corticosteroids - Cardiovascular

A
  • Hypertension
  • Edema
  • Na and water retention
  • Dependent on the mineralocorticoid activity of the corticosteroid
  • Hypokalemia
65
Q

Adverse effects of corticosteroids - CNS

A
  • Euphoria
  • Depression
  • Psychosis
  • Insomnia
66
Q

Adverse effects of corticosteroid - Immune system

A

Increase susceptibility to infection (especially viral and fungal)

67
Q

Adverse effects of corticosteroid - GI

A

Peptic ulcer

68
Q

Adverse effects of corticosteroid - Metabolic

A
  • Hyperglycemia
  • Muscle catabolism
  • Hyperlipidemia altered fat deposition (Moon face, etc)
  • Striae
69
Q

Adverse effects of corticosteroid - Eye

A
  • Cataracts

- Glaucoma

70
Q

Adverse effects of corticosteroid - Osteoporosis

A
  • Negative calcium balance - causes increased parathyroid hormone secretion, cause bone resorption
  • Inhibition of osteoblasts
71
Q

Contraindications for corticosteroids

A
  • CHILDREN: potential for growth and development inhibition
  • Immunosuppresion
  • Corticosteroids can mask viral and fungal infections so should be used with extreme care in immunosuppresed patients and should be avoided if possible
  • PATIENTS ON PROLONGED CORTICOSTEROIDS SHOULD AVOID EXPOSURE TO VIRAL INFECTIONS AND AVOID CONCURRENT LIVE VIRUS VACCINATIONS
  • Systemic corticosteroids should be given with care to patients with CONGESTIVE HEART FAILURE or HYPERTENSION (due to potential weight gain and hypertension induced by steriods)
  • Prolonged steroids can induce OSTEOPOROSIS, LONG BONE FRACTURE and FEMORAL/HUMORAL HEAD NECROSIS so should be used carefully in elderly and post-menopausal women (given high protein diet and calcium and vitamin D supplementation)
  • Use caution in DIABETIC PATIENTS due to increase potential for HYPERGLYCEMIA
  • Use caution in patients with psychosis, emotional disturbances and seizure disorders - can exacerbate these
  • Dexamethasone is a pregnancy category C drug (cleft palate, still birth)
  • Corticosteroids can distribute to baby via breast milk, recommend no breast feeding in systemic steroid treatment
72
Q

Corticosteroid drug interactions

A
  • Induce CYP3A4 and reduce levels of other drugs (estrogen metabolized by 3A4 so some contraceptive may be less effective, several antivirals)
  • Hepatic microsomal enzyme inducers (barbiturates, carbamazepime, phenytoin) will promote corticosteroid metabolism
  • Estrogens induce elevation of corticosteroid binding protein (increasing circulating half-life and reducing free concentration)

PoD - E4 (5 decks)

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