Corticosteroids Flashcards
(72 cards)
1
Q
Time of day when glucocorticoid level at highest and lowest
A
- Highest: morning
- Lowest: late afternoon
2
Q
Glucocorticoids - Calcium
A
Negative calcium balance
3
Q
Glucocorticoids - Cardiovascular
A
- Hypertension
- Polycythemia
4
Q
Glucocorticoids - Bone
A
Reabsorption
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
6
Q
Time of day when mineralocorticoid level at highest and lowest
A
Contant throughout the day
7
Q
Diseases associated with glucocorticoid excess
A
Cushing’s syndrome
8
Q
Diseases associated with glucocorticoid insufficiency
A
- Addison’s disease
- Congenital Adrenal Hyperplasia
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
10
Q
Cushing’s syndrome - Major causes
A
- Corticosteroid therapy (most common)
- Adrenocortical adenoma/carcinoma
- Pituitary hypersecretion - ACTH
- Hypothalamic hypersecretion - CRH
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
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)
13
Q
Aminoglutethimide - Mechanism of Action
A
- Inhibits CYP11A1 and to a lesser extent CYP11B1
- Reduces the synthesis of all corticosteroids
14
Q
Aminoglutethimide - Uses
A
Controlling hypercortisolism in patients with Cushing’s syndrome caused by:
- Adrenal tumor secreting cortisol
- ACTH dependent causes
15
Q
Aminoglutethimide - Pharmacokinetics
A
Orally available
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
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
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)
19
Q
Ketoconazole - Uses
A
Cushing’s disease
20
Q
Ketoconazole - Side effects
A
Adrenal insufficiency
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
22
Q
Metyrapone - Mechanism of Action
A
Selective inhibitor of CYP11B1 reducing the biosynthesis of cortisol
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
24
Q
Metyrapone - Pharmacokinetics
A
Oral administration
25
Metyrapone - Side effects
- HIRSUITISM (due to increased synthesis of adrenal androgens upstream from enzymatic block)
- Nausea, headache, sedation and rash
26
Mifepristone - Mechanism of Action
- Blocks release of glucocorticoid receptors from chaperone proteins
- Also progesterone antagonist (abortion pill)
27
Mifepristone - Uses
- Patients with inoperable ectopic ACTH tumors
| - Adrenal carcinomas unresponsive to other treatments
28
Mifepristone - Side effects
VAGINAL BLEEDING, GI upset, abdominal pain, diarrhea, headache
29
Primary adrenal insufficiency
- 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
Secondary adrenal insufficiency
- Pituitary or hypothalamic deficiency
- Decrease ACTH
- Decrease glucocorticoids and adrenal androgens
31
Primary adrenal insufficiency diagnostic with cosyntropin (synthetic ACTH)
- 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
Secondary adrenal insufficiency diagnostic with cosyntropin (synthetic ACTH)
- Baseline levels of ACTH and cortisol low
| - Symptoms: malaise, anorexia, NO HYPERPIGMENTATION
33
Primary insufficiency - Treatment
- 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
Secondary insufficiency - Treatment
- Treat with HYDROCORTISONE, CORTISONE, or PREDNISONE
| - MINERALOCORTICOIDS ARE NOT NEEDED
35
Congenital Adrenal Hyperplasia - Major Causes
- 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
Congenital Adrenal Hyperplasia - Presentation
- Females: pseudohermaphroditism
- Males normal at birth, precocious puberty
- Non-classic POST puberty presentation (mild androgen excess hirsuitism, amenorrhea, etc)
37
Congenital Adrenal Hyperplasia - Treatment
- 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
Diseases associated with mineralocorticoids
- 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
Diseases associated with mineralocorticoids - Treatment
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
Therapeutic use of glucocorticoids
- 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
Steroids and Rheumatic Disorders
- 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
Steroids and Rheumatoid Arthritis
- 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
Steroids and Respiratory Disease
Asthma and COPD
- Low systemic side effects in inhalation
- Most common side effect is oral candidiasis
44
Steroids and Allergies
- 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
Steroids and GI
- 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
Steroids and Transplant
- Low doses useful in acute rejection
- Higher dose required in established rejection
- ALWAYS GIVE IN CONJUNCTION WITH OTHER AGENTS
47
Steroids and Respiratory Distress Syndrome
- 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
Glucocorticoid used as a standard by which all others are compared
Hydrocortisone
49
Corticosteroids used in mild disease
- Cortisol
- Hydrocortisone
- Cortisone
50
Corticosteroids used in moderate disease
- Prednisone
- Prednisolone
- Methyprednisolone
- Triamcinolone
- FLUDROCORTISONE (go-to drug)
51
Corticosteroids used in severe disease
- Betamethasone
| - Dexamethasone
52
Absorption of corticosteroids
- 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
Transport of corticosteroids
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
Activation of corticosteroids
HSD1, 11-beta-hydroxysteroid dehydrogenase type 1 isoenzyme activates (cortisone to cortisol)
- Found in most glucocorticoid target tissues
55
Deactivation of corticosteroids
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
Metabolism of corticosteroids
- Hepatic conjugation with glucoronides/sulfate (first pass effect varies by steroid)
- Renal excretion
57
Corticosteroid - oral administration
All
58
Corticosteroid - aerosol administration
- Beclomethasone
- Flunisolide
- Flutacisone
- Triamcinolone
59
Corticosteroid - topical administration
- Beclomethansone
- Dexamethasone
- Hydrocortisone
- Triamcinolone
60
Corticosteroid - IV and IM administration
- Dexamethasone
- Hydrocortisone
- Methylprednisone
- Prednisone
61
Corticosteroid - IM administration
- Cortisone
- Deoxycortisone
- Triamcinolone
62
Withdrawal effects from corticosteroids
- 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
Adverse effects of corticosteroids
- 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
Adverse effects of corticosteroids - Cardiovascular
- Hypertension
- Edema
- Na and water retention
- Dependent on the mineralocorticoid activity of the corticosteroid
- Hypokalemia
65
Adverse effects of corticosteroids - CNS
- Euphoria
- Depression
- Psychosis
- Insomnia
66
Adverse effects of corticosteroid - Immune system
Increase susceptibility to infection (especially viral and fungal)
67
Adverse effects of corticosteroid - GI
Peptic ulcer
68
Adverse effects of corticosteroid - Metabolic
- Hyperglycemia
- Muscle catabolism
- Hyperlipidemia altered fat deposition (Moon face, etc)
- Striae
69
Adverse effects of corticosteroid - Eye
- Cataracts
| - Glaucoma
70
Adverse effects of corticosteroid - Osteoporosis
- Negative calcium balance - causes increased parathyroid hormone secretion, cause bone resorption
- Inhibition of osteoblasts
71
Contraindications for corticosteroids
- 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
Corticosteroid drug interactions
- 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)
