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Pharma 2- Semmelweis > B-19/20. Glucocorticoids for oral and parenteral use. Topically applied glucocorticoids and Mineralocorticoids. > Flashcards

B-19/20. Glucocorticoids for oral and parenteral use. Topically applied glucocorticoids and Mineralocorticoids. Flashcards

1
Q

Which interleukins upregulate the hypothalamus and anterior pituitary?
Which neurotransmitters upregulate the hypothalamus?
Which neurotransmitters/hormone downregulates the hypothalamus (CRH neurons)?

A
  1. ) Il-1, Il-2, Il-6, and TNF-alpha upregulate (they are released from the immune system via the lymphocytes, macrophages, monocytes, and neutrophils)
  2. ) Ach, 5-HT, NE upregulate
  3. ) NE, GABA, and cortisol downregulate
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2
Q

What hormones upregulate/downregulate the anterior pituitary (Corticotropes)?

A

CRH upregulates the anterior pituitary and cortisol downregulates it

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3
Q

What hormones upregulate the adrenal cortex (fasciculata cells) and why do we measure it?

A

ACTH upregulates the adrenal cortex leading to the release of cortisol.
It is measured for diagnostic purposes and certain epilepsies in childhood.

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4
Q

What do the different cells in the adrenal cortex get upregulated by, release, and via which CYP enzyme?

  1. ) Zona Glomerulosa?
  2. ) Zona Fasciculata?
  3. ) Zona Reticularis?
A
  1. ) Zona Glomerulosa
    - Upregulated by Angiotensin II/K+ releasing aldosterone via CYP11B2
  2. ) Zona Fasciculata
    - Upregulated by ACTH releasing cortisol via CYP11B1/CYP17
  3. ) Zona Reticularis
    - Upregulated by ACTH releasing DHEA via CYP17
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5
Q

What are the genomic and non-genomic mechanisms of steroid hormone operation?

A

The steroid hormones (aldosteron, cortisol, progesterone, estrogen, and testosterone) act via the…

  1. ) Genomic action where the hormone crosses the lipid membrane and binds an intracellular receptor, transducer, and messenger to bind directly to DNA to amplify and undergo gene transcription
  2. ) Nongenomic action which binds a receptor on the cell surface that activates a tranducer (Alpha, beta + gamma subunits) which upregulate amplifiers that create messengers that have intracellular effect (AC creates cyclic AMP, PI 3-k creates PIP3, and PLC creates DAG and InsP3 which increases intracellular calcium)
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6
Q

What are some specific gene transcriptions can the steroid-glucocorticoid receptor complex activate?

A

It interacts with other transciptions factors like NF-kB and AP1 which are involved in anti-inflammatory and immunosuppressive effects

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7
Q

Glucocorticoid receptor actions (Gene activation)

A
  1. ) Annexin-1 which decreases PLA2 (precursor for eicosanoids, such as prostaglandins and leukotrienes.)
    - Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues.
  2. ) Enzymes of gluconeogenesis and amino acid metabolism (cAMP dependent protein kinase)
  3. ) Adrenergic receptors on vascular and bronchial smooth muscle (permissive effect e.g. B2 agonist effect in bronchial asthma)
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8
Q

Glucocorticoid receptor actions (Gene repression)

A

COX-2, NOS, Cytokines, Interleukins, and Cell adhesion molecules
* 10-20% of expressed genes are regulated by glucocorticoids

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9
Q

Glucocorticoid metabolic effects

  1. ) Carbohydrates?
  2. ) Proteins?
  3. ) Lipids?
A

1.) Carbohydrates
-Decreased glucose uptake and utilization
-Increased gluconeogenesis
(Hyperglycemic tendency)
2.) Proteins
-Increased catabolism
-Decreased anabolism
3.) Lipids
-Redistribution of fat (Cushing type)
-Increased triglycerides
-Increased LDL/HDL

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10
Q

Glucocorticoid regulatory effects part 1:

  1. ) Hypothalamus and anterior pituitary gland?
  2. ) Cardiovascular system?
  3. ) Musculoskeletal?
A
  1. ) Hypothalamus and anterior pituitary gland
    - Negative feedback causes decreased release of endogenous glucocorticoids
  2. ) Cardiovascular system
    - Decreased vasodilation
  3. ) Musculoskeletal
    - Activity of osteoblast decreased and osteoclast activity increases (less bone formation)
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11
Q

Glucocorticoid regulatory effects part 2:

Inflammation and immunity?

A
  1. ) Less influx and activity of leukocytes in acute inflammation
  2. ) Less activity of mononuclear cells, angiogenesis, and fibrosis in chronic inflammation
  3. ) In the blood there will be more neutrophils and less eosinophils, basophils, monocytes, and lymphocytes
  4. ) Lymphoid tissues will have decreased T/B cells clonal expansion and decreased cytokine secreting T action
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12
Q

Glucocorticoid regulatory effects part 3:
Mediators?
Overall effects?

A

1.) Decreased production and action of cytokines (ILs, TNF-alpha, GM-CSF)
2.) Less generation of eicosanoids
3.) Less generation of IgG
4.) Decreased complement components in the blood
5.) Increased release of anti-inflammatory factors (e.g. IL-10 and annexin-1)
Overall effects: activity of the innate and acquired immune systems decrease as well as healing and protective aspects of inflammation

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13
Q

Clinical uses of glucocorticoids (6)

A
  1. ) Replacement therapy (adrenocortical insufficiency, Addison’s disease)
  2. ) Diagnostic purposes (dexamethasone suppression test, Cushing’s syndrome, diff. diagnosis of depression)
  3. ) Stimulation of lung maturation in fetus (premature before week 34)
  4. )Anti-inflammatory/immunosupressive therapy (more in next flashcard)
  5. ) In neoplastic diseases (more in next flashcard)
  6. ) Nausea and vomiting (in chemotherapy and general anesthesia)
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14
Q

Glucocorticoid Anti-inflammatory/immunosupressive therapeutical uses (5)

A
  1. ) In asthma
  2. ) Topically in inflammatory conditions of skin, eye, ear, nose (e.g. eczema, allergic conjunctivitis or rhinitis)
  3. ) Hypersensitivity states (e.g. severe allergic rxn)
  4. ) In diseases with autoimmune and inflammatory components (e.g. RA and other connective tissue diseases, IBD, some forms of haemolytic anaemia, idiopathic thrombocytopenic purpura)
  5. ) To prevent graft vs host rxn (organ or bone marrow transplantation
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15
Q

Glucocorticoid neoplastic diseases therapeutic uses (2)

A
  1. ) In combination with cytotoxic drugs (Hodgkin’s disease, acute lymphocytic leukaemia)
  2. ) to reduce cerebral oedema (metastatic or primary brain tumours; dexamethasone)
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16
Q

Glucocorticoid drugs (11)

A
  1. ) Hydrocortisone (Cortisol)
  2. ) Cortisone
  3. ) Deflazacort
  4. ) Prednisolone
  5. ) Prednisone
  6. ) Methylprednisolone
  7. ) Triamcinolone
  8. ) Dexamethason
  9. ) Betamethasone
  10. ) Fludrocortisone
  11. ) Aldosteron
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17
Q

Which glucocorticoid drugs are prodrugs

A

Cortisone, Prednisone, Deflazacort, and Fludrocortisone

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18
Q

Glucocorticoids of short action (8-12 hours)

A

Hydrocortisone, Cortisone, and Deflazacort

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19
Q

Glucocorticoids of intermediate action (12-36 hours)

A

Prednisolone, Prednisone, Methylprednisolone, Triamcinolone

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20
Q

Glucocorticoids of long action (36-72 hours)

A

Dexamethasone and Betamethasone

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21
Q

Strongest anti-inflammatory Glucocorticoids (3)

A

Dexamethasone, Betamethasone, and Fludrocortisone

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22
Q

Which 2 glucocorticoids have minimal sodium retaining ability

A

Dexamethasone and Betamethasone

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23
Q

Which 2 glucocorticoids have high sodium retaining ability

A

Fludrocortisone and Aldosterone (endogenous mineralocorticoid)

24
Q

Hydrocortisone function

A

Drug of choice for replacement therapy

25
Q

Cortisone function

A

Cheap, inactive until converted to hydrocortisone

26
Q

Deflazacort function

A

Must be converted by plastma esterases into active metabolite, similar utility to prednisolone

27
Q

Prednisolone function

A

Drug of choice for systemic anti-inflammatory and immunosuppressive effect

28
Q

Prednisone function

A

Inactive until converted to prednisolone

29
Q

Methylprednisolone function

A

Anti-inflammatory and immunosuppresive

30
Q

Dexamethasone function

A
  1. ) Anti inflammatory
  2. ) Immunosuppressive, used especially where water retention is undesirable (e.g. cerebral edema)
  3. ) Drug of choice for suppression of adrenocorticotrophic hormone production
31
Q

Bethamethasone function

A

Anti-inflammatory and immunosuppresion (used especially when water retention is undesirable)

32
Q

Fludrocortisone function

A

Drug of choice for mineralocorticoid effects

33
Q

Aldosterone function

A

Endogenous mineralocorticoid

34
Q

Cortisol is deactived to cortisone by which enzyme? Activated by which enzyme?

A

Cortisol is deactivated by 11B-HSD2. Activated 11B-HSD1.

35
Q

Topical administration of glucocorticoids (7) and advantage of topical administration

A

Advantage of topical administration, decreased systemic side effects

  1. ) Bronchial asthma: aersol
  2. ) Allergic rhinitis: nasal spray
  3. ) Ophthalmology: Optical Glucocorticoid Therapy
  4. ) Dermatology: ointment, solution
  5. ) IBD: suppository, enema
  6. ) Joint disease: intra-articular
  7. ) Timed-release tablet (physiology-like cortisol levels; high morning, low evening)
36
Q

Glucocorticoids meds used for bronchial asthma aerosol

A

beclomethasone, fluticasone, mometasone, budesonide, flunisolide

37
Q

Glucocorticoids meds used for allergic rhinitis nasal spray

A

beclomethasone, triamcinolone, budesonide, flunisolide

38
Q

Glucocorticoids meds used for dermatology

A

Flumetazone, triamcinolone, fluocinolone w/ acetonide moiety w/ increased topical activity

39
Q 
Pharmacokinetics of glucocorticoids
Oral absorption?
Transport in blood?
Half life?
Metabolism?
A
  1. ) Good p.o. absorption
  2. ) Transport in blood by
    - 90% corticosteroid-binding globulin (CBG)/a2 globulin
    - 5-10% free
    - 5% albumin (large capacity, low affinity practically considered as free)
  3. ) 60-90 minute half life
  4. ) Metabolism
    - 80% in the liver
    - 20% in the kidney and other MR containing tissue (e.g. colon, salivary glands)
    - 1% unchanged in the urine
40
Q

Unwanted unusual serious side effects

A
  1. ) insomnia, hypomania
  2. ) peptic ulcer
  3. ) acute pancreatitis (rare; only at high dose)
41
Q

Unwanted effects of glucocorticoids (longer than 2 week therapy) (11)

A
  1. ) Response to infection or injury decreased (wound healing decrease, peptic ulceration, oral candidiasis)
  2. ) Iatrogenic Cushing’s syndrome
  3. ) Suppression of endogenous glucocorticoid synthesis
  4. ) Hypokalemia, hypernatremia, edema, hypertension
  5. ) Osteoporosis
  6. ) Aseptic necrosis of femoral head
  7. ) Hyperglycaemia, insulin increased, weight game, DM
  8. ) Muscle wasting, myopathy
  9. ) Inhibition of growth in children (if> 6 months treatment)
  10. ) CNS effects: hypomania, psyhosis (at very large doses), long term: depression
  11. ) Other effects: glaucoma (in genetically predisposed persons), incidence of cataracts increased, intracranial pressure increased
42
Q

What type of diet should patients be on if they are on long term glucocorticoid therapy

A

High protein and K+ enriched diet

43
Q

What is the 2 essential dosage rules of glucocorticoids

A

Driven by seriousness of the disease, duration of therapy.

Keep dosage as low as possible-titrate!

44
Q

Dosage in these cases

  1. ) initial doses?
  2. ) To supress ACTH?
  3. ) Inflammatory and allergic disorders?
    4) Severe autoimmune disease?
  4. ) If large dose required?
  5. ) If large dose for long period required?
  6. ) If large dose is required?
  7. ) How to stop treatment?
A

Dosage in these cases
1.) initial doses
-Higher doses for initial effect, lower dose for maintanence
2.) To suppress ACTH
-Small, frequent p.o. doses or slowly absorbed p.e. preparation
3.) Inflammatory and allergic disorders
-Same quantity in a few doses
4) Severe autoimmune disease
-High, divided dose, gradual reduction later on
5.) If large dose required
Synthetic with minimal mineralocorticoid action
6.) If large dose for long period required
-Try alternate-day administration (side effects decreased sometimes)
7.) If large dose is required
-Medium or intermediate-acting synthetic steroid with little MR action
8.) How to stop treatment
-Slow, gradual cessation, otherwise disease symptoms may reappear or even intensify

45
Q

Mineralocorticoid receptor actions

Genomic? Non-genomic?

A

Genomic
-Na+/K+-ATPase transcription increases
-ENa channel activity increases (Increased Na+ reabsorption and K+ and H+ excretion increased in the collecting tubule and duct)
-Increased expression of profibrotic molecules (e.g. TGF-B)
-Increased NADPH oxidase expression, ROS (proinflammatory effect)
Non-genomic
-Proinflammatory effects (via EGFR and ERK1/ERK2)

46
Q

Clinical uses of mineralocorticoids

A

Replacement therapy in adrenal hypofunction (fludrocortisone) and Chrousos syndreome (genetic: GR inactivation); high dose of synthetic glucocorticoid w/o inherent MR activity

47
Q

Clinical uses of mineralocorticoid antagonist

A
  1. ) Spironolactone: K+ sparing diuretic (also an androgen and progesterone receptor antagonist), preimary aldosteronism (adrenal adenoma)
  2. ) Eplereone: hypertension, heart failure
48
Q

Unwanted effects of the mineralocorticoids (4)

A
  1. ) Edema
  2. ) Increased blood pressure
  3. ) Hypokalemia (weakness, tetany), metabolic alkalosis
  4. ) Pro-inflammatory effect
49
Q

Adrenocortical antagonists

A
  1. ) Metyrapone
  2. ) Mitotane
  3. ) Ketoconazole
  4. ) Aminogluthetimide
  5. ) Etomidate
  6. ) Trilostane
  7. ) Mifepristone
50
Q

Metyrapone MOA and function

A

Inhibitor of 11 B-hydroxylase for diagnostic purposes

51
Q

Mitotane
Derivative of?
Taken?
Function?

A
  • Derivative of insecticide DDT
  • p.o.
  • Used in adrenal carcinoma (cytotoxic for adrenal cortex decreases tumor mass; fairly toxic)
52
Q

Ketoconazole MOA and function

A
  • Inhibits cholesterol to pregnenolone and 17-alpha-OH

- Antifungal drug used in Cushing syndrome

53
Q

Aminogluthetimide function (2)

A
  1. ) In conjunction with ketoconazole or metyrapone in Cushing syndrome due to adrenocortical cancer not responding to mitotane
  2. ) In conjunction with dexamethasone or hydrocortisone to reduce estrogen in breast cancer
54
Q

Etomidate MOA and function

A
  • Inhibitor of 11 B-hydroxylase, I.V. anesthetic

- In severe Cushing syndrome

55
Q

Trilostane function

A

comparable to aminogluthetimide

56
Q

Mifepristone (SPRM) function

A

“Chemical abortion” with antiprogesteron and antiglucocorticoid activity for inoperable ectopic ACTH tumors or adrenal carcinoma

Pharma 2- Semmelweis (43 decks)

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