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

Question 1

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

Answer 1

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

Question 2

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

Answer 2

CRH upregulates the anterior pituitary and cortisol downregulates it

Question 3

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

Answer 3

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

Question 4

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?

Answer 4

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

Question 5

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

Answer 5

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)

Question 6

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

Answer 6

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

Question 7

Glucocorticoid receptor actions (Gene activation)

Answer 7

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)

Question 8

Glucocorticoid receptor actions (Gene repression)

Answer 8

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

Question 9

Glucocorticoid metabolic effects

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

Answer 9

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

Question 10

Glucocorticoid regulatory effects part 1:

1. ) Hypothalamus and anterior pituitary gland?
2. ) Cardiovascular system?
3. ) Musculoskeletal?

Answer 10

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)

Question 11

Glucocorticoid regulatory effects part 2:

Inflammation and immunity?

Answer 11

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

Question 12

Glucocorticoid regulatory effects part 3:
Mediators?
Overall effects?

Answer 12

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

Question 13

Clinical uses of glucocorticoids (6)

Answer 13

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)

Question 14

Glucocorticoid Anti-inflammatory/immunosupressive therapeutical uses (5)

Answer 14

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

Question 15

Glucocorticoid neoplastic diseases therapeutic uses (2)

Answer 15

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

Question 16

Glucocorticoid drugs (11)

Answer 16

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

Question 17

Which glucocorticoid drugs are prodrugs

Answer 17

Cortisone, Prednisone, Deflazacort, and Fludrocortisone

Question 18

Glucocorticoids of short action (8-12 hours)

Answer 18

Hydrocortisone, Cortisone, and Deflazacort

Question 19

Glucocorticoids of intermediate action (12-36 hours)

Answer 19

Prednisolone, Prednisone, Methylprednisolone, Triamcinolone

Question 20

Glucocorticoids of long action (36-72 hours)

Answer 20

Dexamethasone and Betamethasone

Question 21

Strongest anti-inflammatory Glucocorticoids (3)

Answer 21

Dexamethasone, Betamethasone, and Fludrocortisone

Question 22

Which 2 glucocorticoids have minimal sodium retaining ability

Answer 22

Dexamethasone and Betamethasone

Question 23

Which 2 glucocorticoids have high sodium retaining ability

Answer 23

Fludrocortisone and Aldosterone (endogenous mineralocorticoid)

Question 24

Hydrocortisone function

Answer 24

Drug of choice for replacement therapy

Question 25

Cortisone function

Answer 25

Cheap, inactive until converted to hydrocortisone

Question 26

Deflazacort function

Answer 26

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

Question 27

Prednisolone function

Answer 27

Drug of choice for systemic anti-inflammatory and immunosuppressive effect

Question 28

Prednisone function

Answer 28

Inactive until converted to prednisolone

Question 29

Methylprednisolone function

Answer 29

Anti-inflammatory and immunosuppresive

Question 30

Dexamethasone function

Answer 30

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

Question 31

Bethamethasone function

Answer 31

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

Question 32

Fludrocortisone function

Answer 32

Drug of choice for mineralocorticoid effects

Question 33

Aldosterone function

Answer 33

Endogenous mineralocorticoid

Question 34

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

Answer 34

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

Question 35

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

Answer 35

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)

Question 36

Glucocorticoids meds used for bronchial asthma aerosol

Answer 36

beclomethasone, fluticasone, mometasone, budesonide, flunisolide

Question 37

Glucocorticoids meds used for allergic rhinitis nasal spray

Answer 37

beclomethasone, triamcinolone, budesonide, flunisolide

Question 38

Glucocorticoids meds used for dermatology

Answer 38

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

Question 39

``` Pharmacokinetics of glucocorticoids Oral absorption? Transport in blood? Half life? Metabolism? ```

Answer 39

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

Question 40

Unwanted unusual serious side effects

Answer 40

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

Question 41

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

Answer 41

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

Question 42

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

Answer 42

High protein and K+ enriched diet

Question 43

What is the 2 essential dosage rules of glucocorticoids

Answer 43

Driven by seriousness of the disease, duration of therapy. | Keep dosage as low as possible-titrate!

Question 44

Dosage in these cases 1. ) initial doses? 2. ) To supress ACTH? 3. ) Inflammatory and allergic disorders? 4) Severe autoimmune disease? 5. ) If large dose required? 6. ) If large dose for long period required? 7. ) If large dose is required? 8. ) How to stop treatment?

Answer 44

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

Question 45

Mineralocorticoid receptor actions | Genomic? Non-genomic?

Answer 45

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)

Question 46

Clinical uses of mineralocorticoids

Answer 46

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

Question 47

Clinical uses of mineralocorticoid antagonist

Answer 47

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

Question 48

Unwanted effects of the mineralocorticoids (4)

Answer 48

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

Question 49

Adrenocortical antagonists

Answer 49

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

Question 50

Metyrapone MOA and function

Answer 50

Inhibitor of 11 B-hydroxylase for diagnostic purposes

Question 51

Mitotane Derivative of? Taken? Function?

Answer 51

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

Question 52

Ketoconazole MOA and function

Answer 52

- Inhibits cholesterol to pregnenolone and 17-alpha-OH | - Antifungal drug used in Cushing syndrome

Question 53

Aminogluthetimide function (2)

Answer 53

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

Question 54

Etomidate MOA and function

Answer 54

- Inhibitor of 11 B-hydroxylase, I.V. anesthetic | - In severe Cushing syndrome

Question 55

Trilostane function

Answer 55

comparable to aminogluthetimide

Question 56

Mifepristone (SPRM) function

Answer 56

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