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Pharm Block 2 > 4 - Adrenal Steroids > Flashcards

4 - Adrenal Steroids Flashcards

1
Q

How and when are steroids synthesized?

A

They are not stored, they’re made when they’re needed and the rate of secretion equals the rate of synthesis.

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2
Q

How is aldosterone made? Where is it made? What is synthesis controlled by?

A

Zona glomerulosa: Cholesterol made into pregnenolone (rate limiting) -> desoxycorticosterone –> aldosterone

Synthesis controlled by angiotensin II and plasma K.

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3
Q

How is cortisol made? Where is it made? What is it’s synthesis controlled by?

A

Zona fasciculata and reticularis: cholesterol -> pregnenolone -> desoxycortisol -> cortisol

Synthesis controlled by ACTH.

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4
Q

What inactivates steroids?

A

In the liver by:

  • reduction of A ring
  • sulfate conjugation
  • glucuronide conjugation
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5
Q

What are the general mechanisms for corticosteroid effects?

A
  1. binds cytosolic steroid receptor
  2. translocated to nucleus
  3. stimulates transcription of mRNA and stimulates mRNA directed protein synthesis
  4. Proteins mediate glucocorticoid effect
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6
Q

What effects do steroids have on carbohydrate and protein metabolism? What mediates this?

A

Mediated by glucocorticoid receptor:

  • enhances liver gluconeogenesis from protein
  • stimulates aa mobilization
  • increase liver glycogen
  • increase urinary nitrogen excretion
  • reduces peripheral glucose utilization
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7
Q

What effects do steroids have on lipid metabolism?

A

Redistribution of body fat causing moon face and buffalo hump.

Stimulates release of fatty acids from adipose tissue.

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8
Q

What effects do steroids have on mineral and electrolyte metabolism? What receptor does this work through

A

Mediated by mineralocorticoid receptor in kidney.

Cortisol = aldosterone&raquo_space; cortisone

Causes increase Na reabsorption, increase K and H ion excretion, and is responsible for CV effects such as HTN.

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9
Q

What effect do steroids have on the CNS?

A

Sleepiness and lability of mood.

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10
Q

What effect do steroids have on the immune system?

A
  1. Cell traffic/accumulation reduces the access of cells to target tissues
  2. causes lymphocytopenia and monocytopenia
  3. Prevent neutrophil adherence to endothelium
  4. inhibit action of chemotactic factors to decrease accumulation of inflamm cells at site of inflamm
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11
Q

What effects do steroids have on macrophages?

A

Macrophages: inhibits antigen processing, inhibits binding Fc receptors, inhibitirs synthesis and realse of IL-1

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12
Q

What effects do steroids have on T-lymphocytes? What is the result of this?

A

Interfere with actions of lymphokines such as IL-2, macrophage migration inhibitory factor, macrophage aggregating factor, monocyte chemotactic factor and lymphotoxin.

Absence of IL-1 prevents activation.

Reduces IL-2 synthesis

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13
Q

What happens when an immune stimulator like tumor necrosis factor (TNF) binds to its receptors REC? What can prevent this?

A

It leads to IkB detruction, causing it to release from NFkB.

NFkB then moves into the nucl where it activates cytokines and other genes.

By stimulating IkBalpha production, glucocorticoids (GC) can prevent the action of NFkB.

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14
Q

What anti-inflammatory effects do steroids have?

A
  1. Inhibit signs and symptoms of inflammation by inhibitings immune system
  2. Inhibit arachidonic acid release so synthesis of prostaglandings and leukotrienes is reduced.
  3. Inhibits induction of COX-2
  4. Decreases cap permeability
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15
Q

What is the major therapeutic use for steroids? When are they contraindicated?

A

Replacement therapy when the pt isn’t making enough on their own; RA, osteoarthritis, allergic diseases, and cerebral edema.

Contraindicated in TB infections because they suppress the immune system and can cause reinfection/worsening of TB.

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16
Q

What is one use of glucocorticoids that mineralocorticoids are not used for?

A

Inflammatory diseases of the eyes, ears, skin etc.

Used locally.

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17
Q

What are five examples of steroid drugs?

A

Cortisol, dexamethasone, prednisone, fludrocortisone, and aldosterone.

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18
Q

What can cause steroid toxicity?

A

Rapid withdrawl can cause acute adrenal insufficiency, salt wasting, and CV collapse.

Prolonged therapy can suppress pituitary-adrenal axis and cause adrenal insufficiency and atrophy. Requires tapering.

Cushings syndrome.

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19
Q

What are characteristics of cushings syndrome? What are most of these symptoms due to?

A 
Moon face and buffalo hump. 
Poor wound healing 
Thin skin
Hypertension
Thin extremities 
Striae.

Most due to mobilizing proteins away from where they are supposed to be.

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20
Q

What drug blocks 11-beta hydroxylation so synthesis of cortisol is stopped at 11-desoxycortisol? What is the result of this?

A

Metyrapone

11-desoxycortisol doesn’t inhibit ACTH so levels of ACTH increase and stimulate synthesis of 17-hydroxycorticoids as 11-desoxycortisol.

Used as a diagnositc test to see function of pituitary.

21
Q

What drug is a competitive antagonist at progesterone and glucocorticoid receptors and act to terminate pregnancy and treat cushings.

A

Mifepristone.

Can really treat any condition of glucocorticoid excess.

22
Q

What is the action of spironolactone and eplerenone? What are they used to treat?

A

Competitive antagonists at mineralcorticoid receptor.

Used as diuretics, treat hypertension, cardiac hypertrophy and heart failure.

23
Q

What type of receptors does Drospirenon act on? What effect does it have on each?

A

Progesterone receptor agonist.

Mineralcorticoid receptor antagonist.

Androgen receptor antagonist.

24
Q

What effect does drospirenone have on the progesterone receptor? What are the therapeutic uses for it?

A

It acts as an agonist.

Used with estrogen to suppress ovulation and as a hormone replacement therapy in post-menopausal women.

25
Q

What effect does drospirenone have on the mineralocorticoid receptor? What are the therapeutic uses for it?

A

It acts as an antagonist.

Used as a diuretic and antagonizes the salt retaining effects of estrogen.

26
Q

What is the action of Interleukin-1 (IL-1)? What makes it?

A

Made my macrophages in response to virus, bacteria, antigens, or inflamm agents.

Activates lymphocytes and promotes differentiation of AB forming cells.

Endogenous pyrogen (fever).

27
Q

What is the function of IL-2? What makes it?

A

Produced by T-lymphocytes.

Growth factor for T-lymphocytes that promotes prolif of T lymphocytes and enhances tumoricytic activity of them.

28
Q

What makes interferons and what is their function?

A

alpha and beta made by leukocytes. Gamma make by lymphocytes.

Inhibits replication of viruses and enhances phagocytosis and cytotoxicity.

29
Q

What can interferons be used to treat?

A

Beta used to treat viral infections and MS.

Gamma can treat renal cell carcinoma and atopic dermatitis.

30
Q

What is the function of tumor necrosis factor? In what illness is it typically elevated?

A

Stimulates IL-1 synthesis, activates PMNs, stimulates prostaglandin synthesis and collagenase production.

Elevated in RA.

31
Q

What stimulates cytotoxic cells?

A
  1. Macrophage processing of antigen.
  2. Presentation of antigen to T-lymphocyte and expression of IL-1 and IL-2 on T-lymphocyte.
  3. Secretion of IL-1 by macrophages.
  4. IL-1 promotes IL-2 release from helper T’s
  5. IL-2 acts on lymphocytes to promote replication of cytotoxic T cells.
32
Q

What are the uses for immunosuppression?

A

Prevention of allograft rejection and treatment of autoimmune diseases.

33
Q

What is the function of prednisone?

A

Corticosteroid used to reduce the access of cells to target tissues.

Interferes with macropahge antigen processing, blocking action of lymphokines, and inhibits binding to Fc receptors.

34
Q

When is prednisone typically used? What is the associated toxicity? When is it contraindicated?

A

In combo with other drugs in autoimmune disease and to prevent graft rejection.

Can cause suppression of adrenal-pit axis and result in acute adrenal insuff. Cushings.

Contraindicated during infection due to immune suppression.

35
Q

What is the function and action of antiproliferative and antimetabolic drugs? When are they best used?

A

They kill rapidly proliferating immune cells. Given in a low dose daily to block immunoproliferation.

Best used at the time of initial exposure to antigen and will kill precursor cells.

Relevant clone stimulated by antigen will be killed.Other immune cells and clones not stimulated by antigen will be spared.

36
Q

What purine anti-metabolic drug is orally active and metabolized by 6-mercaptopurine? What is the mechanism of action?

A

Azathiopruine.

Inhibits both de novo and salvage purine biosynthesis and thereby inhibits DNA synthesis.

37
Q

What is Azathiopurine used to treat? What is a major side effect?

A

Used to inhibit rejection of transplanted organs and in some autoimmine diseases as RA.

Bone marrow suppression major side effect. GI and hepatic toxicity may occur.

38
Q

What is cyclophosphamide?

A

Orally active alkylating agent that results in cross-linking of DNA to kill replicating and non-replicating cells.

Toxic effects on B cells so more effective in suppressing humoral immunity. T cells also effective but they recover more quickly.

39
Q

What drug is used to treat autoimune diseases in combination with other drugs, but is not effective in preventing graph rejection? What is the major side effect associated with this drug?

A

Cyclophosphamide.

Bone marrow suppression.

40
Q

What is Methotrexate? What is it used to treat and what is the major adverse side effect?

A

Inhibitor of dihydrofolate reductase - inhibits folate dependent steps in purine synthesis to inhibit DNA synthesis.

Used to treat autoimmune diseases.

Can cause hepatic toxicity.

41
Q

What is the mechanism of action of mycophenolate mofetil?

A

Orally active lymphocyte selective immunosuppressant that inhibits IMP dehydrogenase that normally takes IMP to GMP, which is necessary for de novo purine synthesis. (no effect on salvage)

Lymphocytes can’t make GMP via salvage so this is selective for lymphocytes and inhibits their proliferation and expression of CAMs.

42
Q

What orally active drug is a more selective immunosuppressant than azathioprine or methotrexate but equally as effective? When is this drug used?

A

Mycophenolate mofetil.

Used with cyclosporine and corticosteroids to prevent renal allograft rejection. Allwo lowers doses of cyclosporine so less toxicity.

Autoimmune disease like RA or refractory psoriasis.

43
Q

When should mycophenolate mofetil be used with caution? What are some side effects? When is it contraindicated?

A

In pts with GI disease, reduced renal function, and infections.

Side effects: Infection, leukopenia, anemia, GI effecs.

Shouldn’t be used during pregnancy because it can cause loss of baby and congenital malformations.

44
Q

What is the mechanism of action of cyclosporin?

A

Lipophilic peptide antibiotic that binds to cellular receptor cyclophilin and inhibits calcium dependent phosphatase (calcineurin) to block activated of TF NFAT needed for IL-2 production.

This inhibits mRNA synthesis coding for IL-2 thus blocking T helper function and inhibits proliferation and cytotoxicity.

Not lymphotoxic.

45
Q

What orally active drug is used to prevent rejection of transplanted organs and is more effective than other agents used with fewer side effects. (It is also used in some autoimmune diseases.) What is the major side effect?

A

Cyclosporine.

Nephrotoxicity may occur in 25-40% of pts with high doses.

Reversible with reduction in dosage or discontinuation.

Hepatotoxicity may also occur.

46
Q

What is the mechanism of action of Tacrolimus? How does this drug compare to cyclosporin?

A

Calcineurin inhibitor that binds the FK binding protein.

Same mechanism of action as cyclosporine with same spectrum of action, but 50-100 times more potentwith less nerpho and hepatotoxicity

47
Q

What is the mechanism of action of sirolimus?

A

Inhibits T cell activation and proliferation downstream of IL-2.

Binds FKB-12 (complex doesn’t bind calcineurin or affect calcineurin activity) and complex bindsand inhibits mTOR, a kinase involved in cell-cycle progression

This prevents the transition from G1 to S.

48
Q

What are the uses of sirolimus?

A

Same as cyclosporine.

Also used in coating of cardiac stents.

Pharm Block 2 (12 decks)

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