Cause “feedback inhibition” of further glucocorticoid and thyroid stimulating hormone production MUST BE WEANED OFF SLOWLY (if stopped abruptly, you will get symptoms of Addison's disease) Can induce adrenal insufficiency or even death if not weaned

test 4 part 2 Flashcards by Marcus Chlopek

Adrenal cortex = Zona glomerulosa releases

• Mineralocorticoids -> Aldosterone (main one)

- mainly found in exratory organs

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Adrenal cortex = Zona fasciculata releases

• Glucocorticoids -> Cortisol (main one)

- located throughout your entire body

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Adrenal cortex = Zona reticularis releases

• Adrenal androgens -> DHEA (dehydro-epi-angerosterone) goes to turn into other sex hormones

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Adrenal medulla secretes

• Catecholamines -> Epi and norepi

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Corticosteroids

• Bind to specific intracellular cytoplasmic receptors in target tissues
– Widely distributed throughout the body
– Glucocorticoid receptors: widely distributed throughout body
– Mineralocorticoid receptors: excretory organs-kidney, colon, salivary & sweat glands
• Receptor-hormone complex recruits coactivator proteins and translocates into cell nucleus where it alters gene transcription
• Attaches to gene promoter elements
• Turns genes on or off

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Glucocorticoids Function: 1. Increase resistance to stress

– Raise glucose levels and provide the body with energy to combat stress

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Glucocorticoids Function: 2. Promote

– Gluconeogenesis
– Protein catabolism
– Lipolysis

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Glucocorticoids Function: 3. Alter blood cell levels in plasma

• DECREASE:
        – WBC
        – Eosinophils
        – Basophils
        – Monocytes
        – Lymphocytes
• INCREASE:
        – Hemoglobin
        – Erythrocytes
        – Platelets

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Glucocorticoids Function: Catabolic vs anabolic

Catabolic steroids (causing the breakdown of fat and sugar stores)
NOT anabolic steroids (building up)

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Glucocorticoids Function: Immunosuppressiveness

• All glucocorticoids are immunosuppressive even as a single dose (destroying T cells and weakens the immune system)

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Glucocorticoids Function: 4. Have POTENT anti-inflammatory and immunosuppressive activity

most important therapeutic property
• Decrease circulating lymphocytes
• Inhibit ability of leukocytes and macrophages to respond to antigens
• Decrease production and release of cytokines
• Inhibit the precursor of prostaglandins and leukotrienes (anti-inflammatory action)
• Decrease histamine release

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Glucocorticoids Function: 5. Affect other systems at high levels

Bone density loss (most common)
Glaucoma
Personality changes
Increased appetite
Daibetogenic
Moon face & humpback

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HYPERcortisolism disease

Cushing Syndrome

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HYPOcortisolism disease

Addison’s Disease

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Glucocorticoids

Cause “feedback inhibition” of further glucocorticoid and thyroid stimulating hormone production
MUST BE WEANED OFF SLOWLY (if stopped abruptly, you will get symptoms of Addison’s disease)
Can induce adrenal insufficiency or even death if not weaned

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Therapeutic Use of Glucocorticoids

• Addison’s disease
• Relief of inflammatory symptoms
        – Arthritis
        – Inflammatory skin conditions
        – Asthma
        – Inflammatory bowel disease
• Treatment of allergies
        – Allergic rhinitis
        – Drug, serum &amp; transfusion reactions
• Acceleration of fetal lung maturation helping newborns to breathe 
• Post transplant immunosuppression

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Glucocorticoids Pharmacokinetics

• Oral, IV, IM, topical, inhalation, intranasal, intra-articulary
• Metabolized by the liver, excreted by kidney
– Liver dysfunction/failure may increase half-life

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Glucocorticoids with the most anti-inflammatory effect and no salt-retention effect

Dexamethasone (Decadron)

- long acting

Intermediate length with high anti-inflammatory effect with very little salt-retention effect

Prednisone
Prednisolone
Methylprednisolone (Medrol, Solu-Medrol) -> more anti-inflammatory effect and less salt-retention effect

Very short acting and even but little amounts of anti-inflammatory effect and salt-retention effect

-Hydrocortisone

Allograft Rejection types

Hyperacute
Acute
Chronic

direct and indirect allorecognition

direct- using the MHC complex from the donor

- indirect- using the MHC from the recipients body

Hyperacute Rejection

Minutes to hours
Thrombotic occlusion of graft vasculature
Mediated by pre-existing antibodies in host (multiple transfusions, past transplant)

Acute Rejection

• After first week
• Vascular and parenchymal injury
• Mediated by T cells and antibodies
- damage to inside the cell causing occlusion

Chronic Rejection

* Occurs during a prolonged period * Fibrosis and vascular abnormalities * Pathogenesis less understood – T cells, macrophages

Immunosuppressants: Induction Drugs

• used at the time of transplantation

Immunosuppressants: Maintenance Drugs

• required for long term immunosuppression

5 Major Classes of Immunosuppressants

1. Glucocorticoids 2. Calcineurin Inhibitors 3. mTOR Inhibitors 4. Antiproliferative Agents 5. Antibodies

Glucocorticoids

• A standard component of induction and maintenance – Initial high doses that taper over time • D.O.C. for moderate rejection episodes • Complex mechanism – Profoundly suppresses T-lymphocytes - Have the most side effects of any immunosuppressive category when given at high doses over the long term

Calcineurin

• the major T-cell activator

Calcineurin Inhibitors: Cyclosporine

• The “break-through” drug that allowed transplants • Used in combination therapy to reduce dosage and side effects – Nephrotoxicity – Immune suppression – Hepatotoxicity – Lymphoma • Levels must be monitored closely

Calcineurin Inhibitors: Tacrolimus

• More potent & efficacious than Cyclosporine • More nephrotoxic than Cyclosporine - can be more toxic to kidneys • Less cardiovascular toxicities than Cyclosporine – Hypertension – Hyperlipidemia

mTOR Inhibitors

• Block mTOR (an intracellular serine/threonine kinase) – TOR proteins are essential for cellular functions • Binding to mTOR blocks the maturation of activated T cells and their proliferation

Sirolimus (Rapamune)

``` - mTOR Inhibitors • Oral • Nephrotoxic (w/ Cyclosporine) = additive effects cause kidney toxicities • Hyperlipidemia • Delayed wound healing ```

Antiproliferative Agents

• Prevent proliferation of rapidly dividing cells – B lymphocytes – T lymphocytes - often used in combination with corticosteroids and Calcineurin Inhibitors - prevent the transcription of the DNA in the nucleus

Antiproliferative Agents -Azothioprine

• First agent to achieve widespread use in organ transplantation • Works better on acute rather than chronic responses – Because cells are rapidly dividing • Numerous & severe side effects have limited its use – Bone marrow suppression

Antiproliferative Agents -Mycophenolate mofetil

``` • Less severe side effects than Azothioprine • Side effects are GI related – Diarrhea – Nausea – Vomiting – Abdominal pain ```

Antiproliferative Agents -Mycophenolate sodium

• Designed to be a slower releasing and more enterically pleasing form of mycophenolate mofetil – Enteric coating – Releases drug in small intestine • No real evidence that it is more effective or safer

Antibodies

* React with T cell surface structures and deplete or inhibit T cells * Used to treat acute rejection episodes

Antibodies - Monoclonal

• Monoclonal antibodies: contain ONLY one type of antibody that is derived from a single cloned B-lymphocyte - most common - more specific and less variable on where they work - more expensive

Basiliximab (Simulect)

- Monoclonal antibody – Binds to the IL-2 receptor on activated T cells and interferes with proliferation (doesn't activate it) – Blocks the ability of antigens to activate the T cell response system

Antibodies - Polyclonal

• Polyclonal antibodies: contain multiple antibodies - cheaper - less specific and more variable on where they work

Antithymocyte Antibodies

* Used at time of transplant OR for episodes of severe rejection * Bind to circulating T lymphocytes and inactivate them