test 4 part 2 Flashcards
Adrenal cortex = Zona glomerulosa releases
• Mineralocorticoids -> Aldosterone (main one)
- mainly found in exratory organs
Adrenal cortex = Zona fasciculata releases
• Glucocorticoids -> Cortisol (main one)
- located throughout your entire body
Adrenal cortex = Zona reticularis releases
• Adrenal androgens -> DHEA (dehydro-epi-angerosterone) goes to turn into other sex hormones
Adrenal medulla secretes
• Catecholamines -> Epi and norepi
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
Glucocorticoids Function: 1. Increase resistance to stress
– Raise glucose levels and provide the body with energy to combat stress
Glucocorticoids Function: 2. Promote
– Gluconeogenesis
– Protein catabolism
– Lipolysis
Glucocorticoids Function: 3. Alter blood cell levels in plasma
• DECREASE:
– WBC
– Eosinophils
– Basophils
– Monocytes
– Lymphocytes
• INCREASE:
– Hemoglobin
– Erythrocytes
– PlateletsGlucocorticoids Function: Catabolic vs anabolic
- Catabolic steroids (causing the breakdown of fat and sugar stores)
- NOT anabolic steroids (building up)
Glucocorticoids Function: Immunosuppressiveness
• All glucocorticoids are immunosuppressive even as a single dose (destroying T cells and weakens the immune system)
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
Glucocorticoids Function: 5. Affect other systems at high levels
- Bone density loss (most common)
- Glaucoma
- Personality changes
- Increased appetite
- Daibetogenic
- Moon face & humpback
HYPERcortisolism disease
Cushing Syndrome
HYPOcortisolism disease
Addison’s Disease
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
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 & transfusion reactions
• Acceleration of fetal lung maturation helping newborns to breathe
• Post transplant immunosuppressionGlucocorticoids Pharmacokinetics
• Oral, IV, IM, topical, inhalation, intranasal, intra-articulary
• Metabolized by the liver, excreted by kidney
– Liver dysfunction/failure may increase half-life
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
- Glucocorticoids
- Calcineurin Inhibitors
- mTOR Inhibitors
- Antiproliferative Agents
- 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 painAntiproliferative 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
