Block 2: Inflammatory Disorders
Terms
undefined, object
copy deck
- Acute inflammation
- Immediate response to local mediators
- What are the Autacoids
-
Histamine, serotonin, bradykinin, prostaglandins, leukotrienes
*locally acting substances - What is the affect of autacoids?
- Vasodilation, increased vascular permeability chemotaxis, pain
- Chronic inflammation occurs in response to what mediators?
-
Interleukins
Granulocyte-macrophage colony-stimulating factor (GM-CSF)
TNF alpha and beta
Interferons
PDGF - Most common chronic inflammatory condition
- Rhematoid Arthritis
- Which enzyme converts Aracodonic Acid(AA) to Leukotrienes
- Lipoxygenase
- Which enzyme converts AA to prostacyclins, thromboxanes, and prostaglandins
- Cyclooxygenase
- What do leukotrienes cause?
- Bronchoconstricion
- What does thromboxane cause?
- Platelet aggregation
- What do Prostacyclins (PGX, PGI) cause?
- Antiaggregating factor release
- What does PGE2 cause?
- Edema, erythema, pain, fever
- What does PGF2alpha cause?
- Uterine contraction
- Prostacyclin (PGI2) and PGE2 have what local effect?
- Vasodilation
- Phospholipase A2 is inhibited by what?
- Glucocorticoids
- Inhibits Cyclooxygenase
- NSAIDS
- COX 1 Expression
- Constitutively in most tissues, generates LOW levels of prostaglandins
- Function of COX-1
- Protective function (gastric mucosa), vasodilator- determines peripheral resistance to kidney
- Other Functions of COX-1
- Blood clotting, uterine contraction, muscle growth, synaptic transmission at some CNS synapses
- COX-2 constituive or inducible?
- Inducible
- COX-2: Yields high or low levels of prostaglandins and thromboxanes
- HIGH
- When is COX-2 expressed in high concentration
- After induction by inflammatory mediators
- What is the major inflammatory mediator product
- Prostaglandin E2
- NF-kB
- Induces expression of cytokines (IL-1, IL-6), interferon beta, and cell adhesion molecules = ENHANCED INFLAMMATION
- What stimulates NF-kB?
- TNF alpha
- DMARD
-
Disease Modifying Anti-Rheumatic Drugs
- they delay the disease process - Examples of DMARDs
-
Methotrexate
Gold
Low-dose corticosteroids
Leflunomide
TNF alpha inhibitors - Selective Cox-2 inhibitor
- Celecoxib (sell a kox' ib)
- Non selective COX inhibitors (hint: there are 7)
-
Aspirin
Sodium salicylate
Indomethacin
Ibuprofen
Naproxen
Phenylbutazone
Acetaminophen -
Immunosuppresive Agents
(hint: 4 + 3 for gout) -
Glucocortocoids
Gold sodium thiomalate
Methotrexate
Leflunomide
Drugs for gout: allopurinol, probenecid, sulfinpyrazole - TNF alpha blockers
-
Etanercept
Infliximab - How long does it take to have a therapeutic response to DMARD
- weeks or months
- Current recommendation for DMARD
- Early in the course of RA
- Methotrexate
-
most widely used DMARD
anti-inflammatory - How long does it methotrexate to work?
- 4-6 weeks
- Side effects of Methotrexate
- Anorexia, vomiting, abdominal cramps, increased hepatic enzyme activity, immuno-suppresion, bone marrow supression, lymphomas
- What would you combine with methotrexate to make it more effective?
- Cyclosporine or infliximab
- Gold preparations MA
- Retard progression of bone and articular destruction
- Gold sodium thiomalate MA
- Gold accumulates in macrophages decreasing activation, migration, and therefore immune response
- How is Gold sodium thiomalate excreted?
-
Urine (60-90%)
Feces (10-40%) - Gold sodium thiomalate admin.
- I.m.
- Adverse effects of gold sodium thiomalate
-
~1/3 of patients
Dermatitis, thrombocytopenia, aplastic anemia(rare), proteinuria - Etanercept
- TNF alpha antagonist
- Structure of Etanercept
- composed of p75 TNF RECEPTOR coupled to Fc fragments of immunoglobulin
- MA of Etanercept
- Binds TNF alpha and blocks stiumlation of the receptors
- Infliximab
-
TNF alpha chimeric monoclonal antibody
(* on exam: Fc region of IgG + Fab sequences of mouse ANTI-TNF ANTIBODY) - Structure of Infliximab
- Human Fc of IgG + Fab sequence of mouse anti-TNF Ab
- MA of Infliximab
-
Binds free TNF alpha
Reduces joint swelling and damage - Infliximab admin
- I.v.
- Side effects of TNF alpha antagonist?
- Increased risk for infection, allergic rxns, and possibly malignancies
- Aspirin
- Irreversible non-selective COX enzyme inhibitor
- Aspirin MA
- Acetylates COX enzymes
- Ibuprofen/Naproxen
- Reversible non-selective COX enzyme inhibitors
- Side effects of Ibuprofen/Naproxen
- Due to (-) of COX 1, mainly gastric ulceration and bleeding, impaird kidney fxn
- Salicylate
- Weak COX inhibitor, probably a better NF-kB inhibitor (decreased IL-1,IL-6, and INF B)
-
Celecoxib
-advantages? -
COX-2 selective inhibitor
Reduced gastroduodenal damage, platelet aggregation is not impaired - Which COX-2 selective inhibitor was recently taken off the market?
- Rofecoxib (Vioxx)- increased risk of thromboembolic events due to unchecked Thromboxane A2 production
- Acetominophen
-
Analgesic and anti-pyretic
weak COX 1 and 2 inhibitor - New findings about Tylenol
- COX-3 expressed in CNS is very sensitive to acetaminophen inhibition
- Glucocorticoid 3 possible MA
-
Inhibition of AA production by (-) of phospholipase A2
Inhibition of inflam. cytokines (Interleukins,TNFa, IFNy)
Inhibition of NF-kB - Side effect of glucocorticoids
- Cushing's
- Why give aspirin to patients with heart conditions
- Reduces incidence of MI by 40%
- What cancer can aspirin provide protection against?
-
Colorectal
* 4 aspirin/week for 10 years of more - Bartter's Syndrome
-
hyperplasia of renal JG apparatus -- hyperreninemia, hyperaldosteronism, hypokalemic alkalosis, normal BP, elevated PG excretion
USE NSAIDS - Why use NSAIDs to treat Bartter's syndrome
- Reverses the symptoms
- PDA and NSAIDs
- patent ductus arteriosus treatment with NSAIDs as 60-90% success in closing duct
- What is salicylate?
- The deacetylated metabolite of aspirin