Flashcards in Inflammation #3 (Murnane) Deck (69):
T/F OA is an IRREVERSIBLE, DEGENERATIVE, "wear and tear" arthritis
(OA is not an auto immune disease and it is not related to antibodies)
OA may reflect excessive release of enzymes that break down ________
(this cartilage is then replaced by badly aligned or overworked joints)
Where is articular cartilage located?
between the end of the bone and synovial fluid
When does synovitis (swelling or irritation of joints) occur in OA
T/F NSAID should be used instead of steroids in patients with OA
steroids exacerbate bone resorption
Steroids are the most....
profoundly anti-inflammatory substance
OA process causes (4)
-hyaline cartilage breakdown
What are CARDINAL SYMPTOMS of OA? (6)
-Joint tenderness, enlargement, deformity
-limitation of motion
-radiological findings (joint space narrow)
-NO SPECIFIC LAB FINDINGS in plasma
Although inflammation was once though NOT to be involved in OA, it is now considered one of the main contributors, why?
due to proinflammatory cytokines
What is the #1 risk factor for OA?
osteophytes are also known as? what is the purpose of osteophytes?
bone spurs. osteophytes are produced in an attempt to STABILIZE THE JOINT due to bone overgrowth
T/F Inflammation in OA is systemic
T/F If you WERE to test the synovial fluid of a patient with OA, there would be cytokines present
TRUE, however this method is not used routinely
What joints are commonly affected by OA?
joints that are used a lot or bear weight (hip, knee, foot, spine, etc)
Osteoarthritis of the spine is caused by?
slow deterioration of the disks between the bones that make up the backbone
T/F OA is a HETEROGENOUS DISEASE and 2 of the MAJOR symptoms are ACUTE PAIN and INFLAMMATION
What is FIRST LINE therapy for the treatment of OA?
What pharmacological activities does Tylenol have? (2)
What is a major side effect of Tylenol?
hepatotoxicity due to overdose
Describe the analgesic activity of COX inhibitors (4)
1. pain occurs
2. pain mediators (i.e. PGE2) signal
3. increase in growth factors through signaling (i.e. EP)--> increase in transcription/translation of TRPV1 (trafficking or phosphorylation)
4. pain is desensitized
antipyretic effects of APAP:
APAP and NSAIDS inhibits PGE2 production by COX-2 in the _______ in response to circulating _____
What are the major and minor metabolisms of APAP?
minor (P450 enzyme)
Why is the P450 enzyme considered the minor way for metabolism of APAP?
it produces a HIGHLY reactive intermediate (NAPQI) which can build up in the liver (hepatotoxicity)
T/F High doses of APA require cytochrome P450 for metabolism.
TRUE; leading to formation of highly reactive intermediates (e.g., NAPQI), which damage the liver by depleting its antioxidant glutathione
Which NSAID is the ONLY one that IRREVERSIBLY binds to COX?
COX-1 induces homeostatic functions; while COX-2 induces
Why can COX-2 increase its expression at the site of inflammation?
b/c it is induced by cytokines via NfKb pathway
What is a cell derived mediator?
What is a plasma-derived mediator? (3)
NSAID block what types of mediators?
PLASMA derived (prostaglandins) and CELL derived mediators (kinin, clotting, complement systems)
Prostacyclin synthase is found primarily in _______, while thromboxane synthase is found ONLY in _____
endothelial cells; platelets
Prostacyclin synthase cause (2)......., while Thromboxane synthase causes (2).....
-prostacyclin--> vasoDILATION and inhibit platelet aggregation
-thomboxane-->vasoCONSTRICTION and promote platelet aggregation
What is the anti-platelet dose for ASA?
75-325 mg Daily
T/F COX stimulation INCREASES GP IIb/IIIa expression
TRUE; GP IIb/ IIIa allows for cross linking of platelets
During first pass metabolism, ASA is broken down into?
first pass metabolism: occurs in the liver
Prior to first pass effect, ASA travels in the ________ where it has access to platelets
hepatic portal vein, if ASA binds there platelet can no longer resynthesizes COX b/c they do not have nuclei
T/F Higher doses of ASA could escape 1st pass metabolism
T/F If you "knock out" thromboxane, you can still synthesize prostacyclin and cause vasodilation AND inhibit platelet aggregation
TRUE b/c the prostacyclin pathway can only be inhibited at high doses of aspirin
What are 2 major side effects of PROPIONIC ACID and ACETIC ACID NSAID (i.e. ibuprofen, diclofenac)?
What is the first inflammatory mediator response?
the release of cytokines from neutrophils
What are the DIRECT and INDIRECT ways that you can evaluate COX selectivity?
-in VITRO (in cells, bacteria, etc) direct inhibition of COX-1 and COX-2
-in VIVO (in humans) by measuring the ability of the drug to interfere with synthesis of PGs
-in VIVO by evaluating pharmacological effect
Potency vs. Efficacy
-potency: the concentration or amount of the drug required to produce a defined effect
-efficacy: the therapeutic effectiveness of the drug in humans
What is the normal function of PGE2 synthesis? (2)
-replenish the GI tract epithelium
-supports secretion of mucus and bicarbonates
NSAIDs (primarily w/ COX-1 inhibitory activity) can inhibit PGE2, which causes what to happen? (2)
-an INCREASE in acid release
-DECREASE in mucosal bood flow epithelial cell proliferation
Mucous injury can occur from NSAIDs due to (2)
-physiochemical disruption of the gastric mucosa
-prolonged inhibition of gastric mucosal protection
COX-1 is mediates the "house keeping" functions and is ________ expressed in most cells, however COX-2 can be ______ in most cells and mediates acute, transient actions
Selectively inhibiting COX-2, inhibits ______ synthase. What does this cause?
prostacyclin, so you longer have the cardiovascular protection instead Thromboxane synthase induces PLATELET AGGREGATION and VASOCONSTRICTION
T/F Activity of BOTH COX-1 and COX-2 are required to produce adequate levels of PROSTACYCLIN to counterbalance the affects of thromboxane
T/F Drugs that contain Capsaicin deplete the sensory nerve endings of neuropeptides
Capsaicin _______ stimulates TRPV1 receptors
Where are neuropeptides (substance P; calcitonin) synthesized?
in the cell bodies of sensory neurons
T/F Substance P (neuropeptide) functions as a neurotransmitter AND neuromodulator
What is an ANTIDROMIC AP?
an action potential that travels back towards the nerve ending rather than towards the spinal cord
Capsaicin inhibits ______
What is the ALTERNATIVE 1st line therapy for OA patients?
What is the MOA of Tramadol?
Weak Mu agonist with NET and SERT blocking activity
What is the endogenous ligand for Mu receptors?
What part of the brain are Mu receptors (most dense)? (2)
Mu receptors function as an _____ and produces _____
Which neurotransmitters are pain INDUCING? (3)
-CGRP (calcitonin gene related peptide)
Which neurotransmitters are pain REDUCING? (5)
What transporters do Tramadol work on? (3)
-post synaptic opioid receptors (Mu)
Glucocorticoids (steroids) has profounding anti-inflammatory effects because?
they prevent synthesis and release of cytokines
they also decrease proliferation of lymphocytes and macrophages
What is the MOA of glucocorticoid?
modulate gene expression
What is a LONG TERM effect of using steroids?
What are clinical uses for glucocorticoids? (3)
-organ replacement surgeries
What are supplements that can be used to treat OA? (2)
T/F Duloxetine is a SNRI-serotonin norepinephrine reuptake inhibitor like tramadol