NSAIDs & Non-Opiod Analgesics Flashcards
test 4
NSAIDs =
Nonsteroidal anti-inflammatory drugs
T/F: steroids are anti-inflammatory
T
Why is acute inflammation beneficial?
Gets blood to cells: oxygen nutrients, and WBC to area of injury
What do WBC do?
Help clear out infection
What are the mediators involved in the autocoid group? Which one does NSAIDs target?
Histamine
serotonin
bradykinin
prostaglandins
leukotrienes
Prostaglandins
Which is more problematic: acute or chronic inflammation? Why?
Chronic
-Destruction of cell membrane
-alot more WBC in the area
-release of additonal mediators from WBCs
What are the additional mediators released in chronic inflammation & what do they do?
- Interleukins: cytokines that communicate in between WBC to activate additional WBC to bring more into the area
- GM-CSF (granulocyte–macrophage colony stimulating factors): stimulates growth of granulocytes -> neutrophils, eosinophils, basophils & mast cells; all of WBC are increased by this
- TNF: pro-inflammatory
- Interferons: interfere with viral replication
- PDGF: platelet derive growth factor
** all of these increase WBCs, or get more WBCs to the area**
T/F: chronic inflammation is always a problem
T
Briefly describe the cyclooxygenase pathway
Arachidonic acid converted to prostaglandin by COX
AA =
Arachidonic acid
Briefly describe the lipoxygenase pathway
AA converted to leukotrienes by lipoxygenase
Describe AA
Fatty acid molecule with 20 carbons
What is the precursor to AA? What enzyme is used to convert to AA?
Phospholipids
Phospholipase
What is produced from cyclooxygenase? what do they do?
Prostaglandins (increase inflammation response)
thromboxane A2 (plateletlet aggregation)
prostacyclin (inhibits platelet aggregation)
What is produced from lipoxygenase? what do they do?
Leukotrienes:
LTC4/LTD4/LTE4: inflammation
LTB4: phagocyte attraction (calls in more WBC)
Compare COX 1 & COX2
COX1: Constitutive & deals w/ homeostatic functions
-GI
-Renal
-platelet function
-Macrophage differentiation
COX2: Pain-mediated
-inflammatory response
What are our anti-inflammatory drugs?
NSAIDs
Glucocorticoids
Antirheumatic
What is the original NSAID & prototype?
Aspirin
What do NSAIDs do?
- Suppress S/S of inflammation by inhibiting prostaglandin synthesis
- Antipyetics
- Analgesic
How are NSAIDs metabolized?
Phase 2 in the liver (normal)
Phase 1 (abnormal)
Where are NSAIDs excreted?
Urine & Bile
What are general properties of NSAIDs?
Weak acid
well absorbed
highly metabolized
highly protein bound to albumin
Which mediators causes leaky vessels that can cause HA?
Bradykinin
Histamine
ASA =
aspirin
How long does ASA have an effect for?
8-10 days
Irreversible
Where does ASA work at? What happens here?
Ser 529
AA cant get to its site of action to work –> decreasing platelet aggregation
What are side effects almost all NSAIDs can cause?
GI irritants
Nephrotoxicity
heptotoxicity
Unless its COX2 specific
Drugs: Aspirin
ASA = Acetylsalicylic acid
Prototype/Gold standard
Class: NSAID
MOA: Inhibits Cyclooxygenase in AA pathway
COX 1> COX 2
-Peripherally: Vasodilation to lower temp
-CNS: Vasoconstriction to help with HA
Analgesic, antipyretic, antiplatelet
Uses: mild pain, fever, clot prevention, rheumatoid arthritis, rheumatic fever, decrease CV events, lower risk for colon cancer
AE: GI; increase incident of gastric ulcers
enteric coat will help with this
What is the dose for baby aspirin to take daily?
81 mg
Why cant you give aspirin to children?
Reye’s syndrome
hepatic injury & encephalopathy when you take aspirin after a viral infection
Describe the rare hypersensitivity reaction associated with NSAIDs
Excessive shipping of a AA products to LOX pathway when COX pathway is blocked
Aspirin overdose is associated with _____ poisoning and tylenol with ________
salicylate
liver failure
What is the black box warning for NSAIDs?
Avoid in pregnancy over 20 weeks
Use Acetaminophen instead
What is the treatment for aspirin overdose?
Activated charcoal
IV fluids
dialysis
In mild cases, its beneficial to vomit to get it out of the stomach
Drugs: Celecoxib
Class: NSAIDs
MOA: COX2 selective inhibitor
Prescription only
**Take with food- increases absorption
Fewer GI effects
No impact on platelets
SULFA ALLERGY!!
BLACK BOX WARNING
Increased risk of serious CV events d/t prostacyclin inhibition (clots forming)
Uses: Rheumatoid arthritis, osteoarthritis, anything where we want to treat pain without GI distress caused by inhibiting COX 1
–These are expensive d/t complicated production process–
T/F: Adverse CV events related to all NSAIDs except aspirin
T
d/t prostacyclin inhibition
Drugs: Meloxicam
Class: NSAIDs
MOA: inhibits cyclooxygenase
COX 2 > COX 1
Prescription only
Drugs: Diclofenac (Voltaren)
Class: NSAIDs
MOA: Nonslective COX inhibitor
Topical - OTC
PO - prescription
Decreased GI symptoms w/ misoprostol
Drugs: Ibuprofen
Class: NSAIDs
MOA: Nonselective COX inhibitor
Better pain relief than aspirin
PO, cream, gel, IV
OTC
Drugs: Indomethacin
Class: NSAIDs
MOA: potent COX1&2 inhibitor
-inhibits phospholipase (prevents conversion of AA)
Causes decrease neutrophils/WBC migration
- decrease T &B cell proliferation
Uses: patent ductus arteriosus, gout, rheumatism
What is patent ductus arteriosus
a condition where the fetal ductus arteriosus fails to close after birth, leading to abnormal blood flow (oxygenated & deoxygenated blood) between the aorta and pulmonary artery.
Drugs: Ketorolac (Toradol)
Class: NSAID
MOA: Nonselective COX inhibitor
Primary use is pain
IV, IM, PO, IN
Decreases the need for opioids
Drugs: Acetaminophen
NOT AN NSAID
Class: Analgesic/Antipyretic
MOA: COX2 selective inhibitor
-more CNS effects
-has no effects on inflammation
Metabolized in the liver
Toxic to liver & kidneys
Uses: mild - moderate pain
AE: main effects associated w/ liver
Fatal dose 15 grams
Describe the pathways by which acetaminophen is metabolized (1) to harmless products if normal doses are taken and (2) to hepatotoxic products if an overdose is taken
Acetaminophen is normally metabolized by phase 2 conjugation reactions glucuronidation and sulfation to form non toxic byproducts that are excreted through feces and urine.
If you overdose on acetaminophen, Phase 1 metabolism reactions are activated with CYP2E1 and CYP3A4. This builds up reactive toxic intermediates with positive charges that can attach proteins and other negatively charged molecules.
If its not that bad, a glutathione will attach to the charge (another phase 2 conjugation reaction) and the byproduct is swept away.
If it is really bad like a whole bottle, then we eventually run out of glutathione and Nucleophillic Cell Macromolecules (protein-SH) will attach to charge and inactive them and lead to liver cell death.
Where are NSAIDs excreted? What happens if you have a problem with your kidneys?
Kidneys –> urine
You’ll have a problem clearing it out
What type of NSAID is best for patients who are at risk for stomach bleeding?
COX 2 specific
Describe the structure of Glucocorticoids
“Steroid nucleus structure” w/ carbohydrate component
4 ring structure:
-3-6 carbon rings
-1-5 carbon ring
Where is cortisol released from?
Adrenal gland
What is cortisol?
Stress hormone that helps mobile energy stores to help you focus when acute
What does glucocorticoid mimic?
cortisol
What does acute release of cortisol do?
- Suppress inflammation
- mobilize energy stores
- improve cognitive function
- salt and water retention
What does chronic release of cortisol do?
- Immunosuppression
- Diabetes, obesity, muscle wasting
- Depression
- HTN
Drugs: Glucocorticoids
Class: glucocorticoid
MOA: inhibit immune response by blocking transcription/translation
Topical, PO, IV, IM, IHN
Uses: Suppress inflammation
-Addison’s disease: adrenal gland not producing enough cortisol
-Cushing’s disease: have to remove adrenal gland so give to replace cortisol
-Fetal lung maturtion: glucocorticoid increases surfactant production in lungs
T/F: glucocorticoid can freely cross membranes
T
Describe transcription/translation in glucocorticoid
increases transcription:
-Annexin-1: inhinits phospholipase A2 & leukocyte response
-Secretory Leukoprotease inhibitor (SLPI)
-IL-10: immunosuppressive enzyme
decreases transcription:
-Inh-NFkB
Drugs: Abatacept, Rituximab, Adalimumab
Class: Disease Modifying Anti-Rheumatic Drugs (DMARDs)
Monoclonal Antibodies (biologic)
MOA: Abatacept: Blocks T cell activation
Rituximab: Depletes B-lymphocytes
Adalimumab: blocks inflammatory pathway TNF-alpha
Prescription only
Uses: Joint disorders & chronic inflammatory responses
–Reverses damage to joints & bones if taken early
Does not help with pain
Give with NSAID
T/F: DMARDs are only anti-inflammatory, have no pain effects, and can reverse joint disorders
T
What are ways to measure the effects of DMARDs?
- Sed Rate
- C-reative protein: increases 1000x if there’s inflammation in the body
- Rheumatoid Factor (RF): this will tell us if the pt has rheumatoid arthritis
Describe how chronic inflammation contributes to cancer
-Chronic exposure to inflammatory mediators leads to
–Cell proliferation
–Mutagenesis
–Oncogene activation
–Angiogenesis
-Caused by: Release of Reactive oxygen species (ROS)/ Reactive Nitrogen Intermediates (RNI) by WBC in tumor cells → cause mutations in neighboring epithelial cells
-Caused by Cytokines from tumor-infiltrating immune cells activate NF-KB/STAT3 (pro-inflammatory) in premalignant cells → induce production of Cyclins and CDKS → cancer growth/division
-Excessive free radicals and tissue damage → more inflammation
-Therapy = ASA- used for prevention and therapy
–Deplete immune/inflammation cells, sequester chemokines/cytokines
–Prevent Colon Ca, Reduce Breast Ca & Prostate Ca risk (low dose benefits)
What induces production of growth/division proteins in tumors?
NF-kB
STAT3
You should take ____ to help reduce inflammation in malignancies
aspirin
