Lecture 11: Nonsteroidal Anti-Inflammatory Drugs (Exam 2) Flashcards
What is the MOA of NSAIDs
Blocks the cellular expression of COX enzymes in cell membrane
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What is the response to tissue death
Inflammation
What is the first step in the inflammatory cascade
Release of arrachidonic acid (AA) that is mediated by phospholipase A2 (from injured cell membrane)
What do AAs generate
Various eicosanoids like PGs, leukotrienes, & thromboxane A2)
What mediates the production of PGs & TXA2
COX
What do inflammatory mediators lead to
- Increased vascular permeability
- Heat
- Decreased nociceptor threshold
Describe COX-1
- Primary constitutive isoform of COX
- Responsible for basal prostaglandin (pG) production which helps w/ homeostasis in tissues
- Present in the stomach, kidneys, platelets, & the repro tract
- Can be expressed @ the site of inflammation
Describe COX-2
- Induced isoform of COX
- Expressed constitutively in many tissues like neural, repro, & renal
- Has homeostatic function
T/F: COX has a bifunctional role depending on the isoform & target tissue
True
What tissue do NSAIDs work
- CNS
- Peripheral tissue injury sites
What happens when there is inhibition of COX-2 enzyme peripherally blocks the formation of PGs
- Dilates arterioles
- Sensitize peripheral nociceptors to inflammatory mediators (like histamine & bradykinin)
- Produces localized pain & hypersensitivity
What happens to COX-2 when there is traumatic injury & peripheral inflammation in the brain & spinal cord? Then what ha
- Is upregulated
- Neuronal plasticity & central sensitization due to lowering of the threshold for neuronal depolarization
How does PGE2 contribute to inflammatory response
Causes vasodilation & enhancing inflammatory mediators & other cytokines
What mediates the production of PGE2
COX-2
Why do we no longer use drug therapy to target inhibition of COX-2
B/c COX-2 inhibition is detrimental to many normal physiologic functions like gastric ulcer healing
What is the COX-1: COX-2 selectivity ratio
Varies btw/ species
Describe Coxibs
- Subset of NSAIDs developed to have anti-inflammatory effects but reduced toxicity
- COX-2 selective
- COX-1 sparing
- Structured diff so it limits their ability to bind the COX-1 site
What are the 4 coxibs approved for use in animals
- Deracoxib
- Firocoxib
- Mavacoxib
- Robencoxib
What is the PK of most NSAIDs
- Lipid soluble
- Weak organic acids
- Well absorbed following oral admin
- Rapid onset of action
- Duration of effect can be up to 24 hrs
- Small vol of distribution attributable to a high degree of plasma protein binding (enables consistent delivery to target tissue
- Extensive hepatic metabolism to inactive metabolites
- Elimination 1/2 life if variable
Describe the clinical use of NSAIDs
- Only use one NSAID @ a time
- Baseline renal & hepatic fxn prior to use
- Pay attention to dosages, frequency, & offer it with food
- Use lowest effective dose for the shortest duration possible
- 5 - 7 D “wast out” period if switching NSAIDs
When should NSAIDs not be given
- Renal or hepatic insufficiency/impairment
- Active GI disease
- Coagulopathies
- Pregnant/trying to get preg
- Decreased circulating vol
- Active hemorrhage or suspected blood loss
- Significant pulmonary disease
- known sensitivity of NSAIDs
- Currently receiving systemic steroids or other NSAIDs
What are the 9 ways to min risk w/ NSAIDs
- Obtain complete medical hx
- Careful px selection
- Provide verbal & written instruction
- Recognize adverse events & discontinue immediately
- Monitor labwork
- Use a balanced approach to analgesia
- Consider washout periods
- Consider gastroprotectants
- Dose optimization based on lean body wght
What is a critical step that needs to be done when prescribing NSAIDs
Pet owners need to be told what the possible side effects are & their clinical sxs