SM_244a: Pharmacology, Opioids, and Pain Concepts III Flashcards
NSAIDs are related only because ____ and ____
NSAIDs are related only because they inhibit enzyme making prostaglandins and inhibit cyclooxygenase
(different structures)
Describe prostaglandins
Prostaglandins
- Arachidonic acid is major precursor
- Cannot be stored and are released right after synthesis
- Involved in pyretic response
- Acetaminophen (not NSAID) blocks brain prostaglandins (antipyretic)
NSAIDs block ____, preventing formation of ____ from ____
NSAIDs block COX, preventing formation of prostaglandin H2 from arachidonic acid
(note arachidonic acid also converted into leukotrienes via lipooxygenase)
Describe the types of COX
COX
- Both make prostaglandins from arachidonic acid
- Each has its own gene
- COX1: present in most tissues all the time, constitutive, GI tract / platelets / kidneys
COX2: inflammatory, appears when inflammation/injury, responsible for pain, inducible, normally found in CNS / kidneys / uterus
COX __ is inflammatory
COX 2 is inflammatory
(COX-2 specific inhibits such as celexocib)
Describe the systems prostaglandins affect
Prostaglandins affect
- PNS and CNS (pain)
- GI
- Renal and CV
- Platelets (hemostasis)
- Other: bone, reproductive systems
Describe role of prostaglandins in pain
Prostaglandins in pain
- Cause allodynia (touch causes pain) and hyperalgesia (pain amplified)
- Sensitize pain nerve endings: triggered by touch (allodynia)
- Enhance pain in CNS (hyperalgesia)
Describe peripheral mechanisms of pain mediated through COX-2
Peripheral mechanisms of pain mediated through COX-2
- Tissue injury
- COX-2 expressed
- Increased Na influx into nerve
- Threshold becomes less negative
- Nociceptor ready to fire
Prostaglandins ____ the inhibitory pathway and ____ the ascending pathway
Prostaglandins inhibit the inhibitory pathway and upregulate the ascending pathway
(opioids decrease transmission of pain, NSAIDs decrease excitation of pain)
Prostaglandins enhance pain in the CNS via ____, ____, and ____
Prostaglandins enhance pain in the CNS via increased Substance P and glutamate release, increased sensitivity of 2nd order neurons, and decreased release of inhibitory transmitters
NSAIDs ____ but do NOT ____
NSAIDs blunt PNS/CNS sensitization but do NOT block pain transmission
(able to prevent self injury)
(analgesia is peripheral and central)
NSAIDs cause GI toxicity via ____ and ____
NSAIDs cause GI toxicity via direct gastric irritation and decreased cytoprotection in the stomach
- Often silent ulceration
- All but 1 NSAIDs are weak acids
- NSAIDs reduce bicarbonate secretion, blood flow, epithelial cell turnover, and mucosal immunocyte function
GI ulcers after NSAIDs are often ____
GI ulcers after NSAIDs are often asymptomatic
NSAID GI toxicity can be prevented through ____, ____, and ____
NSAID GI toxicity can be prevented through enteric coating, PPIs, and misoprostol
- Enteric coating: moves lesions into duodenum only
- PPIs prevent NSAID upper GI ulcer but not intestinal ulcers
- Misoprostol: synthetic PGE1 that increases mucus formation
Enteric coating protects against NSAID GI toxicity by ____
Enteric coating protects against NSAID GI toxicity by moving lesions into duodenum only
PPIs protect against NSAID GI toxicity by preventing ____ but not ____
PPIs protect against NSAID GI toxicity by preventing upper GI ulcers but not intestinal ulcers
Misoprostol is a ____ that protects against NSAID GI toxicity by ____
Misoprostol is a synthetic PGE1 that protects against NSAID GI toxicity by increasing mucus formation
(causes diarrhea, sold as combo drug)
Discuss prostaglandins in the kidney
Prostaglandins in the kidney
- Renal prostaglandins from COX-1 and COX-2 so COX-2 selectivity is no help
- Affect Na and H20 balance: affect BP
- In decreased perfusion states, PGs dilate afferent blood vessels - needed to prevent ischemia when low volume / BP/ CO
NSAIDs ____ BP in treated hypertensives but not normotensives
NSAIDs increase BP in treated hypertensives but not normotensives
(increases risk for MI or CVA)
Describe renal concerns of NSAID use
NSAID renal concerns
- BP elevation and diuretic interaction: altering prostaglandin levels leads to Na+/H2O imbalance
- Ischemic acute tubular necrosis: by preventing prostaglandin afferent blood vessel dilation in low perfusion states (e.g. hypovolemia, CHF)
Describe hematologic effects of NSAIDs
NSAIDs hematologic effects
- NSAIDs reversibly bind COX: half life normal after a few half lives
- ASA irreversibly acetylates COX-1: need to make more COX to recover, platelets have no nuclei to make more COX, takes 7-10 days to make new platelets
- Low dose ASA is cardioprotective while NSAIDs (even at high dose) are not
NSAIDs block formation of ____ from ____, ____ clotting
NSAIDs block formation of TxA2 from COX-1, decreasing clotting
(note COX-2 selective blockers do not)
Describe NSAID hepatic toxicity
NSAID hepatic toxicity
- Uncommon and not severe
- Idiosyncratic: not dose or duration related, exception is ASA
Contraindications to NSAID use are ____, ____, ____, ____, and ____
Contraindications to NSAID use are ulcer, coagulopathy, renal disease, hepatic disease, and pregnancy
(low dose ASA is acceptable in CV disease)
Describe COX-2 specific inhibitors
COX-2 specific inhibitors
- Celecoxib
- GI ulcer rate reduced by half (same as adding PPI to NSAID)
- Still increases BP and risk of MI/CVA
- No effect on platelets: can use during surgery, no interference with low dose ASA
Describe IV NSAIDs
IV NSAIDs
- Ketorolac: generic potent analgesic, anti-inflammatory effect, worthless orally, limited to 5 days due to toxicity
- Ibuprofen: potent analgesic, anti-inflammatory effect, limited to 5 days due to toxicity
- Acetaminophen (not NSAID): more potent, less toxic when IV
Describe topical NSAIDs
Topical NSAIDs
- Diclofenac: gel, ointment, or patch
- Useful on superficial joints
- Less toxic: no platelet effects, minimal GI effects, warnings are the same as for oral
____ are used when something other than opioids is required during an operation
Perioperative NSAIDs are used when something other than opioids is required during an operation
- Opioids slow GI tract via peristalsis via direct action on gut, cause constipation in outpatients, can mean longer stay due to inability to take orals / leave hospital with ileus / slowed GI function due to pain
