NSAIDs Flashcards
How are NSAIDs related?
only in the fact that they inhibit cyclooxygnase (COX), which makes prostaglandins
What is the mechanism of creation of tissue specific prostaglandins?
cell injury (or other trigger) -> phospholipase A2 -> arachidonic acid -> cyclooxygnase -> prostaglandin H2 -> tissue specific PG synthase -> tissue specific prostaglandins
What are the two types of COX?
each has its own gene, both make PGs from AA
COX1 - the “housekeeping” one and present in most tissues all the time
COX2 - the “inflammatory” one and appears with inflammation and injury, which is the cause of the pain except in the CNS, kidney, and uterus
What systems are affected by prostaglandins?
PNS and CNS (pain)
GI
renal (and CV)
platelets (hemostasis)
other - bone, reproductive
How do prostaglandins affect pain?
causes allodynia and hyperalgesia
- sensitize pain in nerve endings
- enhance pain in CNS
What is the role of COX-2 in peripheral mechanisms of pain?
ramp up PGE2, which bind to prostaglandin receptors
these ramp up PKA and PKC, which causes nociceptors leaky to sodium
resting membrane potential goes up and firing potential goes up
now instead of having a crush, cut, or burn trigger, touch will trigger firing of the nerve
Why do NSAIDs work when there is no inflammation?
headaches
osteoarthritis
hangovers
postop pain (third molar extraction)
work when there is no inflammation - due to role in CNS
How do PGs enhance pain in the CNS?
enhance pain in CNS
increase SP and glutamate release
increase sensitivity 2nd order neurons
decrease release of inhibitory transmitters
Why are NSAIDs not true analgesics?
they only blunt PNS/CNS sensitization
they do not block pain transmission - can still feel acute pain and prevent self-injury
are actually anti-hyperalgesics
What does COX-1 do in the GI system?
protects the GI system
increases mucous layer thickness
decrease pH gradient
increase bicarbonate secretion
incrase mucosal blood flow
What are the NSAID GI toxicities?
two mechanisms:
1) direct gastric irritation (all but 1 acids)
2) decreased cytoprotection in stomach - bicarbonate secretion, blood flow, epithelial cell turnover, mucosal immunocyte function
not often associated with dyspepsia - silent ulceration in 70%
misoprostol
protects GI tract
a synthetic PGE1
increases nucous formation
problem - big time diarrhea
sold as combo drug with diclofenac
What is the role of PG in the kidneys?
renal PGs from COX1 and COX2
affect NA+ and water balance - affects BP
in decreased perfusion states, PGs dilate afferent blood vessels and are needed to prevent ischemia when low volume/BP/cardiac output
What is the effect of NSAIDs in treated hypertensives?
increases BP in treated HTN
increases systolic BP and increases MI risk
normotensives unaffected
What are renal affects of NSAIDs?
BP elevation/diuretic interaction by messing with PG Na+/water balance
ischemic acute tubular necrosis by preventnig PG afferent blood vessel dilation in lower perfusion states
How does PG cause hemostasis?
platelets only contain COX1
forms thromboxane and leads to aggregation
NSAIDS lead to decreased clotting
What is the effect of aspirin on COX1 and 2?
blocks function of the enzyme and irreversibly acetlyates it
platelets can’t make more due to lack of nucleus
7-10 days of protection because that’s how long it takes to make new platelets
to recover need to take more COX
What are the pharmacokinetics of NSAIDs?
all are rapidly absorbed orally
all highly protein bound - relevant in elderly with decreased albumin and can displace warfarin and leed to BLEEDING
all mostly metabolized in liver
different half lives
What are the pharmokinetics of aspirin?
salicylate so irritating that it can only be used externally - methyl salicylate is oil of wintergreen
aspirin is an ester of the salicylic acid - acetylsalicylic acid has a T1/2 of 15 min becoming salicylate
salicylate has T1/2 of 2-3 hours at normal doses
all other NSAIDs are >6 hours, some 24 hours
What are the effects of ASA on NSAIDs?
displaces NSAIDs from albumin
increases toxicity risk
What are pertinent histories that should caution use of NSAIDs?
ulcers
coagulopathy
renal disease
hepatic disease
CV disease - ASA ok (low dose)
What is Reye’s syndrome?
after viral illness in chldren, aspirin causes hepatotoxicity, siezures, coma, and death
ex. URI, chickenpox, etc.
acetaminophen (paracetamol)
the active metabolite of phenacetin
weak anti-inflammatory and no peripheral COX inhibition
reasonable antipyretic and analgesic - mechanisms unclear
What are the side effects of acetaminophen?
no effect on GI, platelet, and renal
max daily dose is 4g (12 pills)
less in drinkers and liver pts
