NSAIDS Flashcards
What are common causes of headaches?
- Neck & jaw tension
- Nasal Pressure
- Lack of sleep
- Caffeine withdrawal
- Eye strain
What are NSAIDs?
Non-Steroidal Anti-Inflammatory Drugs
What are NSAIDs Pharmacological Effects? & what common mechanism do they all seem to be mediated by?
- Analgesic (anti-pain)
- Antipyretic (anti-fever)
- Anti-inflammatory (EXCEPT Acetaminophen)
all by INHIBITION of prostaglandins
What is NSAIDs action?
block COX 1,2, 3 which then inhibits Prostoglandin which mediates pain, inflammation & fever etc.
What are the Cyclo-Oxygenases?
COX-1, COX-2, COX-3
What does Cyclo-oxygenase-1 (COX-1) do?
- Non-inducible-Found in many cell types constitutively (i.e. running ALL of the time in a lot of cell types, esp. in stomach)
- This isoform has critical functions, such as maintaining stomach lining
What does Cyclo-oxygenase-2 (COX-2) do?
*want to inhibit this one
- The form induced in immune cells (upon infection, damage, etc.)
- This isoform is responsible for Pain, Inflammation, & fever
What does Cyclo-oxygenase-3 (COX-3) do?
Highest content in brain & heart
What is inflammation?
Caused by infectious agents, ischemia, antigen/antibody reaction, thermal and other damage
What are the 3 phases of Inflammation?
- Acute Transient Phase (local vasodilation, increased capillary permeability)
- Delayed Subactute Phase (infiltration of leukocytes & phagocytes - attacking)
- Chronic Proliferative Phase (tissue degeneration & fibrosis)
NSAIDs only really useful for Phase 1 & a bit of 2
Where are Prostaglandins released?
- Prostaglandins are released following cell damage, and found in inflammatory exudants
- Injection of PGs cause local inflammation, increased blood flow, and severe pain
- PGs cause uterine cramping - Injection used as an abortifacient. Inhibitors of PG are useful for dysmenorhea, & to delay delivery
*(-) S.E. for pregnant women taking NSAIDs b/c don’t want to artificially inhibit uterine contraction if close to term
Where do NSAIDs work & where does Tylenol work?
NSAIDs - work LOCALLY at site of inflammation & pain (can be in creams)
Tylenol - works ONLY in brain & SC (cannot be in creams b/c won’t do anything)
Describe fever & how it is reduced
- Set point is regulated by hypothalamus balance between heat loss and heat production
- Fever caused by: infection, tissue damage, inflammation, graft rejection, malignancy, etc
- Release of PGs near hypothalamus under these conditions induces fever
- NSAIDs reduce fever, but do not reduce increased body temp due to exercise or ambient heat
– reduced fever produced by prostaglandin release
– won’t help reduce body temp if over heated from sun or workout (makes it worse)
Describe pain & how it’s regulated
- PGs seem to induce pain by stimulating local pain fibers
- In addition, inflammation induces hyperalgesia (increased pain sensitivity - b/c stretch & release of substances at the inflammatory site)
- NSAIDs, listed as minor analgesics, can be superior to opiods (morphine, etc) for inflammation-induced pain, & some post-op pain (great for inflammatory pain - joint pain - good for cramping)
What are the other effects of PGs?
*- PGs are critical to platelet aggregation-formation of clots (accounts for the coronary benefits of ASA)
- PGs are imp. in modulating stomach acidity & mucous lining (accounts for the GI side effects of NSAIDs)
- PGs are imp. for uterine contraction-may account for some cases of dysmenorhea
What are the 2 mechanisms of action for how Aspirin works?
- ASA irreversibly acetylates COX enzymes (mostly only imp. in platelets), thus this effect lasts as long as it takes to replace the enzyme (not dependent upon aspirin elimination)
- A minor metabolite of ASA, gentisic acid, is a competetive inhibitor of COX enzymes, thus this effect depends upon clearance
Describe the Plain vs. Enteric-Coated Acetylsalicyclic Acid
NSAIDs have a ceiling effect
- meaning, you can take more & more of the drug until a certain point & then the drug will have no more (+) effect on what you’re treating
- opposite to Alc or acetaminophen (destroy liver)
- can’t stack NSAIDs
Entrophen
- strong NSAIDs & slow release for ex: Arthritis
- don’t take other NSAIDs
What is Caffeine as?
a coanalgesic
- esp. for headaches
- if someone is taking Aspirin & is having caffeine, it’ll help there headache even more (mech is unknown)
What is the Salicylate Overdose?
- A very common cause of drug overdose in children (acetaminophen is most common)
- 10-30 gram dose can cause fatality
- Pepto-bismol (bismuth salicylate) can cause salicylate toxicity b/c it (tastes good?) (if sensitive to Aspirin it’ll make your stomach worse, not better)
- Methylsalicylate (oil of wintergreen) can be fatal with as little as 4 ml (even when spilt on hands)
- absorbed through skin
What are the signs & symptoms of a Salicylate Overdose?
comes with an alarm system
- Tinnitus - typical of elderly using enteric coating-1st sign of toxicity (massive ringing in ears)
- Marked increase in metabolic rate (SA overdose interfers with oxidative metabolism)
1. Initial hyperventilation-Due to “futile cycle” (certain amount of calories are just burned to make heat) burning of O2, overproduction of CO2
2. Metabolic acidosis-Overproduction of CO2
3. Severe hypoglycemia-Futile cycle uses up the available glucose
What is the Salicylic Overdose treatment?
The immediate danger is hyperthermia, dehydration (sweating all their water out to keep themselves cool), hypoglycemia
- Parenteral fluids and glucose (always and immediately)
- Parenteral sodium bicarbonate solution (Caution: potassium depletion) - to regulate pH
- Acetazolamide (If parenteral bicarbonate does not alkalinize the urine) (Goal urine pH>7)
- Activated charcoal
(only effective within 2 hr of overdose) - gets everything out
- Polyelectrolyte lavage solution
(for modified release salicylate)
- Hemodialysis (for severe overdoses - to get it out of blood (can still keep them alive)
List the NSAIDs classes:
- Salycitates
- Proprionic acid (Ibuprofen, Naproxen)
- Diclofenac
- Indomethacin
Salycilates:
has salycilic acid in it
- Methysalicylate - oil of wintergreen (used as topical ointment)
- Bismuth Salicylate
- Aspirin
Proprionic acid:
Ibuprofen (Advil, etc)
- Generally similar effects to other non-selective COX inhibitors
- Generally less GI side effects (but still a major problem)
Naproxen (Aleve):
t1/2 of 12-18 hrs (*longer t1/2 - major difference *not stronger), effective from 2-12
Naproxen sodium peaks within 1 hour
Can be dosed only twice a day
Diclofenac:
- HIGH POTENCY (*only difference) but also higher GI bleed risk
- Prescription only: Used primarily for inflammatory pain, such as Arthritis, post operative swelling, gout, etc. Sometimes endometriosis
- In gel, used for muscular/joint pain (tennis elbow, muscle strains, low back pain)
Indomethacin:
- Specifically used for gout pain & swelling
- Less common for chronic conditions than diclofenac
What are the GI Side Effects?
since major SE’s are inhibition of COX-1, then cure for that will be something that only inhibits COX-2 (specific COX-2 inhibitors –> thought better but no)
- Primary problem with non
selective COX - PGE2 & PGI2 (products of COX-1) are made by gastric mucosa. These PGs suppress acid production, increase gastric BF, increase secretion of mucin
- Inhibition of COX-1 thus increases acid production & decreases mucous protection, in addition to local effects of drugs
Misoprostol:
IF patient at high risk for SE’s (stomach pain/bleed) or if you know they have problem with their stomach but they need an NSAID, they give them Misoprostol
- (Can take NSAIDs with a) PG analog (similar structure and function) (that only works locally)
- Used to supply the stomach with PG effect lost with non selective COX inhibitor
- Adverse effects & effectiveness - ~1% risk prevention, 15% induction of diarrhea
What are the Adverse Effects & Drug Interactions of NSAIDs?
Reye’s Syndrome-Fatal hepatic encephalopathy in children with viral infection-Associated with SAS (when given Aspirin)
- Chicken Pox, Influenza
Hypertension, Angina
- Increase in circulating volume
Bleeding Disorders (b/c of decrease in platelets)
- inhibition of cyclooxygenase, Alc, Warfarin & Rofecoxib
Where do most SE’s of non-selective COX inhibitors arise from?
inhibition of COX1
- the analgesic, anti-pyretic, & anti-inflammatory effects arise primarily from inhibition of COX-2
- this spurred the search for COX-2 selective inhibitors
What are the COX-2 findings?
doing something that’s massively changing blood/heart system
- Merck pulls Vioxx due to fears of increased HA risk
- Bextra be pulled by Pfizer
- Celebrex still available with “black box” warning
- Cause may be inhibition of prostocyclin, but as yet unclear
What is Acetaminophen?
- Analgesic (acts CENTRALLY (in brain/SC),NO CEILING effect (therefore, more you take, more it kills you)
- Anti-pyretic
- NOT anti-inflammatory
- b/c of Reye’s syndrome, the drug of choice for children
What is the Acetaminophen Overdose Mechanism of Action?
- A minor clearance pathway for a highly reactive metabolite of acetaminophen at low doses is through GLUTATHIONE (GSH) in the LIVER
- GSH is a critical ANTI-OXIDANT
- *At high doses, this reactive metabolite DEPLETES GSH (then rapid advancement to pathologic liver state)
- This causes
1. Oxidative damage to liver cells from loss of anti-oxidant &
2. Direct damage to liver cells from the highly reactive intermediate
(*NO REAL SYMPTOMS)
(not sure where it works, but *in most cases of minor pain control like headaches this is recommended; b/c for lower dose of Acetaminophen, it’s safer than NSAIDs b/c of NSAIDs on gut - but high doses of Acetaminophen are v. dangerous)
What are the Signs & Symptoms of Acetaminophen overdose?
- Severely elevated serum transaminase levels > 1000 U/L (AST, ALT - liver toxicity) - 60% probability with serum acetaminophen > 200 mg/L (NOT GONNA KNOW - v. dangerous)
- Hepatic encephalopathy - 90% probability with serum acetaminophen > 300 mg/L
- Jaundice - by this time treatment is likely too late
