NSAIDS Flashcards
What does NSAIDS stand for?
Non-steroidal anti-inflammatory drugs
Major mediators of inflammation, fever, and pain:
prostaglandins (PGs)
PGs (prostaglandins) act on multiple types and subtypes of:
GPCRs
There are no good receptor antagonists to inhibit GPCRs, so what kind of drugs do we use?
We use drugs that inhibit their SYNTHESIS instead
PGs are synthesized from arachidonic acid (AA) by:
cyclo-oxygenase enzymes (COXs)
T/F. NSAIDs mediate their therapeutic effects by inhibiting the COX enzymes that generate PGs.
TRUE
Because they decrease PG synthesis by COX enzymes, NSAIDs are:
anti-inflammatory, anti-pyretic, analgesic (inflammation, fever, pain)
T/F. NSAIDs are steroidal anti-inflammatory drugs.
FALSE, NSAIDs are NON-steroidal, as opposed to anti-inflammatory steroids (GCs)
How do Gas inhibit COXs and PGs?
by regulating COX expression, not activity
Another name for NSAIDs:
non-opioid analgesics (to contrast them with morphine and related opioid analgesics)
Opioids are required for what?
Relieving strong sharp pain
Are NSAIDs more or less powerful than opioids?
Less powerful, but adequate for mild pain.
What side effects do opioids have?
Sedation, respiratory depression, and tolerance and dependence
T/F. PGs are made by many/most cell types and many/most cell types respond to PGs.
TRUE
In some of these cells, what is the desired therapeutic targets for NSAIDs?
COXs
Why do side effects occur?
Due to NSAID inhibition of COXs and PG synthesis and/or actions in various other call types
Where/how are PGs synthesized?
DE NOVO and immediately released
Why is COX a good drug target to block PG synthesis?
COX activity is a rate-limiting step in PG synthesis
Name for inflammation mediators:
thromboxanes (TXs)
What are precursors to all PGs and TXs?
convert arachidonic acid (AA) to PG-G2 and PG-H2
Why are there multiple COX isozymes?
critical for PG functions and for NSAID actions
T/F. COX-1 and COX-2 are constitutively expressed.
TRUE
COX-1 roles in CNS, stomach, and platelets:
CNS: mediated fever and pain
Stomach: protects mucosal lining
Platelets: increases platelet aggregation and blood clotting (by altering thromboxanes, TXs)
COX-2 roles in CNS, stomach, and endothelial cells:
CNS: mediate SOME pain
Stomach: protects mucosal lining with COX-1
Endothelial cells: decreases platelet aggregation (by altering prostacyclin, PGIs)
COX-2 is an inducible isozyme that is critical for _____.
Inflammation.
What is the key target for NSAID anti-inflammatory effects?
COX-2
Most NSAIDs inhibit both COX-1 and COX-2, but usually stronger on ________ making them useful for treating ________.
COX-1; pain (COX-1 and constitutive COX-2) and fever (COX-1).
What type of NSAIDs are selective for COX-2 compared to COX-1 and what are they used for?
celecoxib; used to treat inflammation and sometimes pain, with fewer unwanted COX-1 related adverse effects
What drug is the critical prototype of all of the NSAIDS and non-opioid analgesics?
Aspirin
Aspirin is ASA. What does ASA stand for?
Acetyl-salicylic acid
Aspirin starts as ASA but then what:
rapidly hydrolyzed (de-acetylated) and becomes salicylic acid (or salicylate ion).
T/F. Salicylates, including the salicylate from aspirin, are irreversible and competitive COX inhibitors.
FALSE. salicylates ARE REVERSIBLE.
Which effects of aspirin are mediated by its salicylate metabolite?
the anti-inflammatory and analgesic effects
What is the standard oral dose of aspirin?
325 mg.
Aspiring has drug interactions due to displacing with which drugs?
warfarin, methotrexate, sulfonamides, others
In regards to pharmacokinetics, what is the mechanism by which aspirin works?
salicylate metabolism and elimination
At low to moderate doses, salicylate is what?
metabolized in the liver by conjugation; first-order kinetics and saturable
At higher doses, salicylate is what?
excreted unmetabolized by kidneys; zero-order kinetics, half life increases with increasing dose
T/F. Higher doses that saturate the liver metabolism and exceed renal elimination are required for sufficient accumulation to achieve therapeutic levels for COX-2 inhibition and anti-inflammatory effect.
TRUE
T/F. Lower doses suffice for COX-1 mediated analogies and anti-pyretic effects.
TRUE
Would you use a low or high dose for analgesic and antipyretic?
low
Would you use a low or high dose for anti-inflammatory doses
high
Low or high doses are associated with conjugation n live, first order kinetics, and saturable?
low
Low or high doses are associated with excretion in the kidney, half life increases, and zero order kinetics?
high
What are the beneficial effects and uses for aspirin?
Analgesia (pain of inflammation) (650-1000 mg/4) hr, antipyresis (decrease fever) (works on hypothalamus)(650-1000 mg/4 hr), anti-inflammatory effects (COX2 effect that requires high dose)(1200 mg or more/ 4 hr)
What are miscellaneous effects and uses aspirin is used for?
reducing GI cancer risk: many cancers ahem elevated COX2
Alzheimer’s disease: possible benefit
Adverse effects of salicylate:
GI irration: gastric irritation, GI bleeding, gastric ulceration and hemorrhage
GI Hemmorrhage is responsible for 16,000 aspirin related deaths in US each year! (most significant limitation in use of these drugs)
How is GI irritation lessened?
using enteric coasted tablets: prevent tablet from dissolving in stomach and damaging GI mucosa, absorption from intestine instead
T/F. There is some dilution of peripheral vessels by large doses of salicylate.
TRUE
How can you avoid Reye’s syndrome?
aspiring should not be used in children <16, stopping aspiring use in children has nearly eliminated occurrence of Reye’s syndrome, we give Tylenol to babies rather than aspirin
What effects can salicylate have on baby maturation?
can cause premature closure of duct arterioles, all NSAIDs can potentially cause premature closure, some NSAIDs are used to promote closure
Term used for MILD toxicity of salicylate:
salicylism
Salicyism usually occurs in what population and what are side effects?
Typically excess chronic use in older adults; ringing in ears (tinnitus), dizziness, headache, confusion, deafness, drowsiness, thirst, nausea, vomiting
Overdose toxicity od salicylate usually occurs when how much is taken?
5-30 grams
How does overdose usually occur?
typically children ingesting large doses acutely (15-100 tablets; >150 tablets is lethal)
Symptoms of overdose:
decrease blood flow, respiratory depression, GI disturbances, CNS disturbances, respiratory failure is eventual cause of death
Treatment of salicylate overdose:
activated charcoal, sodium bicarbonate (salicylic acid pka=3, ion trapping of salicylate in urine by alkalinizing), monitor blood levels of salicylate, monitor urine pH, provide supplemental glucose and potassium; hemodialysis may be required
Equation to known for treating salicylate overdose (regards pka and ph):
pKa-pH = protonated/unprotanated; OR: Ka = [H+][A-]/[AH]
One unique us of aspirin only:
to prevent thrombus formation (blood clotting) and prolong bleeding time
How is aspiring different from other salicylate and NSAIDS:
irreversibly inactivate COXs in some tissues
by covalently acetylating the enzyme: reversible binding of salicylate to COXs can inhibit them reversibly
covalent acetylation of COXs can inhibit them also, but irreversibly
Why are platelets an important target for aspirin?
Platelets near site of GI absorption are the main cells exposed to acetyl-salicylic acid and covalent acetylation of COXs
Besides pain, fever, and antiinflmmation, what can aspirin also be used for?
prevent/reduce risk of MI and stroke; other salicylates do not share this action, this is an acetyl effect
T/F. Platelets are the main cells with acetylated COX.
TRUE
T/F. Anti-inflammatory actions of aspirin are mediated by its salicylate metabolite, after it has lost its acetyl group.
TRUE
Platelets use COX-1 to make:
Thromboxanes (TXs); that increase clotting and thrombosis risk
Endothelial cells use COX-2 to make:
prostacyclin (PGIs); that decrease clotting and thrombosis risk
Low aspiring doses only inhibit COX-1, shifting balance to more anti-thrombotic PGIs formation from endothelial cells.
TRUE
Prolonged inhibition of platelet COX-1 causes sustained reduction in TXs.
TRUE
Aspirin dose for thrombosis prevention:
75-81 mg/day
Aspiring contraindicated in those with:
clotting deficiency
Examples of PROpionic acid derivates:
Ibuprofen and Naproxen
Difference of ibuprofen and naproxen from aspirin:
less toxic, fewer side effects, ONLY reversible and competitive; prolong bleeding time
Ibuprofen and naproxen have specific approval for:
dysmenorrhea (menstrual cramps); pain and cramps mediated by PGs
Ibuprofen 98% binds:
very heavily to albumin, can displace warfarin
All propionic acid derivates show cross-sensitivity with salicylate; because of this what should you not do?
don’t use in patients with aspirin allergy or with aspirin-sensitive asthma
T/F. Only some NSAIDs can cause renal toxicity/failure.
FALSE, ALL NSAIDs can cause renal toxicity/failure
How should toxicity be treated in propionic acid derivatives?
activated charcoal in first 2 hours
When is urine alkalization effective vs. not effective?
NOT effective in ibuprofen, naproxen and other propionic acid derivates (because so much of drug is protein bound). IS effective for aspirin.
Doses for Ibuprofen:
200 mg (analgesia and antipyresis), 400 mg (anti-inflammatory)
What is ibuprofen specifically approved for?
patent ductus arteriosus
Doses for naproxen:
200-250 mg twice a day; enteric-coated delayed-release.
What is naproxen specifically approved for?
gout and for migraine specifically
Acetic acid derivates:
IndomethACin, diclofenAC, ketorolAC
Is Indomethacin more or less potent than aspirin? How much more or less?
10-20x MORE potent than aspiring (works in lower doses)
What is the dose for indomethacin?
25 mg / 4-6 hours.
When is indomethacin mainly used?
in severe inflammation: rheumatoid arthritis, gouty arthritis (use cautiously)
CeleCOXib is an example of what?
selective COX-2 inhibitor
Celecoxib is great for what?
inhibiting COX-2; treat inflammation without serious adverse effects
Dose of Celecoxib:
100-200 mg two days a day, oral, rapidly absorbed, metabolized by liver
Approved uses for Celecoxib:
(for all “itis”): osteoarthritis, rheumatoid arthritis, relief of acute pain, primary dysmenorrhea
How does Celecoxib compare to naproxen?
Celecoxib is equal to naproxen for osteoarthritis and rheumatoid arthritis, but is is poorer than naproxen for acute pain
T/F. Celecoxib has fewer problems for asthmatics than aspirin and other NSAIDs.
TRUE
Drug interactions of Celecoxib:
metabolized by CYP 2C9, may inhibit CYP 2D6 in some patients, can slow metabolism of tricyclic and SSRI anti-depressants, anti-arrythmics
What is the most adverse effects of celecoxib?
edema, GI problems (less than with ibuprofen and naproxen), increased risk of MI (COX2 inhibits platelet aggregation in endothelial cells)
T/F. Celecoxib is an example of a more selective drug causing new problems, even as they solve older problems.
TRUE.
T/F. Now black-box warnings for MI risk can be found on ALL NSAIDs, not just Celecoxib.
TRUE, because all can inhibit COX2
A drug that is a non-opioid analgesia like NSAIDs, but NOT an NSAID:
acetaminophen
Do we know how acetaminophen works?
NO! we do not know mechanism; we THINK inhibition of COXs and PG synthesis.
T/F. Acetaminophen has anti-inflammatory effects.
FALSE, it does NOT have anti-inflammatory effects
Dose for acetaminophen:
325 mg, oral tablet
Reasons to pick acetaminophen over aspirin:
no GI effects of concern, no hematologic effects, no CV effects or concerns, no respiratory effects or concerns, no effects on acid-base balance, no association with Reye’s syndrome; but NO anti-inflammatory effects :(
Major adverse effects and concerns:
hepatic damage/liver damage with long-term persistent use, don’t drink with alcohol, limit dose when taking with opioids and other analgesics, skin rash, drug fever, NEPHRO-toxicity
Overdose toxicity dose of acetaminophen:
10-25 g
overdose reactions to acetaminophen:
hepatotoxicity; jaundice, usually reversible, but hepatic coma and death can occur
What causes the hepatic toxicity from acetaminophen overdose?
a reactive electrophile: NAPZQI (N-acetyl-p-benzo-quinone-amine)
Treatment of overdose toxicity of acetaminophen:
after 4 hr, treat with reactive sulfhydryl reagents (N-acetyl-cysteine): Acetadote to reverse toxicity by restoring endogenous glutathione.
What drug should you use to reverse overdose toxicity of acetaminophen?
n-acetyl-cysteine (acetadote)
