NSAIDS Flashcards
1
Q
What does NSAIDS stand for?
A
Non-steroidal anti-inflammatory drugs
2
Q
Major mediators of inflammation, fever, and pain:
A
prostaglandins (PGs)
3
Q
PGs (prostaglandins) act on multiple types and subtypes of:
A
GPCRs
4
Q
There are no good receptor antagonists to inhibit GPCRs, so what kind of drugs do we use?
A
We use drugs that inhibit their SYNTHESIS instead
5
Q
PGs are synthesized from arachidonic acid (AA) by:
A
cyclo-oxygenase enzymes (COXs)
6
Q
T/F. NSAIDs mediate their therapeutic effects by inhibiting the COX enzymes that generate PGs.
A
TRUE
7
Q
Because they decrease PG synthesis by COX enzymes, NSAIDs are:
A
anti-inflammatory, anti-pyretic, analgesic (inflammation, fever, pain)
8
Q
T/F. NSAIDs are steroidal anti-inflammatory drugs.
A
FALSE, NSAIDs are NON-steroidal, as opposed to anti-inflammatory steroids (GCs)
9
Q
How do Gas inhibit COXs and PGs?
A
by regulating COX expression, not activity
10
Q
Another name for NSAIDs:
A
non-opioid analgesics (to contrast them with morphine and related opioid analgesics)
11
Q
Opioids are required for what?
A
Relieving strong sharp pain
12
Q
Are NSAIDs more or less powerful than opioids?
A
Less powerful, but adequate for mild pain.
13
Q
What side effects do opioids have?
A
Sedation, respiratory depression, and tolerance and dependence
14
Q
T/F. PGs are made by many/most cell types and many/most cell types respond to PGs.
A
TRUE
15
Q
In some of these cells, what is the desired therapeutic targets for NSAIDs?
A
COXs
16
Q
Why do side effects occur?
A
Due to NSAID inhibition of COXs and PG synthesis and/or actions in various other call types
17
Q
Where/how are PGs synthesized?
A
DE NOVO and immediately released
18
Q
Why is COX a good drug target to block PG synthesis?
A
COX activity is a rate-limiting step in PG synthesis
19
Q
Name for inflammation mediators:
A
thromboxanes (TXs)
20
Q
What are precursors to all PGs and TXs?
A
convert arachidonic acid (AA) to PG-G2 and PG-H2
21
Q
Why are there multiple COX isozymes?
A
critical for PG functions and for NSAID actions
22
Q
T/F. COX-1 and COX-2 are constitutively expressed.
A
TRUE
23
Q
COX-1 roles in CNS, stomach, and platelets:
A
CNS: mediated fever and pain
Stomach: protects mucosal lining
Platelets: increases platelet aggregation and blood clotting (by altering thromboxanes, TXs)
24
Q
COX-2 roles in CNS, stomach, and endothelial cells:
A
CNS: mediate SOME pain
Stomach: protects mucosal lining with COX-1
Endothelial cells: decreases platelet aggregation (by altering prostacyclin, PGIs)
25
COX-2 is an inducible isozyme that is critical for _____.
Inflammation.
26
What is the key target for NSAID anti-inflammatory effects?
COX-2
27
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).
28
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
29
What drug is the critical prototype of all of the NSAIDS and non-opioid analgesics?
Aspirin
30
Aspirin is ASA. What does ASA stand for?
Acetyl-salicylic acid
31
Aspirin starts as ASA but then what:
rapidly hydrolyzed (de-acetylated) and becomes salicylic acid (or salicylate ion).
32
T/F. Salicylates, including the salicylate from aspirin, are irreversible and competitive COX inhibitors.
FALSE. salicylates ARE REVERSIBLE.
33
Which effects of aspirin are mediated by its salicylate metabolite?
the anti-inflammatory and analgesic effects
34
What is the standard oral dose of aspirin?
325 mg.
35
Aspiring has drug interactions due to displacing with which drugs?
warfarin, methotrexate, sulfonamides, others
36
In regards to pharmacokinetics, what is the mechanism by which aspirin works?
salicylate metabolism and elimination
37
At low to moderate doses, salicylate is what?
metabolized in the liver by conjugation; first-order kinetics and saturable
38
At higher doses, salicylate is what?
excreted unmetabolized by kidneys; zero-order kinetics, half life increases with increasing dose
39
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
40
T/F. Lower doses suffice for COX-1 mediated analogies and anti-pyretic effects.
TRUE
41
Would you use a low or high dose for analgesic and antipyretic?
low
42
Would you use a low or high dose for anti-inflammatory doses
high
43
Low or high doses are associated with conjugation n live, first order kinetics, and saturable?
low
44
Low or high doses are associated with excretion in the kidney, half life increases, and zero order kinetics?
high
45
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)
46
What are miscellaneous effects and uses aspirin is used for?
reducing GI cancer risk: many cancers ahem elevated COX2
| Alzheimer's disease: possible benefit
47
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)
48
How is GI irritation lessened?
using enteric coasted tablets: prevent tablet from dissolving in stomach and damaging GI mucosa, absorption from intestine instead
49
T/F. There is some dilution of peripheral vessels by large doses of salicylate.
TRUE
50
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
51
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
52
Term used for MILD toxicity of salicylate:
salicylism
53
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
54
Overdose toxicity od salicylate usually occurs when how much is taken?
5-30 grams
55
How does overdose usually occur?
typically children ingesting large doses acutely (15-100 tablets; >150 tablets is lethal)
56
Symptoms of overdose:
decrease blood flow, respiratory depression, GI disturbances, CNS disturbances, respiratory failure is eventual cause of death
57
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
58
Equation to known for treating salicylate overdose (regards pka and ph):
pKa-pH = protonated/unprotanated; OR: Ka = [H+][A-]/[AH]
59
One unique us of aspirin only:
to prevent thrombus formation (blood clotting) and prolong bleeding time
60
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
61
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
62
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
63
T/F. Platelets are the main cells with acetylated COX.
TRUE
64
T/F. Anti-inflammatory actions of aspirin are mediated by its salicylate metabolite, after it has lost its acetyl group.
TRUE
65
Platelets use COX-1 to make:
Thromboxanes (TXs); that increase clotting and thrombosis risk
66
Endothelial cells use COX-2 to make:
prostacyclin (PGIs); that decrease clotting and thrombosis risk
67
Low aspiring doses only inhibit COX-1, shifting balance to more anti-thrombotic PGIs formation from endothelial cells.
TRUE
68
Prolonged inhibition of platelet COX-1 causes sustained reduction in TXs.
TRUE
69
Aspirin dose for thrombosis prevention:
75-81 mg/day
70
Aspiring contraindicated in those with:
clotting deficiency
71
Examples of PROpionic acid derivates:
Ibuprofen and Naproxen
72
Difference of ibuprofen and naproxen from aspirin:
less toxic, fewer side effects, ONLY reversible and competitive; prolong bleeding time
73
Ibuprofen and naproxen have specific approval for:
dysmenorrhea (menstrual cramps); pain and cramps mediated by PGs
74
Ibuprofen 98% binds:
very heavily to albumin, can displace warfarin
75
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
76
T/F. Only some NSAIDs can cause renal toxicity/failure.
FALSE, ALL NSAIDs can cause renal toxicity/failure
77
How should toxicity be treated in propionic acid derivatives?
activated charcoal in first 2 hours
78
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.
79
Doses for Ibuprofen:
200 mg (analgesia and antipyresis), 400 mg (anti-inflammatory)
80
What is ibuprofen specifically approved for?
patent ductus arteriosus
81
Doses for naproxen:
200-250 mg twice a day; enteric-coated delayed-release.
82
What is naproxen specifically approved for?
gout and for migraine specifically
83
Acetic acid derivates:
IndomethACin, diclofenAC, ketorolAC
84
Is Indomethacin more or less potent than aspirin? How much more or less?
10-20x MORE potent than aspiring (works in lower doses)
85
What is the dose for indomethacin?
25 mg / 4-6 hours.
86
When is indomethacin mainly used?
in severe inflammation: rheumatoid arthritis, gouty arthritis (use cautiously)
87
CeleCOXib is an example of what?
selective COX-2 inhibitor
88
Celecoxib is great for what?
inhibiting COX-2; treat inflammation without serious adverse effects
89
Dose of Celecoxib:
100-200 mg two days a day, oral, rapidly absorbed, metabolized by liver
90
Approved uses for Celecoxib:
(for all "itis"): osteoarthritis, rheumatoid arthritis, relief of acute pain, primary dysmenorrhea
91
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
92
T/F. Celecoxib has fewer problems for asthmatics than aspirin and other NSAIDs.
TRUE
93
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
94
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)
95
T/F. Celecoxib is an example of a more selective drug causing new problems, even as they solve older problems.
TRUE.
96
T/F. Now black-box warnings for MI risk can be found on ALL NSAIDs, not just Celecoxib.
TRUE, because all can inhibit COX2
97
A drug that is a non-opioid analgesia like NSAIDs, but NOT an NSAID:
acetaminophen
98
Do we know how acetaminophen works?
NO! we do not know mechanism; we THINK inhibition of COXs and PG synthesis.
99
T/F. Acetaminophen has anti-inflammatory effects.
FALSE, it does NOT have anti-inflammatory effects
100
Dose for acetaminophen:
325 mg, oral tablet
101
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 :(
102
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
103
Overdose toxicity dose of acetaminophen:
10-25 g
104
overdose reactions to acetaminophen:
hepatotoxicity; jaundice, usually reversible, but hepatic coma and death can occur
105
What causes the hepatic toxicity from acetaminophen overdose?
a reactive electrophile: NAPZQI (N-acetyl-p-benzo-quinone-amine)
106
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.
107
What drug should you use to reverse overdose toxicity of acetaminophen?
n-acetyl-cysteine (acetadote)
