Toews: NSAIDS and Other RA Drugs- Pt. II-X

Question 1

Aspirin is the prototype of the A)___-__________ _______-________ drugs and of the B) ___-_____ _________ _____ (which largely overlap); it is the drug by which all others are judged

Answer 1

A) non-steroidal anti-inflammatoryB) non-opioid analgesic drugs

Question 2

Aspirin is ______-________ acid, but it is rapidly hydrolyzed to salicylic acid

Answer 2

A) acetyl-salicylic

Question 3

Most (but not all) of the therapeutic effects of aspirin are mediated by its A)__________ __________, effects shared with all other salicylate NSAIDs.

Answer 3

A) salicylate metabolite

Question 4

Aspirin is different from other NSAIDs because it can A)___________ inactivate COXs in some tissues and cells by covalently B)___________ the enzyme

Answer 4

A) irreversiblyB) acetylating

Question 5

Binding of salicylate to COX can _______ COX activity. Acetylation of COX can _______ COX activity also.

Answer 5

Inhibit

Question 6

What needs to happen to terminate the covalent acetylation component of aspirin action?

Answer 6

Degradation of acetylated COX and synthesis of new COX enzyme molecules is required.

Question 7

Other NSAIDs (NOT ASPIRIN), including other salicylate agents, are A)__________ and B)_________ COX inhibitors.

Answer 7

A) reversibleB) Competitive

Question 8

ASPIRIN is: 1. Well ________ orally 2. ___________ throughout the body, including to the CNS (for fever and pain) 3. _______% protein-bound in plasma; drug interactions from displacing warfarin, methotrexate, sulfonamides 4. Rapidly __________ to salicylic acid

Answer 8

1. Absorbed2. Distributed3. 80-90%4. hydrolyzed

Question 9

At low to moderate doses, salicylate is metabolized how?

Answer 9

in the liver by conjugation, with first-order kinetics and saturable.

Question 10

At higher doses, salicylate is excreted how?

Answer 10

unmetabolized via the kidneys, with zero- order kinetics and a half-life that increases with increasing dose NOTE: These higher doses that saturate the liver metabolism are required for aspirin to achieve therapeutic levels for inhibition of COX-2 and inflammation, which also takes a longer time to achieve

Question 11

Typical NSAID effects and therapeutic uses of aspirin at 650-1000 mg / 4 hrs are: (2)

Answer 11

1. ANALGESIA- For mild to moderate pain, Headache, arthritis, dysmenorrhea, neuralgia, myalgia. NOTE: PGs particularly contribute to pain of inflammation, in part by sensitizing receptors for pain-related peptide mediators (bradykinin, substance P, others). This makes NSAIDs particularly beneficial in inflammation-related pain. (aka pain reliever)2) ANTIPYRESIS- Action in hypothalamus to return thermoregulatory set-point to normal. (aka reduce fever)

Question 12

Typical NSAID effects and therapeutic uses of aspirin at 1300 mg+ / 4 hr are: (1)

Answer 12

Anti-inflammatory effects- Acute rheumatic fever, rheumatoid arthritis, others.

Question 13

A unique effect of aspirin ONLY to prevent thrombus formation and prolong bleeding time is due to…

Answer 13

its ability to acetylate COXs for both irreversible and prolonged action.

Question 14

What drug is a major current use to prevent (reduce risk) of MI and stroke?

Answer 14

ASPIRIN!!!!

Question 15

Aspirin has what effect on platelets?

Answer 15

A unique effect on platelets, because of their inability to make new COX and their long lifetime; platelet effects of aspirin persist for about 7 days.

Question 16

A)_________ and B)________ ___________ cells near the site of absorption are perhaps the only cells that are exposed to acetyl-salicylic acid, due to its rapid hydrolysis before reaching most other cellular targets and tissues.

Answer 16

A) PlateletsB) Vascular endothelial

Question 17

Other cells and tissues experience only the __________ COX inhibition by salicylate

Answer 17

Reversible

Question 18

Aspirin has what effects on TX (Thromboxins)?

Answer 18

1) Prolonged inhibition of platelet COX leads to reduced TX FORMATION, the major COX product from platelets. 2) Decreased TXs reduces platelet AGGREGATION, decreasing the likelihood of clotting and thrombotic events (for better or worse!)

Question 19

What is the current recommendation for preventive use of aspirin – “aspirin regimen”?

Answer 19

1) For reducing MI in men 45-79 and ischemic stroke in women 55-79, use aspirin 75-81 mg/day, if potential benefit of reduced disease risk outweighs potential harm of increased GI hemorrhage. This aspirin dose was called “baby aspirin” when aspirin was still used in children, prior to the Reye’s Syndrome connection.2) Men younger than 45 and women younger than 55 not recommended. Over 80 not recommended.

Question 20

What are 2 miscellaneous uses of aspirin?

Answer 20

1. Colorectal cancer, especially with familial adenomatous polyposis (FAP). NOTE: Many cancers have elevated COX2, and epidemiology studies suggest a benefit, but still an emerging story 2. Alzheimer’s Disease – possible benefit, evidence not strong.

Question 21

What are other salicylate NSAIDs and their characteristics?

Answer 21

A. Sodium salicylate, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine B. Share analgesic, anti-pyretic, and anti-inflammatory effects and uses with aspirin C. DO NOT share platelet-related anti-thrombotic effects and uses, because they are NOT irreversible inhibitors like aspirin so do not have long-lasting effects on platelets

Question 22

Describe GI adverse effects of salicylates, both aspirin and others

Answer 22

NOTE: Because PGs are major GI mucosa protectors 1. Gastric irritation and mild bleeding 2. Gastric ulceration and hemorrhage 3. Exacerbation of peptic ulcers 4. The most common complaint and responsible for many deaths 5. Effects can be moderated with PG analog misoprostol [Cytotec] or proton pump inhibitor omeprazole

Question 23

Describe Cardiovascular adverse effects of salicylates, both aspirin and others

Answer 23

1. No important effects with therapeutic doses 2. Dilation of peripheral vessels by large doses 3. Toxic levels (80 mg%) can cause central vasomotor paralysis 4. Avoid aspirin in patients with blood-clotting deficiencies; not a problem with other salicylates or other NSAIDs)

Question 24

Describe ACID BASE BALANCE adverse effects of salicylates, both aspirin and others at LOW, HIGHER, and TOXIC doses.

Answer 24

1. Low therapeutic doses increase CO2 production via uncoupling oxidative phosphorylation in skeletal muscle 2. At higher doses (40 mg%+), compensation for respiratory alkalosis by bicarbonate excretion 3. Toxic doses (80 mg%+) lead to metabolic acidosis and disturbances in potassium balance (hypokalemia)

Question 25

Describe Respiratory adverse effects of salicylates, both aspirin and others at LOW, HIGHER, and TOXIC doses.

Answer 25

1. Low therapeutic doses (up to 1300 mg / 4 hr or 40 mg%) increase O2 consumption and CO2 production which stimulates stimulates respiration 2. Higher doses (> 1300 mg / 4 hr or > 40 mg%) stimulate respiratory center directly, resulting in respiratory alkalosis 3. Overdose (> 80 mg%) leads to respiratory paralysis and acidosis

Question 26

List some things associated with Mild toxicity -“salicylism” along with Typically how it occurs and how symptoms usually disappear.

Answer 26

1. Typically from excess chronic use by the elderly 2. Ringing in the ears (tinnitus), dizziness, headache, confusion, deafness 3. Drowsiness, thirst, hyperventilation, nausea, vomiting 4. Respiratory alkalosis, but compensation occurs 5. Symptoms generally disappear when dosage is reduced

Question 27

Overdose toxicity (with _-__g aspirin or other salicylates)

Answer 27

5-30 g aspirin or other salicylates= OVERDOSE

Question 28

List some things associated with OVERDOSE toxicity of salicylates along with Typically how it occurs and how symptoms usually disappear.

Answer 28

1. Typically from small children ingesting large doses acutely 2. GI disturbance - nausea, vomiting, anorexia, abdominal pain 3. CNS disturbances (restlessness, incoherence, vertigo, tremor, hallucinations) 4. Fever, dehydration and sweating, especially in children5. Hyperpnea 6. Skin eruptions (hemorrhages) 7. Respiratory and acid-base balance disturbance (as for salicylism) a. Respiratory stimulation followed by respiratory depression ➔ respiratory acidosis b. Central vasomotor paralysis ➔ decreased renal function + other acid-base effects ➔ metabolic acidosis

Question 29

How would you treat salicylate overdose toxicity?

Answer 29

1. Hospitalize and maintain vital signs 2. Prevent continued absorption with activated charcoal 3. Or use whole bowel irrigation for enteric-coated or sustained release products 4. Hasten elimination by volume repletion and alkalinization of urine with SODIUM BICARBONATE (because salicylic acid pKA = 3). 5. Monitor blood levels 6. Provide supplemental glucose and potassium 7. Hemodialysis

Question 30

Other adverse reactions and precautions with salicylates: A. Allergic reactions (__%) B. May induce _______ attack. C. Interactions with other drugs due to ____________ from plasma binding proteins, notably warfarin, methotrexate, sulfonamides D. ________ syndrome – aspirin should not be used in children under age 16; stopping aspirin use in children has nearly eliminated _______ syndrome.E. _________ _______ of ductus arteriosus, so avoid in 3rd trimester of pregnancy. NOTE: Patency (openness) is mediated by PGs, so all NSAIDs can potentially cause premature closure Conversely, some NSAIDs are specifically approved for promoting closure in infants with patent ductus arteriosus. F. ______ and _______ toxicity – uncommon, primarily with long term use

Answer 30

A. 1%B. AsthmaC. displacementD. Reye’sE. Premature closureF. Renal and Hepatic

Question 31

Propionic acid derivatives (Ibuprofen, Naproxen, others): What are actions and uses? (Hint- Similar to aspirin, so focus on differences?)

Answer 31

1. Effective analgesics, antipyretics and anti-inflammatory agents, equivalent to aspirin 2. Same mechanism as aspirin, except only reversible and competitive inhibition of COXs 3. Better than aspirin for treatment of dysmenorrhea 4. Several are used in the treatment of gout

Question 32

Adverse Effects and cautions of Propionic acid derivatives (Ibuprofen, Naproxen, others):

Answer 32

1. Similar GI side effects as aspirin, but to a LESSER extent 2. Most prolong bleeding time initially, but effect disappears quickly 3. Most BIND HEAVILY to albumin and displace warfarin and other drugs 4. All display CROSS-SENSITIVITY to salicylates; should not be used in patients allergic to aspirin or with aspirin-sensitive asthma 5. Toxicities SIMILAR to aspirin and other salicylates a. Symptoms: nausea, vomiting, epigastric pain, GI bleeding, lethargy, drowsiness, seizures, coma after massive doses b. Treatment: activated charcoal within first 2 hr, symptomatic and supportive therapy, monitor respiration and other vital signs c. Low incidence of serious complications

Question 33

Dosage of Ibuprofen (Advil, Motrin, Brufen, Rufen, others) for analgesia, antipyresis, and anti-inflammatory.

Answer 33

1. 200 mg / 4-6 hr for analgesia and antipyresis 2. 400 mg+ / 4-6 hrs for anti-inflammatory effects

Question 34

Ibuprofen:1. Also approved for treatment of ______ ______ __________ (NeoProfen) 2. Chronic use may ________ the risk of a myocardial infarction 3. Can _____ effects of low dose aspirin, so take 8 hr before or 30 min after aspirin

Answer 34

1. Patent ductus arteriosus2. Increase3. block

Question 35

Naproxen: 1. Naproxen sodium (Anaprox, Aleve) is OTC form, ___ mg / 4-6 hr 2. Naprosyn is a ____-______ preparation, given twice a day, 250-500 mg bid 3. Naprosyn SR is ____-_______ preparation, given once-daily 4. Chronic use may not _________ risk of myocardial infarction as much as ibuprofen 5. Chronic use is associated with _______ ulcer risk than most other NSAIDs

Answer 35

1. 200mg/4-6hr2.long-acting3.Slow release4. Increase5. greater

Question 36

Acetic acid derivatives:-Indomethacin (Indocin) is prototype 1. 10-20X more ______ than aspirin (25 mg / 4-6 hr) 2. Limited use for _________ and antipyresis, except in severe cases, because of its severe side effects 3. Mainly used in ______ inflammation such as rheumatoid or gouty arthritis 4. Specifically approved for ______ ______ ___________.

Answer 36

1. potent2. analgesia3.Severe4.patent ductus arteriosus

Question 37

Selective COX-2 inhibitors:-Celecoxib (Celebrex) 100-200 mg bid 1. Rationale: Most inflammation effects are due to ___-, so selective ___- inhibition should treat inflammation and avoid COX-1-related adverse effects. 2. Approved for treatment of ______________ and rheumatoid arthritis, familial adenomatous polyposis

Answer 37

1. COX-22. Osteoarthritis

Question 38

Pharmacokinetics of Celecoxib:a. _______ absorbed b. Metabolized by _____ c. Half-life is __ hours

Answer 38

a. Rapidly absorbed b. Metabolized by liver c. Half-life is 11 hours

Question 39

Clinical properties of Celecoxib:a. _____ to naproxen for osteoarthritis, rheumatoid arthritis b. ______ than naproxen for pain post-dental surgery c. _____ problems for asthmatics than aspirin and other NSAIDs

Answer 39

a. EQUALl to naproxen for osteoarthritis, rheumatoid arthritis b. POORER than naproxen for pain post-dental surgery c. FEWER problems for asthmatics than aspirin and other NSAIDs

Question 40

Drug interactions of Celecoxib:a. Metabolized by ___ ___ and may inhibit ___ in those with genetic variants b. Can ____ metabolism of tricyclic antidepressants, SSRIs, antiarrhythmics

Answer 40

a. Metabolized by CYP 2C9 and may inhibit 2D6 in those with genetic variants b. Can SLOW metabolism of tricyclic antidepressants, SSRIs, antiarrhythmics

Question 41

Adverse effects of Celecoxib:a. _____ is most common side effect – because of decreased kidney function b. __ problems i. Abdominal pain, diarrhea, _________ ii. _____ GI problems than naproxen, ibuprofen, diclofenac iii. Not clear if __ problems will be greater or less with long term use iv. May ____ ulcer (wound) healing c. Patients allergic to sulfonamides (SHOULD/SHOULD NOT) take celecoxib? d. (APPROVED/ NOT APPROVED?) for use during pregnancy e. Increased incidence of ________ __________; now black box warning NOTE: Rofecoxib (Vioxx) and Valdecoxib (Bextra) were removed from the market because of an increased incidence of myocardial infarctions (rofecoxib) or the likelihood of an increased incidence of myocardial infarctions (valdecoxib) in patients taking these drugs

Answer 41

a. EDEMA is most common side effect – because of decreased kidney function b. GI problems i. Abdominal pain, diarrhea, DYSPEPSIA ii. FEWER GI problems than naproxen, ibuprofen, diclofenac iii. Not clear if GI problems will be greater or less with long term use iv. May SLOW ulcer (wound) healing c. Patients allergic to sulfonamides SHOULD NOT take celecoxib d. NOT APPROVED for use during pregnancy e. Increased incidence of MYOCARDIAL INFARCTION; now black box warning NOTE: f. Rofecoxib (Vioxx) and Valdecoxib (Bextra) were removed from the market because of an increased incidence of myocardial infarctions (rofecoxib) or the likelihood of an increased incidence of myocardial infarctions (valdecoxib) in patients taking these drugs

Question 42

Acetaminophen: Pharmacological effects are
analgesia and anti-pyresis
similar to aspirin at similar dose
but NO ____ _____________ action

Answer 42

NO ANTI-INFLAMMATORY ACTION

Question 43

True or False: Acetaminophen
Side effect/toxicity differences from aspirin: 
no GI effects of concern 
no hematologic effects 
no association with Reye's Syndrome
used in place of aspirin in children 
no CV effects or concerns 
no respiratory effects or concerns 
no effects on acid-base balance

Answer 43

TRUE

Question 44

What major adverse effect do you have to worry about with Acetaminophen?

Answer 44

Hepatic damage- alcohol increases hepatic damage

Question 45

What are some other adverse effects of Acetaminophen? (Other than hepatic damage?)

Answer 45

skin rash, drug fever, mucosal lesions can occur
rarely immuno-cyto-toxicity
neutropenia, leukopenia, pancytopenia
chronic abuse can lead to nephro-toxicity also

Question 46

Acetaminophen Toxic metabolism:
1) CYP 2E1 forms a reactive 1)_____________(AC*)

2) ideally gets inactivated by __________ (GS-AC*)

3) reacts with liver proteins if not inactivated
which leads to liver cell death, ______________

Answer 46

1) electrophile (AC*)
2) glutathione
3) hepatotoxicity

Question 47

Treatment of overdose toxicity of Acetaminophen:

1) supportive therapy

2) remove drug promptly
activated charcoal in first 4 hr if conscious (preferred)
vomiting or gastric lavage in first 4 hr
(second choice)

3) after 4 hr, treat with reactive sulfhydryl reagents
usually N-______-____________
to reverse the toxicity
by reacting with the AC* toxic metabolite
and/or restoring endogenous glutathione

Answer 47

N-acetyl-cysteine