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MSK II Exam 1 > 2-23 NSAIDs > Flashcards

2-23 NSAIDs Flashcards

1
Q

What is the NSAIDs drug list? Prototype?

A

Aspirin [generic] - prototype

Ibuprofen [ADVIL, MOTRIN, NUPRIN]

Naproxen [ALEVE, NAPROSYN]

Ketoprofen [ORUDIS]

Indomethacin [INDOCIN]

Etodolac [LODINE]

Ketorolac [TORADOL] (IV, IM)

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2
Q

What are the selective COX2 inhib drugs? Non-NSAID antipyretic/analgesic?

A

¡Selective COX-2 Inhibitors

lCelecoxib [Celebrex]

¡Non-NSAID antipyretic/analgesic

lAcetaminophen [TYLENOL]

la non-narcotic analgesic.

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3
Q

What are the important properties of NSAIDs?

A

¡Analgesic = Pain Relief

¡Antipyretic = Anti-fever

¡Anti-inflammatory

Prototype Drug is ASPIRIN

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4
Q

What are the common mechanisms of action for NSAIDs?

A

All NSAIDS inhibit the enzyme cyclooxygenase (COX).

Cyclooxygenase is a key enzyme responsible for the synthesis of prostaglandins.

Prostaglandins contribute to a number of inflammatory processes.

Common mechanism of action leads to common side effects.

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5
Q

What do COX inhibitors target? Steroids?

A

adg

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6
Q

Why are COX inhibitors and steroids so effective at dealing with pain in different places?

A

Stops precursors that make tissue-specific isomerases

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7
Q

What are some prostaglandin receptors?

A

All GPCRs that make intracellular signals

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8
Q

How does aspirin work?

A

When ASA binds serine, and will covalently bind and inactivate enzymes

  • ASA leaves behind a permanent residue on enzyme
  • all other COX inhib do reversible binding to active spot
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9
Q

What’s the difference between COX1 and COX2

A

COX-1

expressed in most tissues.

Constituitively active, regulated by amt of substrate arachadonic acid

COX-2

Induced by cytokines and other inflammatory mediators. - only shows with inflammation

This enzyme is the “real” target for anti-inflammatory effects

COX-3 – brain, role(?) splice variant of COX-1

Traditional NSAIDs non-selectively inhibit both COX-1 and COX-2.

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10
Q

What is the MOA for COX inhibitors?

A

Mechanism of Action:

aspirin covalently (irreversibly) inhibits COX 1&2

recovery of COX in most tissues is by synthesis of new enzyme.

Platelets cannot synthesize new COX, so inhibition is irreversible.

other NSAIDs produce reversible inhibition of COX.

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11
Q

What are the selective COX-2 inhibitors?

A

¡Celecoxib [Celebrex]

¡Valdecoxib [Bextra] Withdrawn

¡Refocoxib [Vioxx] Withdrawn

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12
Q

What is the specificity, effects, clinical indications and contraindications for COX2 inhib.?

A

Celecoxib [Celebrex]

Valdecoxib [Bextra] Withdrawn

Refocoxib [Vioxx] Withdrawn

Selective for COX-2 (300-400X)

Significantly less GI ulcers [by endoscopy].

Do not effect platelets and bleeding time.

Originally approved for dysmenorrhea, osteoarthritis, and rheumatoid arthritis, acute post-operative pain

lContraindicated in aspirin allergy & 3rd trimester pregnancy

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13
Q

Why were so many COX2 inhib taken off the market?

A

slightly increased risk of MI, but not clear cut what caused MI

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14
Q

What are the advantages & disadvantages of NSAIDs vs aspirin?

A

Advantages: some NSAIDs are marginally superior to aspirin because they:

are more potent

are more efficacious at tolerated doses.

cause less gastrointestinal irritation or other side effects

have longer duration of action so taken less frequently (qd or bid)

Disadvantages

Newer NSAIDs are more expensive than aspirin

Some are more toxic than aspirin.

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15
Q

What is the relative cost of NSAIDs?

A

For standard treatment (1 month) of rheumatoid arthritis:

Enteric coated aspirin (generic) $18.00

Enteric coated aspirin (Ecotrin) $50.40

Ibuprofen (generic) $2.30

Ketoprofen (Orudis) $138.00

Diclofenac (generic) $46.20

Celecoxib (Celebrex) $84.00

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16
Q

How are analgesics effective in relieving pain, other than blocking prostaglandin synthesis?

A

PGE2 sensitizes pain nerve endings to the action of bradykinin, histamine, and substance P. Aspirin blocks PGE2 formation.

NSAIDs are mild analgesics effective against pain of low-to-moderate intensity.

NSAIDs can be superior to opioids for relief of some forms of post-operative pain and pain associated with inflammation.

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17
Q

How do NSAIDs compare to opioids? Effectiveness at relieving pain, side effects, etc.?

A

Efficacy of pain relief provided by NSAIDs is lower than opioids - more mild analgesic effects, but good at alleviating pain in hollow organs.

NSAIDs lack opioid effects of

respiratory depression.

development of physical tolerance/dependence.

Pain from integumental structures is relieved but not pain from hollow viscera.

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18
Q

Other than the analgesic effect, what else are COX inhib effective at relieving?

A

Antipyretics

Temperature control center in hypothalamus regulates body temperature.

Pyrogens (cytokines) from lymphocytes lead to higher temperature set point, i.e., fever.

Heat generation (metabolism) increases and heat loss (vasodilation) decreases.

NSAIDs that can cross BBB effectively suppress this response.

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19
Q

In addition to the antipyretic and analgesic effects, what other effect of COX inhib is helpful?

A

PGE2 and PGI2 cause vasodilation are important mediators of localized erythema and edema in inflammation. NSAIDs inhibit PG formation.

NSAIDs inhibit activation and function of inflammatory cells, may stabilize lysosomal membranes and inhibit phagocytosis.

20
Q

What are the GI effects of NSAIDs?

A

PGI2 inhibits gastric acid secretion.

PGE2 and PGF2a stimulate synthesis of bicarbonate and mucus.

PGE2 promotes mucosal blood flow.

NSAIDs inhibit all of these effects which leads to GI irritation.

21
Q

What is the effect of NSAIDs on the stomach?

A

Fatty acids can convert into prostaglandin

  • this process is blocked by NSAIDs

prostaglandins are then used to downregulate the H+/K+ ATPase pump in parietal cells, leading to decreased acid secretion

prostaglandins upregulate mucous, bicarb production in superficial epithelial state

prostaglandins improve blood flow to the stomach

22
Q

What are the GI ADRs of NSAIDs?

A

Epigastric distress

Nausea

Vomiting

Microhemorrhage

Ulceration

Anemia

23
Q

What the effects of NSAIDs on platelets and the CV system?

A

Platelets have thromboxane synthetase and make TXA2, a potent vasoconstrictor and activator of platelet aggregation and release.

Endothelial cells make PGI2 (prostacyclin) an inhibitor of platelet aggregation and a vasodilator.

Low doses of aspirin irreversibly inhibit COX and platelet aggregation for the life of the platelet (8-11 days)

24
Q

What is ASA, in addition to lifestyle changes, useful in prophylaxis of?

A

Low dose aspirin together with diet and exercise is useful for the prophylaxis of:

coronary artery disease

deep vein thrombosis

unstable angina

prophylaxis and treatment of MI and stroke

25
Q

What are the effects of COX inhibitors on the kidney?

A

Little effect in normal subjects.

PGs oppose effect of vasoconstrictors.

In situations where there are high levels of circulating vasoconstrictors, e.g., compensated congestive heart failure, chronic renal disease, NSAIDs can reduce renal blood flow.

Retention of sodium and water. Reduced effectiveness of hypertensive regimens.

NSAIDs and COX-2s should be used with caution in patients with reduced renal function, heart failure, liver dysfunction, or in patients on ACE inhibitors or diuretics, especially elderly patients

26
Q

What are the disease states leading to increased vasoconstrictors? What is the response of renal blood flow?

A
27
Q

What is Reye’s syndrome?

A

Reye’s syndrome is a rare but often fatal consequence of infection with chicken pox, varicella and influenza viruses. Liver damage and encephalopathy.

Use of aspirin and salicylates are associated with the development of Reye’s syndrome. The use of salicylates in children or adolescents with chicken pox or influenza is contraindicated!

28
Q

What sorts of mild problems are NSAIDs ideal for?

A

Therapeutic uses: Analgesic-Antipyretics

Pain and Fever: symptomatic relief for pain of low-to-moderate intensity.

Headache

Dysmenorrhea

Arthralgia

Myalgia

Neuralgia

Arthritis

29
Q

What are some therapeutic uses for anti-inflammatory agents/NSAIDs?

A

Rheumatoid Arthritis

Osteoarthritis

Gout and Crystal Arthritis

Systemic Lupus Erythematosus

Seronegative Spondyloarthropathy

Arthralgia

Myalgia

Bursitis, Tendonitis

30
Q

As anti-inflammatory agents, which NSAIDs are used and for how long? What are the benefits and limitations?

A

¡NSAIDs other than aspirin are typically used for chronic treatment, e.g., ibuprofen or naproxen.

¡COX-2 specific NSAIDs were preferred for chronic treatment, but there use now (Celebrex) is still controversial.

¡Lesser incidence and less serious GI side effects was the proposed benefit of Celebrex.

¡NSAIDs suppress the clinical signs in rheumatic disease, but subsequent tissue damage is not halted.

¡NSAIDs do not induce remission.

31
Q

Why should you give Tylenol as an antipyretic to kids with fever?

A

Because HSV viruses, influenza, and Reye’s syndrome are all bags of dicks.

32
Q

Why are NSAIDs so effective for dysmenorrhea?

A

¡Prostaglandins released by the endometrium during menstration contribute to severe cramps and pain.

33
Q

A kid is born with a PDA. What do you do?

A

PGE2 keeps ductus arteriosus open following birth.

Indomethacin is the NSAID often used to stimulate closure of the patent ductus arteriosus.

34
Q

Why are NSAIDs useful in familial adenomatous polyposis (FAP)?

A

Studies show reduction in number of polyps with COX-2 inhibitors

COX-2 is overexpressed in several human cancers

Increasing evidence suggest that COX-2 inhibitors, and perhaps NSAIDs in general, may be effective for prevention or treatment of certain cancers, especially for colorectal cancer

35
Q

What is the evidence that ASA prevents cancer?

A

reduces overall cancer risk, <1 case/1000 for low risk up to <12 case/1000 for high risk populations

36
Q

What are the kinetics of ASA?

A

Aspirin displays zero-order elimination kinetics at high doses.

The plateau principle does not apply under these conditions and plasma drug levels increase disproportionately to dose.

Too much aspirin = tinnitus, time to stop

37
Q

What are the ADRs of ASA?

A

Gastrointestinal irritation

epigastric distress, nausea, vomiting, microscopic bleeding, ulceration, anemia

Prolonged bleeding time
(anti-platelet effect)

Patients scheduled for surgery taken off of aspirin for one week prior

38
Q

What is the relationship between hypersensitivity and ASA?

A

Hypersensitivity

asthma, nasal polyps, chronic urticaria predisposed

progresses from hives, nasal secretion and edema to acute asthma attack, severe dyspnea, hypotension, and shock

Hypersensitivity to aspirin is a contraindication to therapy with any NSAID.

(D/t possible overproduction of leukotrienes, triggering asthma)

  • cross reaction with any NSAID too
39
Q

What are the drug-drug interactions of ASA?

A

¡Drug-drug interactions

lantacids

lprotein displacement; phenytoin, thyroxine, thiopental

lrisk of bleeding for patients on anticoagulants

luricosuric effect in gout patients

40
Q

What does overt toxicity of ASA cause?

A

Salicylism - mild intoxication

nausea, vomiting, tinnitus, hyperventilation, headache, mental confusion, dizziness

Overdose = acute medical emergency

fever, dehydration, delirium, hallucination, convulsions, coma, respiratory and metabolic acidosis, death

children especially vulnerable

41
Q

What are the ADRs of ASA during pregnancy?

A

Avoid use during third trimester unless absolutely necessary

low birth weight

increased perinatal mortality

anemia

antepartum and postpartum hemorrhage

prolonged gestation

premature closure of ductus arteriosus

42
Q

What are the uses and limitations of indomethacin?

A

Indomethacin is more potent than aspirin

Very efficacious anti-inflammatory agent

Toxicity (worse than aspirin) limits its usefulness

Not used for routine analgesia

Can be used in resistant rheumatoid disease

Suppression of uterine contraction in preterm labor and closure of patent ductus arteriosus

43
Q

What are the uses of ketorolac (Toradol)?

A

Potent analgesic

Weak antiinflammatory effect

Can be used orally, IM, or IV

Used for post-operative pain, as an alternative to opioids (not obstetrics)

Unlike opioids, it is not associated with tolerance, withdrawal effects, or respiratory depression.

44
Q

What are the uses and limitations of selective COX-2 inhib?

A

¡Celecoxib [Celebrex]

¡Selective for COX-2.

¡Significantly less GI ulcers by endoscopy

¡No effect on platelets and bleeding time.

lBut caution with patients on warfarin.

¡Approved for osteoarthritis and RA.

¡Menstrual pain and acute post-operative pain

¡More expensive

45
Q

What are the uses and limitations of Tylenol?

A

¡Non-narcotic Analgesic

¡Antipyretic

¡Very weak anti-inflammartory activity

¡Not an NSAID, not effective for inflammation

¡Well tolerated, lacks GI and platelet side effects

¡Useful analgesic, antipyretic for children and those with contraindications to aspirin

46
Q

When is Tylenol frequently used? What does an overdose cause?

A

¡Initial drug of choice for treatment of pain in osteoarthritis

¡Combined with opioid agonists for additive postoperative pain relief [Percocet, Lortab, Vicodin, Darvocet, Tylenol with Codeine]

¡ Acute Overdose: can be fatal due to delayed liver damage

MSK II Exam 1 (4 decks)

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