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Pharmacology > Week 9 Non-Opioid Analgesics > Flashcards

Week 9 Non-Opioid Analgesics Flashcards

1
Q

NSAIDs act by inhibiting ____ enzymes

A

COX

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2
Q

MOA of Aspirin

A
  • aspirin (acetylsalicylic acid) transfers its acetyl group to cyclooxygenase which inactivates COX (both isoforms)
  • IRREVERSIBLE REACTION
  • the other NSAIDs are all REVERSIBLE inhibitors of COX
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3
Q

the 3 major therapeutic actions of NSAIDs

A

reduce inflammation
analgesic
antipyretic

not all NSAIDs are equally effective in each action

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4
Q

COX transforms what molecule into prostaglandins?

A

Arachidonic acid

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5
Q

how do NSAIDs decrease pain?

A
  • decrease PGE2 synthesis

- PGE2 sensitizes nerve endings to bradykinin, histamine & other mediators released locally by the inflammatory process

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6
Q

how do NSAIDs decrease fever?

A
  • impede PGE2 synthesis & release

- PGE2 is stimulated by pyrogens such as cytokines which are activated by infection

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7
Q

non-opioid analgesics include?

A

NSAIDs and acetaminophen

It is still a non-opioid analgesic

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8
Q

why is acetaminophen not an NSAID?

A

does not have anti-inflammatory effects

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9
Q

principal uses of non-opioid analgesics?

A
  • relief mild-to-moderate somatic pain (incl. some post-operative)
  • relieve inflammation incl. RA, OA, gout, ankylosing spondylitis (except acetaminophen)
  • reduce fever
  • prophylaxis MI & stroke (Aspirin specifically)
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10
Q

why are NSAIDs not as effective for reducing pain as opioids?

A

NSAIDs display a ceiling effect for analgesia

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11
Q

morphine vs aspirin

** KNOW THIS FOR EXAM

A

opioid (morphine):

  • visceral pain (somatic)
  • moderate to severe
  • acts in CNS
  • tolerance, physical dependence likely
  • high abuse potential

non-opioid (aspirin)

  • somatic pain
  • mild to moderate pain
  • acts locally
  • no tolerance/physical dependence potential
  • no abuse potential
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12
Q

5 classes of anti-inflammatory analgesic drugs

A
  • salicylates (ASA [sulfur-based])
  • propionic acids (ibuprofen)
  • pyrazalone derivatives (phenylbutazone)
  • indole derivatives (indomethacin)
  • remission-inducing / disease modifying drugs (chloroquine)
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13
Q

role of leukotrienes?

A

increase vascular permeability

increase mobilization of endogenous mediators of inflammation

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14
Q

role of PGE2

A

promote edema and leukocyte infiltration

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15
Q

role of PGI2

A

increase vascular permeability, enhance pain producing properties of bradykinin

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16
Q

major chemicals contributing to vascular permeability?

A

histamine & leukotrienes

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17
Q

major chemicals contributing to vasodilation?

A

PGs, bradykinin

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18
Q

major chemical contributor to pain?

A

bradykinin

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19
Q

major chemical contributors to chemotaxis?

A

PGs, LTs

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20
Q

prostaglandins are produced by which tissues

A

virtually all tissues

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21
Q

where do PGs act?

A

act locally on tissues in which they are synthesized

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22
Q

why don’t PGs circulate in the blood?

A

metabolized rapidly to inactive products at their sites of action

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23
Q

ALL Non-opioid analgesics act by inhibiting the synthesis of ____

A

PGs

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24
Q

NSAIDs inhibit Cox-1, Cox-2, or both?

A

both - thereby inhibiting PG synthesis

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25
Q

describe Cox-1

A
  • constitutive enzyme in most cells
  • produces PGs that are cytoprotective to GIT
  • involved in normal homeostasis
  • platelet aggregation, renal homeostasis
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26
Q

describe Cox-2

A
  • inducible enzyme
  • induced in inflammatory cells by stimuli (oxidative stress, injury, ischemia, seizures, neurodegenerative ds)
  • dramatically unregulated during inflammation (10-18x)
  • constitutive in brain, kidney, bone (renal blood flow maintenance, renal electrolyte homeostasis)
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27
Q

ASA/NSAIDs/COX-2 effects and CV risk

A

2005-6 FDA & European regulatory agencies added a warning of increased thrombotic CV risk for all NSAIDs

May cause increased risk of serious CV events, MI, stroke,
Risk may increase w duration of use

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28
Q

nonselective NSAIDs inhibit COX enzymes reversibly or irreversibly?

A

reversibly

29
Q

MOA Selective COX-2 inhibitors

A

inhibit COX-2 irreversibly in time-dependent manner

30
Q

half life of aspirin?

A

3.5 hours
ranges b/w 2-12 hours
first order kinetics

31
Q

where is aspirin absorbed

A

unionized salicylate passively absorbed in small intestine & stomach
dissolution favoured at higher pH of gut

32
Q

distribution of aspirin

A

readily, into most tissues/fluids

cross BBB & placenta

33
Q

metabolism of aspirin

A

rapidly hydrolyzed to salicylate (de-acetylated)
75% conjugate by LV glycine
excreted via kidney
at anti-inflammatory doses (>4g/d) hepatic metabolism becomes saturated & zero-order kinetics observed = half-life 15+hrs

34
Q

which of these 3 effects does acetaminophen not exhibit?

antipyretic; antiinflammatory; analgesic

A

anti-inflammatory

therefore acetaminophen is not considered an NSAID

35
Q

why is aspirin (ASA) avoided in gout or in patients taking probenecid?

A

at low doses (4g-/d) uric acid secretion is unchanged or increased

36
Q

how do NSAIDs circulate in the body?

A

highly bound to plasma protein

37
Q

explain adverse affects of NSAIDs on GI

A
  • range from dyspepsia to bleeding
  • microscopic GI bleeds are universal
  • normally PGIs (prostacyclin) inhibits gastric acid secretion
  • PGE2 & PGF2 stim. synthesis protective mucus in stomach & SI
  • gastritis (damages epithelium)
    = increased risk bleed & ulceration
38
Q

adverse hematologic effects of NSAIDs

A
  • TXA2 enhances platelet aggregation
  • aspirin irreversibly inhibits COX-1 mediated TXA2 formation
  • other NSAIDs reversibly inhibit TXA2 production
  • platelets lack nuclei & therefore can’t synthesize new enzyme; lack of TX persists for life of platelet (3-7 days)
  • therefore aspirin withheld for the week prior to surgery
  • as NSAIDs before more COX-2 selective, expected to have less effect on platelet inhibition
39
Q

adverse renal effects of NSAIDs

A
  • PGE2 & PGI2 maintain renal blood flow (vasodilators)
  • NSAIDs prevent synthesis of these
    = retention sodium & water & may cause edema
  • decrease renal blood flow –> decrease GFR –> water & electrolyte reabsorption in proximal tubule
    hx heart failure/kidney ds at high risk
    can mitigate effects of antihypertensive meds
    can lead to acute renal failure
40
Q

what percent of population has a hypersensitivity reaction to NSAIDs?

A

15%

urticaria; bronchoconstriction; angioneurotic edema

41
Q

what are the major risk factors for developing GI problems with NSAID use

A

prior UGI clinical event (2.5-4x increased risk)
older age; somewhere b/w 50-65 (2-3.5x)
anticoagulation (Warfarin) (3x)
corticosteroid (2x)
high-dose/multiple NSAIDs + low dose aspirin (2-4x)

42
Q

additional adverse effects w/ASA re: blood

A

prolonged bleeding time

43
Q

additional adverse effects w/ASA re: respiration

A
  • pulmonary edema risk in elderly
  • increase RR
  • high doses lead to respiratory depression
44
Q

additional adverse effects w/ASA re: Reye’s syndrome

A
  • use of ASA in children w viral fever

- fatal, fulminating hepatitis w cerebral edema

45
Q

what effect do selective COX-2 inhibitors have on platelet function?

A

COX-2 selective inhibitors have no effect on platelet function even in supra-therapeutic doses
: lack of COX-2 in platelet

46
Q

describe mild salicylism

A 
- mild form of salicylate toxicity
n/v
marked hyperventilation
HA
mental confusion
dizziness
tinnitus**classic symptom
47
Q

describe severe salicylism

A 
restlessness
delirium
hallucinations
convulsions
coma
respiratory and metabolic acidosis
death from respiratory failure
48
Q

who is ASA (aspirin) CI for?

A

asthmatic (block COX –> increase lipoxygenase pathway –> increase LTs ==> severe bronchospasm)
pregnancy (risk premature closure of ductus arteriosus)
viral infections in children (10g can = death)

49
Q

When was Vioxx® approved for use in Canada?

A

1999
despite evidence in the original clinical trials of a nonstatistically significant increase in risk of cardiovascular events and despite the known potential for cardiovascular events associated with any drug that interferes with cyclooxygenase-2 enzyme regulators of prostacyclin — a potent vasodilator and inhibitor of platelet aggregation.

Vioxx® was approved in October, 1999, in liquid and tablet forms for the treatment of acute and chronic signs and symptoms of osteoarthritis, relief of menstrual pain, and relief of acute pain in adults and was first marketed in November, 1999. In April 2003, the acute and chronic treatment of the signs and symptoms of rheumatoid arthritis in adults was granted approval by Health Canada.

50
Q

What was Vioxx® used for?

A

COX-2 inhibitor

51
Q

Why was Vioxx® withdrawn?

A

increased risk of cardiovascular disease, mainly myocardial infarction and stroke

52
Q

When was Health Canada notified about the recall of Vioxx®?

A

Health Canada received official notice of the withdrawal of Vioxx® by letter from Merck Frosst Canada & Co., on the morning of September 30, 2004

53
Q

Has Health Canada tracked any cardiovascular adverse events related to this drug?

A

In 2002, Health Canada issued an advisory, which included preliminary information about increased risk of cardiovascular events related to the use of Vioxx®. The advisory was prompted by the results of a study entitled VIGOR (Vioxx® Gastrointestinal Outcomes Research). Subsequently, Health Canada implemented labelling changes to reflect the findings from the VIGOR study, specifically the inclusion of information that Vioxx® should be used with caution in patients with a history of heart disease.

Health Canada has been looking at post-market information about cardiovascular events as they relate to Vioxx® and other selective COX-2 inhibitor NSAIDs since 2000.

54
Q

What other drugs are similar to Vioxx® ?

A

Other COX-2 selective NSAIDs currently available are Celebrex (celecoxib) and Bextra (valdecoxib).

valdecoxib also removed; we are left with just celebrex.
Celebrex is the only selective COX-2 inhibitor on the market

55
Q

what did the VIGOR (Vioxx GI Outcomes Research) study find when comparing Roficoxib (Vioxx) & Naproxen?

A

4-fold increased risk of acute MI in Roficoxib patients (in high risk patients) (0.4% vs 0.1%,RR0.25) over the 12 month span of the study.
The elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from cardiovascular events between the two groups, nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was by the patients at higher risk of heart attack, i.e. those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina,cerebrovascular accident,transient ischemic attack, or coronary artery bypass).

56
Q

what is the NSAID tug & pull b/w GI benefit & cardiotoxicity?

A

the more specific an NSAID is for COX-1 inhibition, the more GI toxicity we can observe
the more specific the inhibition of COX-2, the more CV toxicity we can predict

57
Q

What is the effect on CV risk that we observe over time w/coxibs?

A

cumulative effect with time
risk persists 30 days after discontinuation
risk within first 10-30 days of Rx

58
Q

what is the Vioxx generic name?

A

rofecoxib

59
Q

what is the relationship b/w the coxibs half life and CV risk?

A

longer T1/2 = more CV events

60
Q

coxibs should not be used in patients with ______?

A

established CAD
stroke
peripheral arterial disease

61
Q

caution when prescribing coxibs in patients with…?

A

CAD risk

HTN, hyperlipidemia, DM, smoking

62
Q

3 CIs to NSAID use

A

renal insufficiency
allergic reaction
concurrent GI injury

63
Q

2 reasons (risk factors) a classical NSAID could not be used (why you would need to use a Cox-2 inhibitor)

A

GI risk

bleeding risk

64
Q

advantage of acetaminophen?

A

doesn’t promote ulcers, bleeding, or renal failure

65
Q

disadvantages of acetaminophen?

A

at high doses, severe hepatotoxicity results

66
Q

acetaminophen metabolism

A
  • most neutralized & eliminated via glucoronidation & sulfation reactions
  • small amount oxidized via p450 resulting in NAPQI (highly reactive metabolite)
  • NAPQI either neutralized by glutathione or (if glutathione is depleted) hepatotoxicity occurs
67
Q

what vitamins and minerals do NSAIDs deplete?

A 
folic acid
iron
potassium
sodium
vit C
68
Q

NSAIDs relationship to insulin

A

decreases insulin clearance

hypoglycemia

69
Q

why should you not take gingko with NSAIDs?

A

increases bleeding potential

Pharmacology (5 decks)

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