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3154 MSK > MSK NSAIDs > Flashcards

MSK NSAIDs Flashcards

1
Q

clinical effects of COXi

A

COX1 : anti-plt
COX1-2: antipyretic, analgesic (CNS)
COX2: anti-inflam, analgesic

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2
Q

ADR of COXi

A

COX1: GI, renal, bleed
COX2: renal, reproductive
wound healing (induced)

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3
Q

eg of NSAIDs

A

Non selective
* Irreversible COX inhibitors: aspirin
*Reversible COX inhibitors: ibuprofen, naproxen, diclofenac
COX2 selective coxibs: celecoxib, etoricoxib

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4
Q

pathway of phospholipase A2 –> Arachidonic acid
(diff enzymes act on AA)

A

1) 15-lipoxygenase –> lipoxins
2) cyclooxygenase –> prostanoids
3) 5-lipoxygenase –> leukotrienes

EICOSANOID (inflam and immune response)

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5
Q

COX pathways (diff prostanoids)

A

diff cells have diff isomerases, tissue signalling etc

1) prostacyclin PGI2 – vasodil, inhibit PLT activation
2) prostaglandins PGE2 – vasodil, pain, vascular perm
3) thromboanes TXA2 – vasoconstrict, pLT aggre

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6
Q

diff wound diff prostanoids eg

A

Open wound, bleeding: more thromboxanes TXA2 (THROMBO = THROMBOSIS)

Closed wound, infection: more prostacyclin
(PGI2 = INHIBIT PLT AGGRE)

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7
Q

non selective COX MOA

A

1) anti-inflam
2) analgesic
3) antipyretic
4) antiplt

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8
Q

anti-inflam

A

PGI2, PGE2
* Typical NSAIDs block
* Vasodilation: heat, redness, swelling
* Decr vascular permeability: swelling
* Inflammation: Pain

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9
Q

analgesic

A
  • Typical NSAID block production of PG, sensitise nociceptive fibres to stimulation by other inflammatory mediators
  • Block sensitisation (not nociceptive inactivation)
    • Tissue injury produce bradykinin, leukotrienes + PROSTAGLANDINS (potentiates pain)
    • NSAIDS block PG production
  • Additional analgesic actions in CNS
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10
Q

Analgesic ceiling: when pain > mild-mod

A

Bradykinin and leukotrienes, ATP, K trigger nerve terminal > blocked PG
* Brain still interprets the pain signals

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11
Q

Antipyretic

A
  • Inhibit production of prostaglandins (PGE2) in brain
    ○ Infection, tissue damage, inflamm
    –> neutrophils –> cytokines (IL1) –> COX –> PGE2 (hypothalamus) –> incr temp
  • No effect on body temp if no fever
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12
Q

antiplt (irreversible)

A
  • PLT COX (inhibit production of TXA2 – promote pLT aggregation)
    ○ Restored only by new formation of PLT (1-2wks)
  • Endothelial cells COX (inhibit PGI2 – this stops the endo function of inhibiting PLT aggregation, PROMOTES NOW)
    ○ But can be restored by synthesis of new COX enzyme (hrs)
    ○ Inhibit PLT > endo (overall antiplt effect)
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13
Q

ADR of aspirin

A
  • COX inhibition (80-325mg)
    - GI intolerance
    - bleed
    - hypersnsitive
  • salicylate toxicity (>1g)
    - tinnitus
    - renal and resp failure
    • Central hyperventilation
    • Respiratory alkalosis
    • Fever, dehydration
    • Metabolic acidosis
    • Respiratory acidosis
    • Hypoprothrombinemia
    • Vasomotor collapse
    • Coma
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14
Q

GI when > __ days

A

○ PG normal function INHIBITED:
* Reduce gastric acid secretions
* Incr mucosal blood flow
* Incr secretion of mucus
* Incr secretion of bicarbonate

○ Typical NSAIDs lead to:
* Dyspepsia, NV, ulcer formation and potential haemorrhage risk in chronic users
* Peptic ulcers risk if use > 5days

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15
Q

risk factors for GI ADR

A

i. >65yo
ii. Hx of ulcer
iii. Use of high dose/chronic NSAIDs
iv. Concurrent CS/ antiplt/ anticoag

High risk: ≥3/4 risk factors. OR complicated ulcer (ulcer + bleed)

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16
Q

manage + refer GI ADR

A
  • Manage: + PPI/ switch to coxib (ibuprofen > naproxen. Coxib. Parace)
  • Urgent referral if on NSAID +
    i. Fatigue sx
    ii. Severe dyspepsia
    iii. Sign of GI bleed (black, tarry stool)
    iv. Unexplained blood loss, anemia
    v. Fe deficiency
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17
Q

renal ADR moa

A

Inhibition of both PGE2 and PGI2 production alters renal blood flow dynamics

  • (PGE2 inhibited): Na retention –> water retention –> peripheral oedema –> hypertension
    * Thick ascending limb (TAL) 25% of Na reasorbed
  • (PGI2 inhibited): suppression of renin & aldosterone secretion –> hyperK –> acute renal failure
    * Less Aldosterone (1-2% Na NOT reabsorption in DCT)
    *Less K+ excretion in blood = HyperK
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18
Q

triple whammy drugs

A
  • NSAIDs (inhibit COX1/ COX2) prevent vasodil of afferent arteriole)
  • Diuretics (reduce renal blood flow)
  • ACEi (inhibit angiotensin converting enzyme, prevent vasoconstriction of efferent arteriole)
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19
Q

risk factors for renal ADR

A
  • incr age > 65yo (HTN, atherosclerosis)
  • pre-existing glomerular disease/ renal insuff
  • vol depletion (loss, effective - HF)
  • ACEi, ARB
  • triple whammy
  • severe hyper Ca, renal art stenosis
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20
Q
  • incr age > 65yo (HTN, atherosclerosis) and AKI
A

narrow renal arterioles, reduce capacity for renal afferent dilation

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21
Q
  • pre-existing glomerular disease/ renal insuff
    and AKI
A

renal afferent dilation required to maintain GFR

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22
Q
  • vol depletion (loss, vol depletion - HF) and AKI
A

loss - GI, renal salts, water/ blood loss, diuretics
depletion - HF, cirrhosis , nephrotic syndrome

  • lowers afferent glomerular arteriolar pressure, stimulates secretion of ANG II
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23
Q
  • use of ACEi or ARB
  • triple whammy, ACEi/ ARB + NSAID + diuretic
A

ACEI, ARB : prevent efferent art vasoconstriction (maintain GFR)
* reduce glomerular hydrostatic pressure and renal filtration fraction, even though renal blood flow and glomerular filtration rate are preserved.

diuretic: vol depletion

24
Q

other drugs and AKI

A

Aminoglycosides, amphotericin B, radiocontrast material
Diuretics, ACEi, ARB (hyperK, hypoNa)

25
Q

allergies

A
  • Pseudo-allergic reaction (Skin rash, swell, itch, nasal congestion, aspirin -exacerbated resp disease )
    * nonimmunologic, hx of asthma/ urticaria/ angioedema
    * avoid particular NSAID, caution COXIBS
  • True (IgE response)
    * urticaria, angioedema, anaphylaxis
    * CI if ANA: all NSAIDs/ COXIBs
    * coxibs (caution), non-selective avoid as maybe have same reaction
26
Q

Asthma reaction MOA

A

shunt from COX enzyme inhibition, incr leuk

excress leukotrienes can trigger bronchospasm in susceptible asthmatic (LTD4) and allergic reaction-like sx

27
Q

reye’s syndrome

A
  • Rare, life-threatening condition
  • Swelling of brain (encephalitis) and liver
  • Incr risk if taken by children w/ viral infections
    ○ CI: no longer available in paediatric formulations
  • Sx:
    ○ V, personality changes, listlessness, delirium, convulsions, loss of consciousness
28
Q

Caution for Aspirin

A
  • in pts w/ sensitivity triad of asthma, chronic urticaria, nasal polyps
  • with aspirin (irreversible COX inhibitor, stronger effect)
  • Surgical procedures when pt on NSAID
  • Risk in combi w/ antiplt therapy (clopi or aspirin)
29
Q

other COX1 inhibitors

A
  • Naproxen
    • More effective in women (Fu >40%, lower dose more potent)
    • T1/2: 12-14hrs
    • Indication: dysmenorrhea, MSK
  • Indomethacin
    • Strongly anti-inflamm due to additional steroid-like Phospholipase A inhibition
    • ADR: 15-25% report confusion, depression, psychosis, hallucination also occur
  • Diclofenac
    • Short plasma t1/2: < 2hr
    • Indication: MSK (RA, OA). Accumulates in synovial fluid, longer t1/2
    • ADR: low GI risk
30
Q

COX2 selective

A

etoricoxib (more gi SAFE) –> celecoxib (LESS)

cox2: anti-inflam, analgesic > anti-plt effect

31
Q

COX 1 VS COX2

A

cox1: TXA2, PGI2, PGE2 (housekeeping pathway)
cox2: PGI2, PGE2 (inflamm, tissue repair pathway)

32
Q

limitations of cox2 selectivity

A

cox2 also found in CNS, KIDNEY, FEMALE REPRO TRACT, SYNOVIUM

1) renal toxicity by COX2i too
2) delay follicular rupture, effect on ovulation (less likely preg)
3) premature close ductus arteriosus (fatal lung bypass) in late preg
4) wound healing slowed (exacerbate ulcers)
- cox1 cause ulcer. stop . start cox2 after healed

5) incr risk of thrombosis

33
Q

incr risk of thrombosis due to

A

heart attack and stroke warning
* renal effect ===> HTN
* prothrombic effects (incr TXA2, more plt aggregation)

34
Q

CVS risk factors

A
  • elderly, hx of CBS/ CVS disease
  • HTN, hyperlipidemia, DM, stroke
    * celecoxib < 400mg/ day

CI: CHF, IHD, PAD, uncontrolled HTN

35
Q

CI for NSAIDs

A
  • 3rd trimester of preg
  • severe kidney impairment < 30ml/min
  • severe HF
  • active GI ulcer/ bleed
  • bleeding disorders (hameophilia)
    & use of systemic CS/ antiplt/ anticoag
  • multiple risk factors for NSAID toxicity (>65yo, HTN)
  • anaphylaxis reaction NERD
36
Q

risk factors and choice of NSAID

A
  • renal toxicity (consult before px)
  • CVS toxicity (avoid COX1,2 selective)
    * celecoxib, ibu (</=5day), paracetamol
  • GI toxicity (avoid non-selective)
    * cox2 selective/ add PPI
  • bronchospasm, pseudoallergy risk (avoid non-selective ibu)
    * cox2 selective with caution (shunting effect)
37
Q

advice on NSAIDs

A
  • take as prescribed (regular > PRN)
  • shortest duration (=/<5d)
  • initiate NSAID+ paracetamol —> para only
  • seek advice if needed =/> 5d
  • not to take w/ food (reduce absorption rate, delay peak conc ) decr efficacy
    – but can reduce gI discomfort
38
Q

paracetamol MOA
adv

A

MOA: poorly understood, involve CNS-selective COX inhibitors

Advantages:
* Good analgesic
* Potent antipyretic
* Spare GIT
* SE few and uncommon
* Few DDI

39
Q

paracetamol DISADV

A

Weak anti-inflamm
NOT ant-inflamm at clinical doses

40
Q

when to combine para + NSAID

A
  • Antipyretic: used alternate
    ○ Similar dosing freq 4-6h, can be alternated in 2-3hr
    ○ Sustained antipyretic effect
  • Pain: used tgt
    ○ Longer and stronger effect. Synergistic effect
41
Q

paracetamol indications

A
  • Mild-mod pain when NSAIDs inappropriate
  • Analgesic & antipyretic action with low incidence of ADR
  • Available in many formulations, strengths & combi
42
Q

ADR of paracetamol

A

1) Toxic dose cause N,V, liver damage

  • Hepatotoxicity should not occur at therapeutic doses in otherwise healthy indiv
  • Exacerbated by overdose, chronic alc use/ abuse
    ○ Incr toxic metabolite — Glutathione depleted
    ○ Replenish with N-acetyl-cysteine

2) Allergic skin reaction may occur

43
Q

caution for paracetamol use

A

Caution:
- Hepatic dysfunction
- Alcohol

Dose reduction:
- Certain circumstances (underweight, sig liver disease, cachectic, frail)

Overdose:
- Can lead to liver damage
- Refer =/> 10g / 24hr to ED
- Incr risk of harm with doses =/> 4g/ 24hr
- 500mg-1g QDS (narrow TI for liver toxicity)

44
Q

manage allergic reaction (IgE) true

A

posible rxn include urticaria, angioedema, anaphylaxis

  • avoid all NSAISs, coxibs if anaphylaxis
45
Q

manage pseudoallergic

A

non immunogenic, related to COX1 inhibition
* possible rxn (aaspirin exacerbated resp disease), bronchospasm - hx of asthma/ urticaria/ angioedema

  • MAY same rxn across diff non-selective NSAID (avoid)
  • coxibs use cautiously
46
Q

BP manage

A

monitor BP
discontinue/ lower NSAID dose if bP incr

47
Q

skin reaction management

A

more likely with
- oxicam, sulindac, diflunisal

48
Q

haematologic effects management

A
  • inhibit PLT function
    stop 3d prior to surgery
    aspirin 1 wk prior
49
Q

CNS complaints management

A

cause drowsy, dizzy, headache, tinnitus

(take ON)

50
Q

Opioid analgesics rank

A

(weak) Tramadol, codeine, morphine, oxycodone, fentanyl (STRONG)

51
Q

opioid MOA

A
  • Opioids are NOT anti-inflammatory
  • MOA: work on transmission of pain signals in nerves

tramadol (inhibits ascending and descending pain pathways)
* reuptake of NE and 5HT, involved in the descending inhibitory pain pathway responsible for pain relief

52
Q

opioid variability in response

A
  • Strong opioids: stronger analgesic and ADR effect
    • Response variable: CYP2D6 polymorphism
      ○ Metabolising amt: eg 15% codeine –> morphine
      ○ Will have stronger analgesic effect than if only 10% convert to morphine

CYP2D6i: Fluoxetine, Paroxetine, Duloxetine, Bupropion

53
Q

pt use opioid caution

A
  • Lowest effective doses or weakest effective opioid for shortest duration
  • Ensure pt is well educated on use, storage and risk of ADR
  • Unused px opioid be misused by others –> risk of addiction
54
Q

indication for opioid use

A
  • Not 1st line for pain
  • NSAIDs (with/ without paracetamol) are often more effective > opioid combi for pain assoc with acute inflamm
55
Q

ADR of opioid

A
  • GI effects (NVC)
  • Hormonal effects
  • Depression
  • Respiratory effects
  • Overdose and death
  • Sedation/ drowsiness (result in accidents, Falls)
  • Tolerance, physical dependence, addiction, withdrawal
  • Opioid-induced hyperalgesia

80% of pt long term opioids will develop at least 1 opioid-induced ADR
* Sig risk of ADR, diversion, opioid (for shortest duration)
* Risk of addiction & abuse, sedation
* Overdose: respiratory depression

56
Q

risk factor for opioid ADR

A
  • combi with other CNS depressants (alc, BZP, gabapentins, antidep)
  • other comorb (mental health)
  • renal, hep insuff, age > 65yo
  • preg
  • presonal/ fam hx of sub abuse
  • previous use of opioid
    * incr risk with incr dose and duration of use
    * risk of diversion (others abuse)
    * risk of opioid use disorder

3154 MSK (9 decks)

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