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end of y3 > pharmacology pain > Flashcards

pharmacology pain Flashcards

1
Q

signs of inflammation

A

heating, redness, swelling, pain

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2
Q

how pain occurs

A

pain transmission through spinothalamic tract

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3
Q

how inflammation symptoms occur

A

cell damage -> cell phospholipid broken down by phospholipase A2 into arachidonic acid

1) Acute inflammation

  • arachidonic acid broken down into prostaglandin H2 -> broken down by isomerase into prostanoids:

** prostacyclin (PGI2): cause vasodilation, inhibit platelet aggregation
** classical prostaglandin (PGE2): vasodilation (redness, heating), vascular permeability (oedema, swelling), pain
** thromboxane (TXA2): vasoconstriction, platelet aggregation

  • types of injury results in different amounts of prostanoids produced

2) chronic inflammatory immune response

  • arachidonic acid broken down by 5-lipoxygenase into leukotrienes -> prolonged inflammation
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4
Q

how does fever occur?

A

inflammation -> neutrophils respond and release cytokines -> increase COX expression -> produce PGE2 in hypothalamus -> change in body thermostat -> fever

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5
Q

COX 1 vs COX 2

A

COX-1 constitutive

  • present all the time in GI, kidney

COX-2 inducible

  • only produced by cells involved in inflammatory and tissue repair
  • so COX-2 selective enzymes have lesser GI and renal AE
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6
Q

types of NSAID to remember

A

1) non-selective COX inhibitor

  • irreversible: aspirin (COX 1&raquo_space;> COX 2)
  • reversible: naproxen (COX 1&raquo_space; COX 2), ibuprofen (COX 1 > COX2), diclofenac, mefenamic acid (COX 2 > COX 1)

2) reversible COX-2 inhibitor

  • celecoxib
  • parecoxib -> valdecoxib
  • etoricoxib
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7
Q

types of non NSAIDs involved

A

1) CNS-selective COX inhibitor

  • paracetamol

2) opioids/narcotic analgesics

  • tramadol, codeine, morphine, oxycodone, fentanyl
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8
Q

aspirin MOA

A

1) anti-inflammatory

  • block COX -> block PGI2, PGE2
    ** block vasodilation -> reduce warmth, redness, swelling
    ** block increased vascular permeability -> reduce swelling
    ** block pain associated with inflammation

2) analgesic

  • block production of prostaglandins -> sensitise nociceptive fibres to stimulation by other inflammatory mediators
    ** reduce pain signals so pain not that intense
    ** result in analgesic ceiling (NSAID not so effective for severe pain)

3) antipyretic

  • NSAIDs block COX -> reduce PGE2 -> reset body thermostat back to normal
  • X alter normal body temperature

4) antiplatelet

  • block COX-1 -> inhibit TXA2 production -> inhibit platelet activation and aggregation -> need to be restored by formation of new platelet
  • block COX-2 -> inhibit PGI2 production -> inhibit platelet aggregation -> restored by synthesis of new COX enzyme
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9
Q

aspirin dose-dependent AE

A
  • mostly caused by salicylate chemical structure

** high dose > 50mg/dL -> salicylate toxicity -> renal/respi failure

  • gastric intolerance: bleeding
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10
Q

aspirin CI

A

X use in children cuz of Reye’s syndrome

  • increased risk if aspirin + child w viral infection
  • encephalitis (swelling of brain) and hepatomegaly (swelling of liver)
  • vomiting, personality change, listlessness, delirium, convulsions, loss of consciousness
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11
Q

naproxen, indomethacin, diclofenac - MOA

A

1) anti-inflammatory

  • block COX -> block PGI2, PGE2
    ** block vasodilation -> reduce warmth, redness, swelling
    ** block increased vascular permeability -> reduce swelling
    ** block pain associated with inflammation

2) analgesic

  • block release of prostaglandin -> sensitise nociceptive fibres to stimulation by other inflammatory mediators
    ** reduce pain signals so pain not so intense
    ** analgesic ceiling so not effective for severe pain

3) antipyretic

  • NSAID block COX -> reduce PGE2 -> reset body thermostat back to normal
  • X alter body normal temperature
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12
Q

naproxen specifics

A
  • long t1/2 so BD dose
  • more effective in women
  • often used in dysmenorrhea
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13
Q

indomethacin specific

A
  • strongly anti-inflammatory due to additional steroid-like phospholipase A inhibition
  • CNS AE: confusion, depression, psychosis, hallucination
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14
Q

diclofenac specific

A
  • can be applied topically
  • short t1/2, lesser GI risk
  • longer t1/2 in synovial fluid
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15
Q

AE for all non-selective tldr

A

1) GI related
2) renal related
3) pseudo-allergic reactions
4) haematological effects: bleeding risk
5) increase BP and HTN
6) CVS problems

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16
Q

non-selective NSAID AE - GI related - role of prostaglandin

A
  • reduce gastric acid secretion
  • increase mucosal blood flow, mucous secretion, bicarbonate secretion
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17
Q

non-selective NSAID AE - GI related - AE caused

A
  • dyspepsia, N/V
  • ulcer formation and potential haemorrhage risk in chronic users (> 5 day use)
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18
Q

non-selective NSAID AE - GI related - risk factors

A

1) > 65 yo
2) history of ulcer
3) use of high dose/chronic NSAIDs
4) concurrent glucocorticoid, antiplatelet, anticoagulants

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19
Q

non-selective NSAID AE - GI related - when to refer?

A

fatigue, severe dyspepsia, signs of GI bleed, unexplained blood loss, anemia, iron deficiency

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20
Q

non-selective NSAID AE - renal related - how does it happen?

A

1) alter renal blood flow
2) inhibit PGE2 production

  • Na & water retention in thick ascending limb -> peripheral oedema -> HTN

3) inhibition of PGI2 production

  • suppression of renin and aldosterone secretion in distal convoluted tubule, not enough to counteract Na action
  • hyperkalaemia -> acute renal failure

4) triple whammy

  • NSAIDs, diuretics, ACEi can all cause renal failure
    ** ACEi/ARB prevent afferent arteriole vasoconstriction required to maintain GFR
    ** diuretics cause volume depletion
  • need to check renal failure if using any 2
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21
Q

non-selective NSAID AE - renal related - risks for AKI

A

1) increase age, chronic HTN, atherosclerosis

  • narrowing of renal afferent arterioles -> reduce capacity for renal afferent dilation

2) pre-existing glomerular disease/renal insufficiency

  • renal afferent dilation required to maintain GFR
  • volume depletion
  • true volume/effective volume
    ** lower afferent glomerular arteriolar pressure -> stimulate secretion of angiotensin II
  • triple whammy
  • aminoglycosides, amphotericin B, radiocontrast material
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22
Q

non-selective NSAID AE - pseudo-allergic reaction - how it happens?

A

inhibit COX -> more arachidonic acid converted to lipoxin/leukotriene -> excess leukotriene cause bronchospasm and allergic like reactions

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23
Q

non-selective NSAID AE - pseudo-allergic reaction - possible symptoms

A
  • skin rash, swelling, itching, nasal congestion, anaphylactic shock
  • trigger bronchospasm in susceptible asthmatics
  • caution in pt w asthma, chronic urticaria (hives), nasal polyps
  • stronger effect for aspirin cuz irreversible
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24
Q

non-selective NSAID AE - haematological problems

A
  • inhibition of COX-1 -> inhibition of TXA2 production -> prevent clot formation
  • greater risk for COX-1 than COX-2 inhibition
  • mild bleeding (gums, nose bleed, small cuts) and serious bleeding (blood in pee/shit, cough blood, unexplained large bruises)
  • stop 3 days before surgery
25
Q

non-selective NSAID AE - increase BP and HTN

A

monitor BP, discontinue/lower dose if BP increase

26
Q

non-selective NSAID AE - CVS problems

A

MI, stroke, vascular death

27
Q

non-selective NSAID CI

A

1) 3rd trimester of pregnancy
2) children, elderly
3) asthma, chronic urticaria, nasal polyps
4) severe renal impairment (eGFR < 15 or CrCl < 30)
5) severe HF, active GI ulcer/bleed, bleeding disorders
6) use of systemic corticosteroids (too immunosuppressive)
7) use of antiplatelet/anticoagulant (high bleeding risk)
8) multiple risk factors for NSAID toxicity
9) cross-sensitivity, hypersensitivity

28
Q

reversible COX-2 selective inhibitors - MOA

A

1) anti-inflammatory

  • block COX -> block PGI2, PGE2
    ** block vasodilation -> reduce warmth, redness, swelling
    ** block increased vascular permeability -> reduce swelling
    ** block pain associated w inflammation

2) analgesic

  • block production of prostaglandin -> sensitise nociceptive fibre to stimulation by other inflammatory mediators
    ** reduce pain signals so pain not so intense
    ** analgesic ceiling: not effective for severe pain

3) antipyretics

  • NSAIDs block COX -> reduce PGE2 -> reset body thermostat back to normal
  • X alter normal body temperature
29
Q

reversible COX-2 selective inhibitors - dosing instruction

A
  • take for shortest duration possible
  • avoid taking > 5 days
30
Q

reversible COX-2 selective inhibitors - AE - tldr

A

1) renal problems
2) ovulation effects
3) pregnancy problems
4) impairment of wound healing
5) increased risk of thrombosis
6) risk of heart attack and stroke

31
Q

reversible COX-2 selective inhibitors - AE - why not free from COX-1 AE?

A
  • constitutive COX-2 still found in CNS, kidneys, female reproductive tract, synovium
  • COX-2 not helpful if patient already have pre-existing GI ulcer
  • still have some renal toxicity
32
Q

reversible COX-2 selective inhibitors - AE - renal toxciity - how it happens?

A

(basically same as non selective, j recapping)

1) alter renal blood flow
2) inhibit PGE2 production

  • Na and water retention in thick ascending limb - peripheral oedema -> HTN

3) inhibition of PGI2 production

  • suppression of renin and aldosterone secretion in distal convoluted tubule, not enough to counteract Na retention

4) triple whammy

  • NSAIDs, diuretics, ACEi can cause renal failure
    **ACEi/ARB prevent afferent arteriole vasoconstriction required to maintain GFR
    ** diuretics cause volume depletion
  • need to check renal failure if using any 2
33
Q

reversible COX-2 selective inhibitors - AE - renal toxicity - risks for AKI

A

(same as non selective, j revising)

1) increased age, chronic HTN, atherosclerosis

  • narrowing of renal afferent arterioles - reduce capacity for renal afferent dilation

2) pre-existing glomerular disease/renal insufficiency

  • renal afferent dilation required to maintain GFR
  • volume deficiency
  • true volume/effective volume
    ** lower afferent glomerular arteriolar pressure -> stimulate secretion of angiotensin II
  • triple whammy
34
Q

reversible COX-2 selective inhibitors - AE - ovulation effects

A

delayed follicular rupture

35
Q

reversible COX-2 selective inhibitors - AE - pregnancy effects

A

premature closure of ductus ateriosus in late pregnancy -> baby problems

36
Q

reversible COX-2 selective inhibitors - AE - impairment of wound healing

A
  • can worsen ulcer
  • caution for
    ** existing ulcer/other ulcer risk
    ** post-surgical analgesia
    ** concern over non-union of fractures and bone repairs
37
Q

reversible COX-2 selective inhibitors - AE - increased risk of thrombosis

A

lesser COX-2 to break down arachidonic acid to PGI2 and PGE2 -> more COX-1 to break down arachidonic acid to TXA2 -> increased platelet aggregation -> increased risk of thrombosis

38
Q

reversible COX-2 selective inhibitors - AE - risk of heart attack and stroke

A
  • renal effect (HTN) + risk of prothrombotic effect
  • greater caution in elderly, history of cerebrovascular/cardiovascular disease
  • risk extends to non-selective NSAIDs
39
Q

reversible COX-2 selective inhibitors - CI

A

(same as non selective j recap)

1) 3rd trimester of pregnancy
2) children, elderly
3) asthma, chronic urticaria, nasal polyps
4) severe renal impairment (eGFR < 15 or CrCl < 30)
5) severe HF, active GI bleed/ulcer, bleeding disorders
6) use of systemic corticosteroids (too immunosuppressive)
7) use of antiplatelet/anticoagulant (high bleeding risk)

40
Q

types of topical NSAIDs

A

1) ketoprofen fastum gel PRN
2) ketoprofen patch PRN
3) voltaren diclofenac gel PRN

41
Q

topical NSAIDs AE

A
  • generally safe
  • mild irritation and redness
  • pseudoallergy or allergy
  • X use in open wound or rashes (eczema/psoriasis)
  • can induce photosensitivity so X go under sun
  • a lot of dermatological caution
42
Q

how to choose the right NSAIDs

A

1) risk of CV toxicity

-use celecoxib or ibuprofen max 5 days
- avoid diclofenac and etoricoxib
- if X use celecoxib/ibuprofen/naproxen then consider paracetamol alone

2) risk of renal toxicity

  • consult doctor, look out for triple whammy

3) risk of GI toxicity

  • use COX-2 selective
  • avoid non-selective NSAIDs
  • consider adjunctive GI protectant (PPi)

4) risk of bronchospasm

  • use COX-2 selective
  • avoid non-selective NSAIDs
43
Q

MOA of paracetamol

A

selectively inhibit COX in CNS -> modulate CNS interpretation of pain -> reduced sensation of pain

44
Q

advantages of paracetamol

A

1) analgesic for mild - moderate pain
2) antipyretic
3) spare GI tract
4) few and uncommon SE
5) few DDI
6) safe for paediatric use

45
Q

disadvantages of paracetamol

A

1) weakly anti-inflammatory
2) toxic doses cause N/V, liver damage
3) possible allergic reaction

46
Q

how does paracetamol cause liver damage?

A

hepatoxicity if overdose/chronic alcohol use/abuse

  • minor metabolism pathway of paracetamol induced by alcohol to form toxic metabolite
  • toxic metabolite metabolised by glutathione but glutathione also depleted by alcohol
  • result in accumulation of toxic metabolites -> hepatotoxicity
  • can replenish glutathione with N-acetyl-cysteine (NAC) so it can be used for paracetamol toxicity/overdose
47
Q

dosing for paracetamol

A
  • max dose 500mg per day due to analgesic ceiling
  • reduce dose for: liver impairment, underweight, frail
  • overdose
    ** if ≥ 4g in 24 hrs then caution cuz increase risk of liver damage
    ** if ≥ 10g in 24 hrs then refer to A&E
48
Q

combination therapy for NSAIDs and paracetamol

A
  • reduce pain: combine dose for synergistic effect
  • reduce fever: alternate dose for sustained effect
49
Q

general opioids

A
  • not first line for pain
  • NSAID (+/- paracetamol) more effective than opioid combination for pain associated with acute inflammation
  • not anti-inflammatory
50
Q

opioids MOA

A

inhibit transmission of nociceptive signals to brain

51
Q

dosing for opioids

A
  • lowest effect dose of weakest opioid for shortest duration
  • X prescribe extra to prevent abuse
52
Q

types of opioids

A

weak opioid: tramadol, codeine
strong opioid: morphine, oxycodone, fentanyl

53
Q

opioid dose conversion

A

based on morphine milligram equivalent (mg/day)

  • codeine 0.15
  • tramadol 0.2
  • oxycodone 1.5
  • methadone 4.7
  • fentanyl (transdermal in mcg/hr) 2.4
54
Q

opioids AE

A

1) GI effects: C, N/V
2) imbalance of hormonal systems
3) depression
4) respiratory depression if overdose
5) overdose and death
6) sedation, drowsiness
7) falls and fractures (cuz sedation)
8) tolerance, physical dependence, addiction +/- withdrawal
9) opioid-induced hyperalgesia

55
Q

CI for opioids

A

1) combination w other CNS depressants
2) other comorbidities (mental health condition)
3) renal, hepatic insufficiency
4) age > 65 yo
5) pregnancy (risk to both mother and fetus)
6) personal or family history of substance abuse
7) already prescribed an opioid

  • increases risk with increase dose and duration of use
  • risk of diversion
  • risk of opioid use disorder
56
Q

orphenadrine indication

A

for muscular pain esp lower back and neck pain

57
Q

orphenadrine MOA

A
  • muscarinic receptor antagonist at basal ganglia
  • tertiary amine that passes BBB
  • H1 antihistamine, NMDA receptor antagonism, norepinephrine and dopamine reuptake inhibitor, Na channel blocker
58
Q

orphenadrine SE

A

1) common

  • N/V, flushing, dilated pupils, dry mouth

2) higher dose

  • tachycardia, ataxia, nystagmus, drowsiness, delirium, agitation, visual hallucination
  • hepatotoxicity, allergic reaction
59
Q

orphenadrine DDI

A

additive effective with 1st gen antihistamines, anticholinergics, anti PD

end of y3 (8 decks)

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