pharmacology pain Flashcards
signs of inflammation
heating, redness, swelling, pain
how pain occurs
pain transmission through spinothalamic tract
how inflammation symptoms occur
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
how does fever occur?
inflammation -> neutrophils respond and release cytokines -> increase COX expression -> produce PGE2 in hypothalamus -> change in body thermostat -> fever
COX 1 vs COX 2
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
types of NSAID to remember
1) non-selective COX inhibitor
- irreversible: aspirin (COX 1»_space;> COX 2)
- reversible: naproxen (COX 1»_space; COX 2), ibuprofen (COX 1 > COX2), diclofenac, mefenamic acid (COX 2 > COX 1)
2) reversible COX-2 inhibitor
- celecoxib
- parecoxib -> valdecoxib
- etoricoxib
types of non NSAIDs involved
1) CNS-selective COX inhibitor
- paracetamol
2) opioids/narcotic analgesics
- tramadol, codeine, morphine, oxycodone, fentanyl
aspirin MOA
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
aspirin dose-dependent AE
- mostly caused by salicylate chemical structure
** high dose > 50mg/dL -> salicylate toxicity -> renal/respi failure
- gastric intolerance: bleeding
aspirin CI
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
naproxen, indomethacin, diclofenac - MOA
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
naproxen specifics
- long t1/2 so BD dose
- more effective in women
- often used in dysmenorrhea
indomethacin specific
- strongly anti-inflammatory due to additional steroid-like phospholipase A inhibition
- CNS AE: confusion, depression, psychosis, hallucination
diclofenac specific
- can be applied topically
- short t1/2, lesser GI risk
- longer t1/2 in synovial fluid
AE for all non-selective tldr
1) GI related
2) renal related
3) pseudo-allergic reactions
4) haematological effects: bleeding risk
5) increase BP and HTN
6) CVS problems
non-selective NSAID AE - GI related - role of prostaglandin
- reduce gastric acid secretion
- increase mucosal blood flow, mucous secretion, bicarbonate secretion
non-selective NSAID AE - GI related - AE caused
- dyspepsia, N/V
- ulcer formation and potential haemorrhage risk in chronic users (> 5 day use)
non-selective NSAID AE - GI related - risk factors
1) > 65 yo
2) history of ulcer
3) use of high dose/chronic NSAIDs
4) concurrent glucocorticoid, antiplatelet, anticoagulants
non-selective NSAID AE - GI related - when to refer?
fatigue, severe dyspepsia, signs of GI bleed, unexplained blood loss, anemia, iron deficiency
non-selective NSAID AE - renal related - how does it happen?
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
non-selective NSAID AE - renal related - risks for AKI
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
non-selective NSAID AE - pseudo-allergic reaction - how it happens?
inhibit COX -> more arachidonic acid converted to lipoxin/leukotriene -> excess leukotriene cause bronchospasm and allergic like reactions
non-selective NSAID AE - pseudo-allergic reaction - possible symptoms
- 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
non-selective NSAID AE - haematological problems
- 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
non-selective NSAID AE - increase BP and HTN
monitor BP, discontinue/lower dose if BP increase
non-selective NSAID AE - CVS problems
MI, stroke, vascular death
non-selective NSAID CI
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
reversible COX-2 selective inhibitors - MOA
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
reversible COX-2 selective inhibitors - dosing instruction
- take for shortest duration possible
- avoid taking > 5 days
reversible COX-2 selective inhibitors - AE - tldr
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
reversible COX-2 selective inhibitors - AE - why not free from COX-1 AE?
- 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
reversible COX-2 selective inhibitors - AE - renal toxciity - how it happens?
(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
reversible COX-2 selective inhibitors - AE - renal toxicity - risks for AKI
(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
reversible COX-2 selective inhibitors - AE - ovulation effects
delayed follicular rupture
reversible COX-2 selective inhibitors - AE - pregnancy effects
premature closure of ductus ateriosus in late pregnancy -> baby problems
reversible COX-2 selective inhibitors - AE - impairment of wound healing
- can worsen ulcer
- caution for
** existing ulcer/other ulcer risk
** post-surgical analgesia
** concern over non-union of fractures and bone repairs
reversible COX-2 selective inhibitors - AE - increased risk of thrombosis
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
reversible COX-2 selective inhibitors - AE - risk of heart attack and stroke
- renal effect (HTN) + risk of prothrombotic effect
- greater caution in elderly, history of cerebrovascular/cardiovascular disease
- risk extends to non-selective NSAIDs
reversible COX-2 selective inhibitors - CI
(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)
types of topical NSAIDs
1) ketoprofen fastum gel PRN
2) ketoprofen patch PRN
3) voltaren diclofenac gel PRN
topical NSAIDs AE
- 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
how to choose the right NSAIDs
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
MOA of paracetamol
selectively inhibit COX in CNS -> modulate CNS interpretation of pain -> reduced sensation of pain
advantages of paracetamol
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
disadvantages of paracetamol
1) weakly anti-inflammatory
2) toxic doses cause N/V, liver damage
3) possible allergic reaction
how does paracetamol cause liver damage?
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
dosing for paracetamol
- 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
combination therapy for NSAIDs and paracetamol
- reduce pain: combine dose for synergistic effect
- reduce fever: alternate dose for sustained effect
general opioids
- not first line for pain
- NSAID (+/- paracetamol) more effective than opioid combination for pain associated with acute inflammation
- not anti-inflammatory
opioids MOA
inhibit transmission of nociceptive signals to brain
dosing for opioids
- lowest effect dose of weakest opioid for shortest duration
- X prescribe extra to prevent abuse
types of opioids
weak opioid: tramadol, codeine
strong opioid: morphine, oxycodone, fentanyl
opioid dose conversion
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
opioids AE
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
CI for opioids
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
orphenadrine indication
for muscular pain esp lower back and neck pain
orphenadrine MOA
- muscarinic receptor antagonist at basal ganglia
- tertiary amine that passes BBB
- H1 antihistamine, NMDA receptor antagonism, norepinephrine and dopamine reuptake inhibitor, Na channel blocker
orphenadrine SE
1) common
- N/V, flushing, dilated pupils, dry mouth
2) higher dose
- tachycardia, ataxia, nystagmus, drowsiness, delirium, agitation, visual hallucination
- hepatotoxicity, allergic reaction
orphenadrine DDI
additive effective with 1st gen antihistamines, anticholinergics, anti PD
