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pr3154 > ic13 analgesics > Flashcards

ic13 analgesics Flashcards

1
Q

what are the types of analgesics

A
  1. NSAIDs
    a) non selective NSAIDs
    i) irreversible COX inhibitor: aspirin
    ii) reversible COX inhibitor: naproxen, ibuprofen, diclofenac, mefenamic acid, idomethacin
    b) selective NSAIDs (COX2 selective)
    i) reversible COX2 inhibitor: celecoxib, parecoxib, etoricoxib
  2. CNS selective COX inhibitor
    i) reversible COX inhibitor: paracetamol
  3. opioids/ narcotics: tramadol, codeine, morphine, oxycodone, fentanyl
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2
Q

where do each type of analgesic exert its action

A

i) brain: paracetamol acts by modulating how the brain is interpreting the pain signal

ii) spinal cord: opioids act by blocking the transmission of pain signals through the nerves of the spinothalamic tract (Adelta/C fibers)

iii) injury site: NSAIDs block the acute inflamm response at site of injury

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3
Q

what is “pain”

A

pain is the unpleasant sensory and emotional experience assoc with actual or potential tissue damage; pain is a subjective experience

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4
Q

what is “nociception”

A

process of detecting and signalling the presence of a noxious stimulus to the CNS

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5
Q

what occurs when there is damage to the cells

A

damage to the cells result in mobilisation of fragments of lipids in the phospholipid cell membrane and these phospholipids are acted on by phospholipase A2 to form arachidonic acid (AA) which are subsequently acted on by various enzymes to form eicosanoids which are lipoxins, prostanoids, leukotrienes

i) lipoxins are produced by 15-lipoxygenase
ii) prostanoids are produced by COX
iii) leukotrienes produced by 5-lipooxygenase

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6
Q

compare the types of inflamm related to prostanoids vs leukotrienes

A

prostanoids are more selective for acute inflamm response while leukotrienes are more selective in chronic inflamm and immune responses

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7
Q

compare the moa between steroids and NSAIDs

A

steroids: exert its action by blocking phospholipase A2 thus decreasing the production of eicosanoids

NSAIDs: exert its action by blocking COX thus decreasing the production of prostanoids which are more involved in acute inflamm; prostanoids include PGI2 (prostacyclin), PGE2 (prostaglandins), TXA2 (thromboxane)

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8
Q

relating to the moa of steroids, why is a common s/e of long term steroid use immunosuppression

A

steroids exert actions through blocking the activity of phospholipase A2 thus decreasing the production of eicosanoids which includes leukotrienes that is responsible for chronic inflamm and immune response (serves to activate the immune system) thus a decrease in leukotrienes results in immunosuppression

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9
Q

explain the rationale behind the clinical presentation of an injury or tissue damage

A

prostanoids produced by COX includes PGI2 (prostacyclin), PGE2 (prostaglandin), TXA2 (thromboxane)

PGI2 is responsible for
i) vasodilation (redness and heat)
ii) inhibition of PLT aggregation

PGE2 is responsible for
i) vasodilation (redness and heat); is technically a vasoconstrictor too but is mostly vasodilator
ii) increase vascular permeability (edema and swelling)
iii) pain

TXA2 is responsible for
i) vasconstriction
ii) promotes PLT aggregation

since different tissue types will have different ratio of various prostanoids produced (different extent of isomerases) thus different types of wounds will have slightly different presentations like open wound would try to produce more TXA2 vs closed wound would have more PGI2 production

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10
Q

explain how aspirin exerts its therapeutic effects

A

aspirin has anti-inflamm, analgesic and anti-pyretic and antiPLT effects

i) anti-inflamm: aspirin irreversibly inhibits COX which blocks the production of prostanoids (PGI2, PGE2, TXA2), and since prostanoids are more assoc with acute inflamm, blocking this acute inflamm suggests it blocks the vasodilation, vascular permeability and pain (vasodilation causes redness, heating and swelling; incr in vascular permeability causes edema and swelling; pain assoc w inflamm)

ii) analgesic: PGE2 sensitises the nociceptive fibers that transmit pain signals to activation by other inflamm mediators, thus aspirin blocking COX which reduces PGE2 production can help relieve pain (however note that since aspirin is blocking the sensitisation and not the direct nociceptive activation, aspirin has an analgesic ceiling)

iii) antipyretic: since aspirin blocks the production of prostanoids from COX and reduces acute inflamm response, it prevents activation of the immune system (neutrophils), as a result of tissue injury, infection and inflamm, in producing cytokines (IL1, TNFalpha, IL6) which typically signal the hypothalamus to incr the expression of PGE2 by COX which would raise the thermal set point of the body thus inducing a fever

iv) antiPLT: aspirin has a greater inhibition of COX1 compared to COX2 which are expressed on PLTs and endothelial cells; PLTs are cell fragments without a nuclei while endothelial cells have nuclei; COX1 in PLTs produces TXA2 while COX1 in endothelial cells produces PGI2; PLTs are unable to regenerate a new COX enzyme and lifespan of PLTs are 7-10d but endothelial cells are able to within a few hrs; TXA2 promotes PLT aggregation while PGI2 inhibits PLT aggregation thus aspirin can serve as an antiPLT

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11
Q

what is the difference between COX1 and COX2 which supports the antiPLT effect of aspirin

A

COX1 is constitutively expressed in most mammalian cells while COX2 is inducible and mainly plays a role in inflamm

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12
Q

do NSAIDs have action in the CNS

A

yes

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13
Q

why does PGE2 sensitise nociceptive fibers (and relate this to the analgesic effect of aspirin)

A

typically when there is tissue injury, bradykinin and leukotrienes are produced, both of which are potent activators of nerve terminals and thus would signal action potential to cause pain response

but when there is an addition of PGE2 production resulting from the tissue injury, the pain signal is heightened and since NSAIDs block the production of PGE2 through inhibition of COX, it can help to reduce the pain by decreasing the pain signal

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14
Q

why does aspirin have an analgesic ceiling (relate this to the severity of the pain)

A

aspirin is only useful in mild to moderate pain because in severe pain, the amount of bradykinin and leukotrienes produced is much larger which would trigger the nerve terminals to a large extent and since aspirin only blocks the production PGE2, the effect on the nerve terminals by bradykinin and leukotrienes is not addressed

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15
Q

what are the s/e of aspirin

A

aspirin has s/e relating to its salicylate chemical structure (which is dose dependent) and the typical s/e resulting from NSAID moa

SALICYLATE CHEMICAL STRUCTURE S/E
i) s/e that occur even within therapeutic range: GI intolerance, bleeding, hypersensitivity
ii) s/e that occur as a result of salicylate toxicity: tinnitus, central hyperventilation, respiratory alkalosis, renal and respiratory failure, HA, metabolic acidosis, dehydration, fever, vasomotor collapse, coma, hyperprothrombinemia
iii) linked to reye’s syndrome (with incr risk in children with viral infection) thus it is c/i in children (but also theres no pediatric formulation also)

TYPICAL NSAID S/E
i) GI related s/e (N/V, dyspepsia, risk of GI ulcer or bleed if chronic use of >5d)
ii) renal related s/e due to role of PGE2 and PGI2 (Na retention, H2O retention, peripheral edema, HTN, suppressed aldosterone and renin secretion, hyper K, AKI)
iii) pseudoallergy rxns
iv) asthma
v) bleeding
vi) effects on ovulation
vii) premature closure of ductus arteriosus (thus c/i in third trimester of pregnancy)
viii) impairment of wound healing (possible stop first then restart after ulcer healed)

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16
Q

what is “reye’s syndrome” and what are the sx and why is it of higher risk in children with viral infection

A

reye’s syndrome is the swelling of the brain and the liver

sx incl vomiting, personality changes, listlessness, delirium, convulsion, loss of consciousness, death (if pressure in brain not alleviated)

during a viral infection, there is rapid accumulation of fats in the liver and the brain

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17
Q

what is the role of prostaglandins (PG) in GI

A

i) decr gastric acid secretion
ii) incr mucosal blood flow
iii) incr secretion of mucus
iv) incr secretion of bicarb

environment in the stomach is very aggressive and thus need these protective mechanisms to protect the stomach wall

18
Q

what are the NSAID s/e and elaborate on the rationale behind the occurrence of these s/e

A
  1. GI related s/e
    i) N/V, dyspepsia
    ii) risk of GI ulcer and bleed (risk incr greatly if chronic use of NSAID of >5d)
  2. renal related s/e: arises as inhibition of PGE2 and PGI2 will alter the renal blood flow dynamics which is important in setting up the gradient for glomerular filtration and electrolyte movements
    i) inhibition of PGE2 secretion results in Na retention, H2O retention, peripheral edema and HTN
    ii) inhibition of PGI2 secretion results in suppressed aldosterone and renin secretion, hyperK and acute renal failure (what are the RF?)
    (at the TAL, PGE2 is responsible for inhibiting the reabsorption of Na which accounts for approx 25% of Na thus inhibiting the production of PGE2 would result in reabsorption of Na at the TAL; at the DCT, PGI2 stimulates the secretion of aldosterone and renin to reabsorb 1-2% of Na but due to the suppressed secretion of aldosterone and renin, this reabsorption of Na does not occur but it is insufficient to correct the 25% Na reabsorption at the TAL)
  3. pseudo allergic rxn (sx incl rashes, swelling, itching, nasal congestion, anaphylactic shock) bc inhibition of COX pathway leads to overflow of AA into the other two paths and thus it results in an increased production of LT such as LTD4 which can cause bronchospasm and allergic rxn like sx
  4. asthma due to bronchospasm
  5. bleeding (esp so for agents with COX1 > COX2 inhibition like aspirin) bc of failure of homeostasis
  6. s/e arising from COX2 inhibition (constitutive COX2i)
    i) renal related s/e (as per above bc kidney has constitutive expression of both COX1 and COX2)
    ii) effects on ovulation
    iii) premature closing of ductus arteriosus
    iv) impairment of wound healing
19
Q

what is the caution and c/i for NSAIDs

A

i) urticaria, nasal polyps and asthma due to the incr risk of bronchospasm and pseudoallergic rxn
ii) caution for surgical procedures esp if pt is on blood thinners
iii) severe kidney impairment (eGFR <30)
iv) severe HF
v) active GI ulcer or bleed
vi) bleeding disorders (eg. hemophilia)
vii) use of systemic corticosteroids or antiPLT or anticoags
viii) multiple risk factors for NSAID toxicity (eg. elderly pt w hx of GI bleed)
ix) third trimester of pregnancy

20
Q

how might you differentiate between a pseudo allergy and a true allergy

A

pseudo allergy would imply that there is similar rxn across drugs of the same class while a true allergy implies that the Ab for the true allergy would be against the chemical structure of that particular drug

21
Q

what are the eg. of typical NSAIDs

A

naproxen, ibuprofen, diclofenac, indomethacin, mefenamic acid

22
Q

compare the properties across the typical NSAIDs (eg. PK properties like F and halflife, indications, therapeutic effects, s/e, formulations)

A

NAPROXEN:
i) more effective in women and thus lower doses can be used (free fraction of drug is >40% greater in females = drug is less bound to plasma protein and more avail)
ii) long half life of 12-14hr allows it to have BD dosing (comparison to aspirin is q4-6hr)
iii) often used for dysmenorrhea

DICLOFENAC:
i) short plasma half life of <2hr but bc longer half life in synovial joint fluid, it is effective for inflamm joint diseases
ii) short plasma half life also decr the extent of GI s/e
iii) can be applied topically

INDOMETHACIN:
i) strongly anti-inflamm due to inhibition of phospholipase A that is similar to steroids
ii) but more CNS s/e like confusion, depression, psychosis, hallucinations
iii) thus used less commonly now and only for RA mostly

23
Q

what are the risk factors for NSAID induced AKI

A

i) age (>65yo), chronic HTN, atherosclerosis: narrowing of renal arterioles which reduces its capacity for renal afferent dilatation

ii) pre existing glomerular disease or renal insufficiency: requires afferent vasodilation to maintain GFR but NSAIDs causes vasoconstriction of afferent arteriole due to inhibition of PGE2 and PGI2

iii) volume depletion (true or effective): true volume depletion causes incl GI or renal salt and water losses, blood loss, diuretic use; effective volume depletion causes incl HF, cirrhosis; volume depletion lowers afferent glomerular arteriolar pressure and stimulates the secretion of angiotensin II (which acts on the efferent arterioles and causes efferent arterioles to contract)

iv) ACEi/ARBs: ACEi inhibits the action of angiotensin II which acts at the efferent arteriole to cause vasoconstriction, thus there is vasodilation in the efferent arteriole (these agents prevents vasoconstriction of efferent arterioles important to maintaining GFR bc glomerular filtration rate is directly proportional to the pressure gradient in the glomerulus)

v) triple whammy of ACEi with diuretics with NSAIDs: diuretics leads to volume depletion thus it reduces renal blood flow, ACEi/ARBs inhibit angiotensin converting enzyme and causes vasoconstriction of efferent arteriole, NSAIDs inhibits COX1 and COX2 which affects PG and causes vasodilation of afferent arteriole

24
Q

differentiate between COX1 and COX2 in terms of ints func and locations where it is mostly found at

A

COX1: constitutive and play a greater role in housekeeping and normal physiological function in cells and tissues, found in stomach, intestine, kidney, PLT

COX2: inducible COX2 more involved with inflamm response and tissue repair occuring after inflamm response, present in macrophages, leukocytes, fibroblasts, endothelial cells; constitutive COX2 also present in CNS, kidney, female reproductive tract, synovium

25
Q

what is the rationale behind the type of s/e selective COX2i have

A

COX2i do not have GI s/e like typical NSAIDs but they have s/e resulting from inhibition constitutive COX2 in the kidney, synovium, female reproductive tract and CNS

26
Q

what are the s/e of selective COX2i

A

s/e of coxibs incl s/e arising from inhibition of consitutive COX2 and also resulting from selective COX2i

CONSTITUTIVE COX2i S/E
1. renal related s/e: due to constitutive expression of both COX1 and COX2 in kidney, both COX1 and COX2 produces PGE2 and PGI2

  1. effects on ovulation: delayed follicular rupture (not c/i for this reason but to note that there is less likelihood of pregnancy)
  2. premature closure of ductus arteriosus aka fetal lung bypus: c/i in third trimester of pregnancy
  3. impairment of wound healing: COX activation allows acute inflamm to set the stage for later wound healing through activation of fibroblasts and other cells that are involved in repair and thus inhibition of COX2 would impair wound healing and may exacerbate ulcers (not c/i in pts w preexisting ulcers or ulcer risk factors, post surgical analgesia but to note and possible withdraw NSAIDs and coxibs first to let ulcer heal then restart)

SELECTIVE COX2i S/E
1. incr risk of thrombosis: selective COX2i results in pooling of AA and subsequent overflow into COX1 pathway and since COX1 produces PGE2, PGI2 and TXA2, the relative incr in TXA2 production (more TXA2 relative to PGI2), favours PLT aggregation which may incr the risk of thrombosis thus used cautiously in pts with risk of thrombotic events (cerebrovascular and CV) and elderly patients
*COX2 only produces PGE2 and PGI2

27
Q

what is the difference in the prostanoids being produced by COX1 vs COX2

A

COX1 produces PGI2, PGE2 and TXA2
COX2 produces PGI2 and PGE2

bc TXA2 is produced by PLTs which only expresses COX1

28
Q

relate the clinical efficacy, GI risk and thrombotic risk to the types of COX inhibitors

A

from aspirin to typical NSAIDs to coxibs

i) anti-inflamm and analgesic effects incr
ii) antiPLT decr
iii) GI safety incr
iv) prothrombicity incr

29
Q

what is the blackbox warning for NSAIDs (except aspirin)

A

caution using NSAIDs in elderly, hx of cerebrovascular or CV diseases due to risk of heart attack and stroke (bc risk of prothrombotic effects and renal effects causing HTN)

also note that there is uncertainty of where the risk of prothrombicity is until thus just caution

30
Q

relate the type of pt risk factor to their respective choice of NSAIDs

A

i) risk of renal toxicity: consult w dr

ii) risk of CV toxicity: avoid diclofenac and coxibs, use celecoxib or ibuprofen limited to 5d or less

iii) risk of GI toxicity: avoid non selective NSAID, use coxib but w caution

iv) risk of NSAID related bronchospasm and/or pseudoallergic rxn: avoid non selective NSAID, use coxib but with caution

31
Q

what are the pt counselling points for NSAIDs

A
  1. take medicine as prescribed
  2. to use for the shortest duration possible (5d or less)
  3. to combine NSAID w paracetamol initially then cease NSAID and continue w paracetamol only
  4. seek medical advice if NSAID still needed after 5d
  5. do not take w food bc will reduce absorption rate, delay peak conc which can decr NSAID efficacy
32
Q

what are the clinical effects and advantages and disadvantages of paracetamol

A

paracetamol is analgesic (drug of choice for mild to moderate pain when NSAIDs are inappropriate) and aa potent antipyretic (bc postulated to be CNS selective)

advantages of paracetamol:
i) spares the GI tract (bc appear to be selective for CNS COX)
ii) few and uncommon s/e
iii) few ddi
iv) relatively safe for pediatric use
v) available in many formulations, strengths and combinations

disadvantages of paracetamol:
i) not anti-inflamm at clinical doses (does not inhibit COX at sites of injury)
ii) caution in hepatic dysfunc and alcohol abuse
iii) dose reduction may b req
iv) overdose can lead to liver damage

33
Q

what dose if considered an overdose for paracetamol

A

> 4g in 24h
if 10g or more in 24h, refer to ED (due to risk of liver damage)

34
Q

how does overdose and chronic alcohol use or abuse contribute to hepatotoxicity of paracetamol

A

paracetamol is metabolised via a major pathway into inactive metabolite and via a minor pathway via 2E1 into a toxic metabolite which can be converted into nontoxic metabolite via glutathione

i) alcohol induces 2E1
ii) alcohol and overdose depletes glutathione
iii) glutathione is replenished by N-acetyl-cysteine (NAC)

35
Q

is glutathione found endogenously

A

yes it is a tripeptide found in most tissues and is esp in high conc in the liver

36
Q

where are opioids derived from

A

from the juice of the opium poppy (papaver somniferum)

37
Q

what is the warning, indication, clinical effects, advantages and disadvantages of opioids

A

warning: risk of addiction and abuse, sedation and overdose of respiratory depression

indication: not first line for pain (NSAIDs w/wo paracetamol often more effective than opioids for pain assoc w acute inflamm)

clinical effects: not anti-inflamm (bc target the pain signal transmission through nerves in CNS)

disadvantages: significant risk of s/e, diversion and misuse

38
Q

what are the requirements if opioids are deemed appropriate for pt

A

i) to use the lowest effective dose of the weakest effective opioid for the shortest duration
ii) ensure pt is well educated on use, storage and risk of s/e

39
Q

rank the opioids based on the potency and the their equivalence to 5mg IV morphine

A

tramadol (PO): 150mg equivalence (weak opioid)

codeine (PO): 100mg equivalence (weak opioid)

morphine (PO): 15mg equivalence (strong opioid)

oxycodone (PO): 10mg equivalence (strong opioid)

fentanyl (TD): 0.00625mg/h equivalence (strong opioid)

40
Q

which opioid has potential for variable response and why

A

codeine bc of 2D6 polymorphisms that can result in 0-15% of codeine being metabolised into the more potent morphine

so those who convert 15% will have much more analgesic effect

41
Q

what are the s/e of opioids and what is the risk of being on long term opioids

A

i) GI effects (N/V/C)
ii) hormonal effects
iii) depression
iv) respiratory effects
v) overdose and death
vi) falls and fractures
vii) sedation/ drowsiness (do not drive or operate machinery)
viii) tolerance, physical dependence, addiction and/or withdrawal
ix) opioid induced hyperalgesia

80% of pts on long term opioids will develop at least one of these opioid induced s/e

42
Q

what are the risk factors for opioid induced s/e

A

i) combi w other CNS depressants (alcohol, benzodiazepines, antidepressants): can exacerbate CNS depression and respiratory depression

ii) other comorbs: eg. mental health conditions

iii) renal or hepatic insufficiency, age >65yo

iv) pregnancy: due to risk to both mother and fetus

v) personal or family hx of substance use disorder

vi) alr on an opioid: incr risk w incr dose and duration of use, risk of diversion, risk of opioid use disorder to both pt and to whoever who has access

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