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ACEM Primary Written > Anaesthesia: Pharmacology - NSAIDs and paracetamol > Flashcards

Anaesthesia: Pharmacology - NSAIDs and paracetamol Flashcards

1
Q

Are NSAIDs acid or base? What is the exception?

A

All but one are weak organic acids
Nabumetone is the exception (ketone prodrug which is metabolised to acidic active form)

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2
Q

What is the main mechanism of action of NSAIDs? What are four other possible mechanisms of action?

A

Inhibit prostaglandin synthesis via COX enzyme inhibition (may be selective or non-selective; all are reversible except aspirin)

Other possible mechanisms of action include inhibition of chemotaxis, decreased IL-1 production, decreased free radicals, interference with calcium-mediated intracellular events

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3
Q

Seven effects of aspirin

A

Analgesia
Anti-pyretic
Anti-inflammatory
Decreased sensitivity of vessels to bradykinin and histamine
Affect lymphokine production by T cells
Reverse vasodilation of inflammation
Inhibition of platelet aggregation (except selective COX-2 inhibitors)

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4
Q

Describe the pharmacokinetics of NSAIDs

A

Absorption: most are well-absorbed, absorption not impaired by food
Distribution: mostly highly protein-bound (98%, predominantly to albumin), all can be found in synovial fluid after repeated dosing
Metabolism: most highly metabolised, either by phase I and phase II reactions or directly by glucuronidation (phase II), in part by CYP3A or CYP2C families of P450 enzymes in the liver
Excretion: varying degrees of enterohepatic circulation (corresponds with degree of lower GIT irritation), final excretion predominantly renal

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5
Q

List eight adverse effects of NSAIDs by organ system

A
  1. CNS: headache, tinnitus, dizziness, rarely aseptic meningitis
  2. CVS: fluid retention, HTN, oedema, rarely MI or CCF
  3. GIT: abdominal pain, dyspepsia, nausea, vomiting, rarely ulcers or bleeding
  4. Haematologic: rarely thrombocytopaenia, neutropenia, aplastic anaemia
  5. Hepatic: deranged LFTs, rarely liver failure
  6. Pulmonary: asthma
  7. Renal: renal insufficiency, renal failure, hyperkalaemia, proteinuria
  8. Skin: rashes (all types), pruritis
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6
Q

What is the mechanism and duration of action of aspirin?

A

Irreversible non-selective COX inhibitor
Antiplatelet effect lasts 8-10 days (lifespan of platelet)
In other tissues, synthesis of new COX enzymes replaces inactivated enzyme so half-life is 6-12hrs

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7
Q

What is aspirin’s chemical name and active metabolite?

A

Acetylsalicylic acid
Active metabolite is salicylate

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8
Q

pKa of aspirin and salicylate

A

Aspirin 3.5
Salicylate 3.0

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9
Q

Describe the concept of “gastric trapping” as it relates to aspirin

A

Weak acid, so is predominantly in its unionised form in acidic environment of the stomach: unionised form is more lipophilic enabling absorption
Aspirin ionises in neutral pH of bloodstream to prevent diffusion back into stomach

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10
Q

Where does the majority of aspirin occur and why?

A

In upper GIT
More readily absorbed in stomach due to “gastric trapping” in setting of acidic pH, however greater total absorption in upper GIT due to large surface area

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11
Q

Describe the pharmacokinetics of aspirin

A

Absorption: well absorbed from stomach and upper GIT, peak concentration 1-3hrs
Distribution: rapidly hydrolysed (serum t1/2 = 15mins) to acetic acid and salicylate by esterases in tissue and blood, non-linearly bound to albumin (saturable: free portion increases with increasing drug concentration)
Metabolism: several pathways after hydrolisation including conjugation with glycine to form salicylurate (50%), glucuronidation (20%), saliacyl glucuronide (10%) and gentisic acid (1%), with 15% excreted unchanged
Excretion: renal (increased by alkalinisation of urine)

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12
Q

What are the main clinical uses of aspirin?

A
  1. Antiplatelet effect (low dose): decreased incidence of TIA, unstable angina, coronary artery thrombosis with MI, thrombosis post CABG
  2. Anti-inflammatory
  3. Anti-pyretic
  4. Analgesia
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13
Q

What is the relationship between longterm aspirin use and risk of colon cancer?

A

Reduced risk of colon cancer with longterm aspirin use

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14
Q

What is Reye syndrome?

A

Syndrome of acute noninflammatory encephalitis and fatty degenerative liver failure in children
Occurs post-viral and associated with aspirin use

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15
Q

Describe the symptoms and signs of aspirin overdose

A

Common features: sweating, tinnitus, blurred vision, tachycardia, hyperthermia, hyperventilation, respiratory alkalosis
Severe overdose: metabolic acidosis, seizures, coma, pulmonary oedema, CV collapse, hypokalaemia, GI bleeding, coagulopathy

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16
Q

Describe the management of aspirin overdose

A

General supportive care (IVT, monitoring)
In massive ingestion: activated charcoal, gastric lavage, whole bowel irrigation, haemodialysis
In moderate ingestion: IV NaHCO3 for urinary alkalinisation to increase excretion

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17
Q

Which two types of NSAIDs do not have antiplatelet activity?

A

Selective COX-2 inhibitors
Nonacetylated salicylates

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18
Q

When are nonacetylated salicylates indicated?

A

For anti-inflammatory effects where COX inhibition is undesirable (e.g. in asthma, bleeding tendency, renal failure)

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19
Q

Four classes of NSAIDs

A
  1. Irreversible non-selective COX inhibitor (aspirin)
  2. Nonacetylated salicylates
  3. COX-2 selective inhibitors
  4. Non-selective COX inhibitors
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20
Q

Give two examples of COX-2 selective inhibitors

A

Celecoxib
Meloxicam

21
Q

Give four examples of non-selective COX inhibitors

A

Diclofenac
Ibuprofen
Indomethacin
Naproxen

22
Q

What is the advantage of COX-2 selective inhibitors over non-selective inhibitors?

A

Same anti-inflammatory and analgesia effects with less gastric effects

23
Q

Which NSAID interacts with warfarin?

A

Celecoxib

24
Q

Which non-selective COX inhibitor is “relatively” non-selective?

A

Diclofenac

25
Q

What is the half-life of ibuprofen?

A

2hrs

26
Q

At what dose range does ibuprofen have anti-inflammatory effects?

A

Analgesia in lowers doses
Anti-inflammatory at higher doses >2400mg/day

27
Q

What is the effect of concomitant administration of ibuprofen and aspirin?

A

Ibuprofen antagonises aspirin’s irreversible platelet COX inhibition

28
Q

What are three other mechanisms of action of indomethacin besides COX inhibition?

A

May also inhibit phospholipase A and C, decreased neutrophil migration, and decreased T- and B-cell proliferation

29
Q

What NSAIDs are used for PDA closure?

A

Ibuprofen
Indomethacin

30
Q

Three specific adverse effects of indomethacin

A

Pancreatitis
Renal papillary necrosis
CNS effects: headache, confusion, depression

31
Q

What is the difference in the pharmacokinetics of naproxen in women vs men?

A

Higher free fraction in women

32
Q

What is the relative incidence of ibuprofen compared with aspirin, and of naproxen compared with ibuprofen?

A

Ibuprofen: less GI irritation than aspirin
Naproxen: incidence of GI bleeding low but double that of aspirin

33
Q

What is the urinary excretion of unchanged ibuprofen?

A

<1%

34
Q

Which NSAID is least likely to cause gastric upset?

A

Ibuprofen

35
Q

What is the mechanism of action of paracetamol?

A

Unclear: has antipyretic and analgesic but not anti-inflammatory effects
Weak COX-1 and COX-2 inhibitor in peripheral tissues

36
Q

Describe the pharmacokinetics of paracetamol

A

Absorption: rapidly and completely absorbed, rate of absorption related to rate of gastric emptying, peak concentration 30-60mins
Distribution: poorly bound to plasma proteins, VD 1L/kg, t1/2 2-3hrs (increased in toxicity or hepatic impairment)
Metabolism: 80% via sulfation or glucuronidation to nontoxic metabolites, 10% undergoes phase I hydroxylation to form intermediate metabolite NAPQI which is then either conjugated to glutathione to form nontoxic metabolite or when this pathway is exhausted forms further hepatotoxic metabolites
Excretion: urine (<5% unchanged)

37
Q

Describe the adverse effects of paracetamol (not in overdose)

A

Mild reversible LFT derangement
Dizziness, excitement, disorientation in larger doses
Renal damage in absence of hepatic damage
Rarely haemolytic anaemia, methaemoglobinaemia

37
Q

What dose of paracetamol may be fatal?

A

15g

38
Q

What acute ingestion of paracetamol (in children and adults) is considered potentially toxic?

A

> 150-200mg/kg in children
7g in adults

39
Q

What daily dose of paracetamol is sufficient to produce LFT derangement?

A

4g/day

40
Q

What paracetamol level at 4hrs post ingestion indicates risk of liver injury?

A

> 150mg/L

41
Q

What is the initial presentation seen with acute paracetamol overdose? How does this progress?

A

Usually asymptomatic initially, may have minor GI upset (nausea, vomiting)
After 24-36hrs: evidence of liver injury (transaminitis, hypoprothrombinaemia)
May progress to fulminant hepatic failure: metabolic acidosis, hypoglycaemia, encephalopathy, death

42
Q

How is paracetamol overdose managed? Within what timeframe should it be given?

A

N-acetylcysteine acts as a glutathione substitute to bind toxic NAPQI and prevent its accumulation
Should be given with 8-10hrs of ingestion

43
Q

What pattern of hepatic damage is seen with paracetamol overdose?

A

Centrilobular necrosis

44
Q

Describe the mechanism of action of tramadol

A

Centrally acting synthetic analgesic structurally related to opioids, but acting on both opioid and nonopioid receptors
Also increases 5HT release and inhibits reuptake of 5HT and NA

45
Q

What is the effect of naloxone on tramadol?

A

Tramadol only 30% antagonised by naloxone (suggests other receptors involved in mechanism of action)

46
Q

How is tramadol metabolised?

A

Via CYP2D6

47
Q

Describe four features of tramadol toxicity

A

Seizures
Serotonin syndrome
Nausea
Dizziness

ACEM Primary Written (150 decks)

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