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PMY2107 Applied Clinical Pharmacology and Therapeutics > Paracetamol and Aspirin > Flashcards

Paracetamol and Aspirin Flashcards

1
Q

What are musculoskeletal diseases?

A

Disorders which affect muscles, bones, joints, ligaments, tendons and nerves.

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2
Q

What are painkillers/analgesics?

A

Drugs which cause analgesia/relief from pain by acting on the peripheral and central nervous system.

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3
Q

Name some painkillers/analgesics.

A

Paracetamol
NSAIDs - ibuprofen, naproxen, aspirin
Opioids - morphine, oxycodone

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4
Q

What are peroxides and an increased amount of these mean what?

A

Peroxides = 2 oxygen atoms linked together by a single covalent bond.
Increased amounts found in an inflammatory environment.

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5
Q

How does high levels of peroxides present affect paracetamol?

A

High level causes oxidation of paracetamol hence blocking its effect.
- hence why paracetamol is not used as an anti-inflammatory.

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6
Q

What is NAPQI?

A

Toxic metabolite of paracetamol.

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7
Q

How is NAPQI excreted normally?

A

Normally conjugated with GSH (glutathione) to enable excretion.

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8
Q

What are TRPA1-receptors?

A

Transient Receptor Potential Ankyrin 1 receptors - these are calcium channels expressed mainly in the neurons but also in the endothelial and inflammatory immune cells.

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9
Q

What is anti-nociception?

A

Blocking detection of painful or dangerous stimuli by sensory neurons.

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10
Q

Explain the MOA of paracetamol (5 steps).

A
  1. Paracetamol metabolite, NAPQI binds to TRPA1 receptors on the spinal cord.
  2. Binding causes the influx of Na+ and Ca2+ ions.
  3. This triggers the release of the excitatory NT, glutamine.
  4. Glutamine inhibits the voltage-gated Na/Ca channels.
  5. This blocks the AP and reduces the sensitivity to pain.
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11
Q

What are cannabinoid receptors?

A

These are GPCRs which are expressed throughout the body and are involved in a range of physiological processes such as appetite, mood regulation and pain sensing.

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12
Q

Explain the MOA of paracetamol via cannabinoid receptors.

A
  1. FAAH facilitates the conjugation of p-aminophenol to arachidonic acid to form N-arachidonoylphenolamine (AM404).
  2. AM404 inhibits the reuptake of anandamide (NT) from synaptic clefts within the neurons.
  3. This increases cannabinoid receptor activation on post-synaptic membrane, inhibits nociception.
  4. Pain relief occurs.
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13
Q

What is FAAH and where is it found?

A

Fatty acid amide hydrolase - found mainly in the CNS

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14
Q

Where is paracetamol metabolised?

A

in the liver

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15
Q

What are the 3 pathways of paracetamol metabolism?

A
  1. glucuronidation
  2. sulphation
  3. N-hydroxylation and GSH conjugation
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16
Q

What enzyme metabolises paracetamol to NAPQI?

-NAPQI = toxic metabolite

A

Hepatic cytochrome P450

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17
Q

How is NAPQI detoxified?

What happens when paracetamol is overdosed?

A

At usual doses, NAPQI reacts with the sulphydryl group of GSH and is detoxified.
At high doses, when paracetamol is taken in an overdose, the detoxification pathway is saturated and NAPQI builds up in the liver - causes liver toxicity.

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18
Q

How is paracetamol metabolised?

A

Metabolised by hydroxylation, conjugated mainly as glucuronide and excreted in the urine.

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19
Q

When does analgesia kick in when administered?

A

over 15 mins after administration

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20
Q

What is the typical dose for paracetamol?

A
  1. 5g-1g every 4-6 hours. Maximum of 4g in 24 hours.

- for a healthy weight - 50kg, healthy kidney and liver

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21
Q

What is the dose of paracetamol to be given to a patient between 10 and 50kg of weight?

A

reduce dose to 15g/kg

22
Q

What is the issue is renal function is poor? And what would the recommended dose of paracetamol in this case?

A

Risk of toxicity as elimination of drug will be delayed - toxic metabolite can build up.
Normal eGFR = 60ml/min. Reduce frequency of dose to 6 hourly if eGFR = <30ml/min.

23
Q

What is the problem is the hepatic function is poor? And what would the recommended dose of paracetamol in this case?

A

Great risk of toxicity because hepatic dysfunction can lead to decreased glutathione levels.
Dose should be reduced to 3g in 24 hours for those under 50kg.

24
Q

What are the side effects of paracetamol?

A
  • usually safe at correct doses

- exceeded dose = liver failure, kidney failure and brain damage

25
Q

What are the signs of paracetamol overdose and poisoning?

A
  • first signs = n&v which settles in 24hrs.
  • return of n&v within 2-3 days with subcostal pain/tenderness on RHS = hepatic necrosis.
  • liver damage peaks 3-4 days post overdose.
  • paracetamol toxicity can cause hepatocellular necrosis and renal tubular necrosis.
26
Q

What can be given as an antidote to paracetamol poisoning?

A

N-acetylcysteine (NAC) can be administered via IV to reduce liver damage. Must be given within the first 8 hours to be effective.

27
Q

What happens physiologically when paracetamol is overdosed?

A

NAPQI detoxified usually by conjugation with glutathione. Following a paracetamol overdose, hepatic glutathione stores are diminished.
Surplus NAPQI binds to hepatocytes causes necrosis and cell death (hepatocellular tissue necrosis).

28
Q

How does N-acetylcysteine help in paracetamol overdose?

A

NAC replenishes hepatic glutathione levels/acts as a substitute and enables NAPQI detoxification.

29
Q

What are the 4 principle effects of aspirin?

Remember it is an NSAID

A

Analgesic
Anti-pyretic
Anti-inflammatory
Anti-thrombotic

30
Q

Why does aspirin have an analgesic effect?

A

It inhibits PGE2 which can desensitize pain receptors.

- PGE2 is one of the eicosanoids generated by the AA pathway = has a role in sensitisation of pain receptors

31
Q

Why does aspirin have an anti-pyretic effect?

A

Inhibits PGE2, allows thermoregulation of the hypothalamus.

32
Q

Why does aspirin have an anti-inflammatory effect?

A

Inhibits PGE2 and PGD2 which cause vasodilation.

Causes reduction in blood supply and fluid extravasation.

33
Q

Why does aspirin have an anti-thrombotic effect?

A

Reduces TxA2 (Thromboxane A2) production in platelets.

34
Q

What is the mechanism of aspirin?

A

Aspirin is an irreversible inhibitor of COX - binds at the active site of the enzyme and prevents arachidonic acid from binding to it.

35
Q

Explain in detail how aspirin is anti-thrombotic?

A

Anti-thrombotic = prevents blood clotting
TXA2 expressed in platelets and is pro-thrombotic which results in activation and aggregation of platelets.
Aspirin irreversibly inhibits COX-1 meaning that platelets cannot be re-synthesised as they have no nucleus, DNA hence no protein production.

36
Q

How long is COX inhibited by aspirin?

A

COX inhibition for the entire lifespan of the platelet = 10 days. Aspirin is an irreversible inhibitor.

37
Q

What is the recommended dose of aspirin for pain?

A

300-900mg every 4-6 hours. Max dose of 4g in 24 hours.

38
Q

When does analgesic effect occur when aspirin is administered?

A

After 15 mins of administration.

39
Q

What is the metabolite of aspirin?

A

Salicylic acid/salicylate is the main metabolite.

40
Q

How and where is aspirin metabolised?

A

Metabolised in the liver.

Aspirin is rapidly hydrolysed (hydrolysis) by esterases in the plasma and tissues.

41
Q

The plasma half-life depends on the dose of aspirin taken. What is the half life when 500mg, 1g and 2g are taken?

A 
500mg = 3 hours
1g = 5 hours
4g = 9 hours
42
Q

What happens when the main metabolite of aspirin is conjugated?

A

Conjugated to glycine/glucuronide - results in salicyluric acid.

43
Q

How are the metabolites of aspirin excreted?

A

Via kidneys.

44
Q

What are the side effects of aspirin and why do they happen?

A

GI tract disturbances such as ulceration and bleeding.
Aspirin inhibits prostaglandin synthesis in the stomach. Prostaglandins are needed to form a protective barrier against stomach acid and helps facilitate mucus secretions.
PG also reduces acid secretions.
Inhibit PG in stomach = reduced mucus secretions, increased acid production.

45
Q

Aspirin can interact with warfarin. What is warfarin?

A

It is an anti-coagulant - used in patients with AF and clotting risks - so taken to prevent blood clots.
Warfarin inhibits Vitamin K reductase synthesis (VitK needed for blood clotting)

46
Q

What happens when aspirin interacts with warfarin?

A

Aspirin interacts causing a risk of bleeding.

  • displaces warfarin from plasma binding site
  • free warfarin concentration in blood increases, resulting in increased risk of bleeding.
47
Q

What are the signs of aspirin overdose or poisoning?

A

N&V, hyperventilation, deafness and tinnitus.

48
Q

What can be given as an antidote to aspirin poisoning?

A

Activated charcoal given within 1 hour of ingesting aspirin and when plasma conc are >125mg/kg
- Haemodialysis required for severe salicylate poisoning >700mg/kg

49
Q

What is the benefit of administering activated charcoal in aspirin overdose?

A

Activated charcoal administered to absorb ingested toxins and prevents systemic absorption of metabolite.

50
Q

What is the dose of charcoal to be administered as an antidote?

A

Initial 50g - oral administration.

50g every 4 hours - monitor and reduce is not tolerated.

PMY2107 Applied Clinical Pharmacology and Therapeutics (21 decks)

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