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36. Non-steroidal antiinflammatory drugs. Aspirin, paracetamol: Difference between revisions

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36. Non-steroidal antiinflammatory drugs. Aspirin, paracetamol (view source)

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(Created page with "Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most widely used drugs in the world, and they're among the most frequently implicated drugs in causing hospital admissions. They all have a similar mechanism of action; they inhibit ''cyclooxygenase'' (<abbr>COX</abbr>). This reduces the synthesis of prostaglandins and thromboxanes. This has three main effects: * Antipyretic effect * Anti-inflammatory effect * Analgesic effect === Antipyretic effect === Pro...")
 
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* Analgesic effect
* Analgesic effect


=== Antipyretic effect ===
== NSAIDs in general ==
Prostaglandins in the hypothalamus increase the set-point temperature during fever.


=== Anti-inflammatory effect ===
=== Indications ===
Prostaglandins induce hyperaemia and oedema during inflammation. By inhibiting these mechanisms, the inflammatory response is decreased.
NSAIDs are mainly used for symptomatic treatment of pain (like headache, toothache, menstrual pain, pain due to influenza) or symptomatic treatment of fever (usually in case of infections). NSAIDs are effective at treating pain associated with inflammation and tissue damage, but not effective in treating visceral pain (like appendicitis, pain associated with gallstones). They’re also not effective at treating neuropathic pain.
 
NSAIDs have some other uses as well:
 
*Induce closure of persistent ductus arteriosus
* Inhibit platelet aggregation (only acetylsalicylic acid)
* Prevention of colorectal cancer (not routinely used)
 
=== Mechanism of action ===
Prostaglandins in the hypothalamus increase the set-point temperature during fever. By inhibiting the formation of these prostaglandins, NSAIDs reduce fever. This is the antipyretic effect.


=== Analgesic effect ===
Prostaglandins induce hyperaemia and oedema during inflammation. By inhibiting these mechanisms, NSAIDs decrease the inflammatory response.
Prostaglandins in the periphery and the CNS increase the sensitivity of nociceptive fibres. By inhibiting COX this sensitization is reduced.


NSAIDs are effective at treating pain associated with inflammation and tissue damage, but not effective in treating visceral pain (like appendicitis, pain associated with gallstones). They’re also not effective at treating neuropathic pain.
Prostaglandins in the periphery and the CNS increase the sensitivity of nociceptive fibres. By inhibiting COX NSAIDs reduce this sensitization.


=== Other medical uses of NSAIDs ===
NSAIDs may reduce the risk of colorectal cancer by interfering with prostaglandin-dependant cancer cell pathways.


* Induce closure of persistent ductus arteriosus – prostaglandins keep this duct open
The embryonic structure ductus arteriosus is kept open in utero by prostaglandins. Some newborns have a persistent ductus arteriosus which doesn't close. Administration of NSAIDs induces closure of the ductus arteriosus.
* Inhibit platelet aggregation
** Via COX1 inhibition
* Prevention of colorectal cancer
* Dysmenorrhoea


=== Cyclooxygenase ===
=== Cyclooxygenase ===
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Both COX1 and COX2 produces prostaglandins that dilate the afferent arteriole in the kidney.
Both COX1 and COX2 produces prostaglandins that dilate the afferent arteriole in the kidney.
 
{| class="wikitable"
The following table sums up the side-effects of inhibiting each COX isoenzyme.
|+The following table sums up the side-effects of inhibiting each COX isoenzyme.
!
!Activation of COX1
!Inhibition of COX1
!Activation of COX2
!Inhibition of COX2
|-
!Effect on kidney
|Vasodilation of afferent arteriole
|Impaired vasodilation of afferent arteriole
|Vasodilation of afferent arteriole
|Impaired vasodilation of afferent arteriole
|-
!Effect on gastric mucosa
|Protection of gastric mucosa
|Impaired protection of gastric mucosa
|No effect
|No effect
|-
!Effect on coagulation
|Thrombocyte aggregation
|Increased bleeding tendency
|Decreased coagulability (not well understood)
|Increased risk of arterial thrombosis
|-
!Effect on inflammation
|No effect
|No effect
|Promotes inflammation
|Inhibits inflammation
|-
!Effect on pain
|No effect
|No effect
|Increased pain sensitivity
|Decreased pain sensitivity
|}


=== Important NSAIDs ===
=== Important NSAIDs ===
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* Most are weak acids
* Most are weak acids
* Strong plasma protein binding
* Strong plasma protein binding (except acetylsalicylic acid)
*Negligible first pass metabolism
*Complete absorption from the GI tract
* Actively secreted into tubules
* Actively secreted into tubules


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* For antiplatelet effect
* For antiplatelet effect
** 300 mg saturation dose
** Initial 300 mg saturation dose followed by 80 – 160 mg/day
** 80 – 160 mg/day
* For analgesic and antipyretic effect
* For analgesic and antipyretic effect
** 0,5 – 1 g/dose
** 0,5 – 1 g/dose
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=== Intoxication ===
=== Intoxication ===
Intoxication causes tinnitus, hyperpnoea and acid-base disorders.
Intoxication with ASA causes tinnitus, tachypnoea. More severe intoxication can cause respiratory alkalosis (due to the hyperventilation), high anion gap metabolic acidosis (due to the acidic nature of ASA), or a mixed acid-base disorder.
 
Treatment involves gastric lavage with activated charcoal, sodium bicarbonate, and dialysis.


== Paracetamol ==
== Paracetamol ==
Paracetamol (also known as acetaminophen in the US) is the weirdest of all NSAIDs. It only has weak COX-inhibiting effect, yet still causes analgesia and antipyretic effects, so many don’t even consider it an NSAID. It does not inhibit inflammation.
Paracetamol (also known as acetaminophen in the US) is the weirdest of all NSAIDs. It only has weak COX-inhibiting effect, yet still causes analgesia and antipyretic effects, so many don’t even consider it an NSAID. It does not inhibit inflammation.


Because of its weak NSAID effects it doesn’t have the classic NSAID side effects either. As such, it's the preferred drug for treating pain or fever when no anti-inflammatory effect is needed. It can also be safely used during pregnancy.
Because of its weak NSAID effects it doesn’t have the classic NSAID side effects either. As such, paracetamol is the first choice for pain or fever when no anti-inflammatory effect is necessary, due to its higher safety than other NSAIDs.. It can also be safely used during pregnancy.
 
=== Indications ===
Pain or fever, when no anti-inflammatory effect is necessary.


=== Mechanism of action ===
=== Mechanism of action ===
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=== Pharmacokinetics ===
=== Pharmacokinetics ===
Metabolized into a toxic metabolite (NAPQI) and a non-toxic metabolite by the liver. This toxic metabolite can be neutralized by glutathione as long as non-toxic doses are used.
Metabolized into a toxic metabolite caleld NAPQI and a non-toxic metabolite by the liver. This toxic metabolite can be neutralized by glutathione as long as non-toxic doses are used.


=== Intoxication ===
=== Intoxication ===
In toxic doses glutathione stores are depleted, so the toxic metabolite accumulates, causing liver necrosis.
In toxic doses glutathione stores are depleted, so the toxic metabolite accumulates, causing liver necrosis. Treatment involves administering N-acetylcysteine, which promotes glutathione synthesis.
 
Treatment involves activated charcoal and N-acetylcysteine. This compound promotes glutathione synthesis.


=== Side effects ===
=== Side effects ===
Produces few significant side effects.
Produces few significant side effects.
[[Category:Pharmacology 1]]
[[Category:Pharmacology 1]]