36. Non-steroidal antiinflammatory drugs. Aspirin, paracetamol

NSAIDs

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 (COX), which reduces the synthesis of prostaglandins and thromboxanes, hormones involved in inflammation, fever, and pain. This has three main effects:

• Antipyretic effect
• Anti-inflammatory effect
• Analgesic effect

The most commonly used NSAIDs are paracetamol, acetylsalicylic acid, ibuprofen, diclofenac, and naproxen. NSAIDs are available over-the-counter, but they can cause severe adverse effects, including kidney injury, cardiovascular events, gastrointestinal ulcers, and hypersensitivity reactions.

Indications

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)

Dosage

NSAIDs are mostly taken p.o. Some are available with enteric coating, which may reduce the gastrointestinal side effects. Some are available in combination with PPIs, which also reduces the GI effects.

Some NSAIDs are available in topical formulation, often as a gel. This is often used to treat pain in joints, as it reduces the risk of systemic side effects.

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.

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 NSAIDs reduce this sensitization.

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

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.

Cyclooxygenase

Two isoforms of COX exist: COX1 and COX2.

COX1 is constitutively expressed in all cells. It produces prostaglandins and thromboxanes involved in maintaining haemostasis. These prostaglandins and thromboxanes are important for platelet aggregation and for protection of the gastric mucosa.

COX2 is found in endothelium and smooth muscle in vessels and is only activated during inflammation, i.e. it's inducible and not constitutively expressed. It produces prostaglandins that promote inflammation by increasing vascular permeability, thereby causing hyperaemia and oedema. These prostaglandins also increase pain sensitivity and produce fever. COX2 also produces prostaglandins that prevent platelet aggregation and possibly decrease blood pressure.

Both COX1 and COX2 produces prostaglandins that dilate the afferent arteriole in the kidney.

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

According to the table above it seems like we can avoid many side effects by making COX2-selective NSAIDs. Indeed, NSAIDs are categorized according to whether they’re selective for COX2 or nonselective:

• COX-nonselective NSAIDs (“traditional NSAIDs”) – these NSAIDs are the least COX2 selective
  • Acetylsalicylic acid
  • Naproxen
  • Indomethacin
  • Ibuprofen
  • (Paracetamol)
• COX2-preferential NSAIDs – these NSAIDs are more COX2 selective than the above
  • (Paracetamol)
  • Diclofenac
  • Celecoxib
  • Meloxicam
• COX2-selective NSAIDs (“coxibs”) – these NSAIDs are the most COX2 selective
  • Parecoxib
  • Etoricoxib

It should be noted that COX selectivity is not binary, some drugs are more or less selective. Whether paracetamol is COX-2 selective or nonselective is disputed, but also not very clinically relevant, as it behaves neither like the other COX-2 selective NSAIDs or the nonselective NSAIDs but more like a separate drug.

Differences between NSAIDs

There is no clinical relevant difference in analgetic and anti-inflammatory effect between different NSAIDs. However, a person may respond to different NSAIDs differently; some people respond better to one NSAID than others. As such, if the effect of one NSAID is insufficient, it's worthwile to try another.

Potential complications NSAIDs

• Gastrointestinal complications
  • Gastritis
  • Erosion of gastric mucosa
  • Peptic ulcers

• Renal complications
  • Acute kidney injury
  • Acute interstitial nephritis
  • Analgesic nephropathy
• Cardiovascular complications
  • Increased risk for myocardial infarction and ischaemic stroke
• Increased bleeding
  • Due to loss of platelet-aggregating thromboxanes produced by COX1
• In utero closure of ductus arteriosus -> abortion
  • NSAIDs should be used with care in pregnant women
• Hypersensitivity reactions
  • Urticaria
  • Aspirin-exacerbated respiratory disease

Side effects are more common in elderly, and so NSAIDs should be used with care or avoided in this population. It should also be noted that the risk of complication occurs from the first administration, i.e. longer treatment is not necessary for a complication to develop.

To prevent systemic complications, topical administration should always be considered.

Gastrointestinal complications

Gastrointestinal side effects occur due to loss of mucosa-protective prostaglandins due to inhibition of COX1. Selective COX2-inhibitors have fewer GI side effects. Patients at risk for gastritis, erosion, and ulceration should be treated with a PPI as well.

Renal complications

Acute kidney injury (AKI), referring to an acute decline in GFR, occurs due to loss of prostaglandins that dilate afferent arteriole, which reduces the glomerular filtration pressure. AKI due to this mechanism is called haemodynamically mediated AKI. This is especially prevalent in case of hypovolaemia, hypotension, or pre-existing kidney disease, as the kidney usually increases prostaglandin synthesis during these insults to counteract the reduced renal blood flow.

Acute interstitial nephriritis, an acute inflammatory kidney lesion, may also occur in case of GFR. Acute interstitial nephritis also causes acute kidney injury, as well as symptoms of allergy (rash, fever, eosinophilia).

Analgesic nephropathy is a form of chronic interstitial nephritis, a chronic inflammatory kidney lesion caused by chronic use of NSAIDs.

Cardiovascular complications

Most NSAIDs are associated with increased risk of cardiovascular complications, including myocardial infarction, heart failure, and stroke. COX-2 selective NSAIDs and diclofenac have the highest risk. Notably, naproxen has lower risk for cardiovascular complications.

Cardiovascular complications may be due to inhibition of COX-2, which produces prostaglandins which protect the endothelium. Inhibition of COX-1 may reduce this increased cardiovascular risk, as inhibition of COX-1 inhibits the platelet function. This may explain the higher risk in COX-2 selective NSAIDs.

Aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease, previously called "aspirin asthma", is a condition characterised by patients with asthma, chronic rhinosinusitis with nasal polyps, and an intolerance to NSAIDs. When these patients ingest an NSAID, they experience sudden worsening of asthma and nasal congestion. Aspirin-exacerbated respiratory disease only occurs in a small percentage of people, but may be present in 5-20% of patients with asthma.

When COX is inhibited, all the arachidonic acid molecules that are produced will be converted into leukotrienes. Leukotrienes cause swelling, increased mucus secretion and bronchoconstriction in the bronchi, worsening asthma.

COX-2 selective NSAIDs

COX-2 selective NSAIDs were developed with the intention of reducing gastrointestinal side effects of conventional NSAIDs, by not inhibiting production of gastric mucosa-protective prostaglandins. However, studies quickly showed that the earliest "coxibs" (rofekoxib and valdekoxib) had severe cardiovascular side effects, including stroke and myocardial infarction, necessitating their withdrawal from the market. Some coxibs are still available, but their labels now indicate their cardiovascular risk and that treatment should be as low dose and as short as possible.

Contraindications

• Peptic ulcer
• Cardiovascular disease (due to increased risk for cardiovascular complications)
• Before surgery (due to the antiplatelet effect)
• Pregnancy
  • Except short-term treatment with aspirin or paracetamol
• Old age

Common pharmacokinetics

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

Drug interactions

• Glucocorticoids - increases risk for GI complications
• ACE inhibitors, ARBs, and diuretics - can cause haemodynamically mediated AKI
• Antihypertensives - NSAIDs can decrease the antihypertensive effect
• Antiplatelets and anticoagulants - due to the combined bleeding risk
• Methotrexate - NSAIDs decrease elimination of methotrexate

Acetylsalicylic acid

Acetylsalicylic acid (ASA), also called Aspirin® and Albyl-E® is the only NSAID not primarily used as an analgesic or anti-inflammatory. The Albyl-E® formulation is low dose and is intended as an antiplatelet.

Aspirin was originally a brand name for ASA by Bayer AG, and they had the name Aspirin trademarked. However, the term "Aspirin" became so widely used so that the US court determined that the term had been "genericized", causing Bayer to lose its trademark and the name "aspirin" to become an "alternative" generic name.

Indications

Given in low doses (75 - 150 mg) to prevent coronary artery disease like AMI or cerebrovascular disease like ischaemic stroke. Used after stent placement to prevent platelets from aggregating on the stents. Rarely used for its analgesic and anti-inflammatory effects.

ASA is contraindicated for children with viral infection, as it may cause Reye syndrome (see below).

Mechanism of action

ASA is the only irreversible COX inhibitor. In low doses it mostly inhibits COX1, which decreases the level of the thromboxane A2, a potent platelet aggregator and vasoconstrictor. This gives ASA an antiplatelet effect.

Platelets don’t have nuclei, so they can’t synthetize new COX enzymes after they have been irreversibly inhibited. For this reason, the effect of ASA lasts for the total lifetime of platelets, 7 – 10 days.

Dosing

• For antiplatelet effect
  • Initial 300 mg saturation dose followed by 80 – 160 mg/day
• For analgesic and antipyretic effect
  • 0,5 – 1 g/dose
  • Maximum 3 g/day
• For anti-inflammatory effect
  • 3 – 8 g/day

Contraindications

See above.

Interactions

See above.

Side effects

See above.

The use of ASA in children under 16, especially those with a preceding viral infection, can cause Reye syndrome. This is characterised by liver failure and encephalopathy.

Intoxication

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.

Paracetamol

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

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.

Mechanism of action

Incompletely understood. Paracetamol weakly inhibits COX in the CNS but does not influence COX in the periphery, hence no anti-inflammatory effect. It might stimulate descending pain inhibitory pathways.

Dosing

Oral, rectal or IV. The maximum oral dose is 4 g/day.

Contraindications

Liver failure.

Pharmacokinetics

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

In toxic doses glutathione stores are depleted, so the toxic metabolite accumulates, causing liver necrosis. Treatment involves administering N-acetylcysteine, which promotes glutathione synthesis.

Side effects

Produces few significant side effects.