NSAIDs & Acetaminophen
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NSAIDs & Acetaminophen
Medication Selection
General Guide
Anti-thrombosis
- Low-dose aspirin. The other NSAIDs can have the opposite effect; they can be thrombogenic (provoke clot formation), so they are generally avoided in patients at risk for thrombotic events.
Mild Pain or Fever
- Acetaminophen (APAP) (aka paracetamol) and many of the NSAIDs (ibuprofen, naproxen, etc…) are used. APAP is NOT an anti-inflammatory agent.
Moderate to Severe Pain
- More potent NSAIDs (eg, ketorolac).
GI Ulcer
- APAP and COX-2 inhibitors.
Specific Conditions
- Example: indomethacin for a subset of headaches, called hemicranias.
Mechanism: cyclooxygenase pathway
cyclooxygenase pathway
- NSAIDs exert their effects, primarily, through the inhibition of cyclooxygenase (COX)-induced conversion of arachidonic acid to prostaglandins and thromboxane.
Membrane Phospholipids
- Membrane phospholipids are broken down (by phospholipase A2) to arachidonic acid.
Arachidonic Acid
- Arachidonic acid is converted to prostaglandin H2 (PGH2) via two forms of cyclooxygenase: Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2).
- An intermediary, prostaglandin G2 (PGG2), is formed in the process.
- Cyclooxygenase oxygenates arachidonic acid to PGG2 and then converts PGG2 to PGH2 via peroxidase activity.
PGH2
- From here, PGH2 is then converted to the four prostaglandins and the two thromboxanes.
- For reference, the four prostaglandins are prostaglandin (PG) E2 (PGE2), prostacyclin (PGI2), prostaglandin D2 (PGD2) and prostaglandin F2alpha (PGF2alpha), and the two thromboxanes are thromboxane A2 (TXA2) and thromboxane B2 (TXB2).
- PGH2 is converted to prostaglandin E2 (PGE2) via prostaglandin isomerase; thromboxane A2 (TXA2) via thromboxane synthase; and prostacyclin (PGI2) via prostacyclin synthase.
COX-1: The Physiologic State
- COX-1 (aka PGH synthase-1) catalyzes prostaglandin and thromboxane production in the normal, physiological state (for housekeeping mechanisms); whereas, COX-2 (aka PGH synthase-2) catalyzes it in the inflammatory and cancerous states.
- COX-1 is constituently expressed primarily in noninflammatory cells and functions in physiologic activities.
- COX-1 is often thought of as the physiologic housekeeper for many activities including vascular homeostasis, maintenance of renal and gastrointestinal blood flow, renal function, intestinal mucosal proliferation, platelet function, and antithrombogenesis.
COX-2: The Inflammatory State
- COX-2 is inducible and is expressed in activated lymphocytes, polymorphonuclear cells, and other inflammatory cells. - COX-2 is involved in a number of "as-needed" or specialized functions including roles in inflammation, fever, pain, transduction of painful stimuli in the spinal cord, mitogenesis (particularly in the GI epithelium, and renal adaptation to stresses. Cox 2 is our primary target to achieve antipyretic, analgesic, and anti-inflammatory effects.
Cyclooxygenase Products: PGE2, PGI2, and TXA2
- PGE2, PGI2, and TXA2 are all products of the COX-1 pathway, whereas on the COX-2 side, both PGE2 and PGI2 are produced but TXA2 is NOT: as we'll see this has important effects on thrombogenicity.
Effect of Cyclooxygenase Inhibition
- NSAIDs block both COX-1 and COX-2 whereas selective COX-2 inhibitors (aka COX-2 inhibitors), as their name suggests, block COX-2, only.
Gastric Mucosa & Renal Function
- Via COX-1, PGE2 helps protect the gastric mucosa and impacts various aspects of kidney function, including afferent blood flow and electrolyte and fluid balance.
Fever & Pain
- Via COX-2, the inflammatory state, inflammatory cells produce PGE2, which produces key inflammatory responses, such as fever and pain.
PGE2 Inhibition
- NSAIDs are used for pain and fever reduction, primarily through COX-2 inhibition PGE2.
Platelet Function
Aspirin
- Aspirin irreversibly inhibits COX-1 (via acetylation), which produces prolonged inhibition of platelet aggregation and is thromboprotective (it reduces thrombogenesis but increases bleeding risk).
NON-aspirin COX Inhibitors
- NON-aspirin COX inhibitors (ie, NSAIDS and selective COX-2 inhibitors) produce reversible inhibition of shorter duration and are thrombogenic (they promote thrombotic events). Note, however, that celecoxib (a COX-2 inhibitor) has been shown to NOT increase thrombotic events.
NSAID Risks
Gastric Ulceration
- NSAIDS can cause GI ulcer because they block the housekeeping activity of PGE2 but selective COX-2 inhibitors should not because they only block PGE2 in inflammatory or cancerous states – they don't affect the gastric mucosa.
Kidney Function
- NSAIDs can cause renal impairment due to effects on electrolyte and fluid balance and blood pressure.
Hypertension
- NSAIDs can produce hypertension due to complicated direct vascular and indirect renal effects.
Bleeding
- Lastly, for completeness, indicate that in addition to being thrombogenic, NSAIDs (especially aspirin), have the risk of causing bleeding.
Specific Medication Effects
NSAIDS
Aspirin
Mechanism
- Aspirin irreversibly inhibits platelet aggregation via covalent acetylation of COX; and therefore, it provides protection against thrombotic events, such as cardiac events (myocardial infarction) or cerebrovascular events (stroke).
Key additional potential side effects:
- Hypersensitivity reaction; note that patients who have nasal polyps are more likely to suffer from this. As well, as it can produce asthma or tinnitus.
- Hypersensitivity can occur with other NSAIDs, in fact the condition is actually referred to as NSAIDs exacerbated respiratory disease (NERD); however, it occurs secondary to COX-1 inhibition and aspirin is one of the leading NSAIDs to produce COX-1 inhibition.
Severe, acute reactions, such as:
- Salicylate overdose, which can cause metabolic derangement, fever, and hyperventilation; rhabdomyolysis and renal failure; and cerebral edema and seizures. Overdose presents with metabolic derangement as follows:
- Medullary stimulation causes hyperventilation and respiratory alkalosis.
- Elevated lactate levels and salicylate metabolites trigger metabolic acidosis.
- Hyperventilation worsens to compensate for the metabolic acidosis but cannot overcome it.
- Ultimately, there is profound hemodynamic instability and end-organ damage.
- Reye syndrome, which is a rare, life-threatening disorder that classically occurs in children who take aspirin in the setting of a current or recent viral illness. It manifests with cerebral edema and hepatic failure.
Other NSAIDs
Common uses:
- Pain, arthritis, gout, dysmenorrhea, migraine, patent ductus arteriosus (PDA) in premature infants, and cancer prevention.
COX-2 selective inhibitors ("-coxibs")
- The major advantage is that they avoid GI ulcers (but note that they still can cause renal impairment).
- Celecoxib does NOT increase the risk of thrombotic events.
acetaminophen
Mechanism:
- Weak peripheral COX-1 and COX-2 inhibitor and that it has NO anti-inflammatory effects. It's possible that it actually acts via COX-3 inhibition in the central nervous system.
- Thus, increase that it is preferred over NSAIDs in patients with hemophilia, GI ulcer, and aspirin hypersensitivities, amongst other conditions.
Acetaminophen Toxicity
- Acetaminophen has some safe metabolic pathways to form non-toxic products.
- It can undergo sulfation or glucuronidation to non-toxic products.
- Or it can undergo P450 metabolism (most commonly CYP2E1 metabolism) to form NAPQI (N-Acetyl-p-benzoquinone imine), which can form a non-toxic product via glutathione conjugation (cysteine and mercapturic acid conjugates).
- If glutathione stores are depleted or overwhelmed, then NAPQI can bind cellular proteins to form toxic byproducts that produce hepatotoxicity.
- In cases of acetaminophen overdose, we administer n-acetylcysteine to replenish glutathione stores and shunt NAPQI to glutathione conjugation to reduce the production of toxic byproducts.
- Consider that patients with any of the following will have an increased risk of acetaminophen toxicity:
- Reduced capacity for glucuronidation or sulfation (think, Gilbert's disease (although the true pathophysiology of acetaminophen toxicity in this condition is more complicated).
- Glutathione deficiency (eg, from liver failure or malnutrition).
- P450 CYP2E1 inducers (eg, isoniazid or chronic ethanol use).