Pharmacology of Acetaminophen and NSAIDs

Acetaminophen

• Potentially hepatotoxic in doses exceeding 4 g/day, especially with chronic use
• Patients with glucose-6-phosphate dehydrogenase deficiency should use caution when taking acetaminophen

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Relieve pain through central and peripheral inhibition of cyclooxygenase (COX) and subsequent inhibition of prostaglandin synthesis
• Rapidly absorbed from the GI tract with high bioavailability
• Extensively metabolized, mainly by glucuronidation, to inactive compounds in the liver
• Elimination occurs primarily through the kidneys
• Onset of activity for naproxen sodium and standard ibuprofen is about 30 minutes
• Duration of activity for naproxen sodium is up to 12 hours and 6-8 hours for ibuprofen
• Analgesic, antipyretic, and anti-inflammatory activity
• Useful in managing mild moderate pain of non-visceral origin

Adverse Effects of NSAIDs

• Most frequent adverse effects involve the GI tract and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain
• Increased risk of severe stomach bleeding, especially in:
  • Those aged 60 or older
  • Those with a history of stomach ulcers or bleeding problems
  • Those taking blood thinning (anticoagulant) or steroid drugs
  • Those taking other drugs containing prescription or nonprescription NSAIDs
  • Those who consume 3 or more alcoholic drinks daily
  • Those who take more or for a longer time than directed

Cardiovascular Risk of NSAIDs

• Associated with increased risk for myocardial infarction, heart failure, hypertension, and stroke
• Cardiovascular risk depends on dose and duration
• Ibuprofen has been associated with a significant increase in cardiovascular risk, whereas naproxen has not

Salicylates

• Inhibit prostaglandin synthesis from arachidonic acid by inhibiting both isoforms of the COX enzyme (COX1 and COX2)
• Reduce the sensitivity of pain receptors to the initiation of pain impulses at sites of inflammation and trauma
• Absorbed by passive diffusion of the non-ionized drug in the stomach and small intestine
• Factors affecting absorption include dosage form, gastric pH, gastric emptying time, dissolution rate, and the presence of antacids or food

Pharmacokinetics of Salicylates

• Protein binding is concentration dependent
• At concentrations lower than 100 mg/mL, approximately 90% of salicylic acid is bound to albumin
• At concentrations greater than 400 mg/mL, approximately 75% is bound
• Salicylic acid is largely eliminated through the kidney
• Urine pH determines the amount of unchanged drug that is eliminated

Therapeutic Uses of Salicylates

• Effective in treating mild moderate pain from musculoskeletal conditions and fever
• Indicated for prevention of thromboembolic events (e.g., myocardial infarction and stroke) in high-risk patients

Clinically Important Drug-Drug Interactions

• Ibuprofen decreases the antiplatelet effect of aspirin
• Ibuprofen displaces phenytoin from protein binding sites
• NSAIDs increase the risk of GI or esophageal ulceration with bisphosphonates
• NSAIDs inhibit the renal clearance of digoxin

Acetaminophen

• Potentially hepatotoxic in doses exceeding 4 g/day, especially with chronic use
• Patients with glucose-6-phosphate dehydrogenase deficiency should use caution when taking acetaminophen

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Relieve pain through central and peripheral inhibition of cyclooxygenase (COX) and subsequent inhibition of prostaglandin synthesis
• Rapidly absorbed from the GI tract with high bioavailability
• Extensively metabolized, mainly by glucuronidation, to inactive compounds in the liver
• Elimination occurs primarily through the kidneys
• Onset of activity for naproxen sodium and standard ibuprofen is about 30 minutes
• Duration of activity for naproxen sodium is up to 12 hours and 6-8 hours for ibuprofen
• Analgesic, antipyretic, and anti-inflammatory activity
• Useful in managing mild moderate pain of non-visceral origin

Adverse Effects of NSAIDs

• Most frequent adverse effects involve the GI tract and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain
• Increased risk of severe stomach bleeding, especially in:
  • Those aged 60 or older
  • Those with a history of stomach ulcers or bleeding problems
  • Those taking blood thinning (anticoagulant) or steroid drugs
  • Those taking other drugs containing prescription or nonprescription NSAIDs
  • Those who consume 3 or more alcoholic drinks daily
  • Those who take more or for a longer time than directed

Cardiovascular Risk of NSAIDs

• Associated with increased risk for myocardial infarction, heart failure, hypertension, and stroke
• Cardiovascular risk depends on dose and duration
• Ibuprofen has been associated with a significant increase in cardiovascular risk, whereas naproxen has not

Salicylates

• Inhibit prostaglandin synthesis from arachidonic acid by inhibiting both isoforms of the COX enzyme (COX1 and COX2)
• Reduce the sensitivity of pain receptors to the initiation of pain impulses at sites of inflammation and trauma
• Absorbed by passive diffusion of the non-ionized drug in the stomach and small intestine
• Factors affecting absorption include dosage form, gastric pH, gastric emptying time, dissolution rate, and the presence of antacids or food

Pharmacokinetics of Salicylates

• Protein binding is concentration dependent
• At concentrations lower than 100 mg/mL, approximately 90% of salicylic acid is bound to albumin
• At concentrations greater than 400 mg/mL, approximately 75% is bound
• Salicylic acid is largely eliminated through the kidney
• Urine pH determines the amount of unchanged drug that is eliminated

Therapeutic Uses of Salicylates

• Effective in treating mild moderate pain from musculoskeletal conditions and fever
• Indicated for prevention of thromboembolic events (e.g., myocardial infarction and stroke) in high-risk patients

Clinically Important Drug-Drug Interactions

• Ibuprofen decreases the antiplatelet effect of aspirin
• Ibuprofen displaces phenytoin from protein binding sites
• NSAIDs increase the risk of GI or esophageal ulceration with bisphosphonates
• NSAIDs inhibit the renal clearance of digoxin

Acetaminophen

• Can be hepatotoxic in doses exceeding 4 g/day, especially with chronic use.
• Patients with glucose-6-phosphate dehydrogenase deficiency should use caution when taking acetaminophen.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Relieve pain through central and peripheral inhibition of cyclooxygenase (COX) and subsequent inhibition of prostaglandin synthesis.
• Are rapidly absorbed from the GI tract with high bioavailability.
• Are extensively metabolized, mainly by glucuronidation, to inactive compounds in the liver.
• Are eliminated primarily through the kidneys.
• Have analgesic, antipyretic, and anti-inflammatory activity.
• Are useful in managing mild to moderate pain of non-visceral origin.

NSAIDs Adverse Effects

• Most frequent adverse effects involve the GI tract and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain.
• May be taken with food, milk, or antacids if upset stomach occurs.
• Can cause severe stomach bleeding, especially in:
  • Patients aged 60 or older.
  • Those with a history of stomach ulcers or bleeding problems.
  • Those taking blood thinning or steroid drugs.
  • Those taking other drugs containing NSAIDs.
  • Those who consume 3 or more alcoholic drinks daily.

NSAIDs Cardiovascular Risk

• Are associated with increased risk of myocardial infarction, heart failure, hypertension, and stroke.
• Cardiovascular risk depends on dose and duration.
• Ibuprofen is associated with a significant increase in cardiovascular risk, while naproxen is considered the preferred, safer option.

Salicylates

• Inhibit prostaglandin synthesis from arachidonic acid by inhibiting both isoforms of the COX enzyme.
• Reduce the sensitivity of pain receptors to the initiation of pain impulses at sites of inflammation and trauma.
• Are absorbed by passive diffusion of the non-ionized drug in the stomach and small intestine.
• Are effective in treating mild to moderate pain from musculoskeletal conditions and fever.

Salicylates Pharmacokinetics

• Protein binding is concentration dependent.
• Are largely eliminated through the kidney.
• Urine pH determines the amount of unchanged drug that is eliminated.

Salicylates Clinical Use

• Aspirin is also indicated for prevention of thromboembolic events (e.g., myocardial infarction and stroke) in high-risk patients.
• The maximum analgesic dosage for self-medication with aspirin is 4 g/day.

Clinically Important Drug-Drug Interactions

• Acetaminophen and alcohol: avoid concurrent use if possible; minimize alcohol intake when using acetaminophen.
• Acetaminophen and warfarin: monitor INR for several weeks when acetaminophen is added or discontinued in patients on warfarin.
• Aspirin and valproic acid: avoid concurrent use; use naproxen instead of aspirin.
• Aspirin and NSAIDs: avoid concurrent use if possible; consider use of gastroprotective agents (e.g., PPIs).

Acetaminophen

• Can be hepatotoxic in doses exceeding 4 g/day, especially with chronic use.
• Patients with glucose-6-phosphate dehydrogenase deficiency should use caution when taking acetaminophen.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Relieve pain through central and peripheral inhibition of cyclooxygenase (COX) and subsequent inhibition of prostaglandin synthesis.
• Are rapidly absorbed from the GI tract with high bioavailability.
• Are extensively metabolized, mainly by glucuronidation, to inactive compounds in the liver.
• Are eliminated primarily through the kidneys.
• Have analgesic, antipyretic, and anti-inflammatory activity.
• Are useful in managing mild to moderate pain of non-visceral origin.

NSAIDs Adverse Effects

• Most frequent adverse effects involve the GI tract and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain.
• May be taken with food, milk, or antacids if upset stomach occurs.
• Can cause severe stomach bleeding, especially in:
  • Patients aged 60 or older.
  • Those with a history of stomach ulcers or bleeding problems.
  • Those taking blood thinning or steroid drugs.
  • Those taking other drugs containing NSAIDs.
  • Those who consume 3 or more alcoholic drinks daily.

NSAIDs Cardiovascular Risk

• Are associated with increased risk of myocardial infarction, heart failure, hypertension, and stroke.
• Cardiovascular risk depends on dose and duration.
• Ibuprofen is associated with a significant increase in cardiovascular risk, while naproxen is considered the preferred, safer option.

Salicylates

• Inhibit prostaglandin synthesis from arachidonic acid by inhibiting both isoforms of the COX enzyme.
• Reduce the sensitivity of pain receptors to the initiation of pain impulses at sites of inflammation and trauma.
• Are absorbed by passive diffusion of the non-ionized drug in the stomach and small intestine.
• Are effective in treating mild to moderate pain from musculoskeletal conditions and fever.

Salicylates Pharmacokinetics

• Protein binding is concentration dependent.
• Are largely eliminated through the kidney.
• Urine pH determines the amount of unchanged drug that is eliminated.

Salicylates Clinical Use

• Aspirin is also indicated for prevention of thromboembolic events (e.g., myocardial infarction and stroke) in high-risk patients.
• The maximum analgesic dosage for self-medication with aspirin is 4 g/day.

Clinically Important Drug-Drug Interactions

• Acetaminophen and alcohol: avoid concurrent use if possible; minimize alcohol intake when using acetaminophen.
• Acetaminophen and warfarin: monitor INR for several weeks when acetaminophen is added or discontinued in patients on warfarin.
• Aspirin and valproic acid: avoid concurrent use; use naproxen instead of aspirin.
• Aspirin and NSAIDs: avoid concurrent use if possible; consider use of gastroprotective agents (e.g., PPIs).

Acetaminophen

• Can be hepatotoxic in doses exceeding 4 g/day, especially with chronic use.
• Patients with glucose-6-phosphate dehydrogenase deficiency should use caution when taking acetaminophen.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Relieve pain through central and peripheral inhibition of cyclooxygenase (COX) and subsequent inhibition of prostaglandin synthesis.
• Are rapidly absorbed from the GI tract with high bioavailability.
• Are extensively metabolized, mainly by glucuronidation, to inactive compounds in the liver.
• Are eliminated primarily through the kidneys.
• Have analgesic, antipyretic, and anti-inflammatory activity.
• Are useful in managing mild to moderate pain of non-visceral origin.

NSAIDs Adverse Effects

• Most frequent adverse effects involve the GI tract and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain.
• May be taken with food, milk, or antacids if upset stomach occurs.
• Can cause severe stomach bleeding, especially in:
  • Patients aged 60 or older.
  • Those with a history of stomach ulcers or bleeding problems.
  • Those taking blood thinning or steroid drugs.
  • Those taking other drugs containing NSAIDs.
  • Those who consume 3 or more alcoholic drinks daily.

NSAIDs Cardiovascular Risk

• Are associated with increased risk of myocardial infarction, heart failure, hypertension, and stroke.
• Cardiovascular risk depends on dose and duration.
• Ibuprofen is associated with a significant increase in cardiovascular risk, while naproxen is considered the preferred, safer option.

Salicylates

• Inhibit prostaglandin synthesis from arachidonic acid by inhibiting both isoforms of the COX enzyme.
• Reduce the sensitivity of pain receptors to the initiation of pain impulses at sites of inflammation and trauma.
• Are absorbed by passive diffusion of the non-ionized drug in the stomach and small intestine.
• Are effective in treating mild to moderate pain from musculoskeletal conditions and fever.

Salicylates Pharmacokinetics

• Protein binding is concentration dependent.
• Are largely eliminated through the kidney.
• Urine pH determines the amount of unchanged drug that is eliminated.

Salicylates Clinical Use

• Aspirin is also indicated for prevention of thromboembolic events (e.g., myocardial infarction and stroke) in high-risk patients.
• The maximum analgesic dosage for self-medication with aspirin is 4 g/day.

Clinically Important Drug-Drug Interactions

• Acetaminophen and alcohol: avoid concurrent use if possible; minimize alcohol intake when using acetaminophen.
• Acetaminophen and warfarin: monitor INR for several weeks when acetaminophen is added or discontinued in patients on warfarin.
• Aspirin and valproic acid: avoid concurrent use; use naproxen instead of aspirin.
• Aspirin and NSAIDs: avoid concurrent use if possible; consider use of gastroprotective agents (e.g., PPIs).