Pharmacology: NSAIDs

• Inflammation is a protective response to tissue injury from trauma, chemicals, or microbes.
• The body uses inflammation to inactivate organisms, remove irritants, and prepare for tissue repair.
• Inflammation subsides when healing is complete, but inappropriate immune activation causes diseases like rheumatoid arthritis (RA).
• RA can lead to joint damage, disability, pain, and reduced quality of life.
• RA pharmacotherapy uses anti-inflammatory and immunosuppressive agents to reduce inflammation, pain, and slow disease progression.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

• NSAIDs are chemically different agents with antipyretic, analgesic, and anti-inflammatory properties.
• NSAIDs include derivatives of salicylic acid (aspirin), propionic acid (ibuprofen, fenoprofen, flurbiprofen, ketoprofen, naproxen), acetic acid (diclofenac, etodolac, indomethacin, tolmetin), enolic acid (meloxicam, piroxicam), fenamates (mefenamic acid), and the selective COX-2 inhibitor (celecoxib).
• They inhibit cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis.
• NSAID safety and efficacy depend on COX-1 or COX-2 enzyme selectivity.
• COX-2 inhibition leads to anti-inflammatory and analgesic effects.
• COX-1 inhibition can prevent cardiovascular events but also causes adverse effects.

Aspirin and Other NSAIDs

• Aspirin is rarely used as an anti-inflammatory due to needed high doses.
• Aspirin is utilized at low doses to prevent cardiovascular events like stroke and myocardial infarction (MI).
• Aspirin is an irreversible COX inhibitor, unlike other NSAIDs.

Mechanism of Action

• Aspirin irreversibly inactivates COX, while other NSAIDs are reversible inhibitors.
• NSAIDs have anti-inflammatory, analgesic, and antipyretic effects, but effectiveness varies.
• Anti-inflammatory actions: NSAIDs decrease prostaglandin formation, modulating inflammation.
• Analgesic action: NSAIDs decrease PGE2 synthesis, reducing pain sensation; COX-2 inhibition is responsible for this activity.
• Antipyretic action: NSAIDs lower body temperature in feverish patients by impeding PGE2 synthesis, increasing heat dissipation through vasodilation and sweating, but have no effect on normal body temperature.

Therapeutic Uses

• Anti-inflammatory and Analgesic Uses: NSAIDs treat RA and conditions needing analgesia, like headaches and muscle pain.
• Combining NSAIDs with opioids can treat malignancy pain, lead to an opioid-sparing effect and salicylate exhibits analgesic activity at lower doses.
• For example, two 325-mg aspirin tablets administered four times daily produce analgesia, whereas 12 to 20 tablets per day produce both analgesic and anti-inflammatory activity.
• Antipyretic Uses: Aspirin, ibuprofen, and naproxen can treat fever, however, avoid aspirin in patients under 19 with viral infections (chickenpox, influenza) due to the risk of Reye syndrome.
• Cardiovascular Applications: Aspirin inhibits COX-1-mediated TXA2 production, reducing vasoconstriction, platelet aggregation, and cardiovascular event risk.
• Low-dose aspirin (75-162 mg) is a prophylactic to reduce recurrent cardiovascular events.
• External Applications: Salicylic acid treats acne, methyl salicylate is a cutaneous counterirritant, and diclofenac is topical for osteoarthritis.

Pharmacokinetics of Aspirin and Other NSAIDs

• Most salicylates cross the BBB and placenta and are absorbed through the skin.
• Salicylate is secreted in urine and affects uric acid excretion; avoid aspirin in gout.
• Most NSAIDs are well absorbed, highly protein-bound, and metabolized in the liver to inactive metabolites; excretion is via urine.

Adverse Events

• Use NSAIDs at the lowest effective dose for the shortest time due to adverse effects.

• Gastrointestinal: common adverse effects include dyspepsia to bleeding.

• Production of prostacyclin (PGI2) inhibits gastric acid secretion, and PGE2 and PGF2a stimulate mucus synthesis.

• COX-1 inhibitors reduce beneficial PGs, increasing gastric acid secretion and GI bleeding.

• Agents with COX-1 selectivity increase GI event risk, take NSAIDs with food to diminish GI upset.

• Increased Risk of Bleeding (Antiplatelet Effect): Aspirin inhibits COX-1-mediated TXA2 formation and reduces platelet aggregation for 3-7 days.

• Platelet aggregation is the first step in thrombus formation, and antiplatelet effect results in prolonged bleeding time.

• Withhold aspirin for at least 1 week before surgery; NSAIDs other than aspirin are not utilized for their antiplatelet effect but can still prolong bleeding time.

• Concomitant NSAIDs and aspirin can prevent aspirin from binding to COX, avoid NSAIDs if possible.

• Renal Effects: NSAIDs prevent PGE2 and PGI2 synthesis, causing sodium and water retention and edema.

• Patients with heart failure or kidney disease are at high risk.

• NSAIDs can decrease antihypertensive medication effects and cause acute kidney injury in susceptible patients.

• Cardiac Effects: Aspirin has cardiovascular protection due to reduced TXA2 production; higher COX-2 selectivity increases cardiovascular event risk.

• All NSAIDs have boxed warnings for increased cardiovascular risk; avoid in patients with established cardiovascular disease.

• Naproxen may be the least harmful if NSAIDs are needed.

• Other Adverse Effects: NSAIDs inhibit PG synthesis but not leukotrienes, use with caution in asthma patients, inhibit prostaglandin synthesis can cause a shift toward leukotriene production and increase the risk of asthma exacerbations.

• CNS adverse events, such as headache and dizziness, may occur.

• Approximately 15% of patients taking aspirin experience hypersensitivity reactions.

• Severe allergy patients should avoid aspirin. including urticaria, bronchoconstriction, and angioedema.

• Drug Interactions: Salicylate is 80-90% protein bound and can be displaced, increasing free salicylate levels.

• Aspirin can displace other protein-bound drugs, e.g., warfarin or phenytoin, increasing their levels.

• Toxicity: Mild salicylate toxicity (salicylism) causes nausea, vomiting, hyperventilation, headache, confusion, and dizziness.

• Large salicylate doses cause restlessness, hallucinations, convulsions, coma, acidosis, and respiratory failure; 10 g can be fatal in children.

• Pregnancy: Only use NSAIDs if benefits outweigh risks; avoid in the third trimester due to the risk of premature closure of the ductus arteriosus.

Celecoxib

• A selective COX-2 inhibitor is more selective for COX-2 than COX-1 inhibition and the inhibition of COX-2 is reversible.

Therapeutic uses

• Treats RA and pain with similar efficacy to NSAIDs.

Pharmacokinetics

• Readily absorbed orally, metabolized in the liver, excreted in feces and urine.
• Has a half-life of about 11 hours; can be dosed once or twice daily.
• Reduce dosage with moderate hepatic impairment; avoid in patients with severe hepatic or renal disease.

Adverse effects

• Common effects include headache, dyspepsia, diarrhea, and abdominal pain.
• It is associated with less GI bleeding and dyspepsia than other NSAIDs, but this benefit is lost when aspirin is added.
• Patients at high risk of ulcers needing aspirin should avoid celecoxib but has a similar risk for cardiovascular events.
• Patients with anaphylactoid reactions to aspirin or nonselective NSAIDs may be at risk for similar effects.

Acetaminophen

• It inhibits PG synthesis in the CNS, leading to antipyretic and analgesic effects.
• It has less COX effect in peripheral tissues due to peripheral inactivation, so it is considered as having weak anti-inflammatory activity.
• It does not affect platelet function or increase bleeding time and is not considered an NSAID.

Therapeutic uses

• Treats fever and relieves pain.
• It is a choice for children with viral infections or chickenpox, due to Reye syndrome risk with aspirin.

Pharmacokinetics

• Rapidly absorbed and undergoes first-pass metabolism.
• It is conjugated in the liver to form inactive metabolites.
• A portion is hydroxylated to NAPQI, a reactive metabolite that reacts with sulfhydryl groups and causes liver damage; acetaminophen and its metabolites is excreted in urine.

Adverse effects

• Few adverse effects at normal doses, however, large doses deplete glutathione, and NAPQI reacts with hepatic proteins, resulting in hepatic necrosis.
• Patients with hepatic disease, viral hepatitis, or a history of alcoholism is at higher risk of acetaminophen-induced hepatotoxicity.
• N-acetylcysteine is an antidote in cases of overdose and should be avoided with severe hepatic impairment.

This lesson covers Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and their role in reducing inflammation, pain, and slowing disease progression, particularly in conditions like rheumatoid arthritis. It explores the different types of NSAIDs and their properties.