Comprehensive NSAIDs and Acetaminophen: Pharmacology, Uses, and Side Effects

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

A class of drugs that are commonly used to relieve pain, reduce inflammation, and lower fever.

Aspirin

The prototype drug for NSAIDs, known for its analgesic, antipyretic, and anti-inflammatory properties.

Non-Selective COX Inhibitors

NSAIDs that inhibit both COX1 and COX2 enzymes, with a greater effect on COX1.

Irreversible COX Inhibitors

NSAIDs that permanently inhibit COX enzymes.

Reversible COX Inhibitors

NSAIDs that temporarily inhibit COX enzymes.

Diclofenac

An example of a non-selective COX inhibitor.

Piroxicam

An example of a non-selective COX inhibitor.

Mefenamic acid

An example of a non-selective COX inhibitor.

Sulindac

An indole derivative that acts as a non-selective COX inhibitor.

Ketorolac

An indole derivative that acts as a non-selective COX inhibitor.

Indomethacin

An indole derivative that acts as a non-selective COX inhibitor.

Aspirin/Acetyl Salicylic Acid (ASA)

A salicylic acid derivative that acts as a non-selective COX inhibitor.

Ibuprofen

A propionic acid derivative that acts as a non-selective COX inhibitor.

Flurbiprofen

A propionic acid derivative that acts as a non-selective COX inhibitor.

Ketoprofen

A propionic acid derivative that acts as a non-selective COX inhibitor.

Naproxen

A propionic acid derivative that acts as a non-selective COX inhibitor.

Selective COX2 Inhibitors (coxibs)

NSAIDs that preferentially inhibit COX2 over COX1.

Meloxicam

A preferential COX2 inhibitor.

Celecoxib

A selective COX2 inhibitor.

Etoricoxib

A selective COX2 inhibitor.

Rofecoxib

A selective COX2 inhibitor that has been withdrawn from the market.

Valdecoxib

A selective COX2 inhibitor that has been withdrawn from the market.

Acetaminophen

A drug that acts as an analgesic and antipyretic but is not a traditional NSAID.

PGI2

Prostaglandin I2 that acts on the hypothalamus to cause fever.

PGE2

Prostaglandin E2 that acts on the hypothalamus to cause fever.

COX1

Constitutive enzyme that is always present in most cells.

COX2

Inducible enzyme that is induced by inflammation in cells.

Ductus arteriosus

A fetal blood vessel that PGE1 maintains patency of during fetal life.

PGE1

Prostaglandin E1 that maintains the patency of the ductus arteriosus in fetal life.

PGF2α

Prostaglandin F2 alpha that initiates and stimulates labor.

LTC4

Leukotriene C4 that causes allergic bronchospasm.

LTD4

Leukotriene D4 that causes allergic bronchospasm.

LTE4

Leukotriene E4 that causes allergic bronchospasm.

NSAIDs

Non-steroidal anti-inflammatory drugs that inhibit COX enzyme pathway.

Analgesic

Pain relief effect caused by NSAIDs.

Anti-pyretic

Fever relief effect caused by NSAIDs.

Anti-inflammatory effects

Effects of NSAIDs that reduce inflammation.

GI side effects

Gastrointestinal side effects caused by NSAIDs.

Renal side effects

Renal side effects caused by NSAIDs.

TXA2

Thromboxane A2 that mediates platelet aggregation.

Prothrombotic events

Significant increase in events like heart attacks and strokes caused by COX2 inhibitors.

Urate excretion

Dose dependent effect of aspirin where low doses cause retention and high doses cause excretion.

GIT effects

Gastrointestinal effects of NSAIDs including irritation of GI mucosa and gastric erosion.

Hypersensitivity

Reactions in susceptible individuals due to inhibition of COX pathway.

Respiration effects

Dose dependent effects of NSAIDs on respiration, including stimulation and depression.

Parturition

Delay or retard labor by inhibition of PG synthesis.

Renal effects

Significant effects of NSAIDs in cases of CHF, hypovolemia, liver cirrhosis, and renal disease.

Analgesic nephropathy

Chronic consumption of NSAIDs leading to renal damage.

Prostaglandin Synthesis Inhibition

Effects of inhibiting prostaglandin synthesis that can have both beneficial and toxic effects.

Nephropathy

↓ renal blood flow, Na+ and H2O retention, renal papillary necrosis

Pharmacokinetics of NSAIDs

Weak acids; all except nabumetone are weak acids; nabumetone is a ketone converted to a weak acid to become active.

Absorption of NSAIDs

Absorbed from the stomach and small intestines.

Metabolism of NSAIDs

Most NSAIDs are metabolized by CYP3A and CYP2C, then undergo glucuronidation prior to renal elimination.

Protein Binding of NSAIDs

NSAIDs are highly protein bound, most >90%.

Kinetics of NSAIDs

First order to zero order kinetics from therapeutic to toxic dose.

Common Therapeutic Uses of NSAIDs

Pain: headache, injury, arthritis, backache, tooth ache, myalgia, joint pains; Fever: effective in fever of inflammatory/infectious origin; Inflammation: injury, arthritis, acute rheumatic fever, post surgical; Menstrual cramps (dysmenorrhea): pain and muscle contraction.

Aspirin Low Dose Use

Low dose → antiplatelet; prevent heart attacks and stroke.

Acetaminophen Uses

Pain: headache, injury (no effect on inflammation due to injury), osteoarthritis pain; Fever.

Less Common Therapeutic Uses of NSAIDs

Low dose aspirin reduces the risk of pre-eclampsia, familial colonic polyposis and colorectal cancer, Alzheimer's disease; high dose ibuprofen slows decline of lung function in cystic fibrosis; can help closure of Patent Ductus Arteriosus; treats niacin induced cutaneous flush and pruritus; can arrest premature labor (<32 weeks).

Methylsalicylate

Also known as oil of wintergreen; external use as counter irritant in balms.

Salicylic Acid

Keratolytic agent used for local treatment of corns/warts.

Sulfasalazine

Used in inflammatory bowel disease for local intestinal anti-inflammatory effects and in rheumatoid arthritis.

Adverse Effects of NSAIDs on GI

Nausea, vomiting, epigastric distress, gastric erosions and peptic ulcers, occult blood in stool.

Adverse Effects of NSAIDs on CNS

Dizziness, drowsiness, confusion, headache, tinnitus and rarely aseptic meningitis.

Adverse Effects of NSAIDs on CVS

Fluid retention, hypertension, edema, and rarely myocardial infarction and congestive heart failure (CHF).

Adverse Effects of NSAIDs on Blood

Aplastic anemia, thrombocytopenia, neutropenia - these are rare.

Adverse Effects of NSAIDs on Hepatic

↑ transaminases, liver failure (rare).

Adverse Effects of NSAIDs on Renal

Na+ and water retention, CRF, interstitial nephritis, papillary necrosis.

Hypersensitivity Reactions to NSAIDs

Rashes, pruritis, asthma, nasal polyps (Aspirin Exacerbated Respiratory Disease).

Hypertension due to NSAIDs

Prostaglandins produced by COX pathway cause vasodilation, increased renal perfusion, diuresis, natriuresis; NSAIDs can cause renal ischemia and renal failure, Na+ and H2O retention, worsening hypertension.

Black Box Warnings on NSAIDs

Warnings regarding serious cardiovascular and gastrointestinal risks.

Reye's Syndrome

Rare and fatal disorder seen in children treated with aspirin for flu and VZV, characterized by hepatic damage and encephalopathy.

Acute Salicylate Poisoning: Clinical Features

Includes vomiting, dehydration, electrolyte imbalance, restlessness, delirium, hallucinations, tinnitus, hyperventilation, respiratory alkalosis, hyperpyrexia, metabolic acidosis, convulsions, coma, and death due to CV collapse, respiratory/renal failure.

Acute Salicylate Poisoning: Treatment

Involves external cooling, IV fluids with Na+, K+, HCO3-, intense monitoring, gastric lavage, forced alkaline diuresis with NaHCO3, and hemodialysis.

TXA2 formation

Occurs via COX1.

PGI2 formation

Occurs via COX2 in platelets.

Aspirin mechanism of action

Irreversibly inhibits COX1/2 via covalent acetylation of a serine.

Low dose aspirin

(< 300 mg/day) primarily irreversibly inhibits COX1 on platelets, reducing clotting.

Aspirin prophylactic use

Used as an antiplatelet (anti-thrombogenic) drug.

Aspirin duration of action

Long duration (7-10 days) since new platelets must be formed.

Higher dose aspirin effect

At larger doses, COX selectivity is lost, but reduced clotting (anti-platelet) remains the net effect.

Bleeding risk with aspirin

Potential side effect when used at higher doses (e.g., anti-inflammatory doses) as it inhibits COX1 > COX2.

Co-administration of NSAIDs with Aspirin

Leads to loss of its anti-platelet/cardioprotective effects.

Other NSAIDs competition

May compete for binding sites on COX-1, preventing aspirin from reaching the serine molecule.

NSAIDs precautions

Should be stopped a week before elective surgery; prolongs bleeding time.

G6PD deficiency

Can cause hemolysis.

Pregnancy and NSAIDs

Risk if taken at or near term.

Peptic ulcer/GI bleeds

Contraindication for NSAIDs.

Chronic liver disease

Contraindication for NSAIDs.

Congestive heart failure

Contraindication for NSAIDs.

Diabetes

Precaution when using NSAIDs.

Aspirin in children

Should not be used in children suffering from chicken pox or influenza.

Acetaminophen mechanism of action

Inhibits PG synthesis when arachidonic acid levels are low; a weak inhibitor of COX1 and COX2 (COX2 > COX1).

Acetaminophen therapeutic uses

Effective analgesic for mild to moderate pain; minimal anti-inflammatory activity.

Reduces/relieves fever

A primary therapeutic use of acetaminophen.

In combination with opioids

Acetaminophen is used to decrease the opioid requirement.

In combination with NSAIDs

Acetaminophen is used to increase the effectiveness of NSAIDs.

Preferred analgesic for patients allergic to aspirin

Acetaminophen is recommended for patients who have an allergy to aspirin.

Preferred analgesic for patients with bronchial asthma

Acetaminophen is suitable for patients suffering from bronchial asthma.

Preferred analgesic for patients with bleeding disorders

Acetaminophen is safe for patients who have bleeding disorders.