Salicylates

Salicylates are a class of medications and naturally derived compounds that are structurally related to salicylic acid. They are best known for their anti-inflammatory, analgesic, antipyretic, and antiplatelet properties. Salicylates encompass both nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin (acetylsalicylic acid) and other topical or systemic agents derived from or metabolized into salicylic acid. These compounds have played a foundational role in pharmacology and therapeutics, dating back to ancient medicinal practices using willow bark (Salix alba), which contains natural salicylates.

Salicylates act primarily through cyclooxygenase (COX) enzyme inhibition, reducing the synthesis of prostaglandins and thromboxanes. The spectrum of salicylate compounds includes oral, topical, and rectal formulations, used in conditions ranging from cardiovascular disease to dermatological disorders, and rheumatologic inflammation to colon cancer prevention.

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1. Classification of Salicylates

Salicylates can be classified into several subtypes based on their chemical structure, formulation, and clinical use.

A. Acetylated Salicylates

These include agents that possess an acetyl group on the salicylic acid backbone. This group has strong antiplatelet effects.

• Acetylsalicylic acid (ASA) – Aspirin

• Primary use: Antiplatelet, analgesic, anti-inflammatory, antipyretic

B. Non-acetylated Salicylates

These retain anti-inflammatory properties but lack irreversible antiplatelet activity.

• Sodium salicylate

• Choline magnesium trisalicylate

• Salsalate

• Diflunisal (a salicylate-like NSAID)

C. Topical Salicylates

Primarily used for dermatological and musculoskeletal conditions.

• Methyl salicylate – Counterirritant used in muscle rubs

• Salicylic acid – Keratolytic agent used for acne, warts, and psoriasis

• Trolamine salicylate – Topical analgesic for joint pain

D. Salicylate Prodrugs and Derivatives

These are metabolized into salicylic acid in the body.

• Mesalamine (5-aminosalicylic acid) – GI-targeted anti-inflammatory

• Sulfasalazine – Used in IBD and rheumatoid arthritis

• Olsalazine and balsalazide – Colon-specific prodrugs

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2. Mechanism of Action

Salicylates exert their pharmacologic effects primarily by inhibiting cyclooxygenase (COX-1 and COX-2) enzymes, which are responsible for converting arachidonic acid into prostaglandins and thromboxanes.

• Acetylsalicylic acid (aspirin) irreversibly acetylates serine residues on COX-1 and COX-2:

  • ↓ Prostaglandins → ↓ inflammation, pain, fever

  • ↓ Thromboxane A2 → ↓ platelet aggregation (antithrombotic)

• Non-acetylated salicylates reversibly inhibit COX activity and may have fewer GI side effects.

• Topical salicylic acid acts as a keratolytic by disrupting the intercellular cement of the stratum corneum, promoting desquamation.

• 5-ASA derivatives (mesalamine, sulfasalazine) inhibit NF-κB and proinflammatory cytokines in the gut mucosa.

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3. Pharmacokinetics

Property	Description
Absorption	Rapid GI absorption; some salicylates are enteric-coated for delayed release
Distribution	Widely distributed; crosses BBB and placenta; high protein binding (ASA ~90%)
Metabolism	Primarily hepatic conjugation (glycine, glucuronic acid pathways)
Excretion	Renal; pH-dependent urinary excretion increases in alkalinized urine
Half-life	Dose-dependent for aspirin; ~3 h (low dose), up to 15 h (high dose, saturation)

4. Clinical Uses and Indications

A. Cardiovascular Disease (Aspirin)

• Primary and secondary prevention of myocardial infarction and stroke

• Atherothrombosis prevention in patients with coronary artery disease

• Post-stenting and post-CABG antiplatelet therapy

• Standard dose: 75–325 mg/day (low dose for antiplatelet effect)

B. Pain, Inflammation, and Fever

• Headache, myalgia, arthritis

• Salsalate, choline magnesium trisalicylate for chronic inflammatory conditions (RA, OA)

• Methyl salicylate, trolamine salicylate for topical muscular pain relief

C. Dermatological Applications

• Salicylic acid:

  • Acne (2% topical)

  • Psoriasis and seborrheic dermatitis

  • Warts and calluses (40% patches)

D. Gastrointestinal Disorders

• 5-ASA derivatives (mesalamine, sulfasalazine):

  • Ulcerative colitis

  • Crohn’s disease

  • Proctitis

• Administered orally, rectally (suppository or enema), or as pH-dependent delayed-release tablets

E. Rheumatologic Diseases

• Salsalate, diflunisal, choline salicylate used in arthritis and musculoskeletal inflammation

• Less risk of gastric ulceration than traditional NSAIDs

F. Cancer Prevention (Investigational/Preventive)

• Long-term low-dose aspirin use associated with decreased incidence of:

  • Colorectal cancer

  • Gastrointestinal cancers

• Mechanism: COX-2 inhibition and anti-inflammatory effects on mucosal tissues

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5. Adverse Effects

Dose-Related Effects

Dose Range	Effects
<325 mg/day	Antiplatelet
325–3,000 mg/day	Antipyretic, analgesic
3,000–6,000 mg/day	Anti-inflammatory
>6,000 mg/day	Toxic effects: tinnitus, hyperventilation, metabolic acidosis

Common Adverse Effects

• Gastrointestinal: Gastritis, nausea, peptic ulcer, GI bleeding

• Hematologic: Bleeding, bruising

• Renal: Reduced renal perfusion, acute kidney injury

• Otic: Tinnitus (salicylism)

• CNS: Headache, dizziness

• Dermatologic: Contact dermatitis (topical use)

Severe or Life-Threatening

• Salicylate toxicity:

  • Tinnitus, vomiting, hyperventilation, respiratory alkalosis → metabolic acidosis

  • Hyperthermia, hypoglycemia, seizures, coma

• Reye’s syndrome:

  • Rare, fatal hepatic encephalopathy in children with viral illness treated with aspirin

• Allergy/anaphylaxis:

  • Bronchospasm in aspirin-exacerbated respiratory disease (AERD)

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6. Contraindications and Cautions

Contraindicated in	Reason
Children with viral illness	Risk of Reye’s syndrome
Active GI bleeding or peptic ulcer	Increased bleeding and mucosal injury
Hypersensitivity to NSAIDs or salicylates	Risk of anaphylaxis, bronchospasm
Pregnancy (3rd trimester)	Risk of premature closure of ductus arteriosus
Renal impairment	Risk of nephrotoxicity
Gout	May decrease uric acid excretion

7. Drug Interactions

Interacting Drug/Class	Outcome	Mechanism
Anticoagulants (warfarin, DOACs)	↑ Bleeding risk	Additive antiplatelet effect
NSAIDs	↑ GI risk	Synergistic COX inhibition
Methotrexate	↑ Toxicity	Competition for renal excretion
ACE inhibitors/diuretics	↓ Antihypertensive effect	Renal prostaglandin inhibition
Uricosurics (probenecid)	↓ Uric acid excretion	Interference with renal elimination
SSRIs	↑ GI bleeding risk	Additive antiplatelet effect

8. Therapeutic Monitoring and Toxicity Management

• Serum salicylate levels: Useful in overdose or chronic toxicity (>30 mg/dL concerning)

• Arterial blood gas (ABG): For metabolic acidosis evaluation

• Urine pH: Alkalinization enhances renal clearance (target pH > 7.5)

• Activated charcoal: Useful in early overdose

• Hemodialysis: Indicated in severe salicylate poisoning (levels >100 mg/dL or severe acidosis)

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9. Summary of Common Generic and Brand Names

Generic Name	Brand Names	Use
Acetylsalicylic acid	Aspirin, Ecotrin	Antiplatelet, analgesic, anti-inflammatory
Salicylic acid	Compound W, Stridex	Topical acne, wart, psoriasis treatment
Salsalate	Disalcid	Rheumatoid arthritis, osteoarthritis
Methyl salicylate	Bengay, Icy Hot	Topical analgesic
Mesalamine	Asacol, Pentasa, Lialda	Ulcerative colitis
Sulfasalazine	Azulfidine	IBD, rheumatoid arthritis
Diflunisal	Dolobid	Analgesia in OA, RA

10. Comparison with Other NSAIDs

Property	Aspirin (Salicylate)	Ibuprofen (NSAID)	Acetaminophen (Non-NSAID)
Anti-inflammatory	Yes	Yes	No
Antipyretic	Yes	Yes	Yes
Antiplatelet	Yes (irreversible)	Weak, reversible	No
GI toxicity	High	Moderate	Low
Renal toxicity	Moderate	Moderate	Low (unless overdose)