Note on aspirin

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I now have comprehensive information from Goodman & Gilman's, Goldman-Cecil Medicine, and Henry's Clinical Diagnosis. Here is a complete clinical note on aspirin:

Aspirin (Acetylsalicylic Acid) - Clinical Notes

1. Drug Class & Chemistry

Aspirin is a salicylate - acetylsalicylic acid (ASA). It is classified as a nonsteroidal anti-inflammatory drug (NSAID) and is unique among NSAIDs for its irreversible COX inhibition. It belongs to the carboxylic acid group of salicylates.

Goodman & Gilman's Pharmacological Basis of Therapeutics - p. 851

2. Mechanism of Action

Aspirin works by covalently acetylating the catalytic subunit of both COX-1 and COX-2, forming a permanent, irreversible bond. This blocks the conversion of arachidonic acid (AA) to prostaglandins, prostacyclin, and thromboxane A2 (TxA2).

Why irreversibility matters in platelets: Platelets are anucleate - they cannot synthesize new protein. Once COX-1 is acetylated, the inhibition lasts for the entire platelet lifespan (7-10 days). Platelet TxA2 formation is therefore suppressed cumulatively with repeated doses (as low as 30 mg/day), and full platelet function recovery takes 8-12 days after stopping aspirin.

Presystemic platelet inhibition: The unique sensitivity of platelets to low-dose aspirin arises from their inhibition in the portal circulation before aspirin is deacetylated to salicylate by first-pass hepatic metabolism. Salicylic acid itself has no acetylating capacity and is only a weak, reversible COX inhibitor.

COX isoform effects:

COX-1 inhibition - impairs platelet TxA2 (vasoconstriction + aggregation) and reduces gastric cytoprotective prostaglandins
COX-2 inhibition - anti-inflammatory; COX-2-derived products also regulate blood pressure and act as endogenous inhibitors of hemostasis
Goodman & Gilman's - pp. 831-832, 851

3. Pharmacokinetics (ADME)

Parameter	Detail
Absorption	Primarily small intestine; peak plasma levels in 1-2 hours. Enteric coating delays and reduces bioavailability by ~50%
Distribution	Widely distributed; crosses BBB and placenta. Salicylate 80-90% protein-bound (albumin); proportion bound falls at high concentrations
Metabolism	Rapidly deacetylated to salicylic acid by esterases in the gut wall, red cells, and liver. Metabolic products: salicyluric acid (glycine conjugate), phenolic glucuronide, acyl glucuronide
Excretion	Renal (salicylates + metabolites). Urinary pH-dependent: clearance is ~4x greater at pH 8 vs. pH 6 (alkalinization used in toxicity management)
Half-life	Aspirin: ~20 min. Salicylate: 2-3 h at antiplatelet doses; 12 h at anti-inflammatory doses; 15-30 h in overdose or toxicity

Half-life is dose-dependent - increases with dose due to saturation of hepatic conjugation pathways (zero-order kinetics at high doses).

Goodman & Gilman's - pp. 857-858; Henry's Clinical Diagnosis - p. XXX

4. Pharmacological Effects & Therapeutic Uses

A. Antiplatelet / Antithrombotic (Low Dose: 75-100 mg/day)

Irreversibly suppresses TxA2 - driven platelet aggregation and vasoconstriction
Secondary prevention of vascular events: reduces MI, stroke, and vascular death by ~20-25% in high-risk patients; reduces non-fatal MI/stroke by ~1/3
Primary prevention: benefit-to-risk ratio is favorable only when 10-year ASCVD risk ≥ 10%; NOT recommended for primary prevention in adults over 70 due to bleeding risk
ACS/PCI: aspirin is a core component of dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor
CABG: recommended postoperatively; dual antiplatelet after off-pump CABG
Peripheral artery disease: aspirin 75-325 mg/day or clopidogrel 75 mg/day

B. Analgesic / Antipyretic (Standard Dose: 325-650 mg q4-6h; max 4 g/day)

Effective for fever, headache, neuralgia, myalgia, arthralgia
Antipyretic mechanism: COX inhibition reduces prostaglandin E2 (PGE2) synthesis in the hypothalamus
Does NOT blunt circadian temperature variation or exercise-induced temperature rise

C. Anti-inflammatory (High Dose: 3-5 g/day)

Used in rheumatoid arthritis, juvenile RA, other rheumatic diseases
Target plasma salicylate: 150-300 µg/mL for anti-inflammatory effect
Significant adverse effects seen above 300 µg/mL

D. Other Uses

Colorectal cancer prevention: aspirin 81 mg daily reduces likelihood of developing colorectal cancer (long-term low-dose)
Systemic mastocytosis: may help control flushing/hypotension mediated by PGD2 (use cautiously after antihistamine cover, as NSAIDs can cause mast cell degranulation)
Niacin-induced flushing: aspirin pretreatment blocks prostaglandin-mediated flushing from niacin
Goldman-Cecil Medicine - p. 835; Goodman & Gilman's - pp. 851-852

5. Adverse Effects

System	Effect
GI	Principal adverse effect: GI bleeding (especially upper GI). Risk lower with 75-100 mg vs. 325 mg. Higher risk with prior acid-peptic disease, coagulopathy, renal/liver disease, or uncontrolled hypertension
Haematologic	Prolonged bleeding time; increased risk of intracranial bleeding (~2-fold increase even at low doses)
CNS/Auditory	Tinnitus, muffled hearing, fullness in ears (classic signs of chronic toxicity/salicylism). In children/elderly with hearing loss, hyperventilation may be the only sign
Renal	Reduced GFR; sodium and water retention; hyperkalemia (especially combined with ACE inhibitors)
Hepatic	Hepatotoxicity (rare); associated with Reye syndrome in children
Respiratory	Aspirin-exacerbated respiratory disease (AERD): bronchoconstriction in susceptible individuals (COX-1 inhibition shifts AA toward leukotriene synthesis)
Hypersensitivity	Urticaria, angioedema; true anaphylaxis is rare

Goldman-Cecil Medicine - p. 835 (adverse effects section); Henry's Clinical Diagnosis - pp. 2401-2413

6. Salicylate Toxicity / Overdose

Monitoring plasma levels:

Analgesic/antipyretic doses: salicylate < 60 µg/mL
Anti-inflammatory: 150-300 µg/mL
Toxic: > 300 µg/mL

Acid-base disturbance pattern (classic triad in adults):

Early: respiratory alkalosis (salicylate directly stimulates central respiratory centers → hyperventilation → CO2 washout)
Later: metabolic acidosis (salicylate uncouples oxidative phosphorylation → lactic acid; blocks Krebs cycle intermediates)
Net picture: mixed respiratory alkalosis + metabolic acidosis (or pure metabolic acidosis in severe cases)

In children: metabolic acidosis predominates early; respiratory alkalosis may be absent.

Management:

Urinary alkalinization with sodium bicarbonate - markedly increases salicylate excretion (clearance ~4x greater at pH 8 vs. pH 6)
Hemodialysis/hemofiltration in severe cases (effectively removes salicylic acid)
Salicylate toxicity is among the most common preventable poisoning deaths
Goodman & Gilman's - p. 858; Henry's Clinical Diagnosis - p. 2409

7. Contraindications

Contraindication	Reason
Children/young adults < 20 years with viral fever	Reye syndrome risk - acute encephalopathy + hepatic failure + fatty infiltration. Aspirin use in children has declined dramatically, and so has Reye syndrome incidence
Active GI bleeding / peptic ulcer disease	Worsens bleeding
Severe renal or hepatic disease	Impaired elimination; increased toxicity
Hypersensitivity to aspirin	AERD, anaphylaxis
Third trimester of pregnancy	Premature closure of ductus arteriosus (via COX inhibition); delayed labour; increased maternal/neonatal bleeding

Acetaminophen and ibuprofen are the agents of choice for antipyresis in children (neither is implicated in Reye syndrome).

Goodman & Gilman's - p. 855 (Reye Syndrome section)

8. Drug Interactions

Drug	Interaction
Ibuprofen / naproxen	Prior platelet COX-1 occupancy by these NSAIDs blocks aspirin's acetylation of Ser529, preventing irreversible platelet inhibition and undermining cardioprotective effect
Warfarin	NSAIDs augment bleeding risk by (a) impairing platelet function and (b) some NSAIDs inhibit warfarin metabolism - increasing warfarin levels; concurrent use should be avoided
ACE inhibitors	Aspirin may attenuate antihypertensive effect (blocks vasodilator PG production); combination can cause marked hyperkalemia, especially in elderly and those with diabetes or CKD
Corticosteroids / SSRIs	Increase frequency/severity of GI adverse effects when combined with NSAIDs
Probenecid	Competes for the same renal tubular transport system; both drugs at full doses mutually block uricosuric effects

Goodman & Gilman's - pp. 855, 858-859

9. Aspirin Resistance

Some patients on aspirin still have detectable TxA2-dependent platelet activity. One mechanism is "pseudo-resistance" due to enteric-coated aspirin - delayed and erratic absorption reduces consistent platelet COX-1 suppression. True pharmacodynamic resistance (failure of COX-1 acetylation at adequate plasma levels) also exists and is associated with increased thrombotic risk.

10. Dose Summary

Indication	Dose
Antiplatelet (primary prevention if indicated)	75-100 mg/day
Antiplatelet (ACS, secondary prevention)	75-325 mg/day
Analgesic / antipyretic (adults)	325-650 mg q4-6h; max 4 g/day
Rheumatoid arthritis	500 mg q4-6h or 650 mg q4h or 1 g q4-6h
Juvenile RA (children)	~3.5 g/day (avoid in viral fever - Reye syndrome risk)
Anti-inflammatory target plasma level	150-300 µg/mL

Sources:

Goodman & Gilman's Pharmacological Basis of Therapeutics (Irreversible COX Inhibition, Cardioprotection, Reye Syndrome, Drug Interactions chapters)
Goldman-Cecil Medicine (Aspirin section, Antiplatelet Agents)
Henry's Clinical Diagnosis and Management by Laboratory Methods (Aspirin pharmacology, toxicology)
Rockwood and Green's Fractures in Adults (Thromboprophylaxis pharmacology table)

I'm a bpt student no need to give in MBBS level

Got it! Here's a simplified, BPT-level note on Aspirin:

Aspirin - Notes for BPT Students

What is Aspirin?

Generic name: Acetylsalicylic Acid (ASA)
Class: NSAID (Non-Steroidal Anti-Inflammatory Drug)
Available as: Tablets (75 mg, 325 mg, 650 mg)

Mechanism of Action (Simple)

Aspirin blocks COX enzymes (COX-1 and COX-2)
This reduces production of prostaglandins (chemicals that cause pain, fever, inflammation)
It also blocks Thromboxane A2 in platelets → prevents blood clot formation
Its COX inhibition is irreversible (unlike other NSAIDs)

Uses (Clinically Relevant for Physio)

Use	Dose
Pain relief (headache, musculoskeletal)	325-650 mg
Fever	325-650 mg
Anti-inflammatory (arthritis)	Higher doses
Prevent heart attacks/strokes (antiplatelet)	75-150 mg/day

Common Side Effects (Know for Clinical Practice)

GI irritation - nausea, gastric pain, ulcers, bleeding
Tinnitus (ringing in ears) - sign of too much aspirin
Increased bleeding time
Allergic reactions in some patients

Important Points for Physio Practice

Patients on aspirin bleed more - be aware before any soft tissue work or invasive procedures
Do not stop aspirin before physiotherapy sessions without consulting the treating doctor (especially cardiac patients)
Aspirin can cause GI discomfort - advise patients to take it with food
NOT given to children under 16 years with viral fever (risk of Reye syndrome - liver and brain damage)

Contraindications (Avoid in)

Children with fever/viral illness
Active peptic ulcer / GI bleeding
Aspirin allergy or asthma triggered by aspirin
Last trimester of pregnancy

Drug Interactions (Basic)

Ibuprofen - reduces aspirin's antiplatelet effect (don't take together)
Warfarin - increases bleeding risk
Avoid combining with other NSAIDs

Key takeaway for BPT: Aspirin is commonly used by your patients for pain, arthritis, or heart conditions. Know its GI side effects, bleeding risk, and the fact that it should not be stopped abruptly in cardiac patients without medical advice.

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