Aspirin Acetylsalicylic Acid

Slide 1 · Aspirin (Acetylsalicylic Acid)

Mechanisms of toxicity, gastric injury and platelet dysfunction

Clinicopathologic lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how aspirin suppresses cyclooxygenase-dependent mediators.

Trace respiratory and metabolic derangements in acute salicylate toxicity.

Recognize chronic salicylism, gastric injury and platelet dysfunction.

Integrate symptoms, morphology and mechanisms in clinical scenarios.

Slide 3 · A useful drug can also produce characteristic injury

Therapeutic effects

Pain and fever control

Anti-inflammatory action

Antiplatelet effect

Potential injury

Acute metabolic toxicity

Gastric mucosal damage

Bleeding tendency

Slide 4 · Salicylates: A long clinical history

Salicin-containing bark

1897: Acetylsalicylic acid

1899: Aspirin

Modern use and toxicity

Sequence is schematic; Individual clinical courses vary.

Slide 5 · Therapeutic actions and adverse consequences

Aspirin

Cyclooxygenase inhibition

↓ Prostaglandins / TxA₂

Benefit + tissue risk

Cyclooxygenase inhibition reduces prostaglandin synthesis.

Prostaglandins have inflammatory and protective roles.

Platelet thromboxane A₂ production is also inhibited.

Slide 6 · Where aspirin fits among therapeutic drug injuries

Direct drug action

COX acetylation

Prostaglandin depletion

Reduced platelet TxA₂

Systemic toxicity

Respiratory center stimulation

Mitochondrial disruption

Acid–base disturbance

Slide 7 · Two clinically distinct patterns

Feature

Acute toxicity

Chronic salicylism

Exposure

Overdose / toxic ingestion

Prolonged high daily intake

Core pathology

Acid–base and energy failure

CNS, gastric and platelet injury

Major concern

Neurologic deterioration

Erosion, hemorrhage, bleeding

Slide 8 · Exposure context matters

Children

Accidental ingestion highlighted

Potential for severe poisoning

Adults

Intentional overdose highlighted

Chronic pain/inflammation exposure also relevant

Slide 9 · Cyclooxygenase: The shared molecular target

Arachidonic acid pathway

COX-1 / COX-2

Prostaglandins + thromboxane

Physiologic effects

Aspirin irreversibly acetylates and inactivates cyclooxygenases.

COX-1 participates in homeostatic prostaglandin generation.

COX-2 is especially active in inflammatory responses, but the division is not absolute.

Slide 10 · COX inhibition has more than one consequence

Inflammation

↓ Pain- and fever-related PGs

Gastric mucosa

↓ Protective PGs

Platelets

↓ TxA₂ activation

Slide 11 · The therapeutic–toxic trade-off is mechanistic

COX acetylation

Altered mediator production

Organ-specific effects

Clinical benefit or harm

One enzyme system generates mediators serving different organs.

A single inhibitor can therefore modify inflammation, gastric defense and hemostasis.

Clinical evaluation should not treat these organ effects as unrelated events.

Slide 12 · Aspirin-associated toxicity pathways

Aspirin exposure

Acute: Acid–base effects

Gastric: Mucosal injury

Platelets: ↓ aggregation

Slide 13 · Acute salicylate poisoning: Mechanistic overview

Salicylate excess

Hyperventilation + impaired ATP production

Alkalosis + metabolic acidosis

CNS toxicity

Early stimulation of the medullary respiratory center causes hypocapnia.

Mitochondrial uncoupling and Krebs-cycle inhibition disrupt energy metabolism.

Acidosis increases the nonionized salicylate fraction reaching the CNS.

Slide 14 · Medullary stimulation occurs early

Salicylate exposure

Medullary respiratory drive ↑

Rate / depth ↑

CO₂ elimination ↑

Salicylate toxicity stimulates the respiratory center in the medulla.

Respirations increase in both rate and depth.

This effect precedes or coexists with later metabolic abnormalities.

Slide 15 · Hyperventilation reduces carbon dioxide

Respiratory drive ↑

Ventilation ↑

CO₂ “blown off”

Respiratory alkalosis

Increased alveolar ventilation expels CO₂ more rapidly.

A fall in CO₂ shifts the blood acid–base system toward alkalinity.

The source describes this initial consequence as respiratory alkalosis.

Slide 16 · Respiratory alkalosis is not the complete disorder

Respiratory component

Increased rate and depth

Excess CO₂ loss

Alkalinizing effect

Metabolic component

Impaired oxidative metabolism

Lactate accumulation

Acidifying effect

Slide 17 · A changing acid–base profile is expected

Medullary stimulation

CO₂ loss

Cellular energy failure

Acid accumulation

Sequence is schematic; Individual clinical courses vary.

Slide 18 · Mitochondrial uncoupling is central to toxicity

Salicylate excess

Oxidative phosphorylation uncoupled

Less efficient energy capture

Heat + energy deficit

Salicylates uncouple oxidative phosphorylation.

Energy capture from oxidative metabolism becomes inefficient.

This change helps explain increased heat generation and metabolic stress.

Slide 19 · Why uncoupling is a systemic problem

Coupled state

Oxidation

ATP generation

Efficient energy transfer

Uncoupled state

Oxidation persists

ATP generation inefficient

Heat / metabolic strain

Slide 20 · The Krebs cycle is also inhibited

Krebs-cycle inhibition

Reduced oxidative flux

Greater glycolytic dependence

Pyruvate / lactate burden

The source identifies Krebs-cycle inhibition during toxicity.

This further compromises aerobic energy metabolism.

The metabolic shift favors dependence on glycolytic pathways.

Slide 21 · Glycolysis becomes more important

Oxidative metabolism impaired

Glycolytic reliance ↑

Pyruvate ↑

Lactate ↑

With oxidative pathways disrupted, cells rely more heavily on glycolysis.

Pyruvate production and subsequent lactate accumulation increase.

This explains why metabolic acidosis is linked to energy derangement.

Slide 22 · Pyruvate and lactate accumulation

Glycolysis ↑

Pyruvate accumulates

Lactate accumulates

Metabolic acidosis

Accumulation of pyruvate and lactate.

These metabolites mark a shift away from efficient oxidative energy production.

The rising acid burden contributes to systemic metabolic acidosis.

Slide 23 · Hyperpyrexia follows disturbed energy coupling

Uncoupled oxidation

Energy dissipated as heat

Heat load ↑

Hyperpyrexia

Mitochondrial uncoupling changes how energy is released.

Heat generation increases rather than being efficiently conserved as ATP.

Severe temperature elevation is a pathophysiologic consequence in the source.

Slide 24 · Metabolic acidosis emerges from energy failure

Mitochondrial dysfunction

Glycolytic shift

Organic acid accumulation

Metabolic acidosis

Oxidative phosphorylation is uncoupled.

Krebs-cycle activity is inhibited.

Greater glycolytic reliance and lactate accumulation produce an acidifying burden.

Slide 25 · Two mechanisms point in opposite pH directions

Mechanism

Primary event

Acid–base direction

Respiratory

Excess CO₂ elimination

Alkalinizing

Metabolic

Pyruvate / lactate accumulation

Acidifying

Slide 26 · Acidemia alters salicylate distribution

Metabolic acidosis

Nonionized salicylate fraction ↑

Brain diffusion ↑

CNS manifestations

Metabolic acidosis increases the nonionized salicylate fraction.

Nonionized salicylate can diffuse into the brain more readily.

This directly links systemic acid–base derangement to neurologic toxicity.

Slide 27 · Why ionization matters for the brain

More ionized

Less lipid-permeant fraction

Less favored brain diffusion

More nonionized

Favored during acidosis

Greater brain entry

Slide 28 · Neurologic toxicity has a clinical spectrum

Nausea

CNS disturbance

Altered consciousness

Coma

Sequence is schematic; Individual clinical courses vary.

Slide 29 · Acute intoxication links organs through physiology

Respiratory

Hyperventilation / CO₂ loss

Metabolic

Heat + lactate generation

Neurologic

Nonionized drug enters CNS

Slide 30 · Acute toxicity: Integrated causal map

Salicylates

Medulla + mitochondria

Respiratory alkalosis / metabolic acidosis

CNS injury + heat

The alkalinizing and acidifying mechanisms arise from different targets.

The CNS effect is promoted by the acidifying component.

Uncoupling also explains hyperpyrexia, not merely acid production.

Slide 31 · Ingested mass does not equal a triage threshold

Potentially fatal ingestion of 2–4 g in children and 10–30 g in adults.

Survival after substantially larger amounts is also described.

These historical textbook ranges are not safe doses or stand-alone prognostic thresholds.

Slide 32 · Case: Early acute intoxication

Hypothetical patient with aspirin overdose develops rapid, deep breathing.

Which organ target explains the respiratory pattern?

What acid–base tendency follows increased CO₂ elimination?

Explain the mechanism before revealing the answer

Slide 33 · Case: Later metabolic deterioration

The same hypothetical patient develops severe temperature elevation and neurologic decline.

What two mitochondrial pathways are disrupted?

Why does acidosis worsen cerebral exposure to salicylate?

Explain the mechanism before revealing the answer

Slide 34 · Chronic salicylism is a prolonged-exposure syndrome

Exposure pattern

Repeated daily use

Long time course

High-dose setting

Affected systems

Central nervous system

Gastrointestinal tract

Platelet function

Slide 35 · Prolonged high-dose use shapes the risk

Chronic indication

Sustained high-dose aspirin

Multisystem adverse effects

Salicylism

Unlike single acute overdose, chronic salicylism reflects cumulative exposure.

The source associates the syndrome with daily ingestion of 3 g or more over long periods.

This is a descriptive source association—not a recommendation or safety cutoff.

Slide 36 · Headache and dizziness may be early clues

Headache is included in the reported chronic syndrome.

Dizziness adds a nonspecific neurologic symptom.

The exposure history gives these common symptoms diagnostic meaning.

Slide 37 · Tinnitus is a characteristic sensory clue

Subjective auditory symptom

Tinnitus

Ringing in the ears

Functional effect

Hearing impairment

May coexist with neurologic complaints

Slide 38 · Mental-status changes are part of salicylism

Prolonged exposure

Confusion

Drowsiness

Convulsions / coma

Mental confusion and drowsiness are described manifestations.

These signify clinically important CNS involvement.

Progression to convulsions or coma marks severe deterioration.

Slide 39 · Gastrointestinal symptoms may precede hemorrhage

Nausea, vomiting and diarrhea are included in chronic toxicity.

Aspirin-related gastric injury adds a structural source of morbidity.

Symptoms alone cannot establish the depth of mucosal injury.

Slide 40 · Chronic toxicity: Symptom clusters

Auditory

Tinnitus; Hearing change

Neurologic

Headache to altered consciousness

Gastrointestinal

Nausea; Vomiting; Diarrhea

Slide 41 · The gastric mucosa normally resists a hostile lumen

Intact mucosal defense

Mucus / bicarbonate shield

Surface epithelium intact

Mucosal blood flow + repair

Aspirin-impaired defense

Reduced mucus / HCO₃⁻

Surface erosion risk

Reduced repair and protection

Slide 42 · Prostaglandins sustain gastric protection

Gastric PGE₂ / PGI₂

Mucus + bicarbonate

Mucosal blood flow

Epithelial restitution

Slide 43 · Aspirin inhibits COX-dependent mucosal defense

Aspirin → COX inhibition

PGE₂ / PGI₂ ↓

Gastric defense ↓

Erosive injury risk ↑

Nonselective cyclooxygenase inhibition lowers gastroprotective prostaglandins.

Reduced prostaglandin action weakens mucus, bicarbonate and epithelial repair.

The result is increased vulnerability to acid and peptic injury.

Slide 44 · Gastropathy, gastritis and erosion are not synonymous

Term

Key tissue finding

Gastropathy

Epithelial injury; few inflammatory cells

Acute gastritis

Neutrophilic inflammation

Erosion

Superficial mucosal defect

Slide 45 · A superficial erosion can become clinically important

Defense weakened

Mucosal epithelial damage

Erosion

GI hemorrhage

The aspirin section emphasizes acute erosive gastritis as a common morphologic consequence.

Erosion exposes fragile tissue to luminal injury.

Bleeding can occur even before deep ulceration is present.

Slide 46 · Gastric ulceration represents deeper injury

Reduced protection

Erosive damage

Ulceration

Potential hemorrhage

Sustained or severe mucosal injury may progress to gastric ulceration.

The Robbins aspirin section identifies ulceration as a possible consequence.

Depth of injury and bleeding risk are not captured by symptom intensity alone.

Slide 47 · GI bleeding is a major morbidity mechanism

Gastric mucosal defect

Vascular disruption

Bleeding

Platelet impairment worsens loss

Erosive gastritis can produce gastrointestinal bleeding.

Gastric ulceration may compound blood loss.

Aspirin-associated platelet dysfunction can further aggravate hemorrhage.

Slide 48 · Primary hemostasis depends on platelet recruitment

Vessel injury

Platelet activation

TxA₂ generation

Platelet aggregation

Platelets adhere and become activated at sites of vascular injury.

Activated platelets release and generate mediators that recruit more platelets.

Thromboxane A₂ is a potent amplifier of platelet aggregation.

Slide 49 · TxA₂ depends on platelet cyclooxygenase

Platelet activation

COX-dependent TxA₂

Further aggregation

Aspirin: Irreversible COX blockade → TxA₂ falls

Slide 50 · Irreversible inhibition differentiates aspirin

Aspirin acetylates COX

Platelet TxA₂ ↓

Aggregation impaired

Bleeding tendency

Aspirin irreversibly inactivates platelet cyclooxygenase.

Platelet thromboxane A₂ synthesis is therefore persistently impaired.

This produces a platelet-function defect rather than direct deficiency of clotting factors.

Slide 51 · Petechiae reflect impaired primary hemostasis

Mechanism

TxA₂ production blocked

Platelet aggregation impaired

Clinical morphology

Petechial hemorrhages

Skin and visceral sites

Slide 52 · Why gastric hemorrhage can be disproportionately severe

Gastrointestinal hemorrhage

Erosion / ulcer: Injured surface

Platelet COX block: Poor aggregation

Slide 53 · Aspirin-related bleeding is an acquired platelet defect

Category

Dominant mechanism

Illustrative pattern

Aspirin-associated

Platelet function impaired

Petechiae / mucosal bleeding

Clotting-factor deficiency

Coagulation activity deficient

Deep bleeding / hematomas

Slide 54 · Aspirin and other COX inhibitors share gastric risk

Drug class

COX inhibition

Gastric protection

Aspirin / nonselective NSAIDs

COX-1 and COX-2

Risk of mucosal injury

Selective COX-2 inhibitors

Predominantly COX-2

Risk reduced in some settings, not abolished

Slide 55 · Aspirin sensitivity may present with respiratory symptoms

COX inhibition

PGE₂ ↓

Leukotriene effects ↑

Asthmatic attack

Uncommon aspirin-sensitive asthma with recurrent rhinitis and nasal polyps.

Even small amounts may provoke urticaria and asthmatic attacks in affected patients.

The implicated pathway involves COX inhibition, reduced PGE₂ and enhanced leukotriene-mediated effects.

Slide 56 · Additional adverse drug findings

Respiratory association

Salicylate-sensitive asthma

Distinct from medullary hyperventilation

Renal association

Tubulointerstitial injury

Papillary necrosis in ADR table

Slide 57 · Acute toxicity and chronic salicylism: A comparison

Domain

Acute toxicity

Chronic salicylism

Metabolism

Acid–base disturbance

Not defining in supplied section

Neuro

CNS entry with acidosis

Tinnitus, confusion, seizures

Stomach

Not the central focus

Erosions and ulcers

Hemostasis

Not the central focus

TxA₂-related bleeding

Slide 58 · Case: Chronic exposure with tinnitus

Hypothetical patient with persistent aspirin use for inflammatory pain develops tinnitus and dizziness.

Later they report dark gastrointestinal bleeding symptoms.

What two independent aspirin effects should be suspected?

Explain the mechanism before revealing the answer

Slide 59 · Case: Interpreting petechiae

A hypothetical aspirin-exposed patient develops petechiae without a documented coagulation-factor deficiency.

Which arm of hemostasis is most directly affected?

Which platelet mediator is decreased?

Explain the mechanism before revealing the answer

Slide 60 · A mechanism-first framework prevents missed connections

Exposure pattern

Dominant mechanism

Target organs

Clinicopathologic syndrome

Recognize exposure pattern before attaching a syndrome label.

Identify respiratory and metabolic disturbances as separate acute mechanisms.

In chronic exposure, assess auditory, neurologic, gastric and bleeding findings together.

Slide 61 · Review: Five relationships worth retaining

Aspirin irreversibly acetylates cyclooxygenase.

Medullary stimulation causes respiratory alkalosis.

Mitochondrial disruption causes hyperpyrexia and metabolic acidosis.

Acidosis favors nonionized salicylate brain entry.

Gastric injury and TxA₂ inhibition cooperate to increase bleeding.

Slide 62 · References and source scope

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026).

Primary: Ch. 9, “Aspirin (Acetylsalicylic Acid),” pp. 385–386.

Context: Ch. 3 (eicosanoids); Ch. 4 (primary hemostasis); Ch. 13 (platelet dysfunction); Ch. 17 (gastric injury); asthma section.