Injury by Therapeutic Drugs Adverse Drug Reactions

Slide 1 · Injury by Therapeutic Drugs (Adverse Drug Reactions)

Pathologic patterns, mechanisms, and clinicopathologic correlations

General pathology • clinicopathologic interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · What should you be able to explain?

Define an adverse drug reaction and distinguish it from overdose toxicity.

Contrast direct drug actions with immune-mediated hypersensitivity.

Recognize organ injury patterns and representative causal drugs.

Link a medication history to morphology without assuming causation.

Slide 3 · ADRs occur at prescribed drug doses

UNWANTED EFFECT DURING THERAPEUTIC USE

An adverse drug reaction is an undesired effect occurring when a medication is taken at its prescribed dose.

This definition makes the exposure context essential to labeling an event an ADR.

An intentional or accidental overdose can also cause drug injury, but is a distinct exposure circumstance.

Slide 4 · Therapeutic benefit and injury coexist

Therapeutic intent

Prevent disease or control symptoms

The same drug has a desired pharmacologic effect

Treatment benefit may justify some risk

Undesired consequence

Unintended tissue or functional injury

Severity ranges from mild to life-threatening

Risk–benefit judgment depends on context

Adverse does not mean the medication was necessarily prescribed incorrectly.

Slide 5 · Exposure context changes interpretation

Therapeutic dosing

Excessive dosing

Reaction arises during prescribed use

Toxicity follows drug amounts beyond prescribed use

The event may be called an ADR

Classify as overdose / poisoning when appropriate

Example: minocycline pigmentation

Example: acetaminophen overdose injury

The same drug can cause different injuries under different exposure conditions.

Slide 6 · Most ADRs are not life-threatening

ADRs are common in clinical practice.

Most are not life-threatening; A minority lead to major organ injury or death.

Drug-induced pathology spans skin, blood, heart, kidney, lung, liver, and nervous system.

The severity of an outcome cannot be inferred from the drug name alone.

Slide 7 · ADRs occur beyond the hospital

Ambulatory care

Medication exposure occurs in outpatient settings

New or persistent symptoms may represent a treatment effect

Long-term care

Nursing-home settings

Medication-related injury must remain in the differential

A medication review matters in every care setting.

Slide 8 · Age over 65 increases ADR susceptibility

HOST SUSCEPTIBILITY

People older than 65 years as more likely to experience ADRs.

Age is a risk marker, not a diagnostic test for drug causation.

The clinical implication is heightened attention to new findings after medication exposure.

Slide 9 · Two major routes to drug injury

Therapeutic drug exposure

Direct drug actions or immune response

Cellular / tissue change

Clinical ADR

Conceptual model: Injury mechanism precedes the observed lesion.

Slide 10 · Direct drug effects are organ-specific

Mechanism

An effect of the medication or its metabolite

May manifest as functional disturbance or tissue injury

Examples

Anticoagulants → bleeding

Anthracyclines → cardiomyopathy

Aminoglycosides → tubular necrosis

A plausible pharmacologic mechanism strengthens—but does not establish—attribution.

Slide 11 · Immune-mediated reactions have varied targets

Drug exposure

Hypersensitivity response

Skin / blood / systemic involvement

Manifest clinical syndrome

The immune pathway can resemble primary immunologic disease.

Slide 12 · Direct injury versus hypersensitivity

Dimension

Direct drug action

Hypersensitivity

Dominant concept

Toxic or pharmacologic action

Immune-mediated response

Representative presentation

Drug-associated bleeding

Drug-associated rash

Other examples

Cardiac or renal toxicity

Drug-induced lupus-like disease

Pathology question

Which organ is directly injured?

Could an immune disorder be mimicked?

Slide 13 · Potent treatments may carry accepted risks

RISK–BENEFIT CONTEXT

Antineoplastic agents are cited as medications with substantial adverse effects.

Such effects may be considered acceptable risks in the context of treatment benefit.

The decision depends on the purpose of treatment and expected consequences—not on morphology alone.

Slide 14 · Map adverse reactions by target tissue

Tissue compartment

Representative injury

Blood / marrow

Cytopenias; hemolytic anemia

Skin

Inflammatory eruption or pigment change

Heart / kidney

Arrhythmia; cardiomyopathy; nephritis

Lung / liver

Pneumonitis; fibrosis; hepatitis; cholestasis

Systemic / CNS

Anaphylaxis; lupus-like syndrome; neurologic effects

Slide 15 · Blood-cell injury spans several lineages

White cells

Granulocytopenia

Red cells

Hemolytic anemia

Platelets

Thrombocytopenia

Distinguish lineage-specific destruction from broader marrow injury.

Slide 16 · Granulocytopenia is a drug-associated pattern

Granulocytopenia appears among the marrow and blood-cell reactions listed by Robbins.

It indicates a marked reduction in circulating granulocytes.

Antineoplastic drugs and chloramphenicol are listed among the major agents for marrow suppression patterns.

Slide 17 · Aplastic anemia and pancytopenia implicate marrow

Aplastic anemia

A marrow-failure syndrome

The primary abnormality involves hematopoietic production

Pancytopenia

Reduction across major blood-cell lineages

A descriptive peripheral-blood finding

These labels are related but not interchangeable.

Slide 18 · Antineoplastic drugs can suppress hematopoiesis

Potent antineoplastic therapy

Injury to hematopoietic compartment

One or more cytopenias

Clinical consequences

Framework linking a potent treatment class to blood-cell deficits.

Slide 19 · Hemolytic anemia reflects red-cell loss

Hemolytic anemia as a possible drug-related blood disorder.

Penicillin, methyldopa, and quinidine appear among the associated drug examples.

Drug-induced hemolysis is a different pathologic pathway from generalized marrow failure.

Slide 20 · Immune thrombocytopenia may be drug-induced

Thrombocytopenia

Reduced platelet number

Drug-induced immune thrombocytopenia is identified

Heparin is among listed drug associations

Anticoagulant-associated bleeding

Impaired coagulation during intended therapy

Warfarin and dabigatran are listed

Platelet loss is not required

Low platelets and anticoagulant hemorrhage are distinct mechanisms.

Slide 21 · Different mechanisms can produce bleeding

Medication exposure

Platelet reduction or coagulation inhibition

Impaired hemostasis

Hemorrhagic manifestation

The observed event is the endpoint; Identify the relevant hemostatic defect.

Slide 22 · Cutaneous ADRs have diverse morphologies

Cutaneous patterns

Additional skin findings

Urticaria

Petechiae

Macules and papules

Exfoliative dermatitis

Vesicles

Fixed drug eruptions

—

Abnormal pigmentation

Pattern recognition identifies the lesion; Medication linkage requires history.

Slide 23 · Urticaria, macules, and papules are common clues

Robbins specifically lists urticaria and maculopapular lesions among cutaneous ADRs.

Such eruptions are compatible with—but not specific for—drug-related hypersensitivity.

The key pathologic distinction is an inflammatory reaction rather than pigment accumulation.

Slide 24 · Vesicles and exfoliation expand the skin spectrum

The cutaneous list includes vesicular lesions and exfoliative dermatitis.

Petechiae are another named manifestation; Not every drug eruption has the same underlying process.

A description of the morphologic pattern should precede a claim about the culprit drug.

Slide 25 · Pigmentation is not necessarily inflammation

Inflammatory eruption

Urticaria, papules, or vesicles

Often considered in hypersensitivity

Drug-pigment deposition

Abnormal skin coloration

May reflect retained drug-related material

The two mechanisms suggest different morphologic questions.

Slide 26 · Minocycline can discolor the skin

MINOCYCLINE-ASSOCIATED PIGMENTATION

Diffuse blue-gray forearm pigmentation following minocycline use.

The pigment is associated with an oxidized metabolite of this antibiotic.

The example shows that an ADR may be visible as a deposition process rather than an acute inflammatory lesion.

Slide 27 · Minocycline pigmentation localizes to the dermis

Schematic skin cross-section

Epidermis

Dermis

Deposited pigment particles

The published example shows drug metabolite, iron, and melanin pigment particles within dermis.

Dermal deposition explains why the clinical change appears as persistent skin coloration.

The drawing is an original schematic, not the textbook photomicrograph.

Slide 28 · The offender list for skin reactions is broad

Examples emphasized in Robbins

Relevant cutaneous outcome

Antineoplastic drugs

Multiple eruption patterns

Sulfonamides

Drug-related skin eruptions

Hydantoins

Drug-related skin eruptions

Various antibiotics

Drug-related skin eruptions

These offender lists show associations rather than establish individual causation.

Slide 29 · Drug-induced lupus can imitate autoimmunity

Clinical-pathologic mimic

Drug reaction resembling systemic lupus erythematosus

An immune-mediated pattern is possible

Associated agents

Hydralazine

Procainamide

Consider drug exposure when a lupus-like syndrome is encountered.

Slide 30 · Anaphylaxis is a systemic drug reaction

Medication exposure

Hypersensitivity response

Systemic anaphylaxis

Potentially severe outcome

Penicillin is a representative drug listed for anaphylaxis.

Slide 31 · Cardiac ADRs affect rhythm or muscle

Arrhythmia

Electrical/rhythm disturbance

Digoxin, theophylline, hydantoins

Cardiomyopathy

Myocardial tissue dysfunction

Doxorubicin, daunorubicin

Both are “cardiac” outcomes, but they are not the same lesion.

Slide 32 · Drug-related arrhythmias

Theophylline, hydantoins, and digoxin are listed as major examples.

An arrhythmia is a functional electrical disturbance; It does not by itself prove structural myocardial injury.

Medication association and the rhythm phenotype should be assessed separately.

Slide 33 · Anthracyclines are associated with cardiomyopathy

MYOCARDIAL TOXICITY

Doxorubicin and daunorubicin are listed as agents associated with cardiomyopathy.

The affected structure is the myocardium rather than primarily the cardiac conduction pattern.

This example illustrates a clinically important adverse effect of potent antineoplastic therapy.

Slide 34 · Drug-induced renal injury has three patterns

Glomerulus

Glomerulonephritis

Tubules

Acute tubular necrosis

Tubulointerstitium / papilla

Tubulointerstitial disease with papillary necrosis

Identify the compartment before selecting a likely drug association.

Slide 35 · Penicillamine is associated with glomerulonephritis

Penicillamine among agents associated with glomerulonephritis.

The glomerular compartment is the named target of injury.

Differentiate glomerular involvement from tubular necrosis or papillary disease.

Slide 36 · Acute tubular necrosis has a drug differential

Renal lesion

Offending drugs listed

Acute tubular necrosis

Aminoglycoside antibiotics

Acute tubular necrosis

Cyclosporin

Acute tubular necrosis

Amphotericin B

Three distinct therapies converge on a tubular injury pattern.

Slide 37 · Papillary necrosis is another renal drug lesion

Lesion

Tubulointerstitial disease

Associated papillary necrosis

Representative agents

Phenacetin

Salicylates

Papillary injury is not synonymous with acute tubular necrosis.

Slide 38 · Pulmonary drug injury has three presentations

Airways

Asthma

Acute lung tissue

Pneumonitis

Interstitial compartment

Fibrosis

The respiratory presentation is not a single uniform toxic syndrome.

Slide 39 · Salicylates can precipitate asthma

Salicylates are listed as agents associated with asthma.

The dominant manifestation is an airway disorder rather than fibrosis.

A respiratory symptom during therapy cannot automatically be classified as an infectious pneumonitis.

Slide 40 · Nitrofurantoin is linked to acute pneumonitis

Drug association

Nitrofurantoin

Named as an acute pneumonitis offender

Diagnostic distinction

Acute lung inflammation pattern

Different from the chronic interstitial fibrosis category

One drug appears in more than one respiratory injury category.

Slide 41 · Several drugs are linked to pulmonary fibrosis

Pulmonary pattern

Drugs listed

Interstitial fibrosis

Busulfan

Interstitial fibrosis

Nitrofurantoin

Interstitial fibrosis

Bleomycin

A fibrotic interstitial lesion has a medication-related differential.

Slide 42 · Hepatic ADRs show three injury categories

Fat accumulation

Fatty change

Hepatocytes

Diffuse hepatocellular damage

Bile flow

Cholestasis

The dominant tissue reaction helps organize causal-drug possibilities.

Slide 43 · Tetracycline can produce hepatic fatty change

Fatty change is one of the hepatic morphologic responses listed by Robbins.

Tetracycline is one drug associated with this hepatic pattern.

Steatosis should not be equated with diffuse hepatocellular damage or cholestasis.

Slide 44 · Diffuse hepatocellular damage has several causes

Pathologic pattern

Representative drug

Diffuse hepatocellular damage

Halothane

Diffuse hepatocellular damage

Isoniazid

Diffuse hepatocellular damage

Acetaminophen

A shared injury category does not imply identical mechanisms or exposure contexts.

Slide 45 · Cholestasis is a distinct hepatic drug pattern

Drug associations

Named hepatic outcome

Chlorpromazine

Cholestasis

Estrogens

Cholestasis

Contraceptive agents

Cholestasis

A drug may disturb bile handling without the dominant morphology being steatosis.

Slide 46 · The hepatic lesion directs the differential

Parenchymal injury

Fatty change or hepatocellular damage

Consider tetracycline, isoniazid, halothane, acetaminophen

Biliary-pattern injury

Cholestasis

Consider chlorpromazine or hormonal agents

Describe the lesion pattern before selecting the most plausible medication.

Slide 47 · Neurologic effects can be sensory or motor

Neurologic manifestation

Medication example

Tinnitus; dizziness

Salicylates

Acute dystonic reactions

Phenothiazine antipsychotics

Parkinsonian syndrome

Phenothiazine antipsychotics

Respiratory depression

Sedatives

Slide 48 · Phenothiazines can cause extrapyramidal syndromes

Acute dystonic reaction

Abnormal movement / sustained muscle contraction

Named adverse reaction

Parkinsonian syndrome

Drug-associated parkinsonian motor phenotype

Named adverse reaction

Neither clinical motor syndrome should be mistaken for a tissue-necrosis pattern.

Slide 49 · Sedatives can depress respiration

Sedative exposure

Depression of respiratory drive

Respiratory depression

Potentially serious clinical injury

A functional disturbance can be life-threatening without a specific biopsy lesion.

Slide 50 · Anticoagulants expose a therapeutic trade-off

Prevention of thrombosis / embolism

Inhibition of coagulation

Reduced thrombotic potential

Increased bleeding susceptibility

Anticoagulant-associated bleeding is explicitly discussed by Robbins.

Slide 51 · Warfarin and dabigatran are bleeding examples

Warfarin

Vitamin K antagonist

Food and drug interactions complicate therapy

Regular blood testing is described

Dabigatran

Direct thrombin inhibitor

Included among DOACs

Bleeding remains a treatment-related risk

Both are therapies for thrombosis prevention; Both can produce serious bleeding.

Slide 52 · Hormonal treatments illustrate population risk

Therapy group

Adverse effect emphasized in Robbins

Menopausal hormone therapy

Thromboembolism and stroke risk vary with regimen and clinical context

Oral contraceptives

Venous thromboembolism; association with hepatic adenoma

Hormonal agents generally

Some agents are associated with hepatic cholestasis

Risk varies by drug formulation and patient context; Avoid treating all formulations as identical.

Slide 53 · Overdose toxicity is a useful contrast—not an ADR

Prescribed-dose ADR

By definition occurs at the prescribed dose

Minocycline pigmentation and drug rashes illustrate the concept

Drug overdose injury

Excessive exposure is the defining circumstance

Acetaminophen and aspirin illustrate major toxic injury

Use exposure context precisely when teaching pharmacotoxicology.

Slide 54 · Acetaminophen toxicity explains reactive metabolites

Acetaminophen

CYP2E1 pathway

Reactive NAPQI

Hepatocellular injury

At ordinary doses, the larger share undergoes detoxification; Overdose increases reactive-metabolite burden.

Slide 55 · Acetaminophen injury targets centrilobular hepatocytes

Excess NAPQI causes covalent protein binding and mitochondrial injury.

Glutathione depletion increases susceptibility to oxidant damage.

The characteristic injury is centrilobular hepatocellular necrosis, which can progress to liver failure.

This exemplifies overdose toxicology, not an automatically presumed prescribed-dose ADR.

Slide 56 · Aspirin toxicity is a distinct exposure scenario

Excess salicylate

Early respiratory stimulation

Later metabolic derangement

Possible CNS toxicity

An early respiratory alkalosis followed by metabolic acidosis.

Slide 57 · Chronic aspirin exposure can cause bleeding

Gastric injury

Acute erosive gastritis

Possible gastric ulceration and GI bleeding

Hemostatic effect

Irreversible platelet cyclooxygenase inhibition

Reduced thromboxane A₂–dependent aggregation

Mucosal injury and defective platelet function can amplify bleeding.

Slide 58 · Case: Delayed blue-gray skin discoloration

A patient receiving prolonged minocycline therapy develops diffuse blue-gray pigmentation on the forearm.

Which tissue-level finding supports the medication association?

Interpretation

Pigment particles containing drug metabolite, iron, and melanin in the dermis; This is a deposition-type ADR.

Slide 59 · Case: Cytopenias after potent treatment

A person undergoing antineoplastic therapy develops simultaneous reductions in multiple blood-cell lineages.

Which hematologic reaction category best explains this finding?

Interpretation

Pancytopenia / marrow suppression; Antineoplastic agents are major listed offenders.

Slide 60 · Case: Drug-related acute kidney injury

A patient exposed to an aminoglycoside antibiotic develops a renal lesion reported as acute tubular necrosis.

Which renal compartment is primarily involved?

Interpretation

The renal tubular compartment. Robbins specifically links aminoglycosides with acute tubular necrosis.

Slide 61 · Case: Two pulmonary drug syndromes

One exposed patient has acute pneumonitis; Another has interstitial pulmonary fibrosis.

Which medication is associated with both patterns?

Interpretation

Nitrofurantoin. The histopathologic pattern, not only the drug name, distinguishes the syndromes.

Slide 62 · Case: Cholestasis rather than hepatocyte necrosis

A patient taking chlorpromazine is evaluated for a hepatic adverse reaction characterized as cholestasis.

What hepatic injury category best describes this finding?

Interpretation

Drug-associated cholestasis—not the separate category of diffuse hepatocellular damage.

Slide 63 · Integrate medication, lesion, and competing causes

Document drug exposure and dose

Describe the clinical / pathologic pattern

Compare known drug associations

Evaluate competing explanations

This is an educational interpretation framework, not a formal causality-scoring tool.

Slide 64 · High-yield injury pattern comparison

Target

Pathologic reaction

Representative drug

Marrow

Cytopenias

Antineoplastic therapy

Skin

Dermal pigmentation

Minocycline

Heart

Cardiomyopathy

Doxorubicin

Kidney

Acute tubular necrosis

Aminoglycosides

Lung

Interstitial fibrosis

Bleomycin

Liver

Cholestasis

Chlorpromazine

Slide 65 · Summary: Five durable distinctions

An ADR is an unwanted effect at the prescribed dose; Overdose is a separate exposure context.

Both direct drug effects and immune hypersensitivity can injure organs.

Anatomic site and lesion pattern organize the medication differential.

One medication can produce different manifestations in different patients.

A compatible drug history does not, by itself, prove causality.

Slide 66 · Reference

Core reading

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

Environmental and Nutritional Diseases Injury by Therapeutic Drugs (Adverse Drug Reactions) Organ-specific toxicities and immune reactions