Injury by Nontherapeutic Agents Drug Use Disorder

Slide 1 · Injury by Nontherapeutic Agents

(Drug Use Disorder)

Pathologic mechanisms • organ injury • clinical correlations

Cocaine · Opioids · Amphetamines · Cannabinoids · Other agents

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Classify common nontherapeutic psychoactive agents by major molecular targets.

Explain cocaine-related sympathetic, cardiovascular, CNS, and pregnancy effects.

Connect opioid pharmacology, contaminants, and injection practices to distinct organ lesions.

Distinguish methamphetamine, cannabis, hallucinogen, and related drug effects.

Interpret characteristic clinicopathologic patterns without assuming exposure from morphology alone.

Slide 3 · What “drug use disorder” denotes

Repeated or chronic use of mind-altering substances outside therapeutic or social norms.

A disorder may progress to addiction and may be complicated by overdose.

The textbook uses a broad, pathology-oriented framing rather than listing formal diagnostic criteria.

Drug-related tissue injury reflects both intrinsic pharmacology and exposure circumstances.

Slide 4 · Drug exposure is not synonymous with use disorder

Exposure measures

Use disorder measures

Includes an individual who used a nonprescription drug at least once.

Does not, by itself, establish a use disorder.

Population exposure denominators depend on year and region.

Identifies a population meeting disorder criteria.

Not interchangeable with lifetime or past-year drug use.

Interpret source epidemiology by its specific definition.

Historical survey estimates refer to 2021; These are not current surveillance figures.

Slide 5 · Scale of global nonprescription drug exposure

UNODC figures quoted (2023 report; Year of exposure 2021)

296 M

People worldwide estimated to have used nonprescription drugs at least once in 2021

5.8%

Approximate share of people aged 15–64 years worldwide (2021)

Slide 6 · US exposure and disorder: Distinct denominators

Separate textbook estimates; Definitions and denominators differ

61.2 M

US residents who used nonprescription drugs in 2021

46.3 M

US people aged ≥12 estimated to meet criteria for drug use disorder in 2021

Slide 7 · US overdose burden reported for 2023

Historical textbook statement; Not a current-year mortality update

≈107,000

Deaths from drug overdose in the United States in 2023

≈70%

Approximate fraction attributed to synthetic opioids, mainly fentanyl

Slide 8 · Major classes of nontherapeutic agents

Classify by major pharmacologic effects and receptor/transporter targets

Opioids

Sedative–hypnotics

Psychomotor stimulants

Dissociatives

Cannabinoids

Hallucinogens

The class predicts some acute toxicity; Route, adulterants, and comorbidity modify tissue injury.

Slide 9 · Primary targets I: Opioids to stimulants

Drug class

Representative agents

Teaching target

Opioid narcotics

Heroin; fentanyl; oxycodone

μ-opioid receptor agonism

Sedative–hypnotics

Barbiturates; benzodiazepines; ethanol

GABA-A receptor effects

Psychomotor stimulants

Cocaine; amphetamines; MDMA

Dopamine transporter and serotonergic toxicity

Simplified targets reproduced Table 9.6; Agents can act at additional targets.

Slide 10 · Primary targets II: Dissociatives to hallucinogens

Drug class

Representative agents

Teaching target

PCP-like agents

Phencyclidine; ketamine

NMDA receptor channel antagonism

Cannabinoids

Marijuana; hashish

CB1 cannabinoid receptor agonism

Hallucinogens

LSD; mescaline; psilocybin

Serotonin 5-HT2 receptor agonism

Slide 11 · Three broad routes to tissue injury

Distinct mechanisms may coexist in the same patient

Drug pharmacology → physiologic toxicity

Adulterants → direct or foreign-body injury

Injection practices → infections

A tissue lesion alone need not disclose which specific substance was used.

Slide 12 · Why route and purity matter

Exposure route

Uncertain product composition

Intranasal cocaine → local septal injury.

Inhaled cocaine or cannabis → pulmonary effects.

Parenteral heroin → skin, venous, and infection-related lesions.

Unknown heroin purity complicates dose estimation.

Fentanyl substitution increases overdose risk.

Talc, quinine, and other contaminants add their own toxicity.

Slide 13 · Cocaine: Forms and exposure routes

Derived from leaves of the coca plant.

Cocaine hydrochloride is water soluble; It may be insufflated or injected.

The crystallized free-base form, “crack,” is heated and inhaled.

Street products may be diluted with powders such as talc or lactose.

Slide 14 · Cocaine hydrochloride and crack

Cocaine hydrochloride

Crack cocaine

Commonly sold as powder.

May be taken intranasally or dissolved for injection.

Local intranasal injury becomes relevant with repeated exposure.

Crystallized alkaloid inhaled after heating.

Same essential pharmacologic actions as cocaine.

Crack as markedly more potent.

Slide 15 · Cocaine: Reuptake blockade at a synapse

Schematic — neurotransmitter persists because presynaptic reuptake is inhibited

Presynaptic neuronal membrane

Postsynaptic target membrane

Reuptake transporter

Reuptake blocked

Synaptic dopamine / norepinephrine

Increased postsynaptic signaling

Slide 16 · Cocaine and the mesolimbic reward pathway

Central dopaminergic action supports cocaine’s strong addictive potential

Blocks dopamine reuptake

Raises synaptic dopamine signaling

Produces intense euphoria

Reinforces repeated use

The source also describes profound craving after discontinuation.

Slide 17 · Cocaine dependence: Craving is central

Euphoria and neurologic stimulation promote repeated administration.

Physical dependence is described as generally limited.

Psychological withdrawal and craving can be severe.

Cravings can be particularly intense in early abstinence and recur long afterward.

Slide 18 · Cocaine amplifies sympathetic neurotransmission

Peripheral catecholamine effects explain characteristic cardiovascular toxicity

Blocks norepinephrine reuptake

Enhances transmitter availability at adrenergic synapses

Excess sympathetic stimulation

Tachycardia • hypertension • vasoconstriction

Slide 19 · Cocaine: Four linked acute responses

Heart rate

Tachycardia increases myocardial oxygen demand.

Vasculature

Peripheral and coronary vasoconstriction alter blood flow.

Pressure

Systemic hypertension raises cardiovascular stress.

Platelets

Increased aggregation supports thrombosis and ischemia.

Slide 20 · Myocardial ischemia: Demand–supply mismatch

Cocaine creates concurrent demand and supply stresses

Tachycardia / hypertension → demand ↑

Coronary vasoconstriction → supply ↓

Platelet aggregation / thrombus

Myocardial ischemia or infarction

Slide 21 · Cocaine-associated coronary thrombosis

Cocaine can increase platelet aggregation and thrombus formation.

Coronary vasoconstriction simultaneously reduces perfusion.

The interaction can produce ischemia even without a preexisting fixed obstruction.

Myocardial infarction is a major possible outcome.

Slide 22 · Arrhythmia: Converging mechanisms

Adrenergic mechanism

Myocardial electrical mechanism

Enhanced sympathetic activity increases cardiac excitability.

Tachycardia and hypertension accompany the catecholamine effect.

Cocaine can disrupt Na⁺, K⁺, and Ca²⁺ transport.

Electrical instability may produce lethal arrhythmias.

Slide 23 · Cocaine toxicity may be unpredictable

Severe cardiovascular effects are not necessarily proportional to dose.

Fatal events may occur in first-time users at a typical mood-altering dose.

Cigarette smoking may amplify coronary vasospasm risk.

No clinical presentation should be considered benign solely on presumed exposure amount.

Slide 24 · Cocaine: Vascular and myocardial endpoints

Cardiac

Cerebrovascular

Myocardial ischemia or infarction.

Lethal arrhythmia.

Chronic dilated cardiomyopathy.

Hypertension-associated stress.

Cerebral hemorrhage.

Cerebral infarction.

Cerebral endpoints also appear in the captioned effects Figure 9.14.

Slide 25 · Acute cocaine injury of the CNS

Hyperpyrexia is an important acute manifestation.

Altered dopaminergic temperature-regulation pathways are implicated.

Seizures may occur during acute toxicity.

Neurobehavioral effects also include euphoria and paranoia.

Slide 26 · Cocaine in pregnancy: Placental perfusion

The source also links chronic maternal exposure with impaired fetal neurologic development.

Maternal cocaine exposure

Acute reduction in placental blood flow

Fetal hypoxia

Potential spontaneous abortion

Slide 27 · Cocaine: Route-specific chronic injury

Nose

Intranasal exposure can cause nasal septal perforation.

Lung

Inhaled cocaine smoke can reduce diffusing capacity.

Heart

Chronic cocaine use can be associated with dilated cardiomyopathy.

CNS

Craving may persist after discontinuation.

Slide 28 · Cocaine-induced septal damage: Morphology

Repeated intranasal exposure is associated with perforation of the nasal septum.

This is a local structural lesion, not simply a transient pharmacologic effect.

History of intranasal exposure provides the essential etiologic context.

The supplied text does not provide a specific histologic diagnostic pattern.

Slide 29 · Cocaine-related chronic cardiomyopathy

Dilated cardiomyopathy is identified among chronic consequences.

It is distinct from the acute coronary ischemia and arrhythmic pathways.

In an individual with cardiomyopathy, drug history is important for attribution.

The provided excerpt does not specify pathognomonic histology for cocaine exposure.

Slide 30 · Cocaine: Clinicopathologic integration

Organ/system

Mechanism / exposure

Characteristic effect

Cardiovascular

Catecholamines; coronary tone; platelets

Ischemia, infarction, arrhythmia

CNS

Dopaminergic effects

Hyperpyrexia; seizures

Placenta/fetus

Reduced placental blood flow

Fetal hypoxia; pregnancy loss

Airway/nose

Inhalation; insufflation

Reduced gas transfer; septal injury

Slide 31 · Case: Chest pain after cocaine exposure

Clinical vignette (hypothetical)

A young adult develops acute chest pain and marked tachycardia after cocaine use. No prior coronary disease is reported.

What two mechanisms jointly make myocardial ischemia plausible?

Slide 32 · Opiates and opioids: Terminology

Opiates are naturally occurring substances obtained from poppy plants, such as morphine.

“Opioids” encompasses related derivatives and synthetic agents.

Prescription opioids may also be used nontherapeutically.

Heroin and fentanyl because of severe public-health injury.

Slide 33 · Representative opioids in the source

Group

Examples

Key context

Poppy-derived / related

Morphine; heroin

Heroin is an illicit derivative related to morphine

Prescription opioids

Oxycodone; hydrocodone; tramadol; methadone

Therapeutic use does not preclude nontherapeutic exposure

Potent synthetic opioid

Fentanyl

Illicit substitution or mixing can be fatal

Slide 34 · Opioid toxicity: Principal fatal pathway

The most emphasized immediate fatal mechanism is respiratory suppression

μ-opioid receptor agonism

Suppression of respiratory drive

Severe hypoventilation / respiratory suppression

Hypoxic injury and death

Slide 35 · Illicit fentanyl intensifies overdose risk

Fentanyl is highly potent and can be mixed with or replace other drugs.

Exposure may be unrecognized by the individual using the substance.

Those without opioid tolerance are particularly vulnerable to profound respiratory suppression.

Appropriate medically supervised fentanyl use is distinct from uncontrolled illicit exposure.

Slide 36 · Opioid deaths: Direct versus accompanying mechanisms

Primary pharmacologic effect

Additional severe effects

Profound respiratory depression is emphasized as the usual cause.

Delayed reversal allows progression to serious hypoxic injury.

Cardiac arrhythmia or cardiac arrest.

Severe pulmonary edema.

Unknown drug content makes overdose risk less predictable.

Slide 37 · Naloxone: Mechanism-based reversal

Naloxone is an opioid receptor antagonist.

It can rapidly reverse opioid-induced respiratory suppression if administered in time.

Reversal does not erase other exposure-related complications, such as infection or tissue injury.

The Robbins passage supports the reversal principle but not a detailed dosing protocol.

Slide 38 · Lost tolerance increases overdose vulnerability

The textbook explicitly cites loss of tolerance during incarceration as an example.

Repeated opioid use → tolerance develops

Abstinence or interruption → tolerance falls

Resumption at a previous dose

Disproportionate toxicity / overdose

Slide 39 · Why heroin-related tissue injury is heterogeneous

These mechanisms can occur together; Pathology may reflect more than heroin itself.

Pharmacologic opioid toxicity

Adulterants / cutting agents

Hypersensitivity to contents

Contaminated needles and injection

Slide 40 · Opioid-related pulmonary edema

Moderate to severe pulmonary edema is described after heroin use.

Edema can accompany severe overdose and sudden death.

Pulmonary complications also include infection and embolic disease.

Do not interpret edema alone as specific proof of opioid exposure.

Slide 41 · Injection-associated tricuspid endocarditis

Staphylococcus aureus is highlighted as a frequent cause.

Nonsterile intravenous injection

Organisms enter venous circulation

Right-sided valve infection (often tricuspid)

Septic emboli to pulmonary vessels

Slide 42 · Infections associated with injection drug use

Skin and subcutaneous tissue infections may accompany injection.

Right-sided infective endocarditis is a characteristic serious complication.

Viral hepatitis is transmitted by needle sharing.

HIV infection has also been linked to contaminated injection equipment.

Slide 43 · Heroin use: Characteristic organ involvement

Skin / veins

Cellulitis, abscesses, ulceration; Scarring and thrombosed veins.

Heart valves

Right-sided, often tricuspid, infective endocarditis.

Lung

Edema, septic emboli, abscess, or foreign-body reaction.

Kidney

Amyloidosis and focal segmental glomerulosclerosis.

Slide 44 · Skin: Acute and chronic injection findings

Acute changes include subcutaneous abscesses, cellulitis, and ulcerations.

Repeated intravenous injection can scar the skin and hyperpigment vein tracks.

Thrombosed veins are a further consequence of recurrent injury.

These changes indicate an exposure pattern rather than an agent-specific chemical fingerprint.

Slide 45 · Talc embolization: Foreign-body lesion

Schematic mechanism; Birefringent talc particles visible by polarized light.

Insoluble adulterant introduced intravenously

Particles reach pulmonary microvasculature

Foreign-body giant-cell response

Granulomatous tissue reaction

Slide 46 · Foreign-body granulomas: Evidence in tissue

Adulterant particles can produce foreign-body granulomas, especially in lungs.

Talc may be visible as crystalline material under polarized light.

Particles can lie within multinucleated foreign-body giant cells.

Granulomas may also involve spleen, liver, and regional lymph nodes.

Slide 47 · Kidney pathology with heroin use

Amyloidosis

Focal segmental glomerulosclerosis

May occur secondary to recurrent skin infections.

Can lead to proteinuria and nephrotic syndrome.

Also associated with heroin use.

Can cause proteinuria and nephrotic syndrome.

These are associations, not a specific etiologic diagnostic test.

Slide 48 · Opioid complications: Mechanism determines lesion

Injury mechanism

Potential morphologic outcome

Exposure context

Respiratory suppression

Hypoxic consequences; pulmonary edema

Overdose

Injection infection

Tricuspid endocarditis; abscesses

Contaminated injection

Adulterant particles

Foreign-body granulomas

Particulate exposure

Recurrent infections / renal injury

Amyloid disease or FSGS

Chronic exposure

Slide 49 · Case: Multiple pulmonary nodules in an injector

Clinical vignette (hypothetical)

A patient with recurrent injection drug use has fever, a new tricuspid vegetation, and multiple lung lesions consistent with infected emboli.

What is the most direct path from right-heart infection to pulmonary injury?

Slide 50 · Methamphetamine: Drug class and potency

Methamphetamine is closely related to amphetamine.

It is a potent addictive psychomotor stimulant.

Stronger CNS effects than those of amphetamine.

Injection is one reported mode of methamphetamine use.

Slide 51 · Methamphetamine and the dopamine pathway

Robbins also describes reduced glutamate release at corticostriatal synapses.

Promotes dopamine release in brain

Alters corticostriatal neurotransmission

Acute euphoria

Subsequent “crash”

Slide 52 · Methamphetamine: Immediate versus prolonged effects

Acute neurobehavioral pattern

Long-term presentation

Intense euphoria.

A post-use crash.

Altered cortical–striatal signaling.

Confusion and violent behavior.

Paranoia and hallucinations.

Psychosis may occur with prolonged use.

Slide 53 · Methamphetamine: Interpreting psychiatric injury

Long-term use may lead to psychosis with paranoia and hallucinations.

Behavioral and cognitive manifestations are prominent.

Co-occurring substance use and mental illness are common in the described population.

Psychosis is a clinical manifestation; The supplied excerpt does not provide a specific brain histologic lesion.

Slide 54 · Cannabis: Material and principal psychoactive agent

Marijuana derives from leaves of Cannabis sativa.

Δ⁹-tetrahydrocannabinol (THC) is the main psychoactive constituent emphasized.

Cannabinoid effects are associated with CB1 receptor signaling.

Nontherapeutic smoking and aerosolized THC exposure are discussed separately.

Slide 55 · Acute cannabis effects: Multisystem profile

Perception

Heightened sensory impressions and altered perception of time.

Behavior

Euphoria, relaxation, laughter, or increased appetite.

Motor control

Impaired coordination and psychomotor performance.

Cardiovascular

Increased heart rate; Sometimes increased blood pressure.

Slide 56 · Cannabis impairs psychomotor judgment

Acute use may distort sensory perception and motor coordination.

With continued use, impaired estimation of time, speed, and distance is described.

The resulting judgment deficits can contribute to motor-vehicle accidents.

Clinical impairment and morphologic injury are not interchangeable concepts.

Slide 57 · Cannabis and ischemic symptoms in susceptible hearts

Robbins specifies risk in individuals with preexisting coronary artery disease.

THC-associated cardiovascular effects

Heart rate increases ± blood pressure rises

Higher cardiac workload

Potential angina with coronary disease

Slide 58 · Smoking cannabis: Airway consequences

Chronic smoking is associated with laryngitis, pharyngitis, and bronchitis.

Cough, hoarseness, and asthma-like symptoms can occur.

Mild but significant airway obstruction is described.

The smoke contains several carcinogens also encountered in tobacco smoke.

Slide 59 · Inhaled cannabis: Combustible smoke versus aerosol

Smoked cannabis

Aerosolized THC products

Respiratory irritation and obstructive airway effects.

Smoke-associated tar and carcinogen exposure.

Severe lung injury has been associated with some vaping products.

Robbins raises possible adulterant involvement; Causation is not universally established.

Slide 60 · Cannabis hyperemesis syndrome

Paradoxical gastrointestinal presentation despite recognized antiemetic uses.

Heavy cannabis exposure

Recurrent severe nausea / vomiting

Intractable hyperemesis episodes

Symptoms remit with cessation

Slide 61 · Cannabis withdrawal and use disorder

Some individuals develop problematic cannabis use with dependence.

Reported withdrawal includes mood changes and sleep difficulties.

Symptoms may persist for up to approximately two weeks in the source.

Variable definitions and uncertainty around addiction estimates.

Slide 62 · Cannabis: Potential therapeutic value and harm

Potential medical applications in source

Nontherapeutic-associated harms

Relief of chemotherapy-associated nausea.

Pain reduction in selected difficult chronic conditions.

Approved cannabis-derived or related prescription products exist.

Impaired coordination and driving judgment.

Airway symptoms or possible vaping-associated injury.

Cannabis hyperemesis and withdrawal in some users.

Slide 63 · Phencyclidine and ketamine: Dissociatives

PCP and ketamine are described as related anesthetic agents.

Both are listed among phencyclidine-like nontherapeutic drugs.

Robbins Table 9.6 emphasizes NMDA receptor channel antagonism.

Therapeutic ketamine derivatives are a separate medically supervised context.

Slide 64 · Other agents: Representative classes

Class / group

Examples

Source-described risk / effect

Hallucinogens

LSD; mescaline; psilocybin

Altered mood, affect, thought

MDMA / ecstasy

3,4-Methylenedioxymethamphetamine

Possible serotonergic depletion with prolonged use

Synthetic cathinones

“Bath salts”; related to khat

Stimulant group, limited chronic-outcome data

Dissociatives

PCP; ketamine

NMDA channel antagonism

Slide 65 · LSD: Acute perceptual and behavioral hazard

LSD is described as a potent hallucinogen.

Acute effects on mood, affect, and thought may be unpredictable.

Behavior can be bizarre or dangerous during intoxication.

The supplied excerpt does not specify a diagnostic tissue lesion for LSD exposure.

Slide 66 · MDMA: Longer-term effects remain uncertain

MDMA is a psychomotor stimulant also known as ecstasy.

Robbins raises possible depletion of CNS serotonin after chronic use.

Potential consequences include sleep problems, depression, anxiety, and aggression.

Use “may” and “potential” for this association; Source emphasizes knowledge gaps.

Slide 67 · Therapeutic investigation is not equivalent to safety

Ketamine derivatives are used therapeutically for severe depression in selected settings.

Clinical trials have investigated hallucinogens for certain psychiatric conditions.

The source reports initial short-term benefit in selected populations.

Controlled clinical use should not be conflated with unregulated exposure.

Slide 68 · Across classes: Mechanism predicts acute phenotype

Agent class

Primary pathway in Robbins

Major acute clinical concern

Cocaine

Dopamine / norepinephrine reuptake blockade

Sympathetic excess; seizures; ischemia

Opioids

μ-opioid agonism

Respiratory suppression

Methamphetamine

Dopamine release

Euphoria, crash; neurobehavioral effects

Cannabinoids

CB1 agonism

Altered perception and coordination

Dissociatives

NMDA channel antagonism

Dissociative psychoactive effects

Slide 69 · Across classes: Recognizable organ injury patterns

Agent / exposure

Organ pattern

Causal interpretation

Cocaine

Myocardial infarction; septal perforation

Vascular tone / intranasal exposure

Injected heroin

Tricuspid endocarditis; septic pulmonary emboli

Contaminated injection

Heroin with insoluble cutting agents

Pulmonary foreign-body granulomas

Particulate embolization

Cannabis smoke

Chronic airway irritation

Repeated inhalational exposure

Methamphetamine

Psychosis / behavioral change

Neurotransmitter dysfunction

Slide 70 · A useful differential: Ischemia versus respiratory failure

Cocaine pattern

Opioid pattern

Sympathetic activation predominates.

Tachycardia, vasoconstriction, thrombosis.

Acute ischemia or arrhythmia is plausible.

Central respiratory suppression predominates.

Hypoventilation and hypoxia drive mortality.

Coexisting infection or adulterant injury may be present.

Slide 71 · Case: Abrupt collapse after unknown drug ingestion

Clinical vignette (hypothetical)

A person becomes profoundly unresponsive with markedly depressed breathing after taking a substance of uncertain composition.

Which drug class and reversible fatal pathway should be considered?

Slide 72 · Case: Chronic intranasal exposure

Clinical vignette (hypothetical)

A patient has a perforated nasal septum and a history of repeatedly insufflating a stimulant powder.

Which source-described drug and route-specific injury fit this pattern?

Slide 73 · Case: Recurrent emesis in a heavy cannabis user

Clinical vignette (hypothetical)

A person with heavy cannabis use experiences repeated episodes of severe vomiting and reports resolution after stopping exposure.

Which syndrome explains this clinical association?

Slide 74 · Four principles for pathology interpretation

Pharmacology

Identify the receptor or transporter mechanism of acute toxicity.

Route

Ask whether nasal, inhaled, or injection injury adds local pathology.

Composition

Adulterants and fentanyl substitution can change the injury pattern.

Association

Use morphology plus history; Avoid assuming lesions uniquely identify a drug.

Slide 75 · Core clinicopathologic synthesis

Cocaine combines reward-pathway effects with severe cardiovascular and CNS injury.

Opioid mortality is dominated by respiratory suppression; Injecting introduces infections and particulate lesions.

Methamphetamine and hallucinogens may produce substantial neurobehavioral toxicity.

Cannabis can cause psychomotor impairment, airway effects, hyperemesis, and withdrawal in some individuals.

Attribution requires exposure history and a mechanism compatible with the observed lesion.

Slide 76 · Primary reading and source boundaries

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

Chapter 9, Environmental and Nutritional Diseases, printed pages 386–389.

Injury by Nontherapeutic Agents; Cocaine; Opioids and Opiates; Amphetamines; Marijuana; Other Drugs.

Source-derived historical epidemiology is explicitly labeled by year.

Conceptual diagrams are original PowerPoint shapes, not reproduced textbook illustrations.