Drug-Induced Pupillary Changes

Introduction

Pupillary changes are an essential indicator of neurological and pharmacological effects in anesthesia and critical care. The size, shape, and reactivity of the pupils can provide crucial information about the patient’s systemic and central nervous system (CNS) status. Several drugs used in anesthesia and critical care can alter pupillary size via their effects on the autonomic nervous system.

Physiology of Pupillary Control

The size of the pupil is regulated by the balance between the sympathetic and parasympathetic nervous systems:

• Miosis (Constriction) → Parasympathetic (Cholinergic) System

• Mediated by the sphincter pupillae muscle via the oculomotor nerve (CN III).

• Acetylcholine (ACh) acts on muscarinic (M3) receptors to constrict the pupil.

• Mydriasis (Dilation) → Sympathetic (Adrenergic) System

• Mediated by the dilator pupillae muscle via sympathetic pathways.

• Norepinephrine (NE) acts on α1-adrenergic receptors, causing pupillary dilation.

Thus, drugs that enhance or inhibit these pathways can alter pupil size and reactivity.

Drug Effects on Pupillary Size

Drug Class

Pupillary Effect

Mechanism

Examples

Opioids

Miosis (Pinpoint pupils)

Mu (μ) opioid receptor activation → inhibits sympathetic outflow

Morphine, Fentanyl, Heroin, Codeine

Anticholinergics

Mydriasis (Dilated pupils)

Blocks muscarinic (M3) receptors, inhibiting parasympathetic tone

Atropine, Glycopyrrolate, Scopolamine

Sympathomimetics

Mydriasis

α1 receptor activation → dilator pupillae contraction

Epinephrine, Phenylephrine, Cocaine

Sympatholytics

Miosis

α1 receptor blockade → prevents sympathetic dilation

Clonidine, Dexmedetomidine

Benzodiazepines

No significant change

CNS depressant effect but minimal effect on pupil size

Midazolam, Diazepam, Lorazepam

Barbiturates

Miosis (Mild)

CNS depression → reduces sympathetic tone

Thiopental, Pentobarbital

Local anesthetics

Mydriasis (if systemic absorption)

Sodium channel blockade, affecting autonomic control

Lidocaine, Bupivacaine (high doses)

Hallucinogens

Mydriasis

Serotonin and dopamine receptor activation

LSD, MDMA, Psilocybin

Sedatives (Propofol, Ketamine)

Variable effects

Propofol causes mild miosis; ketamine causes mydriasis due to NMDA antagonism and sympathomimetic effects

Propofol, Ketamine

Pupillary Responses in Specific Drug Use Scenarios

1. Opioid Toxicity or Overdose

• Classic Triad: Pinpoint pupils (miosis), respiratory depression, altered mental status.

• Mechanism: Opioids act on μ-opioid receptors in the brainstem, reducing sympathetic outflow.

• Management: Naloxone (opioid antagonist, 0.4–2 mg IV) reverses opioid effects and restores normal pupillary size.

2. Anticholinergic Poisoning (Atropine Toxicity, Scopolamine Overdose)

• Pupillary Sign: Mydriasis (fixed, non-reactive pupils).

• Associated Symptoms: Dry mouth, tachycardia, urinary retention, hallucinations (“Mad as a hatter, Blind as a bat, Dry as a bone”).

• Management: Physostigmine (a reversible acetylcholinesterase inhibitor, 1–2 mg IV slow push) can reverse effects.

3. Cocaine or Amphetamine Intoxication

• Pupillary Sign: Mydriasis (dilated pupils, reactive to light).

• Mechanism: Indirect sympathomimetic action → Increased norepinephrine and dopamine.

• Management: Supportive care, benzodiazepines for agitation, avoid beta-blockers (unopposed α-adrenergic effects).

4. Clonidine Overdose (α2-agonist toxicity)

• Pupillary Sign: Miosis (similar to opioid toxicity but without respiratory depression).

• Mechanism: Presynaptic α2 receptor stimulation inhibits norepinephrine release.

• Management: IV fluids, vasopressors (if hypotensive), and supportive care.

5. Benzodiazepine Overdose

• Pupillary Sign: No significant pupillary change (normal or slightly constricted pupils).

• Differentiation from opioid overdose: Respiratory depression occurs in both, but opioids cause pinpoint pupils, whereas benzodiazepines do not.

• Management: Flumazenil (benzodiazepine antagonist, 0.2 mg IV bolus) in selective cases (risk of seizures in chronic benzodiazepine users).