The Autonomic Nervous System and Pupil Control
The size of the pupil is controlled by the iris, which contains two sets of muscles: the iris sphincter and the iris dilator. These muscles are regulated by the autonomic nervous system (ANS), which consists of the sympathetic and parasympathetic branches. The balance between these two branches dictates whether the pupils constrict (miosis) or dilate (mydriasis).
- The Parasympathetic System: Also known as the "rest and digest" system, it causes the iris sphincter muscle to contract, which constricts the pupil. This action is mediated by the neurotransmitter acetylcholine.
- The Sympathetic System: Referred to as the "fight or flight" system, it causes the iris dilator muscle to contract, which widens the pupil. This is primarily mediated by the neurotransmitter norepinephrine.
Drugs that cause mydriasis disrupt this balance, either by blocking the parasympathetic system or activating the sympathetic system.
Anticholinergic Agents: Blocking Constriction
Anticholinergic drugs, also known as parasympatholytics, block the muscarinic acetylcholine receptors on the iris sphincter muscle. By inhibiting the parasympathetic nervous system, they relax the sphincter muscle, leading to unopposed dilation by the sympathetic system. Many of these drugs also cause cycloplegia, which is the paralysis of the ciliary muscle, resulting in a loss of accommodation (the eye's ability to focus).
Examples of anticholinergic drugs that cause mydriasis include:
- Ophthalmic drugs: Atropine, tropicamide, and cyclopentolate are used during eye examinations and for treating specific eye conditions. Atropine is a potent, long-lasting mydriatic, while tropicamide is a faster-acting, shorter-duration option.
- Motion sickness medication: Scopolamine patches and dimenhydrinate (Dramamine) can have anticholinergic effects that cause mydriasis.
- Antidepressants: Certain antidepressants, particularly tricyclic antidepressants like amitriptyline, have anticholinergic properties that can lead to pupil dilation.
- Antihistamines: Many older, first-generation antihistamines, such as diphenhydramine (Benadryl), possess strong anticholinergic effects.
Sympathomimetic Agents: Forcing Dilation
Sympathomimetic drugs, or adrenergic agonists, stimulate the sympathetic nervous system. They act on the alpha-1 adrenergic receptors of the iris dilator muscle, causing it to contract and dilate the pupil. This can be achieved either by mimicking norepinephrine directly or by increasing its release and blocking its reuptake.
Examples of sympathomimetic drugs that cause mydriasis include:
- Stimulants: Cocaine, amphetamines, and methamphetamine significantly increase the levels of norepinephrine and dopamine, leading to pronounced mydriasis.
- ADHD medication: Prescription stimulants like Adderall (a combination of amphetamine and dextroamphetamine) and methylphenidate can also cause pupil dilation.
- Recreational drugs: MDMA (ecstasy) acts as both a stimulant and a hallucinogen, causing mydriasis through a combination of neurotransmitter effects. Bath salts (cathinones) are also amphetamine-like stimulants that cause mydriasis.
- Ophthalmic drugs: Phenylephrine is an alpha-1 adrenergic agonist used in eye drops for diagnostic eye exams.
- Decongestants: Oral decongestants containing pseudoephedrine or phenylephrine, or nasal sprays with adrenergic properties, can cause mydriasis as a side effect.
- Caffeine: High doses of caffeine can cause pupil dilation in some individuals due to its stimulant properties.
Other Drug Classes and Substances
Besides anticholinergics and sympathomimetics, other substances can also cause mydriasis through different mechanisms:
- Hallucinogens: Drugs like LSD, psilocybin (magic mushrooms), and mescaline affect serotonin receptors in the brain, leading to alterations in perception and often causing significant pupil dilation.
- Opioid withdrawal/overdose: While opioids (e.g., heroin, morphine, fentanyl) typically cause miosis (constricted pupils), mydriasis can occur during an overdose or withdrawal.
- Marijuana: Cannabis can cause pupil dilation in some individuals, though its effects are variable and depend on the dose.
- Poisons: Topical exposure to plants containing alkaloids like atropine and scopolamine (e.g., Jimson weed, belladonna) can cause mydriasis. Botulinum toxin (Botox) can also cause toxic pupil dilation.
Comparison of Mydriatic Drug Classes
| Feature | Anticholinergic Mydriasis | Sympathomimetic Mydriasis |
|---|---|---|
| Mechanism | Blocks acetylcholine receptors on the iris sphincter muscle. | Stimulates alpha-adrenergic receptors on the iris dilator muscle. |
| Pupil Effect | Primarily mydriasis (dilation) with an associated loss of accommodation (cycloplegia). | Primarily mydriasis; can also cause vasoconstriction. |
| Associated Signs | Poor or absent pupil reaction to light, blurred vision, dry mouth, urinary retention. | Increased heart rate, elevated blood pressure, potential tremors. |
| Response to Light | Poor or no pupillary constriction to light stimuli. | Residual light reaction may be present. |
| Examples | Atropine, tropicamide, cyclopentolate, scopolamine. | Cocaine, amphetamines, MDMA, phenylephrine. |
| Reversal Options | Can be difficult to reverse pharmacologically. New agents like phentolamine (Ryzumvi) are FDA-approved for reversing induced mydriasis. | Responds more rapidly to reversal agents like pilocarpine. |
Therapeutic and Accidental Mydriasis
Pharmacologically-induced mydriasis is a routine part of many medical procedures. For instance, ophthalmologists use mydriatic eye drops during eye exams to get a clearer view of the retina and optic nerve. In cases of anterior uveitis, mydriatics are used to prevent posterior iris synechiae formation. While intentional mydriasis is medically necessary, accidental exposure can also occur, such as a healthcare worker inadvertently touching their eye after handling an anticholinergic agent.
Clinical Considerations and Risks
While often a temporary effect, drug-induced mydriasis has clinical implications:
- Visual impairment: Blurred vision and increased sensitivity to light (photophobia) are common side effects.
- Acute angle-closure glaucoma: In individuals with a narrow anterior chamber angle, mydriasis can block the drainage of fluid from the eye, leading to a sudden and dangerous increase in intraocular pressure.
- Diagnosis: While dilated pupils can be a sign of drug use, they are not a definitive diagnosis. Medical conditions like brain injury, cranial nerve neuropathy, and certain eye diseases must also be considered.
Treatment of Drug-Induced Mydriasis
In September 2023, the FDA approved Ryzumvi (phentolamine ophthalmic solution) 0.75% for the reversal of pharmacologically-induced mydriasis. Ryzumvi is a nonselective alpha-adrenergic antagonist that effectively reduces pupil diameter. It provides a valuable tool for reversing mydriasis caused by adrenergic agonists and antimuscarinic drugs. Prior to this, other options like pilocarpine were available, but they came with limitations and side effects.
Conclusion: The Pharmacological Drivers of Mydriasis
Answering the question, "Which of the following drugs causes mydriasis?" reveals a complex interaction between pharmacological agents and the autonomic nervous system. The causes range from intentional therapeutic use during eye exams with anticholinergics like atropine and sympathomimetics like phenylephrine, to inadvertent side effects of prescription drugs such as antidepressants and antihistamines. Recreational drugs like cocaine, MDMA, and LSD can also induce profound mydriasis by activating the sympathetic system or altering neurotransmitter balance. Understanding these mechanisms is crucial for both clinical practice and for recognizing signs of substance use, keeping in mind that other medical factors can also cause pupil dilation. The advent of specific reversal agents, such as Ryzumvi, offers new avenues for managing the symptoms associated with pharmacologically-induced mydriasis.
Source: EyeWiki, Pharmacologic Dilation of Pupil: https://eyewiki.org/Pharmacologic_Dilation_of_Pupil
