Autonomic Innervation of the Eye

Trachte

March 4, 2008

Goals

• To understand how the sympathetic & parasympathetic nervous systems: – affect the eye; – how autonomic drugs affect the eye and eyelid; and

– treatments for glaucoma.

Sympathetic Nervous System

1. mydriasis- contract pupillary dilator muscle (1 receptor)

• contract superior tarsal muscle to hold eyelid open (1 receptor)

• Relax ciliary muscle for distant vision (ß2 receptors)

• Enhance aqueous humor formation (ß2 receptors)

• Inhibit aqueous humor formation (2 receptors)

Parasympathetic Nervous System Actions

• focus eye for near vision (ciliary muscle contraction)

• constrict pupil (miosis)-(pupillary sphincter contraction)

• Enhance drainage of aqueous humor (trabecular meshwork & canal of Schlemm)

• All of these effects mediated by muscarinic receptors

Drugs promoting mydriasis (pupil dilation)

• Sympathomimetics (things that stimulate or mimic stimulation of sympathetic nerves)

• Inhibitors of parasympathetic nervous system (Atropine)

Postganglionic

Nerve

Nicotinic

Receptor

NE

NE

NE

Axoplasmic Pump

Granule

Pump

1 receptor

Eye

NE

Amphetamine

Cocaine

(-)

Mydriatics

• Agents releasing norepinephrine• NICOTINE activates nicotinic receptor (also activates

parasympathetics to produce miosis, which is the more common reaction)

• Cocaine blocks axoplasmic pump to increase norepinephrine concentrations in vicinity of adrenergic receptors

– 2 - 4% solution used to diagnose simple anisocoria vs Horner’s syndrome

– no effect of cocaine indicates sympathetic dysfunction (if nerves were intact, cocaine would dilate pupil)

• Amphetamine reverses axoplasmic pump– hydroxyamphetamine (0.1% solution) used to diagnose post-

ganglionic nerve damage vs. a defect prior to the postganglionic nerve (no reaction means postganglionic nerve defect)

– response to amphetamine indicates normal post-ganglionic nerve

Postganglionic

Nerve

Nicotinic

Receptor

NE

NE

NE

Axoplasmic Pump

Granule

Pump

1 receptor

Eye

NE

Amphetamine

Cocaine

(-)

Mydriatics

• Alpha1 adrenergic stimulants

• PHENYLEPHRINE (mydrifrin) is a drug used in eye drops to dilate pupil– 2.5% to 10% solution used to produce mydriasis

– also reverses ptosis in Horner’s Syndrome

• Epinephrine (Epitrate) 0.5 to 2% solution to treat glaucoma– increases aqueous humor outflow

Ionotropic Receptor Ach Na Na NE G protein coupled Receptor

Ca IP3 + DAG

Nicotinic Receptor

Alpha 1 Receptor

G PLC

Mydriatics

Muscarinic receptor antagonists

•ATROPINE (Atriposol)- (0.5 to 3% solution) to produce cycloplegia

Ach

Preganglionic

Nerve

Postganglionic

Nerve

AchAch

Nicotinic

Receptor

Ach

Muscarinic

Receptor

Acetate +

Choline

Acetylcholinesterase

Eye

Drugs producing miosis

• Nicotine activates parasympathetic nerves

• Muscarinic agonists such as Pilocarpine (Pilocar), acetylcholine (Miochol)– Pilocarpine used as 2% solution– 1% solution to differentiate IIIrd nerve

palsy from “Atropinic” mydriasis– If pilocarpine is active (produces miosis)

then the defect must be in the nerve

Ionotropic Receptor Ach Na Na Ach G protein coupled Receptor

Ca IP3 + DAG

Nicotinic Receptor

Muscarinic Receptor

G PLC

Drugs producing miosis

Agents preventing acetylcholine degradation

• Physostigmine (Isopto eserine), Ecothiophate (phospholine iodide), demecarium (Humorsol), isofluorophate (floropryl)

• Alpha1 receptor antagonists– TERAZOSIN-not used to treat eye disease but can

have ocular side effects

• Norepinephrine depleting agents- Reserpine (Serpasil)- have the potential of causing ocular side effects (miosis; ptosis)

Postganglionic

Nerve

Nicotinic

Receptor

NE

NE

NE

Axoplasmic Pump

Granule

Pump

1 receptor

Eye

NE

Amphetamine

Cocaine

(-)

Drugs for Treatment of Glaucoma

• ß Blockers – Timolol (Timoptic); Betaxolol (Betoptic);

Carteolol (Ocupress); Levobunolol (Betagan); Metipranolol (Optipranolol)- they decrease aqueous humor formation

• Muscarinic Receptor Agonists- – Pilocarpine (Pilocar)- enhances aqueous humor

drainage through trabecular meshwork & canal of Schlemm

• Anticholinesterases- – Physostigmine (Isopto eserine), Ecothiophate

(Phospholine iodide)- enhances aqueous humor drainage through trabecular meshwork & canal of Schlemm

Drugs for Treatment of Glaucoma

• Alpha2 Agonists- – Apraclonidine (Iopidine) and Brimonidine

(Alphagan)- reduce aqueous humor formation• Epinephrine (Epinal) or Dipevefrin (Propine) –

Primarily increase aqueous humor outflow but also suppress production

• Most common current treatment is the prostaglandin derivative, Latanaprost (Xalatan)– It increases uveo-scleral outflow of aqueous humor (flow through the ciliary muscle)

– Other prostaglandins include: travaprost (Travatan); bimatoprost (Lumigan); Unoprostone (Rescula)

• carbonic anhydrase inhibitors such as acetazolamide, dorzolamide and brinxolamide

Ionotropic Receptor Ach Na Na Norepinphrine G protein coupled Receptor

PKA (phosphorylation) cAMP

Nicotinic Receptor

Alpha2 Receptor

G AC (-)

Drugs used to treat ptosis

• disruption of sympathetic innervation of superior tarsalis muscle of the eye lid (Horner’s Syndrome)- can reverse with Phenylephrine

• skeletal muscle weakness caused by myasthenia gravis (antibodies to nicotinic receptor)

• injury to, or malfunction of, oculomotor nerve

• Edrophonium (Tensilon)- anticholinesterase that reverses drooping caused by myasthenia gravis

Ionotropic Receptor Ach Na Ca Acetate & Choline Na ‡ depolarization Ca ‡ Contraction

Skeletal Muscle

Nicotinic Receptor

Acetylcholinesterase

Somatic Nerve

Ionotropic Receptor Ach Na Ca Acetate & Choline Na ‡ depolarization Ca ‡ Contraction

Skeletal Muscle

Nicotinic Receptor

Acetylcholinesterase

Somatic Nerve

Edrophonium

Muscle spasms

• Strabismus (deviation of the eyes) & Blepharospasm (spasm resulting in closed eyelids)

• Can treat problems caused by muscle spasms with botulinum toxin (Botox)– inhibits acetylcholine release from somatic nerves

– suppression of acetylcholine release can relieve a muscle spasm causing the strabismus or blepharospasm

Ionotropic Receptor Ach Na Ca Acetate & Choline Na ‡ depolarization Ca ‡ Contraction

Skeletal Muscle

Nicotinic Receptor

Acetylcholinesterase

Somatic Nerve

Botulinum Toxin

Summary

• Mydriatic Agents 1 agonist, phenylephrine– Muscarinic antagonist, Atropine– Agents releasing norepinephine

(amphetamine)– Agents preventing norepinephrine uptake

into the nerve (cocaine)– These can all precipitate closed angle

gluacoma

Summary (cont)

• Miotic Agents– Muscarinic agonist (Pilocarpine,

Acetylcholine)– Alpha1 adrenergic antagonists (Terazosin)– Anticholinesterases (Physostigmine)– Nicotine

Summary (cont)

• Tests for intact sympathetic nervous system– Cocaine

• pupil dilation if the nerves work• Lack of pupil dilation indicates defect in

innervation

– Amphetamine • Pupil dilation if postganglionic nerve is present

and functional

Summary (cont)

• Treatments for Glaucoma– Agents enhancing aqueous humor outflow

• Muscarinic agonists (pilocarpine)• Prostaglandins (Latanaprost)• Epinephrine

– Agents suppressing aqueous humor production • ß adrenergic antagonists (Timolol)2 adrenergic agonists (Aproclonidine)• Carbonic anhydrase inhibitors (Acetazolamide)

Summary (cont)

• Ptosis– Characteristic of sympathetic nerve disruption

• Superior tarsalis muscle holds eyelid open

– Can be caused by other conditions involving skeletal muscle dysfunction or III nerve palsy• Myasthenia gravis• Botulinism• Occulomotor palsy

Summary (cont)

• Muscle spasms (blephorospasm or strabismus) can be treated with botulinum toxin to relax the skeletal muscle

• Botulinum toxin acts to suppress acetylcholine release from nerves