Autonomic Innervation of the Eye
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Autonomic Innervation of the Eye
Trachte
March 4, 2008
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Goals
• To understand how the sympathetic & parasympathetic nervous systems: – affect the eye; – how autonomic drugs affect the eye and eyelid; and
– treatments for glaucoma.
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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)
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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
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Drugs promoting mydriasis (pupil dilation)
• Sympathomimetics (things that stimulate or mimic stimulation of sympathetic nerves)
• Inhibitors of parasympathetic nervous system (Atropine)
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Postganglionic
Nerve
Nicotinic
Receptor
NE
NE
NE
Axoplasmic Pump
Granule
Pump
1 receptor
Eye
NE
Amphetamine
Cocaine
(-)
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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
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Postganglionic
Nerve
Nicotinic
Receptor
NE
NE
NE
Axoplasmic Pump
Granule
Pump
1 receptor
Eye
NE
Amphetamine
Cocaine
(-)
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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
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Ionotropic Receptor Ach Na Na NE G protein coupled Receptor
Ca IP3 + DAG
Nicotinic Receptor
Alpha 1 Receptor
G PLC
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Mydriatics
Muscarinic receptor antagonists
•ATROPINE (Atriposol)- (0.5 to 3% solution) to produce cycloplegia
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Ach
Preganglionic
Nerve
Postganglionic
Nerve
AchAch
Nicotinic
Receptor
Ach
Muscarinic
Receptor
Acetate +
Choline
Acetylcholinesterase
Eye
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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
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Ionotropic Receptor Ach Na Na Ach G protein coupled Receptor
Ca IP3 + DAG
Nicotinic Receptor
Muscarinic Receptor
G PLC
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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)
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Postganglionic
Nerve
Nicotinic
Receptor
NE
NE
NE
Axoplasmic Pump
Granule
Pump
1 receptor
Eye
NE
Amphetamine
Cocaine
(-)
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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
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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
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Ionotropic Receptor Ach Na Na Norepinphrine G protein coupled Receptor
PKA (phosphorylation) cAMP
Nicotinic Receptor
Alpha2 Receptor
G AC (-)
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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
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Ionotropic Receptor Ach Na Ca Acetate & Choline Na ‡ depolarization Ca ‡ Contraction
Skeletal Muscle
Nicotinic Receptor
Acetylcholinesterase
Somatic Nerve
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Ionotropic Receptor Ach Na Ca Acetate & Choline Na ‡ depolarization Ca ‡ Contraction
Skeletal Muscle
Nicotinic Receptor
Acetylcholinesterase
Somatic Nerve
Edrophonium
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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
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Ionotropic Receptor Ach Na Ca Acetate & Choline Na ‡ depolarization Ca ‡ Contraction
Skeletal Muscle
Nicotinic Receptor
Acetylcholinesterase
Somatic Nerve
Botulinum Toxin
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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
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Summary (cont)
• Miotic Agents– Muscarinic agonist (Pilocarpine,
Acetylcholine)– Alpha1 adrenergic antagonists (Terazosin)– Anticholinesterases (Physostigmine)– Nicotine
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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
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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)
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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
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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