Topical Adrenergic and Cholinergic Agents in Glaucoma

Where is the SNS located?

The thoraco-lumbar region of the CNC

Where is the PNS located?

In the cranio-sacral region of the CNS

Is the SNS adrenergic or cholinergic/muscarinic?

Adrenergic

Is the PNS adrenergic or cholinergic/muscarinic?

Cholinergic/muscarinic

What are the ocular targets of the SNS?

• Superior cervical ganglion

• Iris dilator muscle (α1)

  • Phenylephrine; apraclonidine (used for Horner’s) to a lesser extent

• NPCE (β1 and β2)

  • β-blockers for glaucoma treatment

• CB vasculature (α2)

  • α-agonists like Brimonidine (one action, selective) and apraclonidine (two actions)

• Smooth muscles (Mueller's lid muscle - α1)

What are the ocular targets of the PNS?

• Edinger-Westphal nucleus

• CN III and VII

• Ciliary ganglion

• Ciliary (accommodation) & iris sphincter (miosis) muscles

  • Lacrimal gland (basal tears)

What is the cap color for cholinergic agonists?

Pine green

What type of drug is pilocarpine?

Cholinergic agonist

How does pilocarpine work in glaucoma?

It binds to longitudinal muscle of CB, contraction causes it to pull on the scleral spur and open the trabecular spaces for increased aqueous outflow (decreases IOP)

• Also increased accommodation (binds CB)

What are the indications for pilocarpine?

• Treat glaucoma/POAG (not used anymore because of short half-life)

• Treat acute angle closure glaucoma if IOP is usually less than 40mmHg (if higher, CB is ischemic)

• Before a LPI surgery (a treatment for an angle closure – allows the pressure in the AC and PC to normalize) – gives you more iris to shoot the laser at

• 0.125% (diluted) used to diagnose Adie's tonic pupil

How is pilocarpine used to diagnose Adie’s tonic pupil?

Clinical confirmation involves diluted pilocarpine (~0.125%) instilled in both eyes

• Because the postganglionic synapse is hypersensitive to ACh, the affected eye will constrict while the unaffected eye will remain the same

What type of drug is Vuity (pilocarpine HCl ophthalmic solution) 1.25%?

Cholinergic agonist

What drug?

• For presbyopia

• Contracts the iris sphincter muscle, constricting the pupil to improve near and intermediate visual acuity

  • Enhances depth of focus

• Likely not covered insurance

Vuity (pilocarpine HCl ophthalmic solution) 1.25%

What drug?

• Side Effects: induces myopia (binds CB and pushes the lens forward), headaches (induces accommodation), retinal tears and detachments (binds CB and pushes the lens forward, pushing the vitreous forward, pulling on the retina)

Vuity (pilocarpine HCl ophthalmic solution) 1.25%

What are the contraindications of Vuity (pilocarpine HCl ophthalmic solution) 1.25%?

Patients with a history of RD, lattice degeneration, and high myopes

What type of drug is Qlosi (pilocarpine hydrochloride ophthalmic solution) 0.4%?

Cholinergic agonist

What type of drug is LNZ100 (aceclidine)?

Cholinergic agonist

What drug?

• A glaucoma drop back in the day (didn’t work very well)

• Activates iris sphincter muscle (miosis) with less activation of the ciliary muscle

  • Avoids the lens being pushed forward (myopia)

• Longer effect than Vuity and Qlosi

LNZ100 (aceclidine)

What are the contraindications for pilocarpine?

• Inflammatory (uveitis) or Uveitic Glaucoma (it will constrict the pupil leading to greater pain)

• Leads to retinal breaks which can lead to detachments (pushes the lens forward, which pushes the vitreous forward)

• Aphakes (person with no lens) – the vitreous liquifies faster (more likely to get breaks and detachments)

• Young patients (<40): brow aches, headaches, myopic shifts due to ciliary spasms

How do cholinergic antagonists/anti-cholinergics work?

They bind to receptors on iris sphincter leading to pupil dilation and bind to ciliary muscle leading to cycloplegia

• These drugs block binding of ACh at these sites

What are the indications for cholinergic antagonists/anti-cholinergics?

• Cycloplegic refractions - cyclopentolate

• Dilations - tropicamide

• Management of Uveitis - any cholinergic antagonist but tropicamide

  • Stops ciliary spasm

  • Prevents posterior synechiae

  • Stabilizes the blood aqueous barrier

• Myopia treatment - Atropine (low dose)

What type of drug is Atropine (0.5, 1.0, 2.0% solution)?

Cholinergic antagonists

What drug?

• Most potent mydriatic and cycloplegic agent (1-3 hours to kick in)

• Depending on concentration:

  • 7-10 days mydriasis

  • 7-12 days cycloplegia

Atropine (0.5, 1.0, 2.0% solution)

What are the contraindications for Atropine (0.5, 1.0, 2.0% solution)?

Narrow angles (can induce an angle closure), Downs syndrome, infants

What are the toxicities associated with Atropine?

Ocular: IOP elevation, SPK

Systemic (anti-SLUDGE): Dry flushed skin, thirst, hallucination, tachycardia, fever, urinary retention, decreased salivation, lacrimation

If your patient experiences anticholinergic toxicity, what can you do to help?

• Benzodiazepines for treatment

• Physostigmine is usually only given in the case of both peripheral and central signs and symptoms of anticholinergic poisoning (also used for MG)

  • An acetylcholinesterase inhibitor – increases the amount of ACh

What drug?

• Mydriasis for 3-7 days

• Cycloplegia: 5-7 days

• Contraindications/Toxicity: same as atropine

• Discontinued

Scopolamine (0.25%)

What drug?

• Mydriasis: 1-3 days

• Cycloplegia: 1-3 days

• Contraindications/Toxicity: same as others but to a lesser extent

Homatropine (2%, 5%) solution

What drug?

• Mydriasis: 1 day

• Cycloplegia: 1 day

  • Better cycloplegia than homatropine (used the most often)

• Contraindications: narrow angles

• Toxicity:

  • Ocular: SPK, hyperemia

  • Systemic: dose related, relatively safe

Cyclopentalate (0.5%, 1.0%, 2.0%) solution

What drug?

• Mydriasis: 4-6 hours, fastest onset and shortest duration

  • Drug of choice for DFE

• Cycloplegia: 4-6 hours, but not very effective

• Contraindications: narrow angles

• Toxicity: rare, very safe drug

Tropicamide (0.5%, 1.0%, 0.25% with 1% H-amphetamine (Paremyd)

What are the indications for adrenergic agonists/sympathomimetics?

• Pupil dilation (mydriatic) – α1 agonist

  • Phenylephrine

• Conjunctival constriction – α1 agonist

  • Phenylephrine (conjunctival blood vessels constrict – episcleritis), Lumify!

• Used to treat glaucoma – α1, α2 agonists and β1 and β2 antagonists (blockers)

  • IOP spikes with angle closure or after surgical procedures

  • Treatment of POAG

  • Brimonidine and apraclonidine

How does Brimonidine (Alphagan P) work in treating glaucoma?

It activates α2 receptors in CB vasculature to:

• Decreases aqueous humor production initially***

  • When an α2 receptor is bound and activated by an agonist, its G-protein is phosphorylated as well, but the activated G protein to which the α2 receptor is linked is an inhibitory G-protein. As such, α2 receptor binding and G-protein phosphorylation will down regulate adenyl cyclase. This leads to down regulation of cAMP and protein kinase A, causing the sodium potassium ATPase pump in the ciliary epithelium to spin more slowly —> less aqueous

• Increases uveoscleral outflow after long term use - MOA unknown

What are the indications for Brimonidine (Alphagan P)?

• POAG (#1 indication) - not your first choice, use as adjunct

  • Vessel constriction - Lumify

What are the contraindications of Brimonidine (Alphagan P) and Apraclonidine (lopidine)?

Monoamine oxidase inhibitors (MAOIs)

• Used for depression

• Interfere with the metabolism of brimonidine and potentially result in an increased systemic side effect such as hypotension

What are the toxicities associated with Brimonidine (Alphagan P) and Apraclonidine (lopidine)?

Follicular conjunctivitis (C(hlamydia)H(erpes)A(denovirus)T(oxicity)), not seen as much in the brand name b/c the concentration is lower

How does Apraclonidine (lopidine) work in glaucoma?

Same as brimonidine but less selective

• Some α1 as well, but limited

• Better IOP decrease than brimonidine because it’s a higher concentration

What are the indications for Apraclonidine (Iopidine)?

IOP spikes

• Horner's Syndrome: dilates Horner's pupil, won't dilate normal (α1)

• Angle closure, LPI, YAG posterior capsulotomy

• Not used chronic basis (wears off – only used in acute situations)

  • Tachyphylaxis after a few weeks

    • Loss of response of tissues following repeated or continuous administration of a drug

What type of drug is Brimonidine (Alphagan P)?

Adrenergic Agonist

What type of drug is Apraclonidine (lopidine)?

Adrenergic Agonist

What receptor(s) are found in the ciliary body?

β1 and β2

What receptor(s) are found in the heart?

β1

What receptor(s) are found in the lungs?

β2

What would a B2 agonist cause?

Bronchodilation

What would a B2 antagonist cause?

Bronchoconstriction

How do B-blockers work in glaucoma?

Lower IOP by decreasing aqueous production

• The effect is rapid (within an hr) – can use in acute situations

Lower IOP by inhibiting epinephrine binding at beta adrenoreceptors

• Normal situation: β1 or β2 receptors are linked to stimulatory G-proteins which stimulate a bunch of events which leads upregulation of cAMP. This leads to upregulation of PKA

• β-blockers prevent this pathway from occurring so aqueous production is decreased

  • No epinephrine binding —> no G protein activation —> no upregulation of cAMP —> no PKA upregulation —> decreased speed at which a sodium potassium ATPase pump turns in the NPCE membrane, which increases sodium export and aqueous production

What are the contraindications for B-blockers?

• COPD

• Asthma

• Low pulse

• Hypotension

• Caution with diabetics

• Myasthenia Gravis – directly impair neuromuscular transmission making symptoms worse

What are the toxicities associated with B-blockers?

Systemic:

• Mask symptoms of hypoglycemia (rapid heartbeat) – β-blockers will slow heartbeat

• Cough

• Respiratory failure

• Arrhythmia

• Hypotension

• Cardiac arrest

• CNS effects: confusion, fatigue

• Depression

• Headache

Ocular:

• Burning

• SPK

• Dry eye

• Pain

• Hyperemia

What drug?

• Non selective β-blocker

• 25% IOP reduction in about 30 min for 12-24 hours

• Often dosed bid, but many now doing qd (2nd dose doesn't provide much additional effect)

• AM dosing only, SNS is more active during the day

• Cross ever effect (bilateral effect despite unilateral administration)

• Tachyphylaxis

Timolol (0.25%, 0.5%) solution / Timoptic XE-gel based

What are the indications for Timolol?

POAG, angle closure attacks, secondary glaucoma

What is the cap color for 0.25% B-blockers?

Baby blue

What is the cap color for 0.5% B-blockers?

Yellow

What drug?

• Cardio selective

  • Selectively blocks β1 receptors therefore less likely to induce respiratory complications which are β2

  • β1 activity could worsen congestive heart failure

  • Less effective than a non selective agent

Betaxolol (Betopic-S) 0.25% suspension