ocular hypotensive agents

what are the two ways we can target IOP?

• aqueous suppression

• outflow enhancers

what affects treatment adherence?

• lack of understanding for why they need meds

• meds side effects

• cost of meds

• difficulty installing drops

• number of drops/day and bottle confusion

what do we want when prescribing glaucoma meds?

• significant IOP drop

• long duration

• works at nighttime

• simplified dosing

• limited side effects

what are our first line agents for IOP lowering?

• beta blockers (25-30% reduction)

• prostaglandin analogs (25-30% reduction)

what are our second line/additive agents for lowering IOP?

• alpha 2 agonists (20-25% reduction)

• carbonic anhydrase inhibitors (15-20% reduction)

• RhoKinase inhibitors (4-5mmHg reduction)

• miotics (15% reduction)

what is the mechanism of action of prostaglandins?

binds the FP receptors on the ciliary muscle that results in a remodeling of collagen in the extracellular matrix surrounding ciliary muscle fibers resulting in widening space between the longitudinal muscle fibers decreasing resistance to uveoscleral outflow

might also stimulate release of inflammatory cytokines and increase active transport of aqueous through TM

what is the therapeutic effects of prostaglandins?

• highest degree of efficacy, least amount of side effects, and longest duration of action

• peak onset: 8hrs after instillation

• duration of action: 24 hrs

side effects of prostaglandins

• conj hyperemia

• increase pigmentation and growth of lashes (reversible)

• increase pigmentation of periorbital skin tissue (reversible)

• change iris color (permanent)

• sunken sulcus syndrome

• potentially: uveitis, CME, pseudodendrites, questionable recurrence of simplex keratitis

contraindications of prostaglandins

• uveitic glaucoma

• Potential caution: history of simplex, aphakia/pseudophakia with high risk of CME, and concurrent use of miotics

other cautionary uses of prostaglandins

• not for immediate use (takes 8 hrs for effectivity)

• angle recession

• mixed color irides

• unilateral treatment (due to pigment changes)

what do we use prostaglandins for?

• ocular hypertension

• POAG

• pigmentary glaucoma

• pseudoexfoliation glaucoma

• normal tension glaucoma

how do we dose prostaglandins?

one drop, once a day at bedtime (keeps redness side effect at bay)

xalantan (0.005% latanoprost)

• prostaglandin: outflow enhancer

• least likely to induce redness

• prodrug

• preserved with 0.02% BAK

iyuzeh (0.005% latanoprost)

• prostaglandin: outflow enhacer

• preservative free

• not a lot of redness

travatan Z (0.004% travoprost)

• prostaglandin: outflow enhancer

• preserved with SofZia (no BAK unless generic)

• longest duration of action

lumigan (0.01% bimatoprost)

• prostaglandin: outflow enhancer

• prostamide = greater receptor affinity

• preserved with 0.02% BAK

• causes a good amount of redness (especially the generic form)

zioptan (0.0015% tafluprost)

• prostaglandin: outflow enhancer

• preservative free (vials)

• not incredibly effective

vyzulta (0.024% latanoprostene bunod)

• prostaglandin: outflow enhancer

• nitric oxide prostaglandin (NO allows TM to open up even more)

• extremely effective (30-35% reduction)

Omlonti (0.002% omidenepag isopropyl solution)

• outflow enhancer

• non prostaglandin F analog (works on EP2 receptors)

• less likelihood of inducing prostaglandin associated orbitopathy

why would patients switch between prostaglandins?

• formulary/insurance reasons

• need to reduce side effects

• need to get improved efficacy

latisse (0.03% bimatoprost)

• prostaglandin used for the side effect of growing lashes

• used for treatment of hypotrichosis/madarosis of eyelid

• Ohio ODs must have medical condition in order to RX

Rhopressa (0.02% netarsudil)

• Outflow enhancer

• inhibits RhoKinase proteins that are part of TM decreasing cellular rigidity and increasing TM outflow

• also reduces episcleral venous pressure by 10%

• can be an additive to prostaglandins

• also promotes cell adhesion and is anti-apoptotic which can treat Fuch’s or other endothelial issues

• SE: hyperemia, vortex keratopathy, pain, conj heme

pilocarpine/miotics (2%)

• binds muscarinic receptors of iris sphincter causing pupillary constriction, increases outflow by opening up the TM channels through contraction of iris

• decreases IOP by 15%

• rarely used, sometimes as companion drug dosed BID

side effects and contraindications of pilocarpine

• ocular: ciliary spasm, blurred vision, browache, pupillary miosis, decrease VA from cataracts, retinal detachments

• systemic: bradycardia, bronchoconstriction, sweating, salivation, abdominal cramping

• contraindicated in: uveitic and neovascular glaucoma, risk of retinal detachment

• caution in: age<40, asthma, concurrent use of prostaglandins

what do we use pilocarpine for now?

• acute angle closure from pupillary block (helps pull peripheral iris away from angle structures)

• pre-op for all laser PI

• pseudoexfoliation glaucoma

• pigmentary glaucoma

what is the mechanism of action of beta blockers?

• antagonist to both B1 and B2 receptors in the non-pigmented ciliary body epithelium (mostly B2 are involved in aqueous production)

• decreases aqueous production with IOP lowering of 25-30%

• fastest onset of action

what is a big problem with beta blockers?

they are not effective at nighttime, potentially even harmful for nighttime use because it lowers blood pressure but not IOP so less blood is getting to the optic nerve causing more damage.

why do we switch between 0.5 and 0.25% concentrations of beta blockers?

we use 0.25% initially to help limit side effects but if we need more effect we can up the concentration. also, if more iris melanin, then we might need stronger concentration to make sure it gets to the non-pigmented epithelium.

side effects of ophthalmic beta blockers

ocular: stinging, dry eye, corneal anesthesia

systemic: bronchospasm, bradycardia, hypotension, elevate blood lipid levels, depression/lethargy, impotence

contraindications of beta blockers

• asthma/COPD (any pulmonary defect)

• resting bradycardia (pulse <60)

• congestive heart failure

• pregnant/nursing mothers

• caution in: infants and small toddlers, concurrent use with systemic beta blockers, normal tension glaucoma

when do we use ophthalmic beta blockers?

• POAG

• ocular hypertension

• secondary glaucomas: pigmentary, uveitic, steroid induced, pseudoexfoliation

• acute angle closure glaucoma

• topical IOP “rescue” drug of choice

timolol (0.25 or 0.5%)

• beta blocker: aqueous supression

• gold standard

• non-selective b1 and b2 blocker

what are the trade names of timolol?

• timoptic (gel, solution, or PF)

• betimol

• istalol (only 0.5%)

yellow or light blue cap

beta blocker

navy blue cap

beta blocker combo agent

light green cap

non-beta blocker combo agent

orange cap

carbonic anhydrase inhibitors

teal cap

prostaglandin analogs

purple cap

alpha-2 agonist

white cap

RhoKinase inhibitor

red cap

mydriatics/cycloplegics

green cap

miotics

pink cap

steroids

grey cap

NSAIDS

brown/tan caps

anti-infectives

levobunolol (0.5%)

• beta blocker: aqueous suppression

• non-selective beta 1 and beta 2 blocker

• comparable to timolol

carteolol (1.0% carteolol)

• beta blocker: aqueous suppression

• non-selective beta 1 and beta 2 blocker

• only FDA approved for BID because of short half life

• less: bradycardia, hyperlipidemia, sting on instillation

• induces moderate corneal anesthesia

Betoptic-s (0.25% betaxolol)

• beta blocker: aqueous suppression

• selective beta 1 blocker

• BID dosing

• suspension

• most sting

• has calcium channel blocking properties (helps with perfusion to nerve)

  • last ditch effort for normal tension glaucoma

what is the mechanism of action of alpha-2 agonist?

• activates presynaptic alpha2 receptors that prevent release of NE and lessens the stimulation of post-synaptic beta receptors on the non-pigmented ciliary epithelium to decrease aqueous production

• possible secondary: some relaxing effect on ciliary body muscle fibers that provides some enhancement of uveoscleral outflow (primarily aqueous suppression)

• reduce IOP by 20-25% within 1 hour of instillation

side effects of alpha-2 agonist

ocular

• conj blanching

• follicular conjunctivitis (no need to discontinue meds)

• severe allergic conjunctivitis/contact dermatitis (requires discontinuation of meds

systemic

• dry mouth

• headache

• fatigue/lethargy

contraindications of alpha-2 agonist

• concurrent use with MAO inhibitors

• children

Alphagan P (0.1 and 0.15% brimonidine)

• purite preservative (vanishing)

• generic is preserved with BAK

• highly selective alpha2 agonist

• aqueous suppression

• dosed BID as additive agent

• dosed TID as monotherapy

what do we use alpha-2 agonists for?

• second line agents

• additive to 1st line agents

• normal tension glaucoma

• immediate pre-op and post-op to prevent IOP spike with ALT and PI surgery

• off-label to decrease pupil size if glare from lasik

• this is also Lumify

apraclonidine (0.5%)

• alpha 2 and alpha1 agonist (may cause some vasoconstriction)

• onset within 1 hour

• dosed TID as monotherapy

• dosed BID as companion agent

• not used long term because there is high likelihood of allergic conjunctivitis/contact dermatitis

when do we use apraclonidine?

1. immediate pre-op and post-op to prevent IOP spike with ALT and PI surgery

2. lower IOP in acute angle closure

3. short-term therapy awaiting surgical interventions

mechanism of action of carbonic anhydrase inhibitors

inhibition of carbonic anhydrase decreases formation of bicarbonate ions. resulting in aqueous suppression by reducing flow of H2O into the posterior chamber following bicarb and Na

topicals give 15-20% IOP reduction

orals give 45-55% IOP reduction

2.0% dorzolamide and Azopt (1.0% brinzolamide)

• carbonic anhydrase inhibitor: aqueous suppression

• only decrease IOP by 15-20% so not used standalone (does work at night though)

• dosed TID monotherapy

• dosed BID as an additive agent

side effects and contraindications of topical carbonic anhydrase inhibitors

ocular: stinging, fb sensation, may diminish corneal endothelial function

systemic: bitter/metallic taste

contraindications: fuch’s

what are oral carbonic anhydrase inhibitors used for systemically?

• excreted through kidneys—> diuretic effect

• IIH

• altitude sickness

• some epilepsy

• reduces IOP by 45-55%

side effects of oral carbonic anhydrase inhibitors

• numbness/tingling in fingers and toes

• metallic taste

• malaise complex (fever-like symptoms)

• nausea and diarrhea

• systemic acidosis

• blood dyscrasis

• liver damage

contraindications of carbonic anhydrase inhibitors

• renal and liver disease

• COPD

• pregnancy

• sickle cell disease/trait

• sulfa allergy (potentially not a problem anymore)

what are the oral carbonic anhydrase inhibitors?

• acetazolamide: rapid onset but high side effects

• methazolamide: slower onset of action but lower risk of side effects

what do we use carbonic anhydrase inhibitors for ocularly?

• treatment of acute angle closure glaucoma (especially IOP >50 mmHg)

• advanced POAG on maximal medical therapy

Cosopt (0.5% timolol and 2% dorzolamide)

• combo beta blocker and CAI (works at nighttime)

• dosed BID

Combigan (0.5% timolol and 0.2% brimonidine)

• combo beta blocker and alpha 2 agonist (neither work at nighttime)

• preserved with BAK

simbrinza (1.0% brinzolamide and 0.2% brimonidine)

• combo CAI and alpha 2 agonist (works at nighttime)

• 1st combo without beta blocker (okay for asthmatics)

• suspension

• dosed TID

• preserved with BAK

Rocklatan (0.2% netarsudil and 0.005% latanoprost)

• combo RhoKinase inhibitor and prostaglandin agonist

• 1st glaucoma combo with PG

• dosed 1gt QHS

what is the glaucoma medication that is allowed to be used during pregnancy?

CAIs but SLT is most recommended

iDose TR

• sustained-release travoprost implanted into AC angle

• releases meds for 3 yrs and then needs refilled

• iGAP

Durysta

• 10 mcg bimatoprost implant

• lowers IOP by 30% for 12-15wks but only FDA approved for single use

• iGAP

• contraindicated in: Fuch’s, no/open posterior capsule, post pk, narrow angles