ABC's, pilocarpine & rho kinase inhibitors

what was propranol introduced to treat

hypertension

angina

cardiac arrythmias

what is a side effect of propranol

corneal anesthesia

what is a side effect of practolol

immunological problems (oculomucocutaneous syndrome)

what does beta 1, 2 and 3 stimulation cause

beta 1: increase heart rate, cardiac contractility & artroventricular conduction

beta 2: dilation of bronchi & blood vessels

beta 3: mediation of lipolysis

selectivity is relative at ___ concentrations selective beta-adrenergic act on __ beta receptors

high; all

what is the mechanism of action of ocular beta blockers

reduction in aqueous formation (no change in outflow facility)

what is the classic hypothesis on the mechanism of ocular beta blockers

beta blockers inhibits beta adrenergic agonists from binding to its receptors stopping the activation of G-protein, which stops formation of cAMP

what is the evidence against the classic hypothesis

IOP can decrease in response to increase in cAMP

both dextro & levo isomer of timolol decrease IOP (evidence against competitive inhibition)

what is the alternate hypothesis of the mechanism of OBBs

ciliary process are under continuous tonic stimulation to produce aqueous & beta blockers interfere with the tonic stimulation

(no anatomic basis identified yet)

If the amount of drug is not limited how much aqueous humor suppression can occur due to beta blockers?

50%

contraindications of beta blockers

pulmonary disease, bronchial asthma, COPD

sinus bradycardia

overt congestive heart failure

hypersensitivity

which OBB is not contraindicated for pulmonary diseases?

betaxolol

what is the treatment regimen for OBB

once or twice daily in the morning

twice daily may lower IOP more but more side effects

what OBB are the exceptions to taking OBBs twice daily

isatalol QAM

timoptic XE or GFS (gels) qd

betagan qd

which concentration is most commonly used for ocular beta blockers?

0.5%

when would 0.25% concentration of OBBs be used?

if pt has history of asthma or bradycardia

children

why is BAK commonly used in OBBs?

allows it to penetrate corneal epithelium

timolol characteristics

non selective beta adrenergic antagonist

no corneal anesthesia (like propranolol)

greater efficacy than pilocarpine

what is the onset & peak action of timolol

onset: 30 mins

peak: 2 hrs

max: 12 hr & continues lowering for 24 hrs

what is short term escape

efficacy of timolol decreases over time (several weeks)

response of beta receptors to constant antagonist

may be an up regulation of beta receptors in target tissue

what is long term drift

over months to years

control of IOP not as good as once

washing out & re starting helps

how long is a wash out period for

2-6 weeks (clinically 4 weeks)

advantages & disadvantages of gels

advantages: improve bioavailability; decrease systemic absorption

disadvantage: blurs vision if left over in morning

what is timoptic XE preserved with?

benzododecinium bromide

characteristics of istalol (timolol maleate 0.5%)

formulated with potassium sorbate

claims to enhance bioavailability (once daily)

lower BAK concentration

on istalol most visits IOP difference is within __ mm Hg & all visits are within __ mm Hg

1 mm hg; 1.5 mm hg

what was the initial and later concentration of betaxolol hydrochloride

initial: 0.5% solution

later: 0.25% suspension of resin coated beads

what are the advantages and disadvantages of betaxolol suspension (betoptic S)

advantage: less ocular irritation than solution; can be used in patients with pulmonary disease; lower CNS effects

disadvantage: less effective than timolol

is betaxolol lipophilic or hydrophilic

lipophilic (binds well with plasma proteins)

how does betaxolol have neuroprotectic effect

possess calcium channel blocker properties (if Ca enters cells it causes apoptosis)

local side effects of OBBs

discomfort

burning

stinging

what ocular side effects of OBBs does BAK make worse

decreased tear production

decreased goblet cell density

ocular cicatricial pemphigoid

dry eye symptoms

metipranolol is associated with what ocular side effect

granulomatous uveitis

OBBs enter systemic circulation via __

nasolacimral system

peak vs trough plasma levels of OBBs

peak: 50-103 ng/milliliter

trough: 0.8-7.2 ng/milliliter

plasma levels of timolol

5.0-9.6 ng/milliliter

CNS adverse effects of OBBs

anxiety, depression, fatigue, lethargy, confusion, sleep disturbance, memory loss & dizziness

decreased libido men & women

impotence in men

cardiovascular adverse effects of OBBs

lower heart rate

lower bp

decreased myocardial contractility

slowed conduction time

metabolic adverse effects of OBBs

affects lipid metabolism

timolol: 12% increase in triglycerides; 9% decrease in HDL

what systemic condition may beta blockers mask

diabetes hypoglycemia

what are types adrenergic agents

clonidine

apraclonidine

brimonidine

clonidine adverse effects

sedation

systemic hypotension

narrow therapeutic index

apraclonidine characteristics

hydrophilic: does not penerate eyes & BBB

more alpha2 selective

wide therapeutic index

mechanism of action of apraclonidine

decreased aqueous production

improves trabecular outflow

decreased episcleral venous pressure

uses of apraclonidine

FDA approved to prevent post laser treatment spikes in IOP

Adjunctive therapy

mechanism of action of brimonidine

alpha 2 selective: reduction of aqueous production by activation of G-protein receptor, decreased cAMP & production of aqueous humor

peak effectiveness of brimonidine

2 hours

indications for bimonidine

prophylactic to avoid post laser IOP spike

primary or secondary therapy glaucoma & ocular hypertension

contraindications of brimonidine

MAOI bc may interfere with the metabolism of brimonidine and increase systemic side effects (hypotension)

children

adverse effects of brimonidine

conjunctival follicles, ocular allergic reactions and ocular pruritus

headache, blurring, foreign body sensation, sensation/drowsiness

oral dryness

ocular hyperemia, burning & staining

rho kinase inhibitors mechanism of action

changes to trabecular meshwork: cytoskeletal modulating drugs

netarsudil (rhopressa) mechanisms of action

primary: alter TM cells to allow aqueous humor to leave

secondary: changes episcleral venous pressure by making it lower, which causes less resistance for aqueous to leave

tertiary: alters NE transporter to lower aqueous production

what do MLCP and MLCK do to TM

MLCK causes TM to go into phosphorylated stage (contraction)

MLCP causes TM to go into dephosphorylated stage (relaxed)

what does netarsudil do to rho kinase

rho kinase inhibits MLCP (stops TM from relaxing)

netarsudil inhibits rho kinase

dosing of netarsudil

once daily in the evening

netarsudil adverse effects

conjunctival hyperemia

cornea verticillata: decreases contrast not VA

corneal erosions, changes in endothelium

conjunctival hemorrhage

lacrimation increased

how does netarsudil cause cornea verticillate

leaves a lipid sugar byproduct in lysosomes

what is netarsudil combined with that causes better IOP lowering than it alone?

latanoprost (roclatan)

mechanism of action cholinergic agents

contraction of ciliary muscle causes unfolding of meshwork & widening of schlemm's canal

cytoskeleton modulating drug

pilocarpine dosing schedule

drops: QID

gel: bed time

drug concentration of pilocarpine needed for light vs dark irises

light: 2%

dark: 6%

strength of pilocarpine

10-30 mins onset

max IOP reduction: 75 mins

lasts 4-8 hr

IOP lowering 4-14 hrs

side effects of pilocarpine

stinging, burning

prolonged use: risk of failure with surgeries (hyphema)

ciliary spasm, temporal or supraorbital headache & induced myopia

pupillary block

miosis: decrease VA

cause of long term escape of pilocarpine

increasing problems in drainage mechanism

systemic toxicity of pilocarpine

sweating

salivation & lacrimation

gastrointestinal

contraindications of pilocarpine

risk/history of retinal detachment

intraocular congestion like uveitis

any one whom pupil size & accommodation is an issue

what drugs can you combine pilocarpine with

combined with drugs that decrease aqueous humor production (beta blockers, carbonic anhydrase inhibitors)

what do carbonic anhydrase inhibitors do

reduction of bicarbonate ions in posterior chamber that subsequently prevents Na+ movement & hence water movement

dosage of oral carbonic anhydrase inhibitors

acetazolamide max dose 250 mg qid

methazolamide max dose 150 mg bid

contraindications of carbonic anhydrase inhibitors

sulfa allergies

DM susceptible to ketoacidosis

hepatic insufficiency & cannot tolerate the increase in serum ammonia

chronic obstructive pulmonary disease who increase retention of carbon dioxide can cause narcosis

low endothelial cell count

side effects of CAIs

numbness, paresthesias, malaise, anorexia, nausea, flatuelnce, diarrhea, depression, decreased libido, hirsutism, serum urate

durysta (bimatoprost) sustained release implants

releases a pellet & goes to inferior region & slowly releases but can only do it once because over time can cell loss