KMK oc pharm Flashcards
What percentage of topical drug concentration is lost via evaporation?
around 25%
After evaporation what are the three places a topical drug could go in the eye?
- drainage into the nasolacrimal apparatus
- absorption into the systemic circulation by the conjunctival and lid vasculature
- penetration into the cornea
Which layers of the eye and tears are lipid vs. water soluble, (affecting bioavailability of topical drugs)?
lipid soluble: lipid and mucous layer of tears, epi and endothelium of cornea
water soluble: aqueous and mucous layer of tears, stroma of cornea
What drug solubility composition is best for maximizing bioavailability?
small, uncharged (non-ionized), lipid-soluble molecules
Ocular drugs are formulated most often as _______ because this allows more non-ionized portions of the drug and better bioavailability
formulated most often as weak bases
What regions of the CNS are sympathetic cell bodies located
thoraco-lumbar regions
What regions of the CNS are parasympathetic cell bodies located
cranio-sacral regions
Preganglionic neurons are longer in which autonomic pathway?
parasympathetic
Postganglionic neurons are longer in which autonomic pathway?
sympathetic
The sympathetic system acts on which receptors?
alpha and beta
The parasympathetic system acts on which receptors?
muscarinic
What are the major actions of the parasympathetic system?
“rest and digest”, bronchoconstriction, miosis, vasodilation, increase SLUD: salivation, lacrimation, urination, defecation
What are the major actions of the sympathetic system?
“fight or flight”, bronchodilation, mydriasis, vasoconstriction, decrease in secretions
What are the cholinergic receptors in the eye?
M3 in iris sphincter for miosis, M2/M3 in ciliary muscle for accommodation, and M2/M3 in lacrimal gland for tears production
What are the adrenergic receptors in the eye?
a1 in iris dilator, a2 in CB vasculature (reduces aqueous production), b2 in TM and ciliary muscle, and b2/b1 in NPCE (increases aqueous production)
What eye conditions/diseases are cholinergic agonists commonly used to treat?
glaucoma and accommodative esotropia
Why are cholinergic agonists used to treat accommodative esotropia?
Directly stimulating the cholinergic receptors on the ciliary muscle decreases the amount of CNS stimulation to the ciliary muscle resulting in reduced convergence (which depends on CNS stimulation)
What is the MOA of pilocarpine?
stimulates the longitudinal muscle of CB, which pulls posteriorly on the scleral spur and opens up the trabecular spaces for an increase in outflow and decrease in IOP
Clinical uses for pilocarpine:
- utilized after angle closure attack and in preparation for LPI
- 1% pilocarpine used to differentiate a CN3 palsy from a sphincter tear in a patient with a fixed dilated pupil (palsies will still constrict pupil)
- 0.125% pilocarpine used in dx of Adie’s tonic pupil, supersensitized will respond with miosis even to the diluted drug
What are the main side effects of pilocarpine?
brow ache, headache (tension), myopic shifts, miosis, cataracts after long-term use, RRDs, secondary angle closure glaucoma (pupillary block)
What are indirect cholinergic agonists?
anticholinesterase agents (AchE inhibitors) act as indirect agonists by inhibiting acetylcholinesterase which normally breaks down ACh
Edrophonium (Enlon)
an AchE inhibitor, used in dx of myasthenia gravis (Tensilon test), if ptosis improves the test is positive
rapid onset (30-60s) and short duration (10min)
Neostigmine (Prostigmin)
an AchE inhibitor, treatment of myasthenia gravis, and for limb strength eval (Neostigmine test)
Echothiophate (Phospholine)
an AchE inhibitor, can be used for the dx or tx of accommodative esotropia, rarely for glaucoma
Pyridostigmine (Mestinon)
an AchE inhibitor, used for tx of myasthenia gravis
Which AchE inhibitors are irreversible and have more side effects?
Echothiophate and isofluorophate
Pralidoxime (Protopam)
IV drug used to reverse the effects of irreversible AchE inhibitors, usually in cases of pesticide poisoning
What is the MOA for cholinergic antagonists?
these drugs block ACh at muscarinic receptor sites in the ciliary body and iris (sphincter) resulting in dilation and cycloplegia
Which cholinergic antagonist has the fastest onset and shortest duration of mydriatic effects?
tropicamide, mydriasis onset of 20-30min and duration of 6 hours
Which cholinergic antagonist has the highest potential for severe side effects?
Scopolamine - hallucinations, amnesia, unconsciousness, confusion, incoherence, vomiting, urinary incontinence, etc.
Which cholinergic antagonist is commonly used for treating anterior uveitis?
Homatropine is the standard, but atropine and cyclopentolate can also be used
What are the symptoms of atropine toxicity?
dry mouth (usually 1st sign), dry flushed skin, rapid pulse, disorientation, fever
Which cholinergic antagonist has the fastest onset and shortest duration of cycloplegic effects?
Cyclopentolate, average cycloplegic onset of 45mins, (20-45min for mydriatic effect), routine for cycloplegic refractions in pts under 10yo especially
What are the three ways that homatropine helps in treating anterior uveitis?
- dilates the pupil and decreases the likelihood of posterior synechiae formation
- reduces pain by paralyzing ciliary and sphincter muscles
- stabilizes the blood-aqueous barrier by constricting the iris and CB vasculature to limit passage of blood contents into the aqueous humor
How does botulina toxin (Botox) work?
somatic drug that blocks the release of ACh at the neuromuscular junction, which inhibits muscle contraction
Which receptors do epinephrine and norepinephrine act on?
Epinephrine acts on all four adrenergic receptors, a1/a2/b1/b2, and norepinephrine does not act on b2
What is the MOA of phenylephrine (Neo-Synephrine)?
a1 agonist, no effect on beta receptors, allows dilation without cycloplegia
Clinical uses of phenylephrine besides dilation:
- palpebral widening (Mullers muscle)
- blanches conj vessels to indicate episcleritis from scleritis
- dx Horner’s syndrome
- 10% phenyl for breaking posterior synechiae (*adverse CV effects!*)
Phenylephrine 10% is contraindicated in:
patients taking MAOIs, tricyclic antidepressants, atropine, patients with Graves disease and heart conditions
Naphazoline (Naphcon) and Tetrahydrozoline (Visine)
topical ocular decongestants to constrict conj blood vessels, greater alpha effects than beta, have the potential to depress the CNS
What common drop use can cause fixed dilated pupils if used excessively?
Visine, because of alpha effects on the radial muscle of the iris
What is the MOA for alpha2 agonists used for glaucoma treatment?
decreasing aqueous humor production by causing vasoconstriction of the CB vasculature and also increases uveoscleral outflow
Which alpha agonist glaucoma drop is highly selective a2 agonist with no a1 effects?
Brimonidine (Alphagan 0.20%), allows effective IOP lowering and long-term tx of glaucoma
Which glaucoma drops have shown neuroprotective properties?
Brimonidine and Betaxolol
What is the difference between Alphagan-P (0.10 or 0.15%) and Alphagan 0.20% besides concentration?
Alphagan-P has purite as the preservative which is believed to have decreased the incidence of allergic or toxic reactions to the drop that before was causing follicular conjunctivitis (30% of pts had to d/c bc of)
What is the recommended dosing for Alphagan when it is the only drop being used?
TID, relatively short duration of action
What is another use for brimonidine besides in glaucoma patients?
causes miosis, so can be used to reduce glare, halos, and other night vision symptoms for patients after LASIK, PRK, etc.
When is brimonidine contraindicated?
in patients taking MAOIs
What is the most common systemic side effect of brimonidine and apraclonidine?
dry mouth
What receptors does Apraclonidine (Iopidine) act on?
primarily alpha2 agonist, with limited alpha1 activity
What are the clinical uses for Apraclonidine (Iopidine)?
- used to control IOP spikes before and after ocular surgeries such as LPIs, trabeculoplasties, and posterior capsulotomies
- used for rapidly decreasing IOP in an acute angle closure attack
- can be used in dx Horner’s syndrome (causes a Horners pupil to dilate from the weak alpha1 activity, but is not strong enough to dilate a normal healthy pupil)
What % does apraclonidine reduce IOP and how long does it last?
30-40% IOP reduction onset <1hr (peak 3-5hrs), efficacy reduces after 8 days of using drop so is not useful for chronic treatments
How can you diagnose Horner’s syndrome before pharmacological testing?
observe the miotic pupil when turning off lights, a delayed dilation (most apparent in first 5 seconds) will exist due to abnormal sympathetic innervation to the dilator muscle, and with a ptosis is dx of Horners
How do you diagnose Horners pharmacologically?
- cocaine 4% OU blocks reuptake of NE, healthy eyes dilate, but a pupil with lost sympathetic innervation will not dilate
- Apraclonidine 2gtts 0.5% OU causes dilation of affected pupil due to supersensitivity (weak a1 activity is enough to cause dilation), healthy pupils will not be affected (or will have mild constriction from decreased NE release on a2)
How do you determine the location of innervation loss in Horners syndrome pharmacologically?
- hydroxyamphetamine 1% OU will increase NE release and block reuptake, if the damage is preganglionic, both pupils will dilate, if the damage is postganglionic the Horner pupil will not dilate (no NE terminals)
- low concentration adrenaline (1:1000) or phenylephrine 1% - postganglionic Horner pupil will dilate due to supersensitivity
What are the beta-blockers used for treating glaucoma?
Timolol, levobunolol, betaxolol, metipranolol, and carteolol
What are the systemic side effects of beta-blocker drops?
CNS - disorientation, depression, fatigue
CV - bradycardia, arrhythmias, syncope
Pulmonary - dyspnea, wheezing, bronchospasm
GI - nausea, vomiting, diarrhea, pain
Reproductive - ED
Topical beta-blockers are contraindicated when?
in patients with asthma, COPD, bradycardia, or CHF
caution with diabetics (masks hypoglycemic symptoms), hyperthyroidism (masks symptoms), and myasthenia gravis patients (symptoms of weakness can be exacerbated)
What is the MOA of beta-blocker drops?
block beta-adrenergic receptors throughout the body, primarily b2 in the NPCE to decrease aqueous production
Which beta-blocker is the only topical b1 selective drug and what is its advantage?
Betaxolol (Betoptic-S) is the only topical b1 selective drug, it is safer for patients with lung conditions (less lung side effects) and also possibly has neuroprotective qualities, however not as effective as Timolol for reducing IOP and may be worse for pts with CHF
Which beta-blocker drop is the most effective at lowering IOP?
Timolol (Timoptic), around 25% reduction in IOP
Crossover effect with beta-blockers
unilateral use of beta-blocker drop reduces the IOP in the contralateral eye as well
What is the dosage for beta-blocker drops?
typically BID, but can be once daily if dosed in the morning (better daytime efficacy)
What are the combination glaucoma drops with timolol?
Cosopt (0.5% timolol and 2% dorzolamide) and Combigan (0.5% timolol and 0.2% brimonidine) dosed q12hr
What are some advantages of Carteolol (Ocupress) when compared to the other beta-blockers?
does not lower IOP as well, but has intrinsic sympathomimetic activity, significantly reduces nocturnal bradycardia, is more comfortable (less stinging) than timolol, some reduction in cholesterol in pts with hypercholesterolemia, overall less side effects
Summary of glaucoma drug MOA
cholinergic agonists - increased corneoscleral outflow
alpha-adrenergic agonists - decreased production and increased uveoscleral outflow
beta-blockers - decreased production
carbonic anhydrase inhibitors - decreased production
prostaglandins - increased outflow via the uveoscleral route
Rho kinase inhibitors - decrease aq prod, increase corneal scleral outflow
What is the MOA for carbonic anhydrase inhibitor drugs?
block carbonic anhydrase enzyme from catalyzing the formation of bicarbonate from CO2 and H2O, which is believed to increase aqueous production by increasing Cl- and Na+ flux into the posterior chamber. so CAIs block bicarbonate and decrease production of aqueous
When are CAIs contraindicated?
severe COPD, pregnancy, sulfa allergies, caution in pts with liver or renal disease
What are the side effects of oral CAIs?
most common: metallic taste, tingling in hands and feet, metabolic acidosis (compensatory hyperventilation not good in COPD pts)
most serious: thrombocytopenia, agranulocytosis, aplastic anemia (can be fatal!)
other adverse effects: malaise, fatigue, weight loss, anorexia, impotence, depression, diarrhea, and myopic shifts in refractive error
Brinzolamide 1% (Azopt) and Dorzolamide 2% (Trusopt)
topical CAIs
Acetazolamide (Diamox) Methazolamide (Neptazane)
oral CAIs
Travatan Z
new formulation of Travoprost with Sofzia as the preservative instead of BAK
What % of IOP lowering do prostaglandins provide?
27-35%, highest of the glaucoma drops
Latanoprost (Xalatan 0.005%) Bimatoprost (Lumigan 0.03%) and Travoprost (Travatan 0.004%)
prostaglandin analogues
What dosing is recommended for prostaglandins?
QHS, allows for better diurnal control than morning dose, has a daytime peak effect 12-24hrs after administration
What is the MOA for prostaglandin analogues?
act on FP receptors (PGF2a receptors) on ciliary muscle, which causes reduction of neighbouring collagen (via metalloproteinases), decreasing resistance within the uveoscleral meshwork for increased outflow
What are the contraindications for prostaglandin analogues?
pts who are at risk for CME (cataract sx post-op), cases of active inflammation (ex. uveitis), and pts with history of HSV keratitis
What are the side effects of prostaglandin analogues?
iris heterochromia, increased pigmentation and growth of eyelashes, skin darkening around the eyes, MGD, orbital fat atrophies, conjunctival hyperemia (worse with Lumigan, least with Xalatan), pruritis also worse with Lumigan
Summary of % IOP reductions of glaucoma drops
prostaglandins decrease 33%, beta-blockers decrease 25%, brimonidine and dorzolamide both decrease 18%
What is the MOA of topical ocular anesthetics?
local anesthetics block nerve conduction and change membrane permeability by stopping the influx of Na+ ions into the nerve cytoplasm. without Na+ entry, the nerve can no longer be depolarized
What are the differences between amide and ester anesthetics?
Amides have longer duration and are metabolized by the liver so less toxic - ex. lidocaine
Esters have shorter duration and are metabolized locally - all topical anesthetics are esters
Main topical anesthetics we use in the eye
Proparacaine (Ophthaine/Alcaine) and Benoxinate
onset 10-20sec, duration 10-20min
What is the MOA of antihistamines?
block Type I hypersensitivity reactions by blocking the cell receptors that histamine acts on (they don’t prevent histamine release from mast cells and basophils), results in minimizing redness, watering, itching symptoms of allergies
Emedastine difumarate 0.05% (Emadine)
antihistamine, for mild-moderate cases of allergic conjunctivitis, binds to H1 to out-compete histamine, rapid response
1gtt QID, >3yo
What is the MOA for mast cell stabilizers?
act on exposed mast cells and inhibits their degranulation upon re-exposure to the antigen, stabilizes mast cell membranes, preventing Ca2+ influx. Not effective for acute symptoms, used more for chronic allergic conjunctivitis, vernal conjunctivitis, and atopic keratoconjunctivitis
Cromolyn sodium (Crolom), Lodoxamide (Alomide), Pemirolast (Alamast), Nedocromil (Alocril)
mast cell stabilizers
mast cell and antihistamine combination drops
ketotifen fumarate 0.025% (Zaditor, Alaway, Zyrtec eye, Claratin eye, Refresh eye itch relief)
olopatadine hydrochloride 0.10% (Patanol) or 0.20% (Pataday)
bepotastine (Bepreve), epinastine (Elestat), azelastine (Optivar)
What is the MOA of steroid drops?
inhibit phospholipase A2 (arachidonic acid pathway), decreases inflammatory mediators and decreases capillary permeability (significant decrease in immune system response), also decreases fibroblast and collagen formation so prevents healing
What are the most clinically relevant side effects for ocular steroids?
increased risk of secondary infections (~HSV), PSC cataracts, and glaucoma (increase IOP from clogging TM with GAGs), delays healing
“Soft” steroid drops
fluorometholone (FML) 0.1% and loteprednol (Lotemax) 0.5%
Potent steroid drops
prednisolone 1% acetate, rimexolone (Vexol), difluprednate (Durezol), dexamethasone (Maxidex) 0.1%
What is the MOA for NSAID drops?
NSAIDs block cyclooxygenase I and II, which decreases inflammation by inhibiting the conversion of arachidonic acid into prostaglandins and thromboxanes (platelets)
Which NSAID drops are dosed QID?
Diclofenac sodium 0.1% (Voltaren) and ketorolac tromethamine 0.4% (Acular LS)
How are Nepafenac (Nevanec) and Bromfenac (Xibrom) dosed?
BID
Which NSAID drop is the only one approved for once a day dosage?
Bromday (bromfenac)
Which NSAID is used prior to ocular surgery (1gtt q30min, starting 2 hours before sx)
flurbiprofen 0.03% (Ocufen)
When are topical NSAIDs used clinically?
post-op cataract surgery patients, to decrease the risk of CME, recurrent corneal erosions, corneal abrasions, and allergic conjunctivitis, etc.
Which is the only NSAID approved to the topical treatment of seasonal allergic conjunctivitis
ketorolac
What are the ocular side effects for topical NSAIDs?
corneal toxicity, SPK, corneal melt (from repeated use of anesthetics and generic diclofenac), stinging on instillation
fluorescein dye
effective evaluation of tear film quality and epithelial defects
Rose Bengal
stains dead and devitalized cells, also can stain the edges of herpetic dendrite lesion
Lissamine green
similar stain to Rose Bengal but less discomfort
Methylene blue
similar to staining to Rose Bengal but also stains corneal nerves, used to outline blebs and for staining lacrimal sac before dacryocystorhinostomy
Pegaptanib (Macugen)
IVT, antineoplastic agent that binds and inhibits VEGF
Ranibizumab (Lucentis)
IVT, monoclonal antibody (fab portion) that targets VEGF
VEGF promotes…
vascular permeability (macular edema) and new blood vessel formation (neo)
Sodium chloride (Muro 128)
hypertonic solutions that is prescribed for reduction of corneal edema (Fuchs, RCE) as a drop 2 or 5% or in ointment
Glycerine (Osmoglyn)
Restasis (cyclosporin 0.05%)
inhibits T-cell activation by stopping the production of interleukin-2
cellulose esters (carboxymethylcellulose and hydroxymethylcellulose) and polyvinyl alcohol (PVA)
substances used in artificial tears to enhance lubrication
Benzalkonium chloride (BAK)
very common preservative in drops, well-known to cause corneal toxicity (SPK)
Thimerosal
preservative used in Trifluridine (Viroptic), toxicity happens after 3 weeks+ , mercury component
Ethylenediaminetetraacetic acid (EDTA)
chelating agent (binds and inactivates), most commonly sequesters calcium, tx for band keratopathy (in JIA, gout, hyperparathyroidism)
purite/sodium perborate
oxidative preservatives found in Refresh Tears and GenTeal, favoured over chemical preservatives as they are effective but with less toxicity
latanoprostene bunod (Vyzulta)
increases uveoscleral and corneal scleral pathways
Rho kinase inhibitors
vasodilates and decreases episcleral venous pressure which increases corneal scleral pathway outflow and decreases IOP. SE: subconj hemes, caution w/blood thinners
also decreases aqueous production somehow
Mast cell-antihistamine combo acronym
BEZPOP
Bepotastine (Bepreve)
Epinastine (Elestat)
(Zaditor) Ketotifen
(Patanol) olopatadine 0.10%
(Optivar) azelastine
(Pataday) olopatadine 0.20%
Tobradex
tobramycin and dexamethasone
Cosopt
timolol and dorzolamide, q12h
Simbrinza
brinzolamide and brimonidine
Combigan
timolol and brimonidine, q12h
