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Ocular Pharmacology
Dr. med. Markus Tschopp
Pharmacology
Studies the actions and applications of chemicals/drugs
interacting with the body
-> Pharmacodynamics: effect of the drug to body
-Glaucoma, Anti-inflammatory, Mydriatics
-> Pharmacokinetics: body affects drug with time
Ocular Pharmacology - studies the applications and actions
of drugs which affect the eye
Pharmacology
Studies the actions and applications of chemicals/
drugs interacting with the body
Pharmacodynamics: effect of the drug
to body
Pharmacokinetics: body affects drug with
time
Ocular Pharmacology - studies the applications and
actions of drugs which affect the eye
Pharmacokinetics
“body affects drug with time”: is the absorption, distribution,
metabolism, and excretion of the drug
Pharmacology
Studies the actions and applications of chemicals/
drugs interacting with the body
Pharmacodynamics: effect of the drug
to body
Pharmacokinetics: body affects drug with
time
Ocular Pharmacology - studies the applications and
actions of drugs which affect the eye
Drug Absorption
Drug must be absorbed from its site of administration
Diffusion (passive): Non-polar, size, lipid-solubility
Fick‘s law: rate of diffusion= KA(x1- x2 )/D
Active transport (requires energy): carrier mediated
Factors affecting (oral administration): pH, mucus, motility,
flora, blood flow
Drug Delivery in Eyes
Topical
Periocular
Intraocular
Systemic
drop
Subconj.
Intracameral
oral
Subtenon
Intravitreal
intravenous
ointment
gel
Peribulbar
Retrobulbar
Intramuscular
Pharmacology
Studies the actions and applications of chemicals/
drugs interacting with the body
Pharmacodynamics: effect of the drug
to body
Pharmacokinetics: body affects drug with
time
Ocular Pharmacology - studies the applications and
actions of drugs which affect the eye
Drug Distribution
Distribution depends on route of
administration
Intravenous, intramuscular, buccal,
topical à drug availability ↑↑
Oral à first pass
Factors affecting: Plasma protein binding,
tissue protein binding, blood flow,
Ocular Distribution; systemic therapy
Blood-ocular barriers – composed:
1. blood-aqueous
- iris blood vessels and ciliary body
epithelium
- some breakdown with inflammation
- 2. blood-retinal
- retinal pigment epithelium and
capillaries
-harder for drug to penetrate even
during significant inflammation
Pharmacology
Studies the actions and applications of chemicals/
drugs interacting with the body
Pharmacodynamics: effect of the drug
to body
Pharmacokinetics: body affects drug with
time
Ocular Pharmacology - studies the applications and
actions of drugs which affect the eye
Drug Elimination
Distribution depends on route of administration
Intravenous, intramuscular, buccal, topical à drug
availability ↑↑
Oral à first pass
Metabolism (liver):Oxygenation(P450), conjugation (acetyl,
sulphate, glycine)
Factors affecting: Plasma protein binding, blood flow, age,
smoking, alcohol, genetics
Urinary or/and biliary excretion
Ocular pharmacokinetic
Separate from the body
direct absorption
elimination into the body
Difficult clinical evaluation
Ocular Pharmacokinetics (drops)
Absorption, Distribution, Metabolism, Excretion
Ocular absorption: Corneal barrier
it is a lipid - water - lipid layer
the lipid content of the epithelium and the endothelium is 100 times more
than that of stroma; and therefore allows lipophilic rather than to
hydrophilic substance.
because of the dual nature of the corneal barriers, drugs possessing both
lipid and water solubility penetrate the cornea more readily.
Ocular absorption: Corneal barrier
immediate
1 to 2 minutes
Ocular absorption: Sclera
Sclera (14.5 x 10-6 cm/
sec)
X
Ciliary
Body
Cornea
(3.24 x 10-6 cm/
sec)
Penetration/
absorption
Bimatoprost
Sclera is 4fold cornea!
Ocular absorption: eye drops
Rate and extent of absorption in the eye are extremely difficult to measure
experimentally. BUT there is evidence of:
Competition from non-corneal absorption from lids and adnexa
Drainage is responsible for suppressing the absorption
Tear secretion promotes the dilution, and blinking facilitates removal
Drainage more rapid than absorption
-> poor absorption: 1% -8% (systemic > 75%)
Residual time: 3-5 min., improvement by increase of residual time
(ointment gel), or drug modification
Ocular absorption: eye drops
Tear Film
drop added cause an increasing in blinking, squeezing which propels
tears towards the sac.
the drugs passes on
iris & ciliary body
lacrimal sac
nasolacrimal system
bypass the liver
systemic circulation
Ocular absorption: eye drops
Drop (Gutta)- simplest and more convenient
mainly for day time use
1 drop=50 microlitre
Conjuctival sac capacity=7-13 micro liter
so, even 1 drop is more than enough
measures to increase drop absorption:
-wait 5-10 minutes between drops
-compress lacrimal sac
-keep lids closed for 5 minutes after instillation
Ointments
Increase the contact time of ocular medication to ocular surface thus
better effect, may not always increase drug bioavailability
The drug has to be high lipid soluble with some water solubility to have
the maximum effect as ointment
It has the disadvantage of vision blurring
Allergies to lanolin component
Factors influencing local drug
penetration into ocular tissue
Drug concentration and solubility: the higher the concentration the
better the penetration e.g pilocarpine 1-4% but limited by reflex tearing
Viscosity: addition of methylcellulose and polyvinyl alcohol increases
drug penetration by increasing the contact time with the cornea and
altering corneal epithelium
Lipid solubility: because of the lipid rich environment of the epithelial
cell membranes, the higher lipid solubility the more the penetration
Amphipathic- epithelium/endothelium----lipophilic
stroma---hydrophilic
Factors influencing local drug
penetration into ocular tissue
Surfactants: the preservatives used in ocular preparations alter cell
membrane in the cornea and increase drug permeability e.g.
benzylkonium and thiomersal
pH: the normal tear pH is 7.4 and if the drug pH
is much different, this will cause reflex tearing
Drug tonicity: when an alkaloid drug is put in relatively alkaloid
medium, the proportion of the uncharged form will increase, thus more
penetration
Molecular weight and size
Composition (eye drops)
Active drug (or prodrug)
OH
COOCH(CH3)2
Preservative
OH
Buffer
Adhesive
OH
OH
COOH
OH
OH
Composition (eye drops): Drug
Composition (eye drops): Preservative
Composition (eye drops): Buffer
Composition (eye drops): Adhesive
Distribution (Dexamethason)
Trace
(0,1) 0,37
(0,37) 0,3
(0,6) 0,5
(8,6) 9,5
(0,66) 0,8
0,23
0,23
(0,5)
(0,5)
Trace
0,15 (0,1)
Spur
Trace
Dexamethason concentration after 1 (2) h. after drop
Trace
Applications
Intraocular
Parabulbar
Drops
Systemic
100%
10%
1%
0.1%
Periocular injections
They reach behind iris-lens diaphragm better than topical application
Increased local concentrations and avoid systemic toxicity
Increased penetration
Useful in kids or poor compliance patient
Subconjunctival - Good for drugs with low lipid solubility (e.g. penicillins)
Drugs which can’t penetrate cornea due to large size
Penetrate via sclera
Subtenon- ant. Subtenon– disease ant to the Lens
Post Subtenon– disease posterior to the lens
Retrobulbar- Optic neuritis/ papillitis; posterior uveitis; Anesthesia
Peribulbar- Anesthesia
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Intraocular injections
Intracameral
acetylcholine (miochol) during cataract
surgery; antibiotics
Intravitreal
antibiotics in cases of endophthalmitis
Intravitreal in diabetic macular edema, CRVO,
retinal surgeries
Intraocular implants: Gancicyclovir for CMV
retinitis; Ozurdex
Retisert (Fluocinolone) for posterior uveitis
Systemic drugs
Oral or Intravenous
Factor influencing systemic drug penetration into ocular tissue:
•  lipid solubility of the drug: more penetration with high lipid solubility
•  protein binding: more effect with low protein binding
•  better penetration in the inflamed eye
Systemic effect
Why can there be a systemic effect:
no " first pass effect “
Good absorption
Example of systemic effect
Clonidin:
Epinephrin:
Cyclopentalat:
Betablocker:
Lowers blood pressure
Tachycardia
Extrasystole
Hallucination
Epilepsia
Exacerbation of asthma
AV-Block
Pharmacology
Studies the actions and applications of chemicals/
drugs interacting with the body
Pharmacodynamics: effect of the drug
to body
Pharmacokinetics: body affects drug with
time
Ocular Pharmacology - studies the applications and
actions of drugs which affect the eye
Pharmacodynamics
It is the biological and therapeutic effect of the drug
(mechanism of action)
Most drugs act by binding to regulatory macromolecules, usually
neurotransmitters or hormone receptors or enzymes
If the drug is working at the receptor level, it can be agonist or antagonist
If the drug is working at the enzyme level, it can be activator or inhibitor
37
Pharmacodynamics
Autonomic Nervous System
Physiologic antagonists
1. Parasympathetic - cholinergic system
acetylcholine (Ach) neurotransmitter
2. Sympathomimetic - adrenergic system
norepinephrine (Nor) neurotransmitter at
the effector organ
Adrenergic System
“Fight” or “Flight” response
Ach neurotransmitter at
PREganglionic
Norepinephrine (NOR) is the
POSTganglionic neurotransmitter
NOR action terminated by:
– 1. Reuptake
– 2. Transformation by MOA or
COMT
– 3. Diffusion from neuro. junction
Sympathetic system
Two types of receptors:
– 1. Alpha (a) receptors
– 2. Beta (b) receptors
Further subdivided into:
– alpha (a) 1 (smooth muscle contraction)
– alpha (a) 2 (feedback inhib. sympath nerves)
– beta (b) 1 (heart)
– beta (b) 2 (lungs)
Sympathetic system
ALPHA - increase BP, in eye mydriasis
(iris dilator), elevation of lid (Muller’s
Muscle)
BETA - increase heart rate, relaxation of
bronchi; in eye BLOCKADE of receptor
produce decrease in aqueous fluid formation
Cocaine 2-10%
Indirect sympathomimetic agent - blocks
reuptake of NOR
Diagnostic agent - Horner’s
Mydriasis
Local anesthetic - toxic to corneal epithelium
Hydroxyamphetamine
Indirect sympathomimetic causing release
of NOR from terminals.
Diagnostic agent - Horner’s
Testing should not be within a few days of
cocaine testing.
If postganglionic lesion, terminal is
degenerated and pupil will not dilate.
Parasympathetic
Cholinergic innervation
Extraocular muscles, levator palpebrae,
lacrimal & meibomian glands, iris sphincter
& ciliary body
Cholinergic agents are either direct-acting
(imitators of Ach) and/or indirect-acting
(agents preventing breakdown of Ach)
Cholinergic stimulation in eye
1. Miosis
2. Contraction of ciliary muscle with effect
on scleral spur & trabecular meshwork (opens up)
3. Lacrimation
Cholinergic Agents
Direct acting
– Pilocarpine 0.25%-10%
– Acetylcholine (Miochol-E)
– Carbachol 0.75%-3% (Isopto Carbachol, Miostat)
Indirect acting (Anticholinesterases)
– Eiodide 0.03% - 0.25% (Phospholine Iodide)
– Physostigmine 0.25% (Eserine)
Demecarium 0.125-0.25% (Humorsol)
- Edrophonium chloride (Tensilon)
intravenous agents for diagnosis of myasthenia gravis
Pilocarpine
Pilocarpine (Spersacarpine)
- POAG, AACG (if IOP < 60 mm Hg); effective conc. 1-4%
(0.25%-10%); dark pigmented eyes may benefit from higher conc.
Effects
- Miosis, induces accommodation/ myopia,
Ocular inflammation, reverse anticholinergics,
- Diagnose Adie’s pupil 0.0625%-0.25%
Salagen
Pilocarpine
Systemic SE’s - acute poisoning or acute glaucoma.
– diarrhea, abdominal cramping
– salivation, sweating
– difficulty in breathing
– cardiac irregularities
Miotic side effects -ocular
– pupillary constriction (miosis)
– pupil. block (in pts. with narrow <cats.)
– eye or brow ache
– accommodative spasm
– follicular conj.
– allergic derm & conj.
Cholinergic Antagonists
Muscarinic antagonists/anticholinergic
Relaxation of pupillary sphincter
(dilation/mydriasis) - break synechiae,
paralysis ciliary muscles, reduce pain from iridocyclitis.
Caution in narrow angle or POAG
Cholinergic Antagonists
Atropine - 0.5-1% - longest acting (up to 2 weeks); most allergic rxs
Scopolamine 0.25% - last up to 1 week; use in pts allergic to atropine
Homatropine 2 & 5% - few days, weaker cycloplegic, OK atropine
allergy
Cyclopentolate 0.5-2% - up to 24 hours; potent cycloplegic
Tropicamide 0.5-1% - 4-6hr, weak cycloplegic
Mydriatics and cycloplegics
Mydriatics are the drugs which dilate the pupil and
cycloplegics are agents which causes paralysis of ciliary
muscles
Mydriatics
Adrenergic agonist
Adrenaline
Cholinergic antagonists
Phenylephrine
Tropicamide
Phenylephrine (2.5%)Adrenergic agonist
acts on alpha 1 receptors of the dilator pupillae
indication
•  pupil dilation
•  before intraocular surgeries
contraindication
•  hypersensitive
•  narrow angle glaucoma
•  cardiac patients
Side effects
•  systemic side effects include palpitation, tachycardia,
headache, arrythmias
•  reflex bradycardia, pulmonary embolism, myocardial infaction
Adrenaline- Adrenergic agonist
acts on dilator fibres and directly produces dilation after instillation of
four drops of 1:1000 solution
may be combined with procaine and atropine to achieve mydriasis in
severe iritis
Mydriatics and cycloplegics
Mydriatics are the drugs which dilate the pupil and
cycloplegics are agents which causes paralysis of ciliary
muscles
Mydriatics
Adrenergic agonist
Adrenaline
Cholinergic antagonists
Phenylephrine
Tropicamide
Cycloplegic mydriaticsCholinergic antagonists
parasympatholytic agents are commonly used
blocks the action of cholinergic stimulation causing paralysis of
accomodation and pupillary dilation
indication
•  refraction
•  inflamation of uvea
•  malignant glaucoma
adverse reaction
•  transient stinging and burning, increase in IOP, allergic lid reaction,
hyperemia
•  flushing and dryness of skin, blurred vision, dryness of mouth and
nose, anhidrosis, fever, bladder distention and CNS disturbances
Cycloplegic mydriaticsCholinergic antagonists
precautions
•  permanent mydriasis may occur in patients of keratoconus
•  longer acting agents may cause posterior synechiae formation when
treating anterior segment inflammation
•  avoid driving or any other task requiring alertness
overdosage
•  Administer parenteral physostigmine
commonly used agents are atropine sulfate, homatropine,
cyclopentolate, tropicamide
Cycloplegic mydriaticsCholinergic antagonists
Atropine is the most effective cycloplegic followed by Cyclopentolate (1%)
& then Homatropine (2%) & Tropicamide (0.5-1%).
Cyclopentolate should not be prescribed in uveitis as it has chemotactic
effect on leucocytes.
Mydriasis is quickest with Tropicamide among all
parasympathomimetics (in 20 minutes) and is also shortest lasting
2.5% Phenylephrine (selective Alpha-1 agonist) along with
anticholinergics like tropicamide 0.8 % induces maximum mydriasis
Glaucoma
Verstärkung des
Inflow
Kammerwasser-Abflusses
über das Trabekelwerk
Outflow
Cholinergika
α2Sympathomimetika
-agonists/ Miotika
β1-blockers
CA inhibitors
prostaglandins
α2-agonists
cholinergics
Verstärkung des KammerwasserAbflusses uveoskleral
Prostaglandine
KammerwasserSuppression
Betablocker
Carboanhydrase-Hemmer
Outflow: Prostaglandins
The PGs derivates primarily lower IOP by enhancing the uveo-scleral
outflow of the eye.
two possible mechanism exists that have been studied are relaxation of
the ciliary muscle and remodeling the extra cellular matrix of the ciliary
muscle.
first line for open angle glaucoma, ocular hypertension, exfoliation and
pigmentary glaucoma
contraindicated in allergic patient, pregnancy, uveitic glaucoma
Outflow: Prostaglandins
LATANOPROST
TRAVOPROST
• Increases uveoscleral outflow
BIMATOPROST
Decreases resistance
to outflow
• Duration of action 12-24 hrs
• Wash out period 3-4 weeks
• burning stinging, conjunctival hyperemia, iris pigmentation, anterior uveitis,
hypertrichosis of eyelashes
0.005% OD
0.004% OD
0.03%, OD
Safest and most
efficacious
Best in maintenance on
diurnal variation of IOP
Controls diurnal
variation better than
latanoprost
contraindicated with
pilocarpine
stable, safe and well
tolerable
highest incidence red
eye rate
XALANTAN, 9PM
TRAVATAN
LUMIGAN,
CAREPROST
Outflow: Cholinergic agents
Cholinergic drugs either act directly by stimulating cholinergic receptors
or indirectly by inhibiting the enzyme cholinesterase
Topically applied cholinergic agents causes contraction
iris sphincter
miosis
circular muscles of ciliary body
longitudinal muscle of ciliary body
relaxing zonular tension & forward lens
movement
accommodation
Tension on scleral spur
Opening of trabecular meshwork
aqueous outflow
Side effects of cholinergic agents
Lids: orbicularis muscle spasm and lid twitching,
Conjunctiva: irritation,conjunctival hyperemia, allergic conjunctivitis
Cornea: epithelial staining and vascularisation, atypical band keratopathy.
Iris: hyperemia, pigment epithelial cyst formation,
post operative iritis and
synechiae formation.
Lens: cataract, increase lens thickness – myopia
Systemic: sweating, salivation and lacrimation,
nausea, vomiting and abdominal cramps, night mare,
bronchial spasm, asthma and pulmonary edema.
Pilocarpine
In open angle glaucoma
In angle closure glaucoma
Pilocarpine
oldest and most widely used cholinergic agent,
derived from the plant pilocarpus microphylus.
Topical solution is available in two salts:
•  Pilocarpine hydrochloride in the strengths of 0.25, 0.50, 1, 2, 3, 4%.
•  Pilocarpine nitrate in the strengths of 1, 2 & 4%.
produces a reduction in IOP that starts after one hour and lasts for 4 - 8
hours.
IOP decrease is 15-20%
Indications for pilocarpine
First line for acute and chronic angle closure glaucoma, primary
open angle glaucoma
Less certain indications in neovascular glaucoma,uveitis related
glaucoma
Also used in laser trabeculoplasty, accommodative esotropia
Diagnostically in Adie tonic pupil
Outflow and production:
N. Alpha adrenergic agonist
Directly acting sympathomimetics
•  Epinephrine
•  Dipivefrin
Alpha2 adrenergic agonists
•  Apraclonidine
•  Brimonidine
Indicated in
•  open angle glaucoma
•  to control IOP spikes after laser procedures
•  ocular hypertension
Brimonidine
2nd generation α-adrenergic receptor agonist, with high degree selective to α2
receptors.
Dual action:it decreases aqueous humor production like β-blockers and also
increases the uveo scleral out flow like prostagladins.
has binding sites in the iris epithelium, ciliary epithelium, ciliary muscle, retina and
retinal epithelium and choroid
IOP reduction is 26% (2 hrs post dose) and has an additive neuroprotective
action
available in 0.2% (0.15%, 0.1% ) solution. Instil one drop 2-3 times daily.
side effects include ocular allergy, follicular conjunctivitis, lid edema, dry mouth,
headache
contraindicated in patients receiving MAO inhibitor therapy, tricyclic
antidepressant, produces cardiovascular instability in infants and is therefore
contraindicated in the first 5 years of life.
Production: Beta-blockers
Production: Beta-blockers
usually first line agent for treating most types of glaucoma
excellent IOP lowering efficacy/ long duration of action/ few ocular
side effects
first commercially available β blocker
for systemic use , was propanolol
for topical use was timolol
reduce IOP 20-30% with little or no effect on pupil size or accomodation
(blurred vision associated with miotics is not seen here)
Systemic Side effects and
Contraindications of B blockers
Side effects
burning sensation
hyperemia.
superficial punctate Keratitis.
corneal anesthesia.
allergic blepharoconjunctivitis
dry eye
bronchospasm
masking of hypoglycemia in diabetes
heart failure in pulmonary edema
A-V dissociation and cardiac arrest in
patients with pre-existing partial heart
block
Contraindications
bronchial asthma
COPD
sinus bradycardia
2nd or 3rd degree A-V block
sexual dysfunction
Timolol
first β-blocker to be commercially used in ophthalmics in 1978
it is non selective. inhibits both β1 and β2 receptors
peak level of drug within 1-2 hours
clinical effect may last upto 2 weeks after last use
available in 0.25% and 0.5%
administered twice daily, also available in gel solution : hence can be
administered once daily
Short term escape due to receptor alteration
Long term drift due to tachyphylaxis
contraindicated in asthmatic, heart failure patients
Production: Carbonic anhydrase
inhibitors
inhibits enzyme carbonic anhydrase present in pigmented and non
pigmented epithelium of ciliary body
prevents the bicarbonate and sodium influx and decreases aqueous
formation
useful in short term treatment of acute glaucoma
onset of action within 1 hour and maximum effect in 4 hours
Production: Carbonic anhydrase
inhibitors
DORZOLAMIDE
BRINZOLAMIDE
•  local inhibition of CA in ciliary body minimizing side effects
•  adverse effects include burning, stinging, blurred vision, systemic
side effect is rare
•  caution must be exercised in patients with compromised
epithelium
2% solution, TDS
1% solution, TDS
has better penetration
safe and well tolerated
DORZOX, TRUSOPT
AZOPT
Fixed combinations
Advantages
•  Convenience
•  Compliance
•  Effectiveness
•  Cost effectiveness
•  Safety and tolerability
Disadvantage
•  Not always as additive as expected
Best scientific combination
•  one drug from group that reduce aqueous formation
•  one that increases aqueous outflow
Fixed combinations
Few combinations available are
Timolol 0.5% and Dorzolamide 2% (Cosopt, Co-Dorzolamid, ….)
Brimonidine 0.2% and Timolol 0.5% (Combigan)
Latanoprost 0.005% and Timolol 0.5% (Xalacom, Co-Latanoprost)
Travaprost 0.004% and Timolol 0.5% (Duotrav)
Bimatoprost 0.03% and Timolol 0.5 (Ganfort)
Systemic anti glaucoma
Oral
•  Acetazolamide
•  Glycerine
Intravenous
•  Mannitol
Neuroprotective agents
• 
• 
• 
• 
Calcium channel blockers
Nitric oxide synthase inhibitors
Vasodialators
Antioxidants
Acetazolamide
oral carbonic anhydrase inhibitor (Diamox, Glaupax)
Tablet 125mg/250mg, TDS/BD
•  onset of action within 1 hr
•  Peak at 4 hrs
•  Duration of action 8-12 hrs
Slow release capsule
•  Given OD/BD
•  Duration of action upto 24 hrs
Intravenous
•  500mg vials
•  Immediate onset , peak action at 30 minutes
useful in acute glaucoma, cystoid macular edema, altitude sickness,
epilepsy, respiratory stimulant
Adverse effects of oral CAIs
intolerance due to their adverse effects
common in elderly people
neurological/psychiatric
•  Paresthesia, fatigue, malaise,
•  Depression, headache, decreased libido
gastrointestinal
•  metallic taste and discomfort,
•  Nausea, abdominal cramps diarrhea
renal/metabolic
•  Increased micturation frequency
•  Renal stones, hypokalemia (metabolic acidosis)
•  May cause exacerbation of gout
hematological
•  Bone marrow depression,aplastic anemia
teratogenic effect rarely: contraindicated in first trimester
Hyperosmotic agents
Increase the osmolarity of plasma
Leads to absorption of water from ocular tissues (mainly vitreous)
indication
•  acute glaucoma
•  secondary glaucoma, preparation of patients before OT
•  malignant glaucoma
adverse effects
•  headache, nausea, vomitting
•  systemic hypertension
•  congestive heart failure and pulmonary edema
•  urinary retention and hyperglycemia
Hyperosmotic agents
Glycerol: diabetics may have problem due to caloric value, osmotic
diuresis and dehydration
Mannitol 15-25% intravenous agent
- 1.5-2.5gm/Kg.
- causes tissue necrosis and phlebitis
- crystallization
- not metabolized
- peak action-within 30 mins
- duration of action-upto 6hours
- choice for intravenous therapy
Glaucoma Therapy
Prostagladins analogs, beta blockers, alpha2 agonist are reasonable choices for
first line therapy
Prostagladins with once daily dose are most effective agents for IOP lowering
and provide good 24 hr IOP control
Combining drops from different classes (ie, beta blocker plus
prostaglandin, or beta blocker plus carbonic anhydrase inhibitor) can
cause a greater reduction in the intraocular pressure than
monotherapy. Adding a second medication is reasonable if initial
monotherapy is not effective
Ocular allergies
Ocular allergies
Typ I
Type I hypersensitivity reactions are
immediate (occurring within seconds
or minutes) or anaphylactic reactions.
They occur in atopic patients, i.e.,
genetically predisposed patients
producing IgE in excessive quantities.
Type I reactions are characterised by
involvement of specific humoural
factors: IgE and histamine release
from mast cells.
Typ IV
Unlike type I, II and III reactions, type IV reactions involve T-cells
(cellular) and are characterised by a delayed onset of action.
Previously sensitised T-cells interact with the antigen bound to the
surface of a cell. This results in the release of lymphokines and in tissue
injury (inflammation, cell death).
Ocular allergies
Allergene
Lösen sich im Tränenfilm
Dringen in Kornea/
Konjunktiva ein
Binden an IgE-Moleküle, die an Membranen
der Mast-Zellen gekoppelt sind
Mastzell-Stabilisatoren
Mastzell-Degranulation
ca. 50 Mio Mastzellen im Augenlid, in der
Konkuntiva und anderen Geweben des Auges
Antihistaminica
NSAID, Steroide
Steroide
Voltaren, Ultracortenol Ultracortenol
Histamin
PG
Leukotriene
PAF
Jucken
Vasokonstriktoren
Vasodilatation m.
Hyperämie
Papilläre Reaktion
Hyperämie
Vasodilatation
Oedem
Zelluläre
Infiltration
Oedem
PlättchenAktivierung
Human eye has about 50
million mast cells, which
contains preformed chemical
mediators
Ocular allergies- Therapy
Non- pharmacological
•  Avoidance of allergenes (Animals ...)
•  Cold compresses
•  Artifical tears (removal of allergenes)
Pharmacological: z.B. Antiallergic (local, systemic)
Antiinlammatory
Immunosuppression
Allergen desensitisation: reserved for severe cases
Vasoconstrictors
Vasoconstrictors, principally alpha-adrenergic
agonists, reduce ocular redness by constricting blood
vessels and thereby attenuating vascular hyperaemia
associated with the allergic response. Due to their
mechanism of action, they act very fast on acute
symptoms. However, their duration of action is short,
and overdose may result in rebound redness.
Antihistamines
Antihistamines compete with histamine for binding to
the histamine H1-receptors on nerve endings and
vascular endothelial cells and prevent the common
symptoms of itching, redness, and chemosis.
Due to their mechanism of action, they act very fast on
acute symptoms.
However, their duration of action is short, and overdose
may result in rebound redness.
Local antihistaminica offer faster relief of symptoms
than oral agents
Will not prevent the release of more histamine or other
inflammatory mediators (no prophylactic treatment)
Antazolin, Emedastin, Levocabastin
Mast cell stabilisers
Mast cell stabilisers prevent mast cell degranulation and inhibit the release of
histamine and other mediators at their source - the mast cell.
have a slow onset of action and require two to three weeks of treatment to achieve
optimal efficacy. This long pre-treatment time is necessary because mast cell
stabilisers do not act on inflammatory mediators that have already been released.
Some immediate relief of symptoms that can be observed when mast cell
stabilisers are applied topically, is likely to result from the “washing” effect, or
dilution of the offending antigen. Therefore, mast cell stabilisers are more
appropriately used as prophylactics for acute or chronic allergic conjunctivitis than
for the immediate treatment of acute allergic symptoms.
sodium cromoglycate, lodoxamide
Dual action agents
with combined antihistamine/mast cell stabilising activity
provide effective relief from acute symptoms and prophylaxis
Ketotifen, Olopatadine
Class
Mast cell
inhibitor
Generic name
Mechanism
Dosage
Side effects
Cromolyn sodium
inhibit neutrophil,
eosinophil,
monocyte
0.01% BD
does not provide
immediate relief
provides
immediate relief
and prevent
further
degranulation
0.05% BD
ocular burning,
stinging, dry eye
Azelastine HCL
H1 antagonist
+ mast cell
inhibitor
Epinastine HCL
Ketotifen fumarate
Nedocromil
sodium
rapid onset
Olopatadine
H1 antagonist
+
decongestant
Naphazoline HCL/
phenaramine
maleate
0.05%, 0.01% BD/
OD
short term relief for
mild allergy
0.05%/0.01% BD
NSAIDs/Corticosteroids
NSAIDs
inhibit the activity of cyclo-oxygenase and, therefore, production
of prostaglandins from arachidonic acid
have been shown to be effective in relieving itching associated
with allergic conjunctivitis.
often produce significant stinging upon instillation, which may
affect patient compliance
generally not indicated for the treatment of allergic conjunctivitis
prevention of post-op inflammation s/p cataract surgery/pain with
photophobia s/p refractional surgery (ocular penetration better
with topical than oral)
Ketorolac (Acular) , Diclofenac (Voltaren)
Corticosteroide
Corticosteroids block the metabolic pathways involving arachidonic acid
and have general anti-inflammatory and immunosuppressive effects
•  inhibition of lymphocytes proliferation, with a decrease of the
cell-mediated immunity
•  inhibition of the degranulation of neutrophil granulocytes,
macrophages, mastcells and basophil granulocytes.
•  decrease of vascular permeability
•  decrease of prostaglandin production
Potentially prevents both early- and late-phase reactions
,
Corticosteroide
Routes of administration: topical, periocular, intravitreal, oral,
intravenous
May elevate intraocular pressure, worsen diagnosed or
undiagnosed infections, and cause or worsen cataracts
-> must be administered with caution
Prednisolon, Fluorometholon,
Corticosteroide- Indications
•  post surgical inflammation
•  allergic conjunctivitis and blepharitis
•  vernal conjunctivitis, phylectunular keratoconjunctivitis
•  disciform and interstitial keratitis
•  corneal graft rejection
•  scleritis and episcleritis, anterior and posterior uveitis
•  traumatic inflammation of the eye
•  papillitis and retrobulbar neuritis
•  sympathetic ophthalmia
•  herpes zoster opahthalmicus
•  orbital pseudotumor
Topical corticosteroids
available as solution, suspension and ointment
•  Hydrocortisone 0.5-1.5%
•  Prednisolone 0.12, 0.25, 1 %
•  Dexamethasone 0.1%
•  Betamethasone 0.1 %
•  Triamcinolone 0.1%
•  Fluromethalone 0.1%
•  Loteprednol 0.2%,0.5%
•  Difluprednate 0.005%
anti-inflammatory action * prednisolone acetate > fluorometholone acetate
> dexamethasone acetate > betamethasone
rise in IOP- maximum rise due to dexamethasone (0.1%) and
fluorometholone 0.1% is least
Topical corticosteroids
Triamcinolone acetonide (40mg/ml) (Kenacort) was approved by FDA in
2007 for intraocular use in visualization during vitrectomy, chronic non
infectious uveitis, diabetic macular edema
Retisert (flucinolone actetonide) used as intraocular implantation for
chronic uveitis
OZURDEX® (Allergan, dexamethasone intravitreal implant 0.7mg),
indicated in
•  macular edema following retinal vein occlusion
•  noninfectious posterior uveitis
Systemic corticosteroids
Oral prednisolone in a dose of 1-2 mg/kg/day (or alternate days) is
used to treat orbital inflammations, panuveitis, postoperative
inflammation and systemic diseases causing ocular problems
alternate day therapy reduces the suppression of adrenal functions
High dose of methylprednisolone i/v are given in pulses to treat optic
neuropathies
Topical cyclosporine
Topical cyclosporine 1-2%;
Cyclosporine emulsion 0.05% (Restasis)
Control anterior segment external disease especially when
steroids fail
Restasis indicated for mod-severe dry eye. Dosed twice daily
Past uses of compounded product include atopic & vernal
keratoconjunctivitis, Mooren’s ulcer, ligneous
conjunc.,ulcerative keratitis
No measurable serum levels; local SE’s minimal except
local irritation (burning and stinging; no increase in IOP,
no secondary infections)
5-FluorouraciFluorouracil
Antineoplastic agent
– Fluorinated pyrimidine nucleoside analogue
– Blocks thymidylate production interrupts DNA /RNA synthesis
– Uses include:
glaucoma filter (inhibit fibroblasts)
pterygium
prevention of PVR (1mg)
– Subconj. injection 5mg (50mg/ml or 10mg/ml) daily x
1week, then 3 x’s following week
– Possible just peri-operative use also
SE’s - epithelial defects
Mitomycin C
Antineoplastic
– Alkylating agents inhibits DNA synthesis and cross links DNA.
Uses include:
– Pterygium 0.02% - 0.04% topically intraop. (drops 2-4 x’s x 1-2
weeks – Use is cautioned!
SE’s possible sight threatening complications (i.e. scleral/corneal
melt, cataract, glaucomatous changes; contraindicated dry eye,
Sjogren’s, meibomian gland dysfunction, etc.)
– Filtering Surgery - Single topical application
0.2-0.5 mg/ml concentration
Se’s - irrigate thoroughly – wound leak, K endothelial damage,
hypotony, maculopathy, leaking blebs
– Reduce haze after PRK?
Immunosuppressive
not used as primary therapy
cases non responding to steroids or steroids responders or started
having steroid complications
avoided in children and pregnant women
effect may take 1-4 weeks to develop, hence initial therapy with
corticosteroids is needed
Azathioprine, Cyclosporin, Methotrexate are commonly being used
Drug
Formulation
Dosage
Adverse
effects
Special
points
Methotrexate
2.5, 5, 7.5 mg
Weekly
GI symptoms,
hepatotoxic
( LFT)
Less cost,
Well tolerated
Azathioprine
25, 50 mg
1mg/kg
Myelosuppressio
n
Onset take 4-5
weeks
Cyclosporine
25, 50 mg
5mg/kg/day
Nephrotoxic
(urea, creatinine)
Fast onset of
action
More efficacious
Dry eye
0.05%,0.1%
emulsion
Mycophenolate
mofetil
250, 500 mg
1gm BD
Myelosuppressio
n
High cost
Leflunomide
10, 20 mg
100mg/day
GI upset,
hepatotoxic
Still under trial
Antibiotics
PENICILLINS
MOA - Inhibit bacterial cell wall synthesis by
binding to pencillin binding proteins (PBPs),
which in turn inhibit final transpeptidation step of
peptidoglycan synthesis in bacterial cell walls,
thus inhibiting cell wall biosynthesis
Vs. Streptococcus groups A, B, D, S. pneumoniae,
anaerobes (non-penicillinase), Treponema,
Neisseria
Ophthalmic Use (OU) - rare IV 12 million U./day
x 10 days neurosyphilis
SE’s - allergic reaction
ANTISTAPHYLOCOCCAL
PENCILLINS
Vs. gm + especially Staphylococcus aureus.
Includes: cloxacillin, dicloxacillin,
methicillin, nafcillin, oxacillin
If methicillin resistant Staphylococcus
(MRS; MRSA), ALL are resistant
OU - oral - for superficial lid/skin
laceration, adults preseptal cellulits, plastics
SE’s - similar to PCN, cross-reactivity
ANTIPSEUDOMONAANTIPSEUDOMONAL
PENICILLIN (EXTENDED SPECTRUM )
Vs. gm -, Strep. Group, enteric bacilli
(Klebsiella, Proteus), Pseudomonas
aeruginosa
carbenicillin, ticarcillin, piperacillin,
mezlocillin, azlocillin
OU - occasional eye drop in keratitis
SE’s - watch in Penicillin allergic pts.
PENICILLINS, Misc.
Ampicillin/amoxicillin vs gm + (not
Staph.), Neisseria, H. influenzae, Proteus.
Amoxicillin/clavulanate (Augmentin oral) vs. Staph. (penicillinase producing not
MRS), resistant H. influenzae, Strep. Sp.
OU - amoxicillin if relapsing H. influ. conj.
Augmentin in kids with preseptal cellulits - activity vs. H. flu, etc.
SE’s - diarrhea, rash
Imipenem/cilastatin (Primaxin) vs. gm +
aerobes, Staph., gm - (P. aeurginosa)
imipenem penetrates well into vitreous
ticarcillin/clav. (Timentin- IV) vs. gm +,
staph, gm - bacilli
CEPHALOSPORINCEPHALOSPORINS
MOA - Inhibit bacterial cell wall synthesis by
binding to one or more of the penicillin-binding
proteins (PBPs) which in turn inhibit the final
transpeptidation step of peptidoglycan synthesis in
bacterial cell walls
1st generation - very good gm+ esp.. S. pneumo
& viridans, Staphylococcus (not MRS), E. coli,
Klebsiella, Proteus mirabilis: cefazolin,
cephalexin, cephalothin, cephradine, cefadroxil
2nd generation - more gm -, more H.
influenzae/Neisseria (cefuroxime), anaerobic B.
fragilis (cefoxitin, cefotetan) and cefaclor,
cefmandole, cefmetazole
CEPHALOSPORINS (cont.)
3rd generation - better gm - including facultative
bacilli, H. influ., N. gonorrhoeae, P. aeruginosa
(ceftazidime, cefoperozone), B. fragilis
(ceftizoxime, moxalactam), and ceftriaxone,
cefixime (PO), cefotaxime.
4th generation – good enterobacteriaceae,
Pseudomonas, C. freundi. (cefepime, cefpirome)
OU - topical cefazolin 50-133 mg/ml mainstay of
bacterial keratitis, q 15-30’ alternate with
aminoglycoside
CEPHALOSPORINS (cont.)
OU (cont). - IV cefazolin - 1-2 gm q 8hr for
soft tissue, penetrating injury (repeat dose
penetrate vitreous)
- ceftriaxone - vs. H. flu, & Strep. Sp.for
orbital cellulitis (+ nafcillin); Lyme dx,
resistant GC; (concurrent tx of Chlamydia dox/tet/azithromycin)
intravitreal cefazolin 1-2 mg replaced with
vancomycin
CEPHALOSPORINS
(cont.CEPHALOSPORINS (cont.)
ceftazidime
intravitreal 2mg dose combined with
vancomycin 1mg for endophthalmitis
minimal risk of retinal toxicity vs.
aminoglycosides (- risk)
no synergy with vancomycin Vs Bacillus,
enterococcus,etc.; no post-antibiotic effect
(PAE); no concentration dependent killing
effect.
CEPHALOSPORINS (cont.)
SE’s - well tolerated 1-10% cross reactivity
with penicillins
O.K. in penicillin allergy if not life
threatening reaction (i.e. h/o anaphylaxis,
immediate allergic rx).
Bleeding disorders - moxalactam-worst!,
cefmetazole, cefotetan, cefperazone,
cefmandole)
allergic rxs, diarrhea, PM colitis.
AMINOGLYCOSIDES
MOA - Interferes with bacterial protein synthesis
by binding to ribosomal subunits (30S and 50S in
gentamicin) resulting in defective bacterial cell
membrane
Vs. gm - bacilli, including Pseudomonas, Proteus
mirabilis, Serratia, Enterobacter, some S.aureus.
Gentamicin, tobramycin, amikacin, neomycin,
netilmicin, streptomycin
OU - topical fortified gent/tobra - mainstay of
bacterial keratitis 10-15mg/ml. alternate with
cefazolin
AMINOGLYCOSIDES
(cont.AMINOGLYCOSIDES (cont.)
OU - intravitreal amikacin 200-400 mcg
(< retinal toxic/> coverage vs.gent.100 mcg) for
endophthalmitis + vancomycin 1mg
IV gentamicin for penetrating injury prophylaxis or
endophthalmitis (less often used)
SE’s
– topical - epithelial toxic (fort.); neomycin sensitivity
– systemic - nephro. and oto. toxic - monitor serum levels
– intravitreal - retinal toxic esp. gentamicin associated
with > macular infarction (Arch Ophthal 109; 1991)
TETRACYCLINES
MOA - Tetracyclines bind to 30S subunit of the ribosome,
blocking the attachment of aminoacyl-tRNA to messenger RNAribosome
complex and therefore inhibit protein synthesis
Vs. gm- & gm +, esp. Chlamydiae & Rickettsiae.
Inhibit protein synthesis, reduce free fatty acids of normal flora,
anticollagenolytic acitivity.
OU -topical - ophthalmia neonatorum
– systemic - Chlamydiae, phlyctenular keratoconj., blepharitis &
meibomian gland infec.
SE’s - tooth discoloration (PO) in kids; diary, anatacids, & iron
reduce absorption
Doxycycline 50-100mg qd or bid (minocycline 100 mg 1-2x’s
daily) used for lid disease.
VANCOMYCIN
MOA - Inhibits bacterial wall synthesis by blocking
glycopeptide polymerization through binding tightly to
D-alanyl-D-alanine portion of cell wall precursor
Vs. Gm + especially Streptococcus (viridans,
pneumon., pyogenes, faecalis), Staphylococcus aureus
& epidermidis (including MRS), Bacillus
OU
– topical - (25-50 mg/ml)
– intravitreal 1 mg DOC for endophthalmitis
– systemic IV administration
SE’s
– topical - irritating (pH 3.5-4.5)
– systemic - oto/nephro toxic
Vancomycin resistance
CDC published guidelines for controlling
vancomycin resistance in hospitals
(Infection Control Hosp Epidemiol.
1995:16:105-113).
Concerned vancomycin resistant enterococci
(VRE) may pass to S. aureus & epidermidis
Not recommend for topical/irrigating solution
use
treat pseudomembranous colitis with
metronidazole first
implications for Ophthalmology ?
QUINOLONES
MOA - Quinolone antibiotics inhibit DNA-gyrase,
which is responsible mainly for bacterial DNA
replication (4th generation inhibit topoisomerase also)
Excellent spectrum of activity - including most gram aerobic (H. Influenzae, Pseudomonas,
Enterobacteriaceae), gm + bugs, Rickettsia,
Mycobacterium, Chlamydia & Mycoplasma
Less resistance? (especially 4th generation)
OU - Ofloxacin (OcufloxR) and ciprofloxacin
(CiloxanR) ONLY commercial products APPROVED for
bacterial keratitis; norfloxin (Chibroxin) & levofloxacin
(Quixin), moxifloxacin (Vigamox), gatifloxacin
(Zymar) conjunctivitis
QUINOLONES (cont.)
Systemic se’s - GI (N, V, etc.) CNS (HA,
dizziness, etc.), contraindicated in pediatric pts.
(arthropathy)[eye drops O.K. in peds]
Ocular se’s - cipro (pH 4.5) white K ppt.
All other FQ’s in the pH range 6-7 - more soluble,
higher corneal & A.C. levels
Resistance reported with gram + (especially Strep.
Staph.
4th generation FQ’s (gatifloxacin/moxifloxacin)
better gm+ coverage (Strep. Species), P. acnes,
Mycobacterium, Nocardia, good intraocular
penetration & less resistance
SULFONAMIDESULFONAMIDES
MOA - Inhibits bacterial growth by inhibiting
bacterial folic acid synthesis through competitive
antagonism of PABA
Vs. gm (+) and gm (-) bacteria, Chlamydia,
Actinomyces and Toxoplasmosis
bacterial resistance a problem
sodium sulfacetamide 10% common gtt
OU - topical - blepharitis, conjunc.,
systemic - sulfadiazine for toxoplasmosis (1 gm
q6 for 4-6 wks.)
SE’s - hypersensitivity rx’s (SJ synd, rash, etc;
topical - myopia (bilat, trans.)
CLINDAMYCIN
MOA - Reversibly binds to 50S ribosomal
subunits preventing peptide bond formation thus
inhibiting bacterial protein
Bacteriostatic vs. gm +, including some Staph.,
anaerobes, (B. fragilis, P. acnes, etc.) Bacillus
species
safe in penicillin allergy
OU - 300mg P.O. q6 hr x 4-6 wks in toxo
intravitreal - up to 1 mg for P. acnes
SE’s - pseudomembranous colitis (from
Clostridium difficile) - tx
metronidazole/vancomycin
Macrolides (erythromycin)
MOA - Inhibit RNA-dependent protein synthesis at the
chain elongation step; binds to the 50S ribosomal subunit
resulting in blockage of transpeptidation
effective Vs gm + cocci, gm+ bacilli (Clostridium,
Cornebac.,Listeria), N. gonorrhoeae, Chlamydia (not very
effective vs. hospital acquired S. epidermidis).
topical ery. for blepharitis, neonatal conjunctivitis.
clarithromycin (BiaxinR) azithromycin (ZithromaxR) oral only, better tolerated, better spectrum, effective vs. M.
avium.
azithro. single dose 1gm. approved for Chlamydia
urethritis, possibly conjunctivitis