Ocular therapeutics1

OCULAR THERAPEUTICS

Shashi Sharma Ajay Kumar Singh• Department of Ophthalmology• King George‘s Medical University, Lucknow (INDIA)

GENERAL PHARMACOLOGICAL PRINCIPLES

PHARMACODYNAMICS

it is the biological activity and clinical effect of the drug*

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

*American Academy of Ophthalmology Section 2;2010-11

PHARMACOKINETICS

it is the absorption, distribution, metabolism, and excretion of the drug

drug can be delivered to ocular tissue as: locally:

eye drop ointment periocular injection intraocular injection

systemically: oral intravenous

EYE AND TOPICAL MEDICATIONS

Tear Film

under normal circumstances the volume of tear fluid is 5-7 µl with normal rate of secretion about 1-2 µl /min

drop added cause an increasing in blinking, squeezing which propels tears towards the sac.

the drugs passes on lacrimal sac nasolacrimal system

bypass the liver

iris & ciliary body systemic circulation

Cornea

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 allow lipophilic 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.

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 aiding drug penetration

Lipid solubility: the higher lipid solubility the more the penetration

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

OCULAR DRUG DELIVERY

EYE DROPS

one drop = 50 µl

one ml contains approx 20 drops

volume of conjunctival cul-de-sac after drug instillation is 7-10 µl, hence only 20% of the drug is retained

topical medications are be used as

• solutions/suspensions• ointments

OINTMENTS

increase the contact time of ocular medication to ocular surface thus better effect

it has the disadvantage of vision blurring, hence night dosage

the drug has to be high lipid soluble with some water solubility to have the maximum effect as ointment

PERIOCULAR INJECTIONS

bypass the conjunctival and corneal epithelial barrier

subconjunctival, subtenon, retrobulbar injections allow medications behind lens and diaphragm

useful for drugs with low lipid solubility

delivering medications closure to local site of action e.g. posterior subtenon

retrobulbar and peribulbar anesthesia techniques

INTRAOCULAR

Intracameral and Intravitreal

Intracameral is used during surgery : antibiotics,

mydriasis/miosis

Intravitreal in diabetic macular edema, CRVO, retinal surgeries

Intraocular implants : Gancicyclovir for CMV retinitis

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

METHODS OF OCULAR DRUG DESIGN

New ocular drugs are designed aimed at improving penetration, minimizing side effects and improving efficacy

Prodrugs Activated by enzymatic system in the eye Lanatoprost prostagladin F2α

Sustained release devices and gels

Collagen corneal shields

New technology in drug delivery Liposomes* Iontophoresis

*Mishra G, Mahuya B. Recent Applications of Liposomes in Ophthalmic Drug DeliveryJournal of Drug Delivery;Volume 2011,Article ID 863734

Corneal esterases

ANTI INFLAMMATORY

LUBRICANTS

ANTI GLAUCOMA

MYDRIATICS & CYCLOPLEGICS

ANTI INFLAMMATORY THERAPY

CORTICOSTEROID NSAIDs IMMUNOSUPPRESSIVE

MAST CELL STABILIZERS

CORTICOSTEROIDS

useful in control of inflammatory and immunological diseases of eye

routes of administration

Topical Periocular Intravitreal Oral Intravenous

their antiinflammatory and immunosuppressive action 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

Phospholipids from damaged cell membranes

Arachidonic acid

Leucotrienes PG-G2,

Thromboxane

PG-D2, E2, F2

Phospholipase A2 Glucocorticoids

Lipo-oxygenase

Cyclo-oxygenase I & II

NSAIDS

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 ophthalmicus orbital pseudotumor VKH syndrome

contraindications

TOPICAL SYSTEMIC

• acute viral infections •fungal diseases

• ocular TB

• acute conjunctivitis

• caution in pregnancy and lactation

S- psychosis, headaches, pseudotumour cerebri.

T- thrombosis (venous)

E- endocrinal- suppressed hypothalamic pituitaryadrenal axis, retarded growth, cushingoid state.

R- retention of fluid & sodium but loss of potassium & systemic alkalosis.

O- osteoporosis & myopathies.

I- immunosuppression with secondary infections esp. TB & fungal,

D- diabetes & hypertension, duodenal & gastric (peptic)ulcers.

Side effects

TOPICAL SYSTEMIC

• glaucoma • cataract (PSC)

• dry eye

• reduced resistance to bacterial, fungal and viral infections and secondary infections

• scleral melting

• delayed wound healing

• eyelid skin atrophy

• ocular

•suppresion of hypothalamic pitutiary adrenal axis

• hyperglycemia

• peptic ulcer

• osteoporosis

• psychiatric disturbances

• cushing’s habitus

• fetal abnormalities

• susceptibility to infections

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

*Samudre S, Lattanzio F, Williams P, Sheppard J. Comparison of topical steroids .J Ocul PharmacolThe. 2011;20:533-47.

rise in IOP- maximum rise due to dexamethasone (0.1%) and fluorometholone 0.1% is least

Loteprednol 0.2%- “soft” steroid- minimal effect on IOP & systemic side effects, approved for allergic conjunctivitis and combined with

tobramycin 0.3% for superficial bacterial infection with inflammation

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

RECENT ADVANCES….

DIFLUPREDNATE 0.05%( Diflucor, Diflupred) prednisolone derivative, in emulsion form exhibits enhanced ,

strong efficacy and low side effects indicated in post operative inflammation and uveitis only qid dosing is required

OZURDEX® (Allergan)

(dexamethasone intravitreal implant 0.7mg),

indicated in macular edema following retinal vein occlusion noninfectious posterior uveitis

ORAL CORTICOSTEROIDS

Short acting

Hydrocortisone 20mg/day rapid acting mineralocorticoid

activity

Cortisone 20-100mg/day

Intermediate

Prednisolone 1-2mg/kg/day 4 times more potent than

hydrocortisone

Methyprednisolone 4-32mg/day Selective than prednisolone

Triamcinolone 4-32mg/day Only glucocorticoid action

Long acting

Dexamethasone 0.5- 5mg/day Highly selective

glucocorticoid Marked pitutiary

axis suppressionBetamethasone 0.5- 5 mg/day

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

DEFLAZACORT(Defcort)

Recent glucocorticoid, derivative of prednisolone with less complications

6mg of deflazacort is equivalent to 5 mg of prednisolone

NON STEROIDAL ANTIINFLAMMATORY DRUGS

Has 3 types of effects Anti-inflammatory Analgesic Antipyretic (COX-2)

Inhibits the cyclooxygenase pathway

ORAL NSAIDS

Non selective COX inhibitor

Propionic acid derivative

Ibuprofen 400mg/day potent analgesic

Aryl acetic derivative

Diclofenac

Aceclofenac

50mg tds analgesic, antipyretic,

antiinflammatory

COX 2 inhibitor

Nimesulide 100mg bd analgesic,antipyretic

Poor anti inflammatory

Paraaminophenol

Paracetamol 300-600mg antipyretic

OCULAR INDICATIONS FOR USE OF NSAIDs

prevention of intraoperative miosis

reduction of postoperative inflammation

prevention and treatment of cystoid macular edema

non infectious uveitis

scleritis and episcleritis

allergic and giant papillary conjunctivitis

after refractive surgery

FLURBIPROFEN KETOROLAC DICLOFENAC

Salient features 0.03% solution 0.5% solutionanalgesic and anti-inflammatory

0.1% solutionpotent NSAID with analgesia

Indicationinhibition of intraoperative miosis

ocular itching due to seasonal allergic conjunctivitisForeign body sensation and photophobia

iatrogenic inflammation, post cataract surgery pain

Dosage1 drop every 30 minutes, 2 hrs preoperatively (total of four drops)

TDS QID

Side effects

• transient burning and stinging• may cause increased bleeding tendency of ocular tissues during surgery

• transient burning and stinging• decrease in corneal sensitivity

NEWER DRUGS

Nepafenac 0.1% and Bromfenac 0.09%are topical, nonsteroidal anti-inflammatory, recently introduced

Nepafenac is a prodrug, converted by ocular tissue hydrolases to amfenac, which inhibits the action of prostaglandin H synthase(cyclooxygenase)

patients treated with these drugs were less likely to have ocular pain and measurable signs of inflammation (cells and flare) in the early postoperative period as compared to ketorolac*

indicated for the treatment of post operative pain and inflammation, cystoid macular edema

*Ke TL, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation.. Inflammation. 2000;24(4):371-84

MAST CELL STABILIZERS AND ANTIHISTAMINES

Human eye has about 50 million mast cells, which contains preformed chemical mediators

Allergic conjunctivitis

IgE mediated hypersensitivity reaction

Mast cells and basophils

Histamine Leucotrines Chemotactic factors

capillary dilatation stimulates nerve endings

increased permeability

pain and itching

conjunctival injection and swelling

Class Generic name

Mechanism Dosage Side effects

Mast cell inhibitor

Cromolyn sodium

inhibit neutrophil, eosinophil, monocyte

0.01% BD does not provide

immediate relief

H1 antagonist+ mast cell

inhibitor

Azelastine HCLprovides

immediate relief and prevent further

degranulation

rapid onset

0.05% BD ocular burning, stinging, dry

eye

Epinastine HCL

Ketotifen fumarate

Nedocromil sodium

Olopatadine 0.05%, 0.01% BD/OD

H1 antagonist

+decongestan

t

Naphazoline HCL/phenaram

ine maleate

short term relief for mild

allergy0.05%/0.01%

BD

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 Myelosuppression

Onset take 4-5 weeks

Cyclosporine 25, 50 mg

0.05%,0.1% emulsion

5mg/kg/day Nephrotoxic (urea,

creatinine)

Fast onset of actionMore

efficaciousDry eye

Mycophenolate mofetil

250, 500 mg 1gm BD Myelosuppression

High cost

Leflunomide 10, 20 mg 100mg/day GI upset, hepatotoxic

Still under trial

MYDRIATICS AND CYCLOPLEGICS

Mydriatics are the drugs which dilate the pupil and cycloplegics are agents which causes paralysis of ciliary muscles

Mydriatics

Adrenergic agonist Cholinergic antagonists

Adrenaline Phenylephrine Tropicamide

PHENYLEPHRINE (2.5%)

most common sympathomimetic agent used

acts on alpha 1 receptors of the dilator pupillae

indication pupil dilation refraction before intraocular surgeries

contraindication hypersensitive narrow angle glaucoma cardiac patients elderly patients

Side effects initial stinging and burning systemic side effects include palpitation, tachycardia,

headache, arrythmias reflex bradycardia, pulmonary embolism, myocardial infaction

ADRENALINE

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

CYCLOPLEGIC MYDRIATICS

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

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

ATROPINE(1%)

HOMATROPINE (2%)

TROPICAMIDE (0.5,1%)

CYCLOPENTOLATE (0.5,1)

Instillation regime

rice grain size thrice a day for 3 days

6-8 drops 10 min apart

2 drops 5 min apart

2 drops 5 min apart

Onset 18 hr after last instillation

40 min after 2nd drop



Recovery 10-14 days 3 days 4 hours 2 days

Indications refraction children <7 yrs, strongest cycloplegic

acts more quickly and shorter action, early recovery

diagnostic procedures refraction, fundus examination

short acting

Other Uses drug of choice in anterior segment inflammation, penalisation in amblyopia

low grade Uveitis

pre and post operatively, provocative test for glaucoma

most commonly used post cataract surgery

Side effects dose related side effects

Similar as discussed before

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

TOPICAL HYPEROSMOTIC AGENTS

these agents are helpful in treating corneal edema of diverse etiology

epithelial edema is more responsive as compared to stromal edema

osmotic gradient is created between epithelium and tear film by these agents

water is then drawn towards the more osmotic compartment and is thus eliminated from the epithelium and stroma

commercially available are Topical NaCl solution (2% & 5%) Topical NaCl ointment (6% gel)

dosage is 5 to 6 times a day for drops and 2-3 times a day for gels till the desired response is achieved

gel form is more superior in terms of efficacy and tolerability

OCULAR LUBRICANTS available as drops, gels and ointments indication

protection and lubrication exposure keratitis, decreased corneal sensitivity, recurrent

corneal erosions

Hydrogels are the viscosity enhancing active ingredients of artificial tears

Reduce the risk of bacterial contamination in multidose containers, and to prolong shelf life. E.g. benzalkonium Chloride, oxychloro complex

adverse effects of tear substitute redness stinging and temporary blurring of vision hypersensitivity reactions

various tear substitutes available can be categorized as Cellulose derivatives Polyvinyl polymers Carboxymethyl cellulose (CMC) Hydroxyethyl cellulose (HEC) Hydroxypropyl cellulose (HPC) Hydroxypropylmethyl cellulose (HPMC)

Polyvinyl alcohol Polyvinyl pyrrolidone Polyethylene glycol

CELLULOSE DERIVATIVES POLYVINYL ALCOHOL BASED

polysaccharides synthetic polymer

mix well with other ophthalmic products

does not mix well with other ophthalmic products

only benefit in aqueous defeciency

beneficial in lipid, aqueous and mucin layer defeciencies

hypromellose can cause crusting of lids mimicking blepharitis

short retention time on ocular surface

available as 0.5%, 1% soultion 1%, 1.4% solution

blurring of vision is common water soluble, does not blur vision

OINTMENTS

major advantage is that ointment is retained longer than solution

available as petrolatum, lanolin, mineral oil topical ointment

dosage bed time is preferred Solution should be instilled prior to application of ointment

recent advances Carbopal 980(polyacrylic acid) containing gel is developed

minimises blurring and less dose is required

ANTI GLAUCOMA DRUGS

Beta blockers Alpha Agonists(sympathomimetics)

Prostaglandin analogues

Carbonic anhydrase inhibitors

Cholinergic (parasympathomimetic)Non

selectiveSelective

Timolol Betoxolol Brimonidine0.2%

Latanoprost 0.005%

Dorzolamide2%

Pilocarpine

Levobunolol Apraclonidine 0.5-1%

Bimatoprost - 0.03%

Brinzolamide1%

Carbachol

Metipranolol Dipivefrin0.1%

Travoprost – 0.004%

Carteolol Epinephrine 1-2%

Unoprostone 0.15%

CHOLINERGIC AGENTS

Cholinergic drugs either act directly by stimulating cholinergic receptors or indirectly by inhibiting the enzyme cholinesterase

Topically applied cholinergic agents causes contraction

1] iris sphincter miosis

2] circular muscles of ciliary body relaxing zonular tension & forward lens movement accommodation

3] longitudinal muscle of ciliary body 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

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%

In open angle glaucoma

In angle closure glaucoma

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

CARBACHOL

It is a synthetic derivative of choline.

longer acting than pilocarpine.

indications intracameral use 0.1% during anterior segment surgery can be used in patients who are allergic to pilocarpine

Β– 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

MECHANISM OF ACTION

decrease aqueous humour production by inhibition of catecholamine stimulated synthesis of c-AMP

effective in glaucomatous and normotensive eyes, indicated in

primary and secondary open angle glaucoma secondary angle closure glaucoma after penetrating

keratoplasty aphakic and pseudophakic glaucoma acute and chronic primary angle closure glaucoma developmental glaucoma

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

β blockers

NON SELECTIVEβ1 β2

TIMOLOL CARTE

OLOL

SELECTIVEβ1

BETAXOLOL

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 in B.D. dose

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

BETAXOLOL CARTEOLOL LEVOBUNOLOL

• Cardioselective B1 blocker

•Non Selective (Beta 1 and Beta 2) blocker

• Non selective β1, β2 blocker

• safely used in asthmatic and cardiac patients

•It has fewer side effects, better for cardiovascular patients

The long term drift is less than timolol.

• 0.25%, 0.5% in BD dosage

•1, 2% BD • 0.25% and 0.5%

•IOP lowering effect 26% •response may require few weeks to stabilise

•IOP lowering effect is 32%.

•IOP lowering effect is 30% •used in OD dosing as longer half – life

• OPTIPRESS (0.5%) • OCUPRESS (1%) • BETAGAN (0.5 %)

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

recently introduced 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 (5, 10, 15ml Packs). 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.

Brimonidine’s effectiveness may be reduced by concomitant administration of NSAIDs *

*Sponsel WE, et al: Latanoprost and brimonidine therapeutic and physiologic assessment before andafter oral nonsteroidal anti-inflammatory therapy,Am J Ophthalmol 133:11, 2002

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

DORZOLAMIDE BRINZOLAMIDE

• local inhibition of CA in ciliary body minimizing side effects

• adverse effects include burning, stinging, blurred vision ,lsystemic 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

TOPICAL CARBONIC ANHYDRASE INHIBITORS

PROSTAGLADINS

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

less certain indications in angle closure,neovascular glaucoma

contraindicated in allergic patient, pregnancy, uveitic glaucoma

LATANOPROST TRAVOPROST BIMATOPROST

• Increases uveoscleral outflow 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

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

Few combinations available are

Timolol 0.5% and Dorzolamide 2% Brimonidine 0.2% and Timolol 0.5% Latanoprost 0.005% and Timolol 0.5% Travaprost 0.004% and Timolol 0.5% Bimatoprost 0.03% and Timolol 0.5

.

SYSTEMIC ANTI GLAUCOMA

Oral Acetazolamide Glycerine

Intravenous Mannitol

Neuroprotective agents Calcium channel blockers Nitric oxide synthase inhibitors Vasodialators Antioxidants

ACETAZOLAMIDE

oral carbonic anhydrase inhibitor

a) Tablet 125mg/250mg, TDS/BD onset of action within 1 hr Peak at 4 hrs Duration of action 8-12 hrs

b) Slow release capsule Given OD/BD Duration of action upto 24 hrs

c) 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

Oral Glycerol 50% solution in dose of 1.5 to 3 ml/kg body weight poorly penetrates into the eye diabetics may have problem due to caloric value, osmotic

diuresis and dehydration

Mannitol 20% concentration 1-2gm/kg body weight or 5-10ml/kg body weight peak action-within 30 mins duration of action-upto 6hours choice for intravenous therapy

NEUROPROTECTIVE AGENTS

To protect the optic nerve damage by- Block the endogenous substances which may have damaging

effect on ganglion cells Prevent neuronal degeneration and promoting regeneration

Endogenous substances released during glaucoma are Excitotoxins-glutamate and aspartate Elevated intracellular Ca++ Nitric oxide Free radicals

Agents that promote regeneration Calcium channel blockers Nitric oxide synthase inhibitors Antioxidants Vasodilators

Prostagladins analogs, beta blockers, alpha2 agonist are resonable choices for first line therapy

However, prostagladins with once daily dose are most effective agents for IOP lowering and provide good 24 hr IOP control

THANK YOU

Education

Ocular therapeutics1