Pharmacotherapy of corneal ulcer

PHARMACOTHERAPY OF CORNEAL ULCER

Presented by-Dr. Rajesh A Kamtane,3rd year PG,Dept. of Pharmacology,MIMS

Ulcerative Keratitis (corneal ulcer) is seen in-

A.Infective Keratitis---Bacterial, Viral or Mycotic corneal ulcer

B.Protozoal Keratitis---Acanthamoeba Keratitis

C.Allergic Keratitis---Phylectenular, Vernal or Atopic Keratitis

D.Peripheral Ulcerative Keratitis---associated with connective tissue disorders, Mooren’s Ulcer or Rosacea Keratitis

E. Trophic Corneal Ulcers---Neurotrophic or Exposure Keratopathy

Bacterial Corneal Ulcer

Common bacteria associated with corneal ulceration are---Staphylococcus aureus, Streptococcus pneumoniae, E.coli, Proteus, Klebsiella, Pseudomonas, N. gonorrhoea, N. meningitidis, C. diptheriae

Specific treatment-

Topical antibiotics-Initial therapy (before C & S reports are available) should be combination therapy to cover both gram positive and negative organisms.

Any of the following 2 drugs can be instilled---

Fortified cefazolin + fortified tobramycin orFortified vancomycin + one of the commercially available fluoroquinolone eye drops (0.3 % cipro/ oflox/ gati or 0.5% moxi)

Frequency of instillation-

The chosen two drugs should be instilled alternately as below—

1 hourly round the clock for first 48 hours.

2 hourly during day and 4 hourly at night till healing is ensured.

4 hourly till healing occurs.

Once favorable response is obtained, fortified drops can be substituted by commercially available eye drops.

Subsequent therapy-

No need to change initial antibiotics if response is good.If response is poor, immediately change the antibiotics as per C & S reports.

Systemic antibiotics-Usually not required.

However, a cephalosporin or an aminoglycoside or oral ciprofloxacin (750 mg BD) may be given in fulminating cases with perforation or when sclera is also involved.

Non-Specific treatment:

Cycloplegic drugs.

Topical/ Systemic NSAIDs to relive pain and edema.

Vitamins (A, B- complex & C) help in early healing of ulcer.

Non-Specific treatment…..

Secondary glaucoma can occur due to fibrinous exudates blocking the angle of anterior chamber. Anti-glaucoma drugs can be given to lower IOP (details in further slides).

Topical steroids in selected cases. E.g. marginal catarrhal ulcer which is caused by hypersensitivity reaction to Staphylococcal toxins (details in further slides).

Mycotic Corneal Ulcer

In recent years its incidence is increased due to injudicious use of antibiotics and steroids.

Specific treatment

Topical antifungals:

Natamycin (5%), Amphotericin B and either Fluconazole (0.2%) or miconazole or voriconazole (10% )eye drops to be instilled one hourly round the clock, then taper slowly over 6-8 weeks. These are effective against Aspergillus and Fusarium.

Nystatin (3.5%) eye ointment, five times a day is effective against Candida.

Systemic antifungal drugs may be required for severe cases of fungal keratitis. Tablet fluconazole or ketoconazole may be given for 2-3 weeks.

Non-specific treatment-NSAIDs’, cycloplegics, vitamins

Viral Corneal Ulcer

Herpes Simplex Keratitis

Specific treatment:

Antiviral drugs are first choice presently.

Usually after 4 days of therapy, lesion starts healing which is completed by 10 days. After healing, taper the drug and withdraw in 5 days.

If after 7 days of initial therapy, there is no response, it means that virus is resistant to this drug. Hence change the drug and / or do mechanical debridement.

Commonly used antiviral drugs are as follows-

Acyclovir –

1. 3% ointment, 5 times a day until ulcer heals and then 3 times a day for 5 days.

2. It is least toxic and most commonly used antiviral drug.

Ganciclovir -

3. 0.15% gel, 5 times a day until ulcer heals and then 3 times a day for 5 days.

4. It is more toxic than acyclovir.

Triflurothymidine 1% drops, 2 hourly until ulcer heals and then 4 times a day for 5 days.

Vidarabine 3% ointment, 5 times a day until ulcer heals and then 3 times a day for 5 days.

Systemic antiviral drugs for a period of 10 to 21 days are used in recurrent and acute cases. Tb. Acyclovir 400 mg BD/ TID Tb. Famcyclovir 250 mg BD Tb. Valacyclovir 500 mg BD

Non specific treatment-Same as earlier.

Herpes Zoster Opthalmicus

Systemic therapy for Herpes Zoster

Oral antiviral drugs- Tb. Acyclovir 800 mg 5 times a day for 10 days or Tb. Valacyclovir 500 mg TID

Analgesics-Pain during first 2 weeks of an attack is very severe and should be treated by combination of mephenamic acid and paracetamol or pentazocin or even pethidine (when very severe).

Systemic Steroids-

They inhibit development of post herpetic neuralgia when given in high doses. However, the risk of high doses of steroids in elders should be considered.

They are commonly recommended in cases developing neurological complications such as third nerve palsy and optic neuritis.

Cimetidine 300 mg QID for 2-3 weeks reduces pain and pruritis in acute zoster, by histamine blockade.

Amitriptyline to relieve depression in acute phase.

Local therapy for Herpes Zoster

1. For skin lesions-Antibiotic- steroid ointment or lotions-- three times a day till skin lesions heal.

2. For zoster keratitis-

• Topical steroid eye drops 4 times a day.

• Cycloplegics such as cyclopentolate eye drops or atropine eye ointment OD.

• Topical acyclovir 3% eye ointment, 5 times a day for 2 weeks.

3. For secondary infections-Topical antibiotics

4. For secondary glaucoma-0.5% timolol or betaxolol eye drops BD and Tb. Acetazolamide 250 mg QID.

5. For mucous plaques-Topical mucolytics like acetyl cysteine 5 to 10%, TID.

6. For persistent epithelial defects-Lubricating artificial tear drops.

Protozoal Keratitis

Acanthamoeba keratitis

Specific treatment:

Topical antiamoebic agents include-

Diamidines: propamidine isethionate (0.1%), hexamidine (0.1%)

Biguanides: polyhexamethylene biguanide (0.02%), chlorhexidine (0.02%)

Aminoglycosides: neomycin, paromycin

Imidazoles: clotrimazole and miconazole

Multiple drug therapy is required for 3-4 months for early epithelial lesions and 6-12 months for stromal lesions.

Allergic Keratitis

Local therapy

1. Vasoconstrictors like adrenaline, ephedrine and naphazoline.

2. Topical steroids— Their use should be minimized as much as possible, because they frequently cause steroid induced glaucoma. Commonly used steroids are fluorometholone, medrysone, betamethasone or dexamethasone. First two are safest of all these.

3. Mast cell stabilizers such as sodium chromoglycate (2%) drops 4-5 times a day.

4. Topical antihistaminics-Azelastine eye drops

5. Acetyl cysteine (0.5%) has mucolytic properties and is useful in treating early plaque formation.

6. Topical cyclosporine (1%) drops effective in severe unresponsive cases.

Systemic therapy-Oral antihistaminics and oral steroids in severe cases.

Peripheral ulcerative keratitis associated with connective tissue

disorders, Mooren’s Ulcer

Topical medication with antibiotics, cycloplegics, steroids, lubricating drops.

Systemic medication includes immunosuppresants (steroids, cyclosporine, cyclophosphamide), doxycycline and oral vitamin C.

Rosacea Keratitis

Topical treatment with steroids, but recurrences are very common.

Systemic therapy—Most essential and effective treatment is long course of systemic tetracycline (250 mg QID for 3 weeks, TID for 3 weeks, BD for 3 weeks and OD for 3 months).

Common ocular therapeutics

Antibacterial agents

Sulphonamides:

1. Bacteriostatic.

2. Act by inhibiting folic acid synthesis in susceptible microorganisms by competing with PABA which is essential for bacterial cell nutrition.

3. Used in treatment of chlamydial infections.

Beta lactam antibiotics:

Two important groups included are penicillins and cephalosporins.

All of them act by interfering with synthesis of bacterial cell wall.

Penicillins-

Commonly used preparations are –

Benzyl penicillin, procaine penicilln, ampicillin, amoxycillin.

Methicillin, cloxacillin, flucloxacillin, carbenicillin---these are penicillinase resistant, useful in infections caused by staph, proteus, pseudomonas and coliform organisms.

Cephalosporins-

First generation (narrow spectrum)-1. Active against gram positive cocci, hence useful against

staphylococcus.2. Includes---cefazolin, cephradine, cephalexin, cephadroxyl

Second generation (intermediate spectrum)-3. These have antistaphylococcal activity and are also effective

against certain gram negative organisms.4. These include—cefuroxime, cefoxitin, cefamandole.

Third generation (wide spectrum)-5. Mainly effective against gram negative organisms.6. These include—cefotaxime, cefixime, cefotetan

Aminoglycosides-

Bactericidal.

Primarily active against gram negative organisms.

These are ototoxic and nephrotoxic.

Aminoglycosides……..

Commonly used preparations are—

Gentamicin- 1. Most commonly used aminoglycoside for acute infections,

broader spectrum of action, effective against Pseudomonas aeruginosa.

2. Topically , it is used as 0.3% eye drops.

Tobramycin-3. More active against Pseudomonas and Proteus as

compared to gentamicin. 4. Topically, it is used as 1% eye drops.

Aminoglycosides……

Amikacin-It is recommended as reserve drug for hospital acquired infections with gram negative bacilli, where gentamicin resistance is increasing.

Neomycin and Framycetin-1. Wide spectrum of activity.2. Active against most gram negative and some gram positive

cocci. 3. Used only topically, due to high systemic toxicity.

Tetracyclines and Chloramphenicol-

1. Broad spectrum bacteriostatic agents.

2. Active against gram positive, gram negative organisms as well as some fungi, Rickettsiae and Chlamydiae.

3. Topically used as 0.5 % eye drops.

Polypeptides-

1. Bactericidal.

2. Includes polymyxin B, bacitracin, colistin.

3. Polymyxin B and colistin—active against most gram negative bacteria, notably Pseudomonas.

4. Neosporin (neomycin-polymyxin-bacitracin)—broad spectrum antimicrobial, but has a disadvantage of high incidence of sensitivity due to neomycin.

Fluoroquinolones-

1. Broad spectrum of activity against gram positive and gram negative organisms.

2. Bactericidal drugs. Inhibit bacterial DNA synthesis.

Commonly used are—

3. First generation—cipro, norfloxacin

4. Second generation– ofloxacin, lomefloxacin, pefloxacin.

5. Third generation– sparfloxacin

6. Fourth generation—gati, moxifloxacin

Ocular antifungal agents

Polyene antifungals-

1. Mainstay of antifungal therapy.

2. MOA—work by binding to the sterol groups in fungal cell membrane, making them impermeable. This leads to lethal imbalance in cell contents.

3. These include— Nystatin, natamycin, amphotericin B.

Ocular antifungal agents….

Imidazole antifungal drugs-These include clotrimazole, econazole, fluconazole, miconazole, itraconazole.

Other antifungals-Flucytosine

Silver sulfadiazine—highly effective against Aspergillus and Fusarium species.

Anti-glaucoma drugs for treating secondary glaucoma

Timolol, Betaxolol-

Class---beta blockers

MOA---they block beta 2 receptors in the ciliary processess, resulting in decreased aqueous production, thus lowering the IOP.

These drugs should be used cautiously in patients with bronchial asthma, emphysema, COPD, heart blocks, CCF and cardiomyopathy.

Timolol, betaxolol…….

Ocular side effects-Burning sensation, hyperemia, superficial punctate keratopathy, corneal anesthesia.

Systemic side effects-CVS---result from blockade of beta 1 receptors.These include—bradycardia, arrhythmias, heart failure, syncope.

RS---result from blockade of beta 2 receptors.These include—brnchospasm and airway obstruction, especially in asthmatics.


Timolol-

1. It is non selective beta 1 (cardiac) and beta 2 (smooth muscles, respiratory tract) blocker.

2. Available as 0.25 and 0.5% eye drops.

3. Its action starts within 30 minutes, peak reaches in 2 hours and effects last up to 24 hours. Hence, used once or twice daily.


Timolol…..

4. The phenomenon of “short term escape” and “long term drift” is seen with timolol.

“Short term escape” implies marked initial fall in IOP, followed by a transient rise with continued moderate fall in IOP.

“Long term drift” implies slow rise in IOP in patients who were well controlled with many months of therapy.


Betaxolol-

1. Is a cardioselective beta blocker, has 10 times more affinity for beta 1 receptors than beta 2 receptors. Hence, can be safely used in patients prone to attack of bronchial asthma; advantage over timolol.

2. Available as 0.5 % and 0.25% suspension, is used twice daily.

3. Action starts within 30 min, reaches peak in 2 hours and lasts for 12 hours.

4. Slightly less effective than timolol in lowering IOP.


Anti-glaucoma drugs for treating secondary glaucomaAcetazolamide-

1. Is a carbonic anhydrase inhibitor.

2. Lowers IOP by reducing formation of aqueous humour.

3. Used as additive therapy for short term in management of all types of acute and chronic glaucomas.

4. Side effects—paresthesias, urinary frequency, serum electrolyte imbalance, abdominal discomfort, nausea, diarrhoea.

Anti-glaucoma drugs for treating secondary glaucomaAcetazolamide….

4. Available as tablets, capsules and injection for i.v. use. 250 mg tablet is used 6 hourly.

5. Action starts within one hour, reaches peak in 4 hours and lasts for 6-8 hours.

Other carbonic anhydrase inhibitors—Dorzolamide, Brinzolamide—can be used topically.

Anti-glaucoma drugs for treating secondary glaucomaMannitol, Glycerol-

1. These are hyperosmotic agents, administered systemically.

2. Used as additive therapy for rapidly lowering IOP in emergency situations.

3. MOA– they increase the plasma tonicity. Thus, osmotic gradient created between blood and vitreous draws sufficient water out of the eyeball, thereby lowering IOP.

Anti-glaucoma drugs for treating secondary glaucomaGlycerol-

1. Dose-1 to 1.5 gm/kg

2. Action starts in 10 minutes, peaks in 30 minutes and lasts for about 5-6 hours.

3. It is metabolised to glucose in the body, hence repeated use is not recommended in diabetics.

Anti-glaucoma drugs for treating secondary glaucomaMannitol-

1. Dose-1-2 gm/kg

2. Administered very rapidly over 20-30 minutes.

3. Action peaks in 30 minutes and lasts for about 6 hours.

4. It doesn’t enter glucose metabolism, hence safe in diabetics.

Corticosteroids

They have potent anti-inflammatory, anti-allergic and anti-fibrotic actions.

Short acting-Hydrocortisone, cortisone, prednisolone, methylprednisolone, prednisone.

Intermediate acting-Triamcinolone, fluprednisolone

Long acting-Dexamethasone, betamethasone.

Corticosteroids …….

Commonly used topical preparations are cortisone acetate, hydrocortisone, dexamethasone, betamethasone, medryson, fluromethalone, loteprednol.

Commonly used systemic preparations are –Prednisolone—5 / 10 mg tablet,Dexamethasone– 0.5 mg tablet,Betamethasone– 0.5 / 1 mg tablet.

Corticosteroids …….

Side effects-

Injudicious use of topical steroids can cause glaucoma, cataract, activation of infection (if given in herpertic, fungal or bacterial keratitis), dry eye, ptosis.

Misuse of systemic steroids can cause ocular side effects as mentioned above and systemic side effects such as peptic ulcer, HTN, osteoporosis, worsening of DM, cushingoid state and reactivation of tuberculosis and other infections.

Non steroidal anti-inflammatory drugs (NSAIDs)

They have anti-inflammatory, analgesic and antipyretic actions.

MOA– act by irreversibly blocking COX enzyme, thus inhibiting PG synthesis. Also block other local mediators of inflammatory response.

Non steroidal anti-inflammatory drugs (NSAIDs)…………

Topical opthalmic NSAIDs preparations available are-

1. Indomethacin 0.1 % suspension

2. Flurbiprofen 0.3 % eye drops

3. Ketorolac 0.5 % eye drops

4. Diclofenac 0.1% eye drops

5. Bromefenac 0.09% eye drops

6. Nepafenac 0.1 % eye drops

Systemically used NSAIDs-Paracetamol, diclofenac, acelcofenac, ketorolac, ibuprofen flurbiprofen, naproxen, mefenamic acid, etc.

Cycloplegics

These are the drugs which cause paralysis of accommodation and dilatation of the pupil.

Commonly used drug is atropine sulfate 1% eye ointment or drops instilled 2-3 times a day.

In case of atropine allergy, other cycloplegics like 2% homatropine or 1% cyclopentolate (short acting) eye drops may be instilled 3-4 times/ day.

Alternatively for more cycloplegic effect, a subconjunctival injection of 0.25 ml mydricain (mixture of atropine, adrenaline and procaine) can be given.

Cycloplegics……

Mode of action of atropine-1. Gives comfort and rest to the eye by relieving spasm of iris

sphincter and ciliary muscle.

2. Prevents formation of synechiae and may break already formed synechiae.

3. Reduces exudation by decreasing hyperemia and vascular permeability.

4. Increases blood supply to anterior uvea by relieving pressure on anterior ciliary arteries. As a result more antibodies reach the target tissue and more toxins are absorbed.

Thank you

Education

Pharmacotherapy of corneal ulcer