| CHAPTER | 4 | Ocular Therapeutics |
▃Introduction (PH1.58)
The drugs available for the treatment of ocular diseases include:
•Antibacterials.
•Antiviral agents.
•Antifungal agents.
•Anti-inflammatory drugs.
•Antiallergic drugs.
•Mydriatics and cycloplegics.
•Antiglaucoma drugs.
•Drugs used for dry eye.
•Anti-VEGF agents.
•Pharmacological agents used in intraocular surgery.
▃Routes of Administration
The therapeutic substances can be delivered by four routes (Flowchart 4.1).
■Instillation
Topically instilled drugs are used in the form of drops, ointment, gel, and suspension. Ointment impairs the vision, hence must be applied at night.
Absorption and Bioavailability of Drug
The drug instilled into the conjunctival sac is absorbed largely through the cornea. The corneal layers have different selective permeability. The epithelium is more permeable to fat/lipid soluble substances, while the stroma is permeable to all water-soluble substances. The drug absorption is regulated by:
•Duration of drug contact in the eye, which is enhanced by the use of viscous carriers such as hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol, and hyaluronic acid.
•Pressing the lower punctum by thumb to delay its nasal absorption.
Flowchart. 4.1 Routes of therapeutic substance.
Sustained release of the drug may be achieved by ocuserts placed in upper/lower fornix or by drug-impregnated contact lenses. The corneal epithelium forms the main barrier against drugs entering the eye. It is disrupted by local anesthetic or abrasion.
■Periocular Injections
Subconjunctival Injections
Both antibiotics and steroids can be administered into the eye by subconjunctival injections. Antibiotics which do not penetrate the cornea, owing to their large molecular size, enter the eye through this route, as sclera allows the free transit of molecules of considerable size.
Subtenon Injections
Subtenon injections are employed for sustained release of steroids. These injections are used in the treatment of intermediate (pars planitis) and posterior inflammations. Depot preparation of corticosteroids (triamcinolone acetonide) is useful for the management of chronic intraocular inflammation without systemic side effects.
Peribulbar Injections
This route is used for administration of anesthetics, steroids, or antibiotics in the management of posterior uveitis. This route is preferred over retrobulbar injections for injecting anesthetics or steroids in muscle cone, as retrobulbar injections may cause perforation of globe or damage to optic nerve.
■Systemic Administration
Systemic therapy (oral or parenteral) is required in the inflammations/infections of posterior retina, optic nerve, or orbit that cannot be controlled by local applications alone. This route has certain limitations because of the impermeability of blood aqueous barrier. Lipid-soluble drugs (chloramphenicol, sulphonamides, etc.) can penetrate the barrier and enter the eye easily. The blood–aqueous barrier prevents the large-sized molecules (such as penicillin) or water-soluble drugs.
■Intraocular Injections
In desperate cases, the drugs are injected either into the anterior chamber (intracameral injection) or in the vitreous (intravitreal injection). Intracameral injections of antibiotics are used in acute endophthalmitis. Intravitreal injections of antibiotics and antifungals are indicated in bacterial or fungal endophthalmitis, respectively. The effective concentrations of antibiotics in intravitreal injections last longer than in intracameral injections. Vitreous implants have been used for the treatment of cytomegalovirus (CMV) retinitis.
Gram +ve cell walls are thick and made of peptidoglycan (70–80%); the lipid content in the wall is very low and contains teichoic acid. It can be completely dissolved by lysozymes due to digestion of peptidoglycan layer except in Staph. aureus in which the cell wall is resistant to the action of lysozymes. These primarily produce exotoxins. It is more susceptible to antibiotics.
Gram −ve cell walls contain a thin peptidoglycan (10–20%) layer (without teichoic acids) that is surrounded by a thick plasma membrane adjacent to the cytoplasmic membrane. The lipid content in the wall is 20 to 30%. These primarily produce endotoxins. Periplasmic space is present in these bacteria. It is more resistant to antibiotics because their outer membrane comprises a complex lipopolysaccharide (LPS) whose lipid portion acts as an endotoxin.
Unlike mammalian and bacterial cells, fungal cell membranes comprise large amounts of ergosterol (Fig. 4.1).
▃Antimicrobial Agents
Antimicrobial drugs are synthetic as well as naturally obtained drugs that act against microorganisms.
Antibiotics are the substances obtained from the microorganisms which selectively kill other microorganisms at a very low concentration.
■Classification
Antibiotics may be classified in a variety of ways:
On the Basis of Type of Action
Antibiotics may be bacteriostatic or bactericidal (Table 4.1).
On the Basis of Spectrum of Activity
Antibiotics may be narrow-spectrum or broad-spectrum. Narrow-spectrum antibiotics inhibit either gram +ve or gram −ve bacteria, for example, penicillin, streptomycin, erythromycin, and aminoglycosides. Broad-spectrum antibiotics inhibit both gram +ve and gram −ve as well as rickettsiae, chlamydia, spirochetes, and protozoa, for example, tetracyclines and chloramphenicol.
On the Basis of Mechanism of Action
Fig. 4.2 depicts the drugs having varying mechanisms of action.
1.Drugs inhibiting cell wall synthesis, these are bactericidal drugs and include:
•Penicillin.
•Cephalosporins.
•Vancomycin.
•Bacitracin.
2.Drugs affecting cell membrane function:
•Polymyxins.
•Amphotericin B.
•Nystatin.
•Natamycin.
3.Drugs acting on ribosome 50-S, these are bacteriostatic drugs and inhibit protein synthesis. These include:
•Chloramphenicol.
•Erythromycin.
•Clindamycin.
Table 4.1 Types of antibiotics on the basis of action | |
Bacteriostatic drugs | Bactericidal drugs |
•Tetracyclines •Chloramphenicol •Erythromycin •Clindamycin •Sulphonamides | •Penicillins •Cephalosporins •Vancomycin •Aminoglycosides •Fluoroquinolones |
Fig. 4.1 Cell wall of: (a) gram positive bacteria and (b) gram negative bacteria.
Fig. 4.2 Drugs with their mechanisms of action. Abbreviations: DNA, Deoxyribonucleic acid; mRNA, messenger ribonucleic acid; PABA, Para-aminobenzoic acid; PAS, Para-aminosalicylic acid.
4.Drugs acting on ribosome 30-S, these are bactericidal drugs and include:
•Aminoglycosides.
•Tetracyclines.
5.Drugs acting on nucleic acids, these are bactericidal drugs, inhibit DNA gyrase and include fluoroquinolones.
6.Drugs interfering with DNA synthesis:
•Acyclovir.
•Zidovudine.
7.Drugs interfering with intermediary metabolism:
•Sulphonamides.
•Ethambutol.
•PAS.
Penicillins
Penicillins have narrow antibacterial spectrum and are effective against cocci and gram +ve organisms. In gram +ve bacteria, the cell wall is almost entirely made of peptidoglycan and extensively cross-linked. In gram −ve bacteria, it consists of alternating layers of lipoprotein and peptidoglycan. This may be the reason for higher susceptibility of gram +ve bacteria to penicillin.
Routes of Administration
•Topical: Penicillin G (benzyl penicillin) may be administered locally in the form of drops (100000 units/mL) instilled frequently specifically in gonococcal infections.
•Subconjunctival injections: Penicillin G as subconjunctival injections (0.5 million units).
•Systemic.
Common penicillins include the following:
Cloxacillin is penicillinase-resistant and is not affected by staphylococcal penicillinase. Therefore, it is used for treating staphylococcal infections which are resistant to other penicillins. Dose: 250 to 500 mg every six 6 hours. It is given orally/IM/IV.
Ampicillin is a broad-spectrum antibiotic. It is acid-resistant and penicillinase sensitive. Hence, it is administered orally and used for the organisms which do not produce penicillinase. Diarrhea is frequent after oral administration.
Dose: 250 to 500 mg every 6 hours. It is given orally/IM/ IV.
Amoxicillin is a broad-spectrum penicillin. Oral absorption is better. Hence, administered orally. Food does not interfere with its absorption. Dose: 250 to 500 mg every 8 hours.
Carbenicillin: The special feature of Carbenicillin is its activity against Pseudomonas aeruginosa and proteus which are not inhibited by penicillin G, ampicillin, or amoxicillin. It is not acid resistant, hence it is inactive orally.
Cephalosporins
Cephalosporins act in the same way as penicillins, that is, by inhibition of bacterial cell wall synthesis.
Cephalosporins are classified into four generations, depending on the antibacterial spectrum as well as potency (Table 4.2).
Routes of Administration
•Topical: Fortified cephazolin: Add 2.5 mL
sterile water in 500 mg inj cerfazolin (dry powder). The reconstituted cefazolin 500 mg in 2.5 mL is added to 7.5 mL of preservative-free artificial tears to make 10 mL of solution. Thus, fortified cefazolin drops are prepared 5% (50 mg/mL). It is stable for 24 hours at room temperature or 96 hours if kept in a refrigerator. Cefazolin is most commonly used for Gram +ve organisms.
Problems with fortified antibiotics is its cost, short shelf life, need for refrigeration, and decreased sterility.
Vancomycin (Glycopeptide)
It is a bactericidal to gram + ve cocci and methicillin-resistant staphylococcus aureus (MRSA). It acts by inhibiting bacterial cell wall synthesis.
Routes of Administration
•Topical: Fortified vancomycin: Add 2.5 mL sterile water in 250 mg inj. vancomycin (dry powder). The reconstituted vancomycin 500 mg in 2.5 mL is added to 7.5 mL of artificial tears to make 10 mL of solution. Thus, fortified vancomycin drops are prepared. Refrigerate and use within 4 days.
•Systemic: It is not absorbed orally and administered intravenously (500 mg every 6 hours).
•Intravitreal injection: 1 mg in 0.1 mL of vancomycin is administered intravitreally. It is a drug of choice in endophthalmitis along with amikacin or ceftazidime.
Aminoglycosides
•All are bactericidal and not absorbed orally.
•They are active against aerobic Gram
−ve bacilli. They do not inhibit anaerobes because transport of aminoglycosides into the bacterial cell requires oxygen.
•They exhibit synergism when combined with b-lactam antibiotics. Therefore, cephazolin (b-lactam antibiotic) and fortified genticyn/tobramycin eye drops are effective in corneal ulcer cases.
•All exhibit ototoxicity and nephrotoxicity.
Table 4.2 Classification of cephalosporins | ||
Cephalosporins | Drugs | Spectrum |
First generation | Cefazolin (P), Cephalexin, and cefadroxil (O) | Narrow spectrum. They are highly effective against Gram +ve cocci. |
Second generation | Cefuroxime (P) and Cefaclor (O) | Intermediate spectrum. They are more active against Gram −ve but do not inhibit pseudomonas. |
Third generation | Cefotaxime, Ceftriaxone, and Ceftazidime (P) Cefixime and Cefpodoxime proxetil (O) | Wide spectrum They are more active against Gram −ve but some inhibit pseudomonas. |
Abbreviations: O, oral; P, parenteral.
•Streptomycin.
•Gentamicin.
•Kanamycin.
•Tobramycin.
•Amikacin.
•Sisomicin.
•Netilmicin.
•Neomycin.
•Framycetin.
Inhibitors of bacterial wall synthesis (penicillin, cephalosporin,s and vancomycin) enhance entry of aminoglycosides and exhibit synergism.
Routes of Administration
•Topical: Fortified gentamicin/tobramycin: Add injection gentamicin/tobramycin 80 g in 2 mL (40 mg/mL) in commercially available 0.3% gentamicin/tobramycin drops (5 mL).
Thus, fortified gentamicin/tobramycin 1.3% (13.6 mg/mL) drops are prepared. Refrigerate and use within 14 days.
Gentamicin (0.3%) and tobramycin (0.3%)—drops are used topically.
Neomycin (0.5%) and framycetin (0.5%)– drops or ointments are used topically.
•Subconjunctival injection: Gentamicin (20–40 mg), and tobramycin can be used subconjunctivally.
•Intravitreal injection: Amikacin is administered intravitreally (0.4 mg) along with vancomycin in the treatment of endophthalmitis.
Polypeptides
All are powerful bactericidal agents, but not used systemically due to toxicity. These include polymyxin B and bacitracin.
Bacitracin
Mechanism of action—It inhibits cell wall synthesis.
Route of administration—Its use is restricted to topical application generally in combination with neomycin and polymyxin B.
Polymyxin B
Mechanism of action—It has high-affinity for phospholipids and causes leakage from bacterial cell membrane. It is effective against gram −ve bacteria.
Route of administration—It is used topically in combination with neomycin, bacitracin, and gramicidin.
Chloramphenicol
It is a broad-spectrum antibiotic.
Mechanism of actions: It is bacteriostatic drug and inhibits bacterial protein synthesis.
Spectrum: It is similar to that of tetracyclines, that is, it is effective against gram +ve and gram −ve bacteria, spirochaetes, chlamydiae, rickettsiae, and mycoplasma. Like tetracyclines, it is ineffective against mycobacteria, pseudomonas, proteus, viruses, and fungi.
Routes of Administration
•Topical: It is used topically as drops (0.5%) or ointment (1%). It is least toxic to corneal epithelium.
•Systemic: It is lipid-soluble, so ocular penetration is better on systemic administration. Orally, it is administered in the dose of 250 to 500 mg every 6 hours.
Adverse effects:
•Bone marrow depression. Topical administration may rarely lead to blood dyscrasias.
•Gray baby syndrome.
Macrolides
These include:
•Erythromycin.
•Azithromycin.
Erythromycin
Erythromycin is bacteriostatic and inhibits protein synthesis.
Spectrum—It is a narrow-spectrum antibiotic effective mostly against gram +ve and a few gram −ve bacteria.
Route of administration—It is administered orally (250–500 mg every 6 hours).
Azithromycin
It is less active against gram + ve cocci but highly effective against gram −ve organisms, Chlamydia trachomatis, and Toxoplasma gondii.
Dose: 500 to 1500 mg (20–30 mg/kg) as a single dose.
Uses: It is used in the treatment of trachoma and toxoplasmosis.
Tetracyclines
These include:
•Tetracycline.
•Chlortetracycline.
•Oxytetracycline.
•Doxycycline.
Mechanism of action: These are bacteriostatic drugs and inhibit protein synthesis.
Spectrum: These are broad-spectrum antibiotics. They are effective against both gram +ve and gram −ve organisms and spirochetes. All rickettsiae and chlamydiae are highly sensitive.
Routes of Administration
•Topical: Tetracycline is used as drops and ointment (1%) for superficial ocular infections.
•Oral: Doxycycline 200 mg for one day then 100 mg/day for 9 days is administered orally in staphylococcal lid infections and trachoma.
Adverse effects—Tetracyclines have chelating property. Calcium-tetracycline chelate gets deposited in growing bones and teeth. Hence, tetracyclines should not be used during pregnancy, lactation, and in children.
Fluoroquinolones
They are bactericidal and include:
•Ciprofloxacin.
•Norfloxacin.
•Ofloxacin.
•Lomefloxacin.
•Pefloxacin.
•Levofloxacin.
•Gatifloxacin.
•Moxifloxacin.
Mechanism of action: They inhibit the bacterial DNA-gyrase enzyme and DNA synthesis.
Spectrum: These contribute toward their activity against gram +ve bacteria. Ciprofloxacin has a broad-spectrum activity, with the most susceptible ones are the aerobic gram −ve bacilli, while gram +ve bacteria are inhibited at relatively higher concentrations. It has good intraocular penetration. These drugs get deposited in the growing cartilage and hence contraindicated in children.
Table 4.3 Routes of administration of fluoroquinolones | |
Fluoroquinolones | Administration |
Ciprofloxacin | Topical (0.3%) drops or ointment. Systemic—orally (500 mg every 12 hours) IV 200 mg every 12 hours |
Norfloxacin | Topical (0.3%) drops or ointment. Systemic—orally (400 mg every 12 hours) |
Ofloxacin | Topical (0.3%) drops or ointment. Systemic—orally (200–400 mg every 12 hours) |
Gatifloxacin | Topical (0.3%) drops or ointment. |
Moxifloxacin | Topical (0.5%) drops or ointment. It is self-preserved 0.5% ophthalmic solution and has better intraocular penetration than other fluoroquinolones. |
Route of administration: It could be topical and oral (Table 4.3).
These are bacteriostatic but in high concentration they may be bactericidal.
Spectrum: They are effective against many gram +ve and gram −ve bacteria, chlamydiae, actinomyces, nocardia, and toxoplasma. Anaerobic bacteria are not sensitive to sulphonamides.
Route of Administration
•Topical: 10 to 30% sulphacetamide is used in the treatment of trachoma.
•Systemic: They can also be administered orally. They are lipid-soluble and pass blood–aqueous barrier easily. Therefore, their concentration in aqueous is high.
Adverse effects:
• Stevens–Johnson syndrome.
• Crystalluria.
▃Antiviral Agents
Viruses contain only one type of nucleic acid (DNA or RNA). So, viruses are either DNA viruses or RNA viruses.
DNA viruses:
•Adenovirus.
•Herpes simplex virus (HSV).
•H zoster virus (VZV).
•Epstein–Barr (EB) virus.
RNA viruses—HIV (human immunodeficiency virus)—a retrovirus.
Antiviral agents are selectively active against either RNA or DNA viruses. Viruses can replicate only inside the host cells and utilize the host enzyme systems. Therefore, targeting the virus selectively is very difficult. Hence, antiviral drugs often produce severe toxic effects.
Antiviral agents are of two types:
•AntiHerpes agents (drugs used against herpetic infection)–
♢Purine derivatives.
–Acyclovir.
–Ganciclovir.
–Valacyclovir.
–Famciclovir.
–Vidarabine (adenine arabinoside/Ara-A).
♢Pyrimidine derivatives.
–Idoxuridine (IDU or 5-Iodo 2-deoxyuridine).
–Trifluorothymidine (TFT/F3T).
There purine or pyrimidine analogues are incorporated to form abnormal viral DNA.
•Antiretroviral agents (drugs used against HIV infection), for example, foscarnet and zidovudine.
■AntiHerpes Agents
Pyrimidine Derivatives
Idoxuridine (IDU)
It is a thymidine analogue that acts against DNA viruses. It substitutes thymidine in DNA synthesis and inhibits virus replication. It is a virustatic drug.
Preparation and use—It is used topically as 0.1% eye drops and 0.5% eye ointment for herpes simplex keratitis. The drops are instilled every 1 to 2 hours during day and ointment at night. It does not cure stromal keratitis or prevent recurrence.
Adverse effects:
• Superficial punctate keratitis.
• Follicular conjunctivitis.
• Punctal occlusion.
Trifluorothymidine (TFT/F3T)
It is also a pyrimidine analogue and has the same mechanism of action as IDU. It is soluble and is more effective than IDU.
Preparation and use—It is used as 1% eye drops instilled five times a day for 2 weeks in herpes simplex virus infections.
Adverse effect—It induces less epithelial toxicity than IDU.
Purine Derivative
Acyclovir
It is a selective virustatic drug. It is selectively active against herpes group of viruses: HSV-1, HSV-2, and varicella-zoster virus (VZV).
Order of sensitivity—HSV-1 > HSV-2 > VZV ≈ E.B. virus.
Cytomegalovirus (CMV) is practically not affected. So, it is used for the treatment of:
•Genital herpes (HSV-2).
•Mucocutaneous herpes (HSV-1).
•H. simplex keratitis (HSV-1).
•H zoster.
•Chicken pox.
Mechanism of action—Acyclovir is converted to its active form, acyclovir triphosphate, which inhibits DNA synthesis and viral replication. It is activated by herpes virus thymidine kinase to inhibit DNA polymerase; thus, selectively active against herpes group of viruses. (Flowchart 4.2)
Note: As acyclovir is activated by viral thymidine kinase in virus-infected cells, acyclovir has low-toxicity for host cells.
Advantages over IDU, TFT, and Ara-A:
•It penetrates intact corneal epithelium and stroma and produces therapeutic concentrations in aqueous.
•It demonstrates less epithelial toxicity then IDU, TFT, and Ara-A.
Flowchart. 4.2 Algorithm explaining the mechanism of action of acyclovir.
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