This document discusses antiviral and antifungal drugs used in ophthalmology. It defines antiviral drugs and outlines the life cycle of viruses in hosts. Several antiviral drugs are described for treating herpes simplex virus, herpes zoster virus, and CMV retinitis. Newer antiviral drugs like ganciclovir and foscarnet are also discussed. The document also covers various classes of antifungal drugs including polyenes, imidazoles, and pyridines. Specific drugs from these classes like natamycin, miconazole, fluconazole, itraconazole and voriconazole are described in detail for treating fungal infections.
Fungal infections of eye cause one of the most dangerious infections. Accurate diagnosis and proper institution of anti-fungal therapy is essential. Here we discuss the various anti-fungal agents available to be used in ophthalmology.
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RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
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2. Definition
• Antiviral drugs are a class of medication used
specially for treating viral infections.
• Like antibiotics for bacteria, specific antivirals
are used for specific viruses.
• Unlike most antibiotics, antiviral drugs do not
destroy their target pathogen; instead they
inhibit their development.
3. 1. Adsorption
2. Entry
3. Uncoating
4. Transcription
5. Virus component synthesis
Life cycle of virus in hosts
5. ANTIVIRAL DRUGS
• These are more often used locally in the eye. Currently
available antiviral agents are virostatic.
• They are active against DNA viruses; especially herpes
simplex virus. Antiviral drugs used in ophthalmology
can be grouped as below:-
For herpes simplex virus infection
• Idoxuridine
• Vidarabine
• Trifluridine
• Acyclovir
• Famiciclovir
7. For CMV retinitis
• Ganciclovir
• Foscarnet
• Zidovudin
Non selective for viruses-
• Interferons
• Immunoglobulins
8. 1. Idoxuridine (IDU, 5-iodo-2 deoxyuridine). It is
a halogenated pyrimidine resembling
thymidine.
Mechanism of action:- It inhibits viral DNA
synthesis and thus prevents replication of
virus.
• Topically it is used as 10% eye drops.
• Preparations- It is available as 0.1% eye drops
and 0.5% eye ointment.
9. • Indications and doses:- Since the intraocular
penetration of topically applied IDU is very
poor, it is not of much value in the treatment
of chronic stromal herpetic keratitis.
• It is mainly used in acute epithelial herpetic
keratitis.
• IDU drops are used one hourly during day and
two hourly during night and has to be
continued till microscopic staining disappears.
10. • Side-effects include follicular conjunctivitis,
lacrimal punctal stenosis and irritation with
photophobia.
• Contraindications. It is known to inhibit
corneal stromal healing, hence its use is not
advisable during first few weeks after
keratoplasty.
12. 2. Adenine arobinoside (Ara-A, Vidarabine). It is a
purine nucleoside. It has antiviral activity against
herpes simplex, cytomegalo, vaccinia and zoster
viruses.
• It is more potent and less toxic than IDU and is
also effective in IDU resistant cases. It has no
cross allergenicity with IDU or TF3 and thus can
be used with IDU.
• Mechanism of action: It is metabolized to tri-
phosphate form which inhibits DNA polymerase
and thus the growth of viral DNA is arrested.
13. • Preparations: It is available as 3% ophthalmic
ointment.
• Dose: It is used 5 times a day till epithelization
occurs and then reduced to once or twice
daily for 4-5 days to prevent recurrences.
• Side-effects are superficial punctate keratitis
and irritation on prolonged application.
14. 3. Cytosine-Arabinoside (Cytarabine). It is a purine
nucleoside.
Mechanism of action: It blocks nucleic acid synthesis by
preventing conversion of cytosine ribose to cytosine
deoxyribose.
• Preparation: It is not commercially available at present.
5% solution used as drops has been found
experimentally effective for treatment of herpes
simplex keratitis.
• Side-effects. It causes profound corneal epithelial
toxicity with superficial punctate keratitis and iritis.
• So it is not recommended for clinical use.
15. 4. Triflurothymidine (TF3). It is a pyrimidine
nucleoside.
• It has the advantage over IDU of higher solubility,
greater potency, lack of toxicity and allergic
reactions.
• It is also effective in IDU-resistant cases.
Mechanism of action: It is a DNA inhibitor with
same mechanism as IDU.
16. • Preparation: It is available as 1% eye drops.
• Dose: One drop is instilled 4 hourly. If no
improvement occurs in 14 days, it is better to
change to some other antiviral drug.
• Toxicity: It is least toxic. It may cause mild
superficial punctate keratitis on prolonged
use.
18. 5. Acyclovir (Acycloguanosine). is a purine analog of
guanosine.
• It has proved to be an extremely safe and effective agent
and is also effective in most forms of herpes simplex and
herpes zoster infections.
• Mechanism of action: It is converted to active tri-phosphate
form by the viral and host cell enzyme, this active tri-
phosphate form inhibits DNA synthesis and viral replication.
• It penetrates into deeper layers and thus is very effective in
stromal keratitis.
• Preparation. It is available as 3% ophthalmic ointment and
also as tablet for oral use and injection for intravenous use.
19. Doses of Acyclovir:-
1. Topical – 3% Ointment
2. Systemic – 1000mg/ 24 hr for 10 days
3. Intravenous-
5 mg/ kg 8 hrly for 5 – 10 days
20. Indications and doses of acyclovir-
• (a) Topical 3% ointment is used 5 times a day for epithelial
as well as stromal herpes simplex keratitis
(b) Oral acyclovir 800 mg, 5 times a day for 5-7 days, may be
considered in following situations:
(i) After penetrating keratoplasty in patients suffering from
herpes simplex keratitis.
(ii) Recalcitrant stromal or uveal disease caused by HSV.
(iii) To reduce ocular complications of keratitis and uveitis
in herpes zoster ophthalmicus.
Side-effects: A few cases show slight punctate epithelial
keratopathy which ceases once the drug is stopped.
21. 6. Valaciclovir. It is used for treatment of herpes
zoster ophthalmicus in a dose of 500-700 mg
TDS for 7 days.
It is as effective as acyclovir in acute disease and
is more effective in reducing late neuralgia.
7. Famiciclovir. Its use, dose and effectivity is
similar to valaciclovir.
22. 8. Interferons. These are non-toxic, species-
specific proteins possessing broad-spectrum
antiviral activity. However, it is still not available
for commercial use.
9. Immunoglobulins. These preparations may be
useful in the treatment or prophylaxis of certain
viral diseases especially in patients with immune
deficiencies.
23. (1) GANCICLOVIR-
Ganciclovir is Guanine analogue and Structurally
related to acyclovir
INDICATIONS-
1. CMV Retinitis
2. Acute herpetic keratitis
Contraindications-
Hyperesensitivity to acyclovir or ganciclovir
Some Newer anti-Viral drugs-
24. Doses of Ganciclovir-
In CMV retinitis-
(a) For Induction regime-
5mg/kg BD for 14-21 days f/b
(b)Maintenance regime-
5 mg/kg IV OD daily for 5 out of 7 days.
25. • Ganciclovir ophthalmic 0.15% gel,(ZIRGAN)5
times a day until ulcer heals and then 3 times
a day for 5 days.
• It is more toxic than acyclovir.
• It is a topical ophthalmic antiviral that is
indicated for the treatment of acute herpetic
keratitis.
26. • Most common adverse reactions reported in
patients were blurred vision (60%), eye
irritation (20%), punctate keratitis (5%), and
conjunctival hyperemia (5%).
• Safety and efficacy in paediatric patients
below the age of 2 years have not been
established.
27. • Foscarnet Inhibits viral DNA replication
• Used in Acyclovir and Ganciclovir resistant
infections.
Doses of foscarnet in CMV Retinitis:-
• Induction dose-
60 mg/Kg TDS for 2-3 weeks f/b
• Maintenance dose:-
90 – 120 Mg/Kg OD daily
(2) FOSCARNET
28. Anti-Fungal Drugs
INTRODUCTION:-
• Fungal infection is the raising prevalence in
recently trends because of increased use of
broad spectrum antibiotics, corticosteroids,
anticancer, immunosuppressant drugs and
emergence of AIDS.
• As a result of breakdown of host defence
mechanisms by the above agents, saprophytic
fungi easily invade the living tissues.
• A number of antifungal agents have become
available in the recent years.
29. • These can be broadly classified on the basis of
their chemical structure into
A. polyene antibiotics,
B. imidazole derivatives,
C. pyrimidines and
D. silver compounds.
30. (A) Polyene antifungals
• is the 1st effective antifungals
- These have been the mainstay of antifungal therapy.
These are isolated from various species of
Streptomyces and consist of a large, conjugated,
double-bond system in a lactose ring linked to an
amino acid sugar.
- Mechanism of action:-
They work by binding to the sterol groups (ergosterol)
in fungal cell membranes, rendering them permeable
followed by alters membrane permeability and
disrupts the fungal cell, consecutive leads to lethal
imbalances in cell contents.
31. • Polyenes do not penetrate well into the
cornea and are not beneficial in deep stromal
keratitis.
• Use is restricted due to insolubility, irritation
on application.
• This group includes following drugs-
32. (1) Nystatin
• 1st polyene antibiotic in 1950, derived from
Streptomyces noursei.
• It is fungistatic and is well tolerated in the eye as
3.5% ointment.
• It has a medium level of activity in ocular
infections caused by Candida or Aspergillus
isolates.
• Because of its narrow spectrum and poor
intraocular penetration, its use is restricted.
33. (2) Amphotericin B (Fungizone)
• This antibiotic may act as fungistatic or
fungicidal depending upon the concentration
of the drug and sensitivity of the fungus.
• Topically, it is effective in superficial infections
of the eye in the concentration of 0.075 to
0.3% drops.
• Sub-conjunctival injections are quite painful
and more than 300 mg is Poorly tolerated.
34. • Amphotericin B may be given intravitreally or/ and
intravenously for treatment of intraocular infections
caused by Candida,Histoplasma,Cryptococcus and
some strains of Aspergillus and others.
• Total daily dosage may range up to 1.0 mg/kg
per day or up to 1.5 mg/kg when given on
alternate days.
35. 3. Natamycin (Pimaricin).
• Natamycin derived from Streptomyces
natalenses.
• It is a broad-spectrum antifungal drug having
activity against Candida,Aspergillus, Fusarium and
Cephalosporium.
• Topical application of 5% pimaricin suspension
produces effective concentrations within the
corneal stroma but not in intraocular fluid.
• It is the drug of choice for fusarium solani
keratitis.
36. • It adheres well to the surface of the ulcer,
making the contact time of the antifungal
agent with the eye greater.
• It is not recommended for injection.
• 5% topical suspension drops 4-6 times/day
• Adverse reactions: irritation, burning, allergic
reactions.
37. (B) Imidazole antifungal drugs
• Various imidazole derivatives available for use in ocular
fungal infections include:- miconazole, clotrimazole,
ketoconazole, econazole and itraconazole.
(1) Miconazole. It possesses a broad antifungal spectrum
and is fungicidal to various species of Candida, Aspergillus,
Fusarium, Cryptococcus,Cladosporium, Trichophyton and
many others.
• Topical (1%) instilled every hourly and subconjunctival (5-10
mg) every 48 hrs for 2-3 doses, application of miconazole
produces high levels of the drug in the cornea which is
more dramatic in the presence of epithelial defect.
38. (2) Clotrimazole
• It is fungistatic and is effective against
Candida, Aspergillus and many others.
• Its 1% suspension is effective topically and is
the treatment of choice in Aspergillus
infections of the eye.
39. (3) Econazole.
• It also has broad-spectrum antifungal activity
and is used topically as 1% ointment and
drops 4-6 times daily.
• Because of its poor intraocular penetration, it
is effective only in superficial infections of the
eye.
40. (4) Ketoconazole.
• It is effective after oral administration and
possesses activity against common fungi But
highly effective for treatment of
keratomycosis.
• It is an adjunctive systemic antifungal agent in
fungal keratitis complicated by
endophthalmitis.
41. • It is given as single oral dose of 200-400 mg daily
up to at least one week after the symptoms have
disappeared.
• Topical 1-5% drops also used and well tolerated.
• Reactions: relatively safe, but GIT upset, abnormal
LFT, hypersensitivity and Reversible hepatotoxicity
is occurs.
42. (5) Fluconazole.
• 1st antifungal with good pharmacokinetic
profile & relative low side effect
• It is fungistatic drug active against Candida,
Aspergillus and Cryptococcus.
• It is used Orally, 200-600mg/day for 3 weeks
for candida and 10-12 weeks in cryptococcus
infection and also for topical use 0.2% eye
drops every 4hrly.
43. (6) Itraconazole.
• It is prescribed for treatment of fungal
infections caused primarily by
Aspergillus,Histoplasmosis, Blastomycosis.
• It has moderate effect against Candida and
Fusarium infections.
• It is available for oral and topical use.
• Oral dose is 200 mg twice daily for a week and
Topically it is used as 1% eye drops.
44. (7) Voriconazole
• Voriconazole is a new generation triazole
antifungal agents, with broad-spectrum
activity and high intraocular penetration.
• Voriconazole eye drops have been used for
the treatment of ophthalmic fungal keratitis.
• The voriconazole eye drops used are of
topically 1% concentration, well tolerated by
the eye, and are stable..
45. • Have Good bioavailability and Good
therapeutic concentrations
• Completely inhibits ergosterol synthesis and
more effective than fluconazole
• Commonly used for invasive systemic and
ocular infections specially aspergillosis and
candidiasis
• Oral dose of Voriconazole 200mg BD.
46. • S/E- Transient visual disturbances, fever, rash,
vomiting, headache, abdominal pain.
• Faster and deeper penetration
• Highly effective in fungal keratitis with deep
abscess
• Outclasses all other antifungals.
47. (C) Pyridine
• This group includes flucystosine, which is fluorinated
salt of pyrimidine.
MOA- After uptake into fungal cells, it is converted into
5-fluorouracil and then to 5-fluorodeoxyuridylic acid
which is an inhibitor of thymidylate synthesis.
Thymidylic acid is a component of DNA.
• The drug is very effective against Candida species and
yeasts.
• It is used as 1.5% aqueous drops hourly.
• It can also be given Orally 50-150mg/kg/day divided in
4 doses for a week.
48. (D) Silver compounds-
• Combination of silver with sulfonamides and with
other anti-microbial compounds significantly
increases the activity against bacterial and fungal
infections.
• In this context several silver compounds have
been synthesized. Most frequently used is silver
sulphadiazine which is reported to be highly
effective against Aspergillus and Fusarium
species.
• It is used to 1% drops hourly.