Immunosuppressive agents in ophthalmology- ocular pharmacology

1. IMMUNOSUPPRESSIVE AGENTS
IN OPHTHALMOLOGY
Dr. CHRISTINA SAMUEL
PG- M.S OPHTHALMOLOGY
MMCH & RI

2. CLASSIFICATION
ALKYLATING AGENTS
ANTIMETABOLITES
ANTIBIOTICS

3. ALKYLATING AGENTS
CLINICAL INDICATIONS:
o Behcet’s disease
o Sympathetic Ophthalmia
o Rheumatoid arthritis
o Polyarteritis nodosa
o Wegener’s granulomatosis
o Relapsing polychondritis
o Bullous pemphigoid
o Malignancy

4. CYCLOPHOSPHAMIDE
 A natural product of fungi.
 Mechanism of action: The active metabolites alkylate purines in DNA and
RNA resulting in cross linking which results in cell death. It decreases the
number of activated T lymphocytes.
 Has a prominent immunosuppressive property.
 Less damaging to platelets.
 Chloramphenicol retards the metabolism of cyclophosphamide.
 Dosage:- 1-2mg/kg/day i.e 150-200mg/day in empty stomach. To
monitor WBC on Day 1,3 and 7. To reduce dosage by 25-50mg to stabilize
the WBC at about 3000 cells/micro Lit. Once stabilized to monitor WBC
and CBC with differential count weekly and then after a fortnight.

5. CHLORAMBUCIL
 MOA:- Suppression of T cell lymphocytes (cell mediated immunity) and to a
lesser extent B cells( antibodies) function. It is an alkylating agent.
 DNA to DNA cross linking and DNA to protein cross linking occurs which leads
to interference in DNA replication, DNA transcription and nucleic acid
function.
 Indications: Behcet’s disease, Sympathetic Ophthalmitis
 Patients typically require concomitant oral corticosteroids initially, and one
goal of chlorambucil therapy is to taper and discontinue oral corticosteroids
over a 2 month to 4 month period
 Dosage:- 0.1-0.2mg/kg/day and increase every 3-4 days to a total dosage of
10-12mg/kg if there is no idiosyncratic reaction.
 To monitor WBC, CBC and DC.

6. ADVERSE REACTIONS
 Thrombocytopenia
 Anemia
 Opportunistic infections
 GIT disturbances
 Pulmonary interstitial fibrosis
 Renal toxicity
 Testicular atrophy
 Myelo/ Lympho proliferative malignancy
 Hemorrhrhagic cystitis- indication to discontinue medication

7. ANTIMETABOLITES
 The antimetabolites used in Ophthalmology are:
 Azathioprine which interferes with purine metabolism.
 Methotrexate which interferes with folate action.
 Both functions are essential for nucleic acid synthesis.

8. Clinical Indications
 Rheumatoid arthritis, pemphigoid and regional
ileitis.
 Sympathetic ophthalmia and VKH syndrome.
 Pars planitis and Bechet’s disease.
 Recalcitrant cases of intermediate uveitis.

9. AZATHIOPRINE
MOA:- It affects the differentiation and function of T cells
and inhibits the cell mediated immunity.
Absorbed orally.
Metabolized by Xanthine oxidase and inhibited by Allopurinol.
Bone marrow depression is the main toxic effect.
Inhibits De Novo synthesis and damages DNA.
Its dosage starts at 1-2 mg/kg/day gradually increasing to 2.5
mg/kg/day.
 The usual dose range is 100-200 mg/day in one or divided
doses.
 Patient WBC , CBC with differential are taken at regular
intervals.

10. Adverse reactions
 Uncontrolled leukopenia.
 Thrombocytopenia.
 Hyperuricemia.
 GIT disturbances.

11. METHOTREXATE
It is a folate antagonist.
It is one of the oldest and highly efficient anti neoplastic drugs.
MOA:- It inhibits Dihydrofolate reductase which is required convert DHFA to
Tetrahydro folic acid which is an essential Co enzyme required for carbon
transfer in De Novo Purine synthesis and amino acid conversion.
It kills cells in ‘S’ phase, inhibits DNA synthesis, also affects RNA and protein
synthesis.
Depresses cytokine T cellular production immunity anti inflammatory
property.
FOLINIC ACID rapidly reverses the effect of methotrexate.
Thymidine also counteracts methotrexate property.
DHFRase
DHFA THFA

12.  Its dosage is variable due to high drug toxicity.
 Generally for 1-4 weeks oral,IM or IV dose of 2.5 – 15 mg is
given over 36-48 hours until a therapeutic response is
noted.
 Maintained as per hemolytic (weekly) and renal (monthly)
monitoring.

13. Adverse effects
 Leukopenia and Thrombocytopenia.
 Hepatic and renal toxicity.
 GIT disturbances.
 Interstitial pneumonitis.
 CNS toxicity.
 Sterility.

14. ANTIBIOTIC CYCLOSPORIN A
 It is a cyclic polypeptide with 11 amino acids.. Selectively inhibits T cell lymphocyte
proliferation, IL-2, other cytokine production and response of inducer T cells to IL-1 without
any effect on suppressor T cells. Lymphocytes are arrested in G0 –G1 phase.
 Cyclosporine binds to an intracellular protein “CYCLOPHILIN” and this complex inhibits
Calcium Calmodulin activated enzyme “ CALCINEURIN’’.
 Normally after activation this T cell receptor, calcineurin activates the cytokine gene through
Nuclear Factor of Activated T cells resulting in transcription of cytokine genes and production
of IL-2 and other cytokines. These pathways are inhibited by Cyclosporine.
 Dosage of 2.5-5 mg/kg/day given orally in an olive oil – ethanol solution with milk or juice.
 Maximum dose is 10 mg/kg/day.

15. Adverse effects
 Systemic hypertension.
 Partially reversible renal toxicity.
 Opportunistics infections.
 Hyperuricemia.
 Hepatotoxicity.

16.  Monthly and if required weekly blood tests (CBC
with differential and WBC) should monitor these
effects.
 Combination of steroid (prednisolone 10-20
mg/day) and cyclosporin A therapy may augment
each other.
 Short term may allow a lowering of the cyclosporin
A dosage with no loss of therapeutic efficacy.

17. Chlorambucil or Cyclophosphamide and
Steroid Management Module
 It involves initial treatment with Prednisolone 1 mg/kg/day along with
cytotoxic drug.
 Should be continued for 4 weeks until the disease is suppressed then
steroids tapered and stopped over 2 months.
 The cytotoxic drug dosage is adjusted to keep the WBC at 3000-4000
/micro lit and continued for one year to induce remission before being
stopped.
 Monitor the CBC and urine analysis weekly until stable than at every 2
weeks.

18. New Immunosuppressive Agents
Tacrolimus
 It is an immunomodulator.
 Mechanism of action: It inhibits activation of T lymphocytes by inhibiting
transcription in these cells.
 Indications:-The main use for ocular illness is in infectious uveitis.
 Dose: Initial dose of 0.05 mg/kg/day
 Monitoring of blood counts is necessary.
 Tacrolimus should not be given with cyclosporine because of the similar risks
of renal toxicity.

19. Daclizumab
 Mechanism of action:- The IL-2 receptor system is a well characterized
lymphokine receptor system that plays a central role in the induction of
immune responses. Daclizumab builds to the alpha chain of IL-2 receptor
and blocks the IL-2 mediated responses.
 Indication: Non infectious uveitis
 Dose: 1 mg/kg two weekly
 Side effects: Cutaneous lesions, Upper respiratory infections, Bronchitis,
Herpes zoster infections.

20. Infliximab
 It is a chimeric monoclonal antibody directed against tumor necrosis factor – alpha. It interferes with the
binding of TNF to the receptors. TNF enhances leucocyte migration and activates the pro inflammatory
cytokines like interleukin-1 and interleukin – 6.
 Infliximab by interfering with the binding of TNF to the receptors, decreases proinflammatory cytokines.
 Indications:
HLA B 27 associated anterior uveitis, Behcet’s disease
 Dose: 5mg/kg
1st dose on the first day of therapy
2nd dose at the end of 2 weeks &
3rd dose at the end of 6 weeks
 Infliximab is available as 100 mg lyophilized powder which has to be reconstituted with 10 ml sterile water.

21. Side effects:-
1. Major side effect is increased risk of infections, particularly tuberculosis and
histoplasmosis capsulatum, aseptic meningitis.
2. The use of infliximab may enhance brain lesions associated with multiple sclerosis.
3. Autoimmunity – Lupus like syndromes
4. Rarely malignancies
 Tradename: Remicade

22. Oral retinal S antigen
 Oral tolerance is an approach that has received much clinical interest
recently.
 Indications:- Pars planitis, Behcet’s disease, Multiple sclerosis, Rheumatoid
arthritis
 Dose: 30 mg of S antigen 3 times a week. No specific significant toxic effects
attributable to S antigen therapy has been reported.
 Patients on immunosuppressive therapy require strict, periodic follow up
with periodic complete blood counts, liver function tests, renal function
tests etc.

23. Ocular drug toxicity of Immunosuppressive
Agents in Ophthalmic conditions
 Decrease in vision.
 Visual hallucination.
 Lids or conjunctiva redness, conjunctivitis, subconjunctival haemorrhage
and hypertrichosis.
 Eyelashes or brow loses.
 Retinal haemorrhages.
 Retinal pigment epithelial disturbances.
 Cortical blindness (cyclosporine).