IMMUNOSUPPRESSIVE AGENTSIN OPHTHALMOLOGY

Dr. CHRISTINA SAMUEL

PG- M.S OPHTHALMOLOGY

MMCH & RI

CLASSIFICATION

ALKYLATING AGENTS

ANTIMETABOLITES

ANTIBIOTICS

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

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.

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.

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

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.

Clinical Indications

Rheumatoid arthritis, pemphigoid and regional

ileitis.

Sympathetic ophthalmia and VKH syndrome.

Pars planitis and Bechet’s disease.

Recalcitrant cases of intermediate uveitis.

AZATHIOPRINEMOA:- 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.

Adverse reactions

Uncontrolled leukopenia.

Thrombocytopenia.

Hyperuricemia.

GIT disturbances.

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.

DHFA THFADHFRase

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.

Adverse effects

Leukopenia and Thrombocytopenia.

Hepatic and renal toxicity.

GIT disturbances.

Interstitial pneumonitis.

CNS toxicity.

Sterility.

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.

Adverse effects

Systemic hypertension.

Partially reversible renal toxicity.

Opportunistics infections.

Hyperuricemia.

Hepatotoxicity.

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.

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.

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.

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.

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.

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

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.

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).