This is a slideshow presentation about common antimetabolites usage in ophthalmology. It included the summary of mode of actions, indication, contraindication, preparation, pharmacokinetic and pharmacodynamic of each drugs.

1. ANTI-METABOLITE IN
OPHTHALMOLGY
Prepared by Dr Robin Goh Chon Han
Ophthalmology Postgraduate Master Student (UM)
Hospital Tuanku Jaafar Seremban, Malaysia
(2020)

2. • Antimetabolite is a chemical that inhibits the use of a metabolite,
which is another chemical that is part of normal metabolism
• Antimetabolites often similar in structure to metabolite that they
interfere with
•
• competitive inhibition occur
• causes toxic effects on cells, such as halting growth and cell
division

4. Mitomycin
Methotrexate, 5-FU

6. Classification of antimetabolite
Folate Antagonist Methotrexate, Premetrexed
Purine Antagonist Azathioprine, 6-Mercaptopurine,
Fludarabine, 6-Thioguanine,
Pyrimidine Antagonist 5-Fluorouracil, Gemcitabine,
Capecitabine, Cytarabine

7. 1
Folate Antagonist

8. Folate Antagonist (Methotrexate)
INTRO • One of the antimetabolite drugs
• Chemotherapy & immune system supressant
• eg: Methotrexate
MOE • Inhibits enzymes responsible for nucleotide synthesis
• Prevent cell division and leads to anti-inflammatory action
• Inhibits dihydrofolate reductase (DHFR) which is required to convert
DHFA to TFA. Purine & thymidine synthesis inhibited, so DNA & RNA
synthesis hibited
• Kills cell in “S” phase
• Depresses T cell production, alters production of cytokines and
humoral response, extracellular release of adenosis (anti-inflammatory
mediator)
INDICATION • Antineoplastic agent (eg. Leukemia, Choriocarcinoma, Burkitt
Lymphoma, Breast Ca, Head & Neck Ca)
• Immunosuppresant (MG, SLE, Giant cell arteritis)
• Immunomudulating agent/DMARD (eg. Psoriasis, Rheumatoid
Arthritis, Crohn Disease, Lupus, Eczema, Vasculitis, MS
• Abortifacient agent (terminate pregnancy, ectopic pregnancy, molar
pregnancy)

10. OPHTHALMOLOGICAL USE
Uveitis (associated with JIA), Corticosteroid-resistant uveitis
Panuveitis (sarcoidosis related)
Scleritis (rheumatoid arthritis)
Episcleritis
Behcet disease
Vogt-Koyanagi Harada disease
Ocular cicatrical phemphigoid
Sympathetic Ophthalmia
Birdshot chorioretinopathy

11. ADVERSE EFFECT • Bone marrow supression (leukopenia & thrombocytopenia)
• Hepatic toxicity (cirrhosis)
• Renal Toxicity
• GIT disturbance
• Interstitial pneumonitis, Pulmonary fibrosis
• CNS toxicity (Subacute meningeal irritation)
• Sterility
• Alopecia
• Rash
CONTRAINDICATION Avoid in pregnancy (Teratogenic)
Avoid in breast-feeding
ROUTE OF
ADMINISTRATION
Oral/IM/IV/Subcutanous/Intrathecal/Intravitreal
Dosage: Oral 7.5mg once (increased to 15mg/week) for weeks to months
Intraocular lymphoma: IVT 400ug in 0.1ml 2x week for 4 weeks then weekly x8/52 then monthly x 9/12
PHARMACOKINETIC A: Bioavailabiility of 64-90%
D: 50% bound to plasma proteins
M: Metabolied by folylpolyglutamate synthase in liver and tissues
E: Urine (>80% unchanged), (<20% in bile)
DRUG INTERACTION Protein bound drugs (salicylates, phenytoin, sulfonamides) displace MTX bound to albumin and
increases toxicity
Penicillin & Probenacid decrease MTX renal clearance
Oral antibiotics (tetracycline, CMC) decrease GI absorption of MTX (reduced bowel flora)
Metablism of warfarin can be increased
t1/2 = 3-15 H
Folinic acid (Leucovorin), folate
coenzyme = rescue normal cells from
methotrexate toxicity

12. 2
Purine Antagonist

13. Purine Antagonist (Azathioprine)
INTRO • One of antimetabolites
• Immunosuppresive pro-drug
• Imidazolyl derivative of mercatopurine
MOE • converted to 6-Mercaptopurine (6-MP)
• inhibits purine synthesis necessary for proliferation of cells,
especially leukocytes & lymphocytes (Suppress cell mediated
immunity)
• Competitively inhibits purine synthesis, block DNA replication
and RNA synthesis (cytotoxic)
INDICATION Ophthalmic use
• Ocular inflammatory disease & uveitis syndrome
• VKH Syndrome, Behcets
• Multifocal choroiditis
• Sarcoidosis
• Necrotizing scleritis
• Iridocyclitis
• Sympathetic ophthalmia

14. SYSTEMIC
• FDA approved
symptomatic treatment of RA & kidney transplant rejection
• Non FDA approved
1. Immunosuppressive: Inflammatory bowel disease, Autoimmune hepatitis, Chronic ITP (2nd line),
Severe myasthenia gravis, Psoriasis, Cutaneous vasculitis, Glomerulonephritis, Bullous pemphigoid,
pemphigus vulgaris, severe refractory atopic dermatitis, lichen planus
2. Anti-inflammatory: Relapsing polychondritis, Dermatomyositis/Polymyositis
3. DMARD agent: Lupus nephritis, Multiple sclerosis, Crohn disease
ADVERSE EFFECT • Bone marrow suppresion (leukopenia, anemia, thrombocytopaenia)
• Skin rashes
• Drug fever
• GIT disturbance
• Hepatotoxicity (high ALP with jaundice)
• Neoplasia (NHL)
• Others (Alopecia, interstitial pneumonitis, arthralgia)
CONTRAINDICATION Immunosuppressed pt
Pregnancy & breastfeeding
Monitor FBC, LFT 2 weekly for
1st month then 4-6 weekly

15. ROUTE OF
ADMINISTRATION
Oral 1-3mg/kg/day (50mg Tablet)
IV: Max dosage: 150mg/day
PHARMACOKINETIC A: Well absorbed from GIT
D: 30% bound to serum protein
M: Metabolized to mercaptopurine. Rapidly oxidized or methylated in RBC and liver
E: Urine
DRUG INTERACTION Allopurinol: Synergistic bone marrow suppresion
Warfarin: Decrease anticoagulant effect of warfarin
ACE-inhibitor: Concomitant use may lead to severe leukopenia
t1/2 = 5H

16. 3
PyrimidineAntagonist

17. Pyrimidine Antagonist (eg. 5-FU)
INTRO • One of the antimetabolites
• Inexpensive, low rate of sight threatening adverse effect when applied topically
MOE • (Prodrug) 5-FU converts to 5-fluoroxyuridine monophosphate (FUMP)
• Irreversibly inhibit Thymidylate synthase
• preventing pyrimidine nucleoside synthesis
• Blocks methylation reaction of deoxyuridylic acid to thymidylic acid
• So interfere with DNA synthesis & less extend inhibit RNA synthesis (Cytotoxic effect)
• Only affect cells in mitotic phase of cell cycle S and G2 phase
INDICATION Systemic
1. Antineoplastic
(slow growing solid tumor: colorectal, breast, ovarian, pancreatic and gastric ca)
(superficial basal cell carcinoma)
2. Dermatological
Actinic keratoses, skin cancers and Bowen's disease

20. Ophthalmology
* Delay fibroblast proliferation
1. Bleb survival (Antifibrotic) in trabeculectomy
2. Needling after trabec
3. Ocular malignancy (1% drops for conjunctival malignancy, 5% for superficial BCC)
4. Multiple actinic or solar keratosis (2% solution)
ADVERSE EFFECT • GIT disturbance
• Oral or mucosal ulceration
• Alopecia
• Bone marrow suppression
• Hand-foot syndrome
(extended infusions) “Palmar-Plantar Erythrodysesthesia”
• Local reaction (dermatitis, crusting, weeping, local pain)
• Cardiotoxicity (unknown, ?coronoary vasospasm)
CONTRAINDICATION Pregnancy & breastfeeding
Pretient with bone marrow suppression
Ocular Side Effects:
SPK (Photophobia, irritation)
Filamentary Keratopathy
Conjunctival scarring
Blepharitis
Conjunctivitis
Tear duct stenosis

21. ROUTE OF
ADMINISTRATION
IV or topically (1%)
Soaked sponge placed on scleral surgical site (adjunct for high risk trabec failure - uveitic or
rubeotic glaucoma.
Post trabec sub conjunctival injection
Topical
Palliative intralesional injection (ca of colon, esophageal, gastric, rectum, breast, stomach...)
PHARMACOKINETIC A: Limited oral bioavailability (28-100%) because gut mucosa has high concentration of
dihydropyrimidine dehydrogenase
D: 10% protein binding
M 80% metabolised by Liver
E 20% excreted by kidney unchanged in 6 H
DRUG INTERACTION increase INR in patient with Warfarin
Efficacy is reduced if used with allopurinol
t1/2 = 20mins

22. ANTI-TUMOUR ANTIBIOTICS

23. Mitomycin
Methotrexate, 5-FU

24. Mitomycin C
INTRO • antimetabolite/ antineoplastic / antibiotic agent
• isolated from soil bacterium Streptomyces caepitosus
• chemical formula C15H18N4O5
MOE • Affecting cell cycle during late G1 and early S phase
• anti-proliferative effect on cells by inhibiting DNA synthesis
• DNA is inhibited by cross-linking at the N position of Adenine and at 06, and N position of
Guanine
• Generate o2 radicals, alkylates DNA, produces interstrand DNA crosslink, inhibits DNA synthesis
INDICATION Ophthal:
• Pterygium surgery (reduce recurrence)
• Glaucoma filtering surgery
• Ocular surface tumors (SCC, melanocytes, lymphocytic resident cells of conjunctival stroma)
• Dacryocystorhinostomy (reduce fibrous tissue growth over sewn flaps and osteotomy site)
• Squint surgeries (reduce post op scarring and adhesions)
• Refractive surgery (in PRK for myope >-5.00D with cornea thickness inappropriate for LASIK to
reduce haze and regression)
• Allergic conjunctivitis (as an effective alternative to topical azelastine)
Systemic:
• Chemotherapy(M
MC)
• Advanced cancer
• Gastric/Pancreatic
/ Breast/Bladder/
Cervical/GI/
Prostate

25. ADVERSE EFFECT Ophthal
• Ocular pain, lacrimation
• Photophobia
• SPK
• Scleral ulceration
• Necrotizing scleritis
• Perforation
• Uveitis
• Cataract
• Glaucoma
• Symblepharon
CONTRAINDICATION Pregnant women, hypersensitive
Relative C/I: Only seeing eye, elderly, patient predisposed to corneal ulceration or poor healing
(Immunocompromised, Sjogren's syndrome, atopic keratoconjunctivitis, acne rosacea or herpetic keratitis)
ROUTE OF ADMINISTRATION • Topical Gt Mitomycin 0.04% QID
• Subconjunctiva 0.02% (<0.2ml)
• Intraperitoneal
• Intravesical (bladder)
• IV bolus (10-15mg/m2)
PHARMACOKINETIC A: Delivered to the eye in a complete solubilized form, in presence of conjunctival or corneal epithelial defects.
Hydrophobic character favors penetration into denuded cornea and conjunctiva. Oral absorption is erratic.
D:: High bioavailability to the target tissue. Distributed widely. Mitomycin eyedrops even at highest dose does not
result in detectable levels in blood. Not cross BBB
M: Metabolized by hepatic microsomal enzymes. Biodegradation by spleen, kidney, brain and heart
E: Excreted in urine (10% as unchanged). Small portion in bile and feces
DRUG INTERACTION Interact with Vinca alkaloids: Severe bronchospams
Systemic
• Bone Marrow Toxicity (Thrombocytopenia
& leucocytopenia)
• Alopecia
• Stomatitis
• Tissue necrosis
• Liver disease (veno-occlusive liver disease)
• Hemolytic urecmic syndrome (rare)
• Penumonitis (rare)
• Cardiac failure (rare)
Distribution t1/2: 2-10mins
Elimination t1/2: 25-90mins

28. Thank you
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