Cytotoxic agents used in dermatology

cytotoxic drugs used in dermatology

1. CYTOTOXIC AGENTS used in Dermatology 1 Dr. Chandini Rao Moderator – Dr. Padmaja Udaykumar HOD Dept of Pharmacology

2. Overview - Introduction Classification Mechanism of action Pharmacokinetics Indications Therapeutic guidelines Drug interactions Adverse effects Contraindications 2

3. Introduction Cytotoxic drugs ( A nti- neoplastics ) – Drugs that contain chemicals toxic to cells, preventing their replication or growth  inhibit or prevent the function of cells P rimary role - Cancer Rx 3

4. Others – Rheumatoid diseases, steroid-resistant muscle conditions, severe dermatologic diseases M any normal cells are damaged along with cancer  cells. Myelosuppression , mucosal irritation, carcinogenesis, teratogenesis etc 4

5. Cytotoxic drugs (commonly used in Dermatology) 5 Antimetabolites Methotrexate Azathioprine Mycophenolate mofetil 5-Fluorouracil Hydroxyurea Alkylating agents Cyclophosphamide Chlorambucil

6. Cytotoxic agents & cell cycle 6 Antimetabolites

7. Alkylating agents Act independently of the cell cycle Direct damage to DNA - Alkylation: ( N7) guanine in DNA: main target Cross linking, Abnormal base pairing   7

8. Bifunctional agents: I ntra- & interchain cross-linking Interferes with replication & transcription Cell death (Apoptosis)   8

9. Cyclophosphamide D erived from nitrogen mustard ( M echlorethamine ). 1 st synthesized in 1957 Effective cytotoxic & immunosuppressive agent - Antineoplastic Highest T.I. 9

10. 10 Dermat – Immunosuppressive & “steroid-sparing’ agent . Oral & IV preparations Cytotoxic effects independent of the cell cycle.

11. Cyclophosphamide  B cells > T Cells  Suppressor T cells > Helper T cells (Rx of A dvanced cutaneous T cell lymphoma & as Immunosuppressant) Resistance - cellular penetration - improved DNA repair - drug metabolism.   11

12. Pharmacokinetics 12 Well absorbed orally , high B.A. (~75 %). t 1/2 ~ 7 hrs

13. Therapeutic guidelines - AntiCa dose: 100mg/ /day oral 500mg/ /day IV Dermatological dose - 2-3 mg/kg/day in divided doses , 4-6 wk delay in onset of action. IV pulse therapy: - 0.5-1 g along with Dexamethasone(100mg) - very severe or refractory Pemphigus .   (fewer A/E than daily oral dosing)   13

14. Adverse effects Haemorrhagic cystitis & Bladder Ca – 5-41% of patients Metabolite responsible – Acrolein Rx: MESNA - conjugates acrolein in the bladder & irritation. - Orally or IV. - prolonged or high-dose Rx with Cyclophosphamide - fluid intake Unchecked bladder toxicity  Bladder Ca   14

15. Drug interactions Potentiate myelosuppressive immunosuppressive or carcinogenic effects Alefacept ( antipsoriatic ) Anti- retrovirals ( Zidovudine etc ) Cytotoxic & Immunosuppressive agents ( Chlorambucil , Azathioprine etc ) 15

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17. Chlorambucil Another derivative of Nitrogen mustard Rarely used than Cyclophosphamide MOA – - direct damage to DNA via cross-linking. 17

18. PK – - Given orally (87 % B.A.) Highly bound to albumin (99%), t 1/2 ~ 1.5 hrs M etabolism doesn’t yield acrolein (no risk of haemorrhagic cystitis) TG: 2mg tablet RD: 0.05-0.2 mg/kg daily od 18

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20. A/E of Alkylating agents Bone marrow suppression Dose-limiting a/e Leukopenia &/or thrombocytopenia (Less common with Cyclophosphamide) Opportunistic infections ( P.jiroveci , fungal infs , reactivation of Hep B) 20

21. Carcinogenesis Non Hodgkin’s Lymphoma, leukemia & SCC Cyclophosphamide - high doses for long durations Chlorambucil - lower doses & for shorter duration Gastrointestinal Mucosal toxicity  Nausea, Vomiting Rx: Ondansetron & Dexamethasone . 21

22. Effects on Skin Alopecia, Pigmentation Pigmented band on teeth Urticaria & SJS - rare Reproductive Amenorrhoea Azoopsermia (irreversible) Teratogenicity Seizures & mood alterations - Chlorambucil 22

23. Contraindications - Absolute – Drug allergy Depressed bone marrow function Pregnancy & lactation Relative – Active infection Impaired hepatic & renal function Seizure/Mood disorder ( Chlorambucil ) 23

24. Antimetabolites D rugs that interfere with >/=1 enzymes or their reactions necessary for DNA synthesis. Act as substitutes to actual metabolites used in normal metabolism Inhibit cell division @ S phase of cell cycle 24

25. Methotrexate 25 Folate antagonist 1940: 1 st synthesized 1953: approved as an antiCa drug Structure – analogue of F olic acid

26. MOA - 26 Potent comp antagonist of DHFR enz .

27. PK – Well absorbed orally (except @larger doses) Route: IV (preferred), im , intrathecal Metabolism: @high doses - Nephrotoxic (7-OH-methotrexate) Elimination: Renal (90% - unchanged) Highdose MTX therapy: Leucovorin rescue (100mg/ ) – prevents toxicity to normal cells   27

28. TG - Starting dose - 5-7.5mg/ wk ( max of 15mg/ wk ) gradually to 10-25mg/ wk if needed 2 methods of weekly administration:   28 O nce wkly regimen (10-25mg) 3 divided doses/ wk (2.5mg each orally over a 24 hr period) Max – 30mg/ wk

29. D/I - Cotrimoxazole Probenecid Salicylates Dapsone Sulphonamides 29 Compete with MTX for protein binding Plasma concns B one marrow suppression.  

30. 30 MTX levels Antibacterials (AMGs, TCs) NSAIDs Anti- convulsants (phenytoin) Anti-psychotics ( Phenothiazines ) MTX levels Antibacterials (Ciprofloxacin, Penicillin) Anti-platelets ( Dipyridamole ) Antibacterials (AMGs, TCs) NSAIDs Anti- convulsants (phenytoin) Anti-psychotics ( Phenothiazines ) Antibacterials (Ciprofloxacin, Penicillin) Anti-platelets ( Dipyridamole )

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32. 5-Fluorouracil (5-FU) 1 st demonstrated in 1950. Since then - IV chemotherapeutic agent in Rx of various Ca. 1963 – Used as topical agent (20 % FU used to treat extensive Actinic keratosis . Structure – analogue of Uracil . 32

33. MOA - 33 5-FU 5-fluoro-2 ′-deoxyuridine-5 ′- (inactive) monophosphate ( FdUMP )

34. PK - Route: Dermatology – Topical (15-75x absorption) - Intralesional inj ( keratoacanthomas , warts etc ) Metabolism – Active metabolites (in skin) - FdUMP , FdUTP , FUTP 5-FU D ihydrofluorouracil DPD ( DHFU). TG - 1, 2 & 5% solutions ( bd ) & 0.5 , 1 & 5% creams (od ).   34 Duration: 2-8 wks

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36. Azathioprine Purine antimetabolite. (6-mercaptopurine derivative) 1961: 1 st introduced as Immunosuppressive agent (renal transplantation) Also has Anti-inflammatory properties. Dermatology – Steroid-sparing agent for Auto-immune & inflammatory dermatoses . 36

37. MOA - Azathioprine 6-thioguanine (structurally similar to purines) Incorporated into DNA & RNA Inhibit purine synthesis & cell division . Also T-cell & B-cell functions   37

38. PK - Well absorbed orally Metabolized to 6-mp Inactivation – Xanthine oxidase (dose when given with allopurinol) TG – Starting dose: 1-2 mg/kg/day . Started early (requires 6-8 wks for effect)   38

39. D/I - Others: XO inhibitors: Allopurinol (most important) ACEIs Folate antagonists myelosuppressive action of Azathioprine.   39

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41. Mycophenolate mofetil Semisynthetic derivative of Mycophenolic acid ( Penicillium ) Structure: 2-morpholinoethyl ester of Mycophenolic acid (MPA ) 41

42. MOA - Purine synthesis inhibitor MMF ( prodrug ) MPA (active drug) Inosine monophosphate dehydrogenase ( guanine nucleotide synthesis) proliferation of T & B cells, production of cytotoxic T cells.   42

43. PK - Oral & IV ~ 97% bound to Albumin (t 1/2 ~ 16-18 hrs ) Inactivated by Glucuronidation inactive glucuronide Urine TG – 1-2g/day orally - Rx inflammatory & AID   43

44. D/I - Serum MMF levels Antibacterials ( Cephalosporins , FQs, Penicillins ect ) Antacids Iron supplements (chelation with MMF) Serum MMF levels Salicylates, Probenecid Antibacterials ( Cephalosporins , FQs, Penicillins ect ) Antacids Iron supplements (chelation with MMF) Salicylates, Probenecid 44

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46. Hydroxyurea 1 st synthesized by Dressler & Stein in 1869. Rx: Hematological Ca & Sickle cell anemia Dermatology - Psoriasis . Structure 46

47. MOA - Hydroxyurea 47 1. Ribonucleotide diphosphate reductase DNA bases Strand breakage Cell death   Prevents cells from repairing damage d/t ultraviolet or ionizing radiation. Alters gene expression - benefit in Psoriasis

48. TG - 500mg capsules 1-2g daily: divided dose of 20-30mg/kg/day. Older patients & those with renal impairment - starting dose of only 500mg/day. 48

49. A/E of Anti-metabolites Bone marrow suppression Leukopenia, thrombocytopenia, anemia Pure red cell aplasia (MMF) Mild megaloblastic changes ( Hydroxyurea ) Carcinogenesis (MTX, Azathioprine) Lymphomas SCC 49

50. Infections related to Immunosuppression Eg . Herpes v, HPV, scabies (Azathioprine) CMV  Sepsis (MMF) GI Nausea, vomiting, diarhoea Ulcerative stomatitis + severe diarrhoea (MTX) 50

51. Hepatotoxicity Long-term Rx (psoriasis) – MTX (>4mg/kg) & Azathioprine Life-threatening - LFT monitoring mandatory Nephrotoxicity H igh dose MTX (50-250 mg/ ) Precipitation of MTX in renal tubules . Teratogenicity Birth control necessary   51

52. Cutaneous Alopecia Hypersensitivity syndrome (Azathioprine) Dermatomyositis -like eruption, lichenoid drug eruption ( Hydroxyurea ) Local effects Topical preparations (5-FU) Erythema , pruritis , hypo-/ hyperpigmentation, allergic contact dermatitis etc 52

53. Contraindications to Antimetabolites - Absolute Pregnancy Lactation Drug allergy Immunosuppressed patients 53 Relative Impaired hepatic, renal & cardiopulmonary function 2) Allopurinol use (Azathioprine) DPD deficiency (5-FU)

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55. References - Comprehensive Dermatologic Drug Therapy – Stephanie E. Wolverton Pharmacological Basis of Therapeutics – Goodman & Gilman Basic & Clinical Pharmacology – Katzung & Trevor Rang & Dale’s Pharmacology 55