2.5 Policastrao Chemotherapeutics4.27.12 - ACMT · 2012. 11. 6. · Adverse.effects. •...
Transcript of 2.5 Policastrao Chemotherapeutics4.27.12 - ACMT · 2012. 11. 6. · Adverse.effects. •...
Chemotherapeu+cs
Michael Policastro, MD Director, Medical Toxicology, QESI
Clinical Assistant Professor, WSU
Cancer treatment strategy
• Cell surface receptor • Intracellular signal pathway
• Cell maintenance process
Classifica+on Chemotherapeu+cs
• Alkyla@ng Agents: Busulfan,Dacarbazine, Melphalan, Mustards (Chloramphenical Cyclophosphamide, ifosfamide, Mechlorethamine)
Nitrosureas ( carmus+ne)
Pla+noids (cispla+n,carbopla+n), Procarbazine ( hydrazine)
• An@bio@c: Anthracyclin (Danorubicin, Doxorubicin, Idarubicin,)
Mitoxantrone, Bleomycin, Mithramycin,Mitomycin, Mitoxantrone
• An@metabolite:-‐ Methotrexate, fludarabine, mercaptopurine, pentostain,thioguanine, cyctaarabine, Fluorouracil ( 5-‐FU)
• An@mito@c:Vinblas+ne, Vincrisi+ne,Paclitaxel, etoposide, teniposide
• Biologics • Radionuclides
Targeted Sites Of Ac+on
DNA duplica@on
Interphase: All phases except mitosis
Adverse effects
• Alkyla@ng Agents: Transamani+s, pulm fibrosis, renal failure, sz
*Cylophosphamide-‐ hemorrhagic cys++s due
to ACROLEIN *carmus+ne-‐toxic encephalopathy,
*Cispla+n-‐ ototoxicity,re+nal tox, renal failure, ↓ lytes
• An@bio@c:Mucosi+s, myelosuppression, dysrhythmias, cardimyopathy
*Bleomycin-‐ Pulm fibrosis, BOOP
* Mitomycin C-‐ Hemoly+c uremic syndrome
• An@metabolites: mucosi+s, n,v, transamini+s, pancrea++s, hyperuricemia,myelosuppression, renal failure
* 5 FU –Cardiomyopathy, CHF
*carmus+ne-‐hypersensa+vity, skin reac+ons, BM suppression
• An@mito@cs: Autonomic dysfunc+on, dysrhythmias, myelosupression, SZ, Peripheral neuropathy, SIADH
* Taxol-‐ GI perfora+on
Methotrexate (MTX)
MTX Inhibits *Dihydro folate reductase (DHFR) * Thymidylate synthetase (TYMS)
N5-‐formyl FH4 (Leucovorin)
Methotrexate
• Inhibits DHFR, TYMS
• Tri-‐phasic clearance, ( 2nd phase-‐ renal clearance, 3rd phase +ssue redistribu+on into plasma)
• Acidosis, renal failure, doses 100-‐1000mg/m2 associated with toxicity, folate deficiency
• Toxicity primarily dependent on DURATION of exposure • Toxicity: Mucosi+s,hepa++s,renal failure, pancytopenia,
seizures, hemiparesis,alopecia,olgiospermia,hypersensa+vity pneumoni+s
Treatment of MTX Toxicity
• Leucovorin 15mg/m2
• q 6 hrs x 2-‐ 3 days un+l MTX <5 x 10-‐8
• IVFS • Urinary Alkaliniza+on • Hemodialysis
• Thymidylate IV, carboxypep+dase
• Intrathecal MTX: CSF drainage/exchange
Neurologic Adverse Effects
• AMS/SZ: MTX, Vincris+ne, Mustards (Chloramphenical Cyclophosphamide, ifosfamide, mechlorethamine,carmus+ne)
• SZ: Chlorambucil/Ifosfamide-‐ toxin (chloroacetaldehyde) • Cerebellar ataxia: 5-‐FU • Peripheral Neuropathies: vinca alkaloids , cispla+n -‐( vincris+ne>vinblas+ne; sensory + motor and ascending)
-‐ taxol-‐ primarily sensory • Cranial N ( 3-‐7, 10): vinca alkaloids • Tinnitus, hearing loss, re@nopathy: cispla+n
An+-‐Microtubules
• Colchicine: Colchicum autumnale, Gloriosa superba
-‐ Meta-‐phase ( M) arrest -‐ 3 phases tox: GI, Muli-‐organ failure,
alopecia, Diabetes insipidus -‐ TX: MDAC, G-‐ CSF
• Vinca Alkaloids: Catharanus roseus -‐ Vincris+ne most reported chemo OD in
lit. , -‐ Severity: Vincris+ne>vinblas+ne -‐ Vincris+ne: Cri+cal Neuro , SIADH ( sensory/motor, ascending) -‐ Vinblas+ne: bone marrow -‐ TX: Glutamic acid-‐ neuro,
Hyaluronidase-‐ extravasa+on injuries
• Paclitaxel: Taxus brevifola • Podophyllotoxin : Podophyllum
peltatum -‐ derivates: etoposide, teniposide -‐ Podophyllin more tox than
derivates, similar tox colchicine -‐ Podophyllin-‐ M-‐ phase -‐ Etoposide-‐ inter-‐phase,
topoisomerase II inhibitor -‐ No specific an+dote
Renal/Electrolyte Adverse Effects
• SIADH: Vincris+ne • Diabetes Insipidus(DI) : Colchicine • Hemorrhagic cys@@s: Cyclophosphamide,Ifosfamide
**toxin= acrolein
• Renal Failure, Distal tubular necrosis: Cispla+n • Hypomagnesium,Hypocalcemia: Cispla+n
Cardiac Adverse Effects
• Athracycline abx (Danorubicin, Doxorubicin, Idarubicin) —irreversible conges+ve cardiomyopathy —immediate : dysrhythmia, pericardi+s,myocardi+s
• Cyclophosphamide —CHF, hemorrhagic pericardi+s, myocardial necrosis
• 5-‐FU —vasospasm, myocardial ischemia, cardiogenic shock • Vinca Alkaloids ̶ Platelet aggrega+on, coronary spasm
Pulmonary Adverse Effects
• Bleomycin: pulm fibrosis, BOOP, nodular lesions
• Methotrexate ( MTX): hypersensa+vity pneumoni+s, Hilar adenopathy
• Cytosine arabinoside: non-‐cardiogenic pulmonary edema
• Busulfan: alveolar-‐inters+al proteinosis • Nitrosureas :Upper lobe pulmonary fibrosis
Mucosi+s
• MTX • 5FU • Bleomycin
• Doxorubicin
An+dotes • Dexaroxane : Anthracycline ABX ( Doxurubicin) cardiomyopathy : Iron chelator • NA Thiosulfate: Cispla+n • MESNA ( 2-‐mercaptoethane sulfonate sodium): cyclophosphamaide-‐ inac+vates
acrolein to thioether • Methylene Blue: Ifosfamide encephalopathy • Amifos@ne: Cispla+n; ac+vated intracellular by alkaline phosphatase, scavages free radicals • Folinic Acid: MTX • Glutamic Acid: Vincrisi+ne – preven+on neuropathy • DDTC (diethyldithiocarbamate) /Disulfuram: Cispla@n, also recall Ni, Ni Carbonyl • KI: 131 Iodine • Prussian Blue: Thallium • DTPA: Plutonium • G-‐CSF: colchicine, most chemo agents • Pyridoxine: Procarbazine ( hydrazine)
Occupa+onal Disulfuram Agents
Clinical Environmental Health and Toxic Exposures .Sullivan and Kreiger.2001 . Table 18-‐4. P.238
Goldfrank’s Toxicologic Emergencies. 6th edi+on. 2006. Figure 77.1 p.1177
Decontamina+on/Elimina+on
AC: MTX, busulfan, melphalan, chlorambucil
MDAC: colchicine Urinary Alkaliniza@on: MTX
Plasmapharesis: Cispla+n,Vincrisi+ne
Biologics ( MAB)
An@-‐Inflammatories
• TNF inhibitors • T cell inhibitors • IL inhibitors • Leukocyte Integrin Blockers
An@-‐cancer • GF/ Tyrosine Kinases ( VEGF, PDGF, EGF) • Serine/threonine kinase ( ATK) • Intracellular protein kinases ( RAS, RAF, APC) • Transcrip+on factors/genes • G proteins • Phospholipases
Extravasa+on An+dotes
• Dimethyl sulfoxide (DMSO): topical: Antracyclines,Mitomycin: limits free radicals; compress-‐ ICE
• Dexrazoxane: IV: Anthracyclines: limits free radicals • Sodium thiosulfate: IV: Mechlorethamine: prevents +ssue
alkyla+on
• Hyaluronidase: SubQ : Vinca alkaloids,epipodophyllotoxins: degrades hyaluronic acid; compress-‐ WARM
Regulatory Laws
EPA Resource Conserva@on and Recovery Act 40 CFR
Regulates 9 an+-‐neoplas+cs: arsenic trioxide, chlorambucil, cyclophosphamide, daunomycin, melphalan, mitomycin c, napthylamine mustasrd, streptozocin, uracil mustard
** Review Regulatory Laws and Programs
Transplant Immunosuppressive Agents
Transplant Biologics
Calcineurin Inhibitors: cyclosproin/tacrolimus Side effects
• Hypertension, Hyperlipidemia • Nephrotoxicity ( inhibi@on pep@dyl, prolyl-‐cis transisomerase)
• Cardiovascular death increase • CSA: hirsui+sm, gingival hyperplasia
• Tacrolimus:DM
Calcineurin inhibitors : cyp3A4 drug interac+ons
Increased levels • CCB • Emycin • Fluconazole • Allopurinol • Bromocrip+ne • Colchicine • Metoclopramide • Protease inhibitors • Grape fruit juice
Decreased levels
• Rifampin
• CBZ, Phenobarb, Phenytoin • Octreo+de • St. John’s Wort
Sirolimus (Rapamycin)
• Macrolide compound, 3A4 • Inhibits IL-‐2/5, binds to kinase MTOR also known as FRAP, RAFT
• MTOR: signal transduc+on of GF, PI3 kinase, AKT/ protein kinase B pathway
• Side effects:Hyperlipidemia, cytopenia, arthalgias, apthous ulcers, inters++al pneumonia, hepa@c artery thrombosis, wound dehiscence ( liver transplant)
Mycophenolate Mofe+l ( MMF) (Cellcept)
• Blocks purine nucleo+de synthesis inhibits type 2 IMPDH ( inosine monophosphate dehydrogenase) = inhibits conversion of IMP to GMP
• No effect on cytokines • Side effects: GI, heme
• Do not give with Azathioprine or other an@-‐metabolites
MMF drug interac+ons
Increased levels
• Acyclovir,ganciclovir • Probenicid • Salicyaltes • Sirolimus
Decreased levels
• Antacids: Al/Mg
• Iron • Metronidazole
• Norfloxacin • rifampin
TNF-‐alpha contraindica+ons
• Latent TB or Hep B • Chronic Heart failure • Vaccina+ons with live organisms
• Other possible side effects: infx, autoimmune disorders, uvei+s, mul+ple sclerosis, psoriasis, lymphoma
TNF-‐alpha
Pregnancy And Immune Modulators
Pregnancy and Biologicals
SERMs ( Selec+ve estrogen receptor modifying drugs)
Side effects • Tamoxifen , toremifene ( Fareston), fulvestrant(Faslodex)
• Hot flushes, decreased bone mineral density premenopause
• Thrombosis ( DVT, PE, Stroke)
• Increased endometrial thickness, vaginal bleeding, ovarian cyst
Aromatase Inhibitors
• Anstrazole (Arimadex), exemestane (Aromasin),letrozole (Femara)
• Side effects: menopause symptoms, muscle cramps
• NO increase in endometrial cancer
• Less effects than SERMS
Signal Transduc+on Inhibitors: Tyrosine Kinase Inhibitors, side effec
ts • EGFR:gefi+nib(Iressa),erlo+nib(Tarceva),cetuximab(erbitu
x),panitumumab(Vec+bix),( RASH-‐papulopustular, inters@@al lung disease, diarrhea)
• VEGF:Vandetanib(Zac+ma),Sorafenib(nexavar), suni+nib(sutent), pazopanib (Votrient)
( coagulopathy, thrombosis) • Her-‐2:tratuzamab(Hercep+n),lapa+nib(Tykerb),
pertuzumab (Omnitarg), fever, chills ( Anthracycline + her-‐2 = ventricular dysrhythmias, CHF)
• BCR-‐ABL:ima+nib mesylate ( Gleevac) ( edema) • Fusion protein EML4-‐ALK: Crizo+nib(Xalkori)
Signal Transduc+on Inhibitors: mTOR
• Temsirolimus (Torisel) • Everolimus (Afinitor) • Hypersensi+vity reac+ons, hyperglycemia • Opportunis+c infec+on • Bowel Perfora+on • Coagulopathy • Avoid Live vaccines • CYP 3A4 interac+ons
Signal transduc+on: serine/threonine kinase BRAF
• Vemurafenib (Zalboraf) • Rash, LFTS
Gene Expression/Cell Func+on Inhibi+on
• HDAC( Histone Deacytylase):Vorinostat (Zolinza), Romidespsin (Istodax)
Thrombocytopenias, rash
• Re+noids: Bexarotene (Targre+n),Alitre+noin (Panre+n), Tres+noin(Vesanoid)
Pregnancy X, cataracts, rash/photosensi@vity, LFTS
Angiogenesis Inhibitor Bevacizumab (Avas@n)
• Endothelial VEGF • HTN, Thromboembolism, Bleeding
• Proteinuria, impaired wound healing
Apoptosis Inducer
• Proteosome:Bortezomib (Velcade) • An@folate: Pralatrexate (like MTX):accumulates in cells express RFC-‐1 protein
Immune Cell Modulators
• CD3: orthoclone OKT3 • CD20: Rituximab ( Rituxan), ofatumumab (Arzerra),
ibritumomab (Zevalin),tositumomab HSV , dyspnea, inters@@al pneumoni@s • CD30:Brentuximab (Adcentris) • CD33:Gemtuzumab • CD52: Alemtuzamab ( Campath) (ITP, autoimmune
thyroid) • CTLA-‐4: Ipilimumav (Yervoy) • IL-‐2: Denileukin (Ontak), daclizumab (Zenapax) (CD25 ,
alpha chain IL-‐2)
Rituximab( Rituxan) Side effects
• Monoclonal/chimeric an+-‐ CD 20 • HSV , dyspnea, inters++al pneumoni+s
Natalizumab (Tysabri) Side effects
• MAB against integrin • progressive mul+focal leukoencephalopathy (PML) caused by reac+va+on of the JC virus,
• hepatotoxicity