Principles of Drug Action
Antituberculin, Antivirals, Cancer
Antituberculin
 Tuberculosis
 Caused by Mycobacterium tuberculosis
 Thought be eradicated ~1960, but wasn’t being treated properly & AIDS
 Problems
 Slow-growing
 Treated chronically `6-18 months but patients are noncompliant
 Side effects become prominent, possible drug toxicity
 Development of resistance – must use combination therapy
 HIV/AIDS patients  Mycobacterium avium complex (MAC)
 includes M. avium, M. intercellulare – disseminated (throughout body?) infection
 Mt - normally pulmonary
 1st Line
 Isoniazid (INH)
 A - well absorbed po, IM
 D - extensively distributed, inc. CSF
 Tx intracellular and extracellular org
 Inhibits biosynthesis of mycolic acid (unique to mycobacteria for construction of cell wall)
 M - acetylationinactive (bimodal – slow and rapid acetylators)
INH hydrolysishydrazine (toxic), AcetylhydrolyzedacetylhydrazineHepTox
 <20, 0% HepTox
 >50, higher incidence of HepTox
 Main AE – NeuroTox: peripheral neuritis, muscle twitches, convulsion
 prevented by adm. of B6 (pyridoxine) – competive inhibitor
 Rifamycin
 Rifampin – an antibiotic
 inhibits DNA-dependent RNA polymerase
 also tx G+, G-, carrier formof N. meningitides (normal form DOCPen G)
 A - po, D- inc. CSF,
 E – bile, potent Phase I/II inducer (microsomal enzymes)
 Brightly colored, red-orange, colors body fluids (sweating blood)
 AE – thrombocytopenia, GIU
 Rifapentine – same as rifampin, but longer half-life
 Rifampin qd,
Rifapentine - 2q week
 Ethambutol
 Interferes with arabinose glycan (component of cell wall) specific for mycobacteria
 A – po, D-widely, M- alcohol (non-P450)carboyxlic acid,
 AE – optical neuritis (↓visual acuity) – get baseline optical exam
 Pyrazinamide
 Unclear MOA, might be prodrug?
 M – hydrolyzed to pyrazinoic acid (active)
 AE – HepTox, hyperuricemia
 1st Line for MAC
 Clarithromycin + Ethambutol
 Rifabutin (also rifamycin)
 Recommended w/ clarithromycin + ethambutol (nFDA)
 Azithromycin may be used in place of Clarithromycin
 Prophylaxis – Clarithromycin, Azithromycin, or Rifabutin (FDA)
 Duration?- indefinite
 2nd Line (used with allergic reactions, unacceptable side effects)
 Aminoglycosides
 Streptomycin (used to be 1st, but must be given parenterally)
 only active against extracellular organisms
 Kanamycin
 Amikacin
 very polarIV, nephro, otoTox
 tx Gram -, mycobacterium, Gram + (?)
 Fluorinated Quinolones
 Moxifloxacin
 Ciprofloxacin
 Paraaminosalicylic acid (PASA) – antimetabolite of PABA
 Cycloserine
 Capreomycin
 Therapeutics
 Mycobacterium
 Tuberculosis, Fansasie, Leprosy
 Predisposed – Homeless, Smokers, drug users, HIV/AIDS
 Also Mycobacterium Avian Complex (MAC)
 in immunocompromised, HIV/AIDS, Transplant, Chemotherpay patients
 First Line
 Rifampin(HepTox), Isonizazid(SLE), Pyrazinamide, Ethambutol, Streptomycin(or 2nd?)
 95-98% treated with Rifampin and Isoniazid over 9 months
 Adding Pyrazinamide reduces DOT 6 months
 If ResistantPyrazinamid and Ethambutol added
 Post-exposure prophylaxis – Ciprofloxacin/Levofloxacin 14 days
 Prophylaxis in Immunocompromised – Azitromycin
 Malaria
 Chloroquin (Plaquenil)
 PCP
 Bactrim
 Leprosy
 also mycobacterial – Mycobacterium Leprae (even slower growing, > 2years)
 Dapsone
 po, ~sulfonamide, tx 2years – life
 hemolytic anemia by inhibiting Glucose-6-phosphate dehydrogenase
 G6PH->NADPHreduces glutathione involved in RBC membrane
 Methemoglobinemia
 aromatic group metabolizes Fe2(red)Fe3 (blue), doesn’t bind O2 as well
 can withstand 15% conversion (normally 1%),
 changed back to nornal hemoglobin with methemoglobin reductase
 Cyanide poisoning
 Treat with NaNO2 methemoglobinemia, Fe3+ CN +thiosulfateNa thiosulfate
 Specific antidote – methylene blue
 Strong possibility of resistance, never use alone Rifampin + Dapsone +Clofazimine
 Clofazimine
 po, binds to guanine nucleotides of M. leprae (specific)
 antiinflammatory reaction, counters Erythema Nodosum Leprosum (ENL)
 AE - Red discoloration of skin
 Thalidomide
 Immunomodulatory (?) Agent po tx suppress ENL
 AE – sedation, teratogenic
 FDA System for Thalidomide Education and Prescribing Safety (STEPS) Program
Antivirals
 Hepatitis
 A – spontaneously resolved, no antibiotics required
 B – reverse transcriptase virus
 Acute (resolves spontaneously) Chronic – when it doesnt resolve
 Monotherapy – NRTI or PEG-Interferons
 Nucleoside reverse transcriptase inhibitors (NRTI)
 Reverse transcriptase – RNA-dependent DNA polymerase
 Nucleoside (Base with sugar) nucleotide (base +sugar+phosphate) in vivo
 Entecavir (Baraclude) po, not Nephrotoxic
 less likely to provoke resistance
 Adefovir (Hepsera)
 prodrug po, NephTox
 Lamivudine (Epivir)
 also tx HIV/AIDS, resistance possible,
 Use if patient undergoing Highly Active Antiretroviral Therapy (HAART)
 Tenotovir (Viread)
 nucleotide (base + phosphate) analogue prodrug
 Telbivudine (Tyzeka)
 AE
 Severe acute exacerbation, requiring reinstitution of therapy
 Lactic Acidosis with Steatosis + Hepatomegaly
 Possible resistance to HIV meds unless on HAART
 Interferons – naturally-occurring antiviral proteins
 Pegylated to improve DOA, given once a week, sq, ~ug
 Peg interferon alfa 2a (Pegasys)
 Peg interferon alfa 2b (PEG-Intron)
 Serious Psychiatric side Effects
 C
 Acute:tx Pegylated interferons for 6 -24 weeks
 If viral RNA not cleared after 3 monthschronic tx Ribovirin (Copegus/Rebatol)
 Nucleoside analogue, azole – Interferes with viral RNA Replication
 Metabolized by deribosylation and amide hydrolysis (not P450)
 AE – teratogenic, 120hr t1/2, direct hemolytic anemiacardiac
 Avoid in CVD, may MI
 Newer Tx – Protease Inhibitors
 Hep C has vDNApolyproteins (protease) fxnl proteins maturation/replication
 Telaprevir (Incivek) – 750mg q7-9hrs po, P450 + inhibitor
 Begin tx w/ PEG-Inteferon + Ribovirin
 AE – skin rash, pleuritis, Ha
 Boseprevir (Viktrelis) – 800mg q7-9hrs po, met aldoketoreductase, P450+ inhibitor
 Begin after 4 weeks PEG-I and Ribovirin
 AE – fatigue, N, Ha
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 HIV/AIDS
 1987 – Zidovudine (NRTI)
 Now 26 drugs – 8 NRTI (1 nucleotide), 5 NNRTI, 10 Protease inhibitors,
1 fusion inhibitor, 1 entry inhibitor, 1 integrase inhibitor
 Combination therapy most effective, 6 different ones
 NRTI – Nucleoside (1 Nucleotide) Reverse Transcriptase Inhibitors
 po qd, -sine –dine, -bine
 All must be converted to triphosphate form before working
 Zidovudine (Retrovir)
 Met→ glucuronidation on ribose-hydroxyl groups
 AE – Granulocytopenia
 Abacavir (Ziagen)
 M - not p450, but by alcohol dehydrogenasecarboxyl acid + glucuronidation
 heavy drinkingethanol will compete w/ abacovir↑ Abacavir
 AE – severe hypersensitivity (5%) – don’t challenge it
 Tenofovir (Viread)
 nucleotide, tx resistant strains of HIV qd
 Emtricitadine (Entriva)
 Least toxic
 Didanosine
 purine, metxanthine oxidase, inhabitied by allopurinol
 Lamivudine (Epivir)
 Commonly used with other drugs in combinations
 Stavudine
 NNRTI – Non-nucleotide Reverse Transcriptase Inhibitors, “-vir-“
 Non-competitive inhibitors of the enzyme
 Used with NRTIS synergistically
 “-vir-“
 but not Enfurvirtide and Maraviroc – entry inhibitors
 po
 M – by P450, Nevirapine + Etravirine can induce its
 N+E – insomnia, hallucinations, psychosis
 Nevirapine (Viramune)
 Etravirine (Intelence)
 Delavirdine ~ not used
 Efavirenz (Sustiva)
 Rilpirivine-sedation
 AE – Skin rash, Steven-Johnson syndrome (more common with N+E)
 Protease Inhibitors –
 -vir except Abacavir(NRTI), Tenovir (NRTI), Raltegravir (Integrase inhibitor)
 M – P450 to different extents + inhibit +induce (except Atazanavir (Reyataz))
 Ritonavir –used with other protease inhibitors to block their metabolism
 Lopinavir(only with Ritonavir) - Lopinavir + Ritonavir (Kaletra)
 Saguinavir (Fortivase?) least potent inhibitor
 AE – Diarrhea (exc Indinavir (Crixivan)skin rash)
 po, should be taken with food (exc Indinavir w/ empty stomach)
 Atazanavir (Reyataz) – requires acidic medium to absorb
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Ritonavir
Ritonavir/Lopinavir (Kaletra)
Indinavir (Norvir)
Amprenavir
 formulated w/ Vitamin E and PEG to enhance absorption taken with meal (but not high
fat)
 Fosamphenavir – phosphate ester, no PEG, no worry about meals
 Tirpranavir (Aptiva)
 Must be Adm/ Ritonavir HepTox, intereferes with plateltsintercranial bleeding,
 bid
 Fusion inhibitor
 Prevents fusion of virus with cell preventing entry
 Enfurvirdide (Fuzion)
 binds to protein on virus (GP-41)
 Synthetic 36 amino acid peptide very expensive
 sq, only sq AIDS drug
 not metabolized by p450, but proteolysis
 AE – injection site reactions (Erythema, induration pain)
 Entry inhibitor
 Prevents virus from entering cell after fusion
 Maraviroc (Selzentry)
 binds to a chemokine (CCRI) receptor on host cell
 more so to CCR5 (tropism), test to see if CCR5 present
 A-po, M-P450*
 AE – Cough, URI, allergy, HepTox
 Integrase inhibitor
 Inhibits integration of viral DNA into host DNA
 Raltegravir (Isentress)
 po
 M - not P450 but glucuronidation
 enhanced by Rifampin and Rifabutin
 Highly Active AntiRetroviral Therapy (HAART)
 Reduces viral load allowing immune system to recover
 Opportunistic Infection Treatment
 Pneumocystic jiroveci pneumonia – Bactrim
 Bactrim, Septra
 Pentamidine Inhaler – prevention once a month, not DOC
 MAC/Tuberculosis
 Rifabutin (MAC), Rifampin (TB) – but nFDA
 Both induce hepatic microsomal enzymes
 Toxoplasmosis (Toxoplasma gondii)
 Pyrimethamine + Sulfadiazine – sequential blockade of folate metabolism in fungus
 Pyrimethamine – inhibits DHFA reductase
 Sulfadiazine – inhibits incorporation of PABA into DHFA
 Folinic acid (Leucoverin) – antagonist to inhibition of DHFA reductase
 reversing toxicity in humans (can only be taken up by active transport in humans)
 Cytomegalovirus (CMV) retinitis
 Ganciclovir – purine analog
 Foscarnet – phosphoric acid derivative
 Cidovir – pyrimidine analog
 Complicated dosing regimen, at first IV, then injected into eye topically
 Cryptococcus neoformans
 Cryptococcosis  Cryptococcus meningitis
 Tx Amphotericin B + Flucytosine o/ Fluconazole
 Candidiasis
 Kaposis Sarcoma – slow-growing cancer
 Immune System Recovery Inflammatory Syndrome (IRIS)
 After HAART, when immune system begins to recover, it responds to previously acquired
opportunistic infections (indolent or residual)
 Reacts with overwhelming inflammatory response
 Tx Corticosteroids, NSAIDS
 Antiretrovirals with Sulfamido Group (RSO2NHR)
 ~ Cross-reactivity with other sulfamides
 diuretics, sulfa antibiotics, Viagra, Ibutilide(Covert), Dofetilide,
 Anprenavir (Agrenase), Delavirdine, Famovudine, Darunavir(Prezista), Tipranovir (Aptivus),
 HIV/AIDS Therapeutics
 2 Strains (HIV-1, HIV-2) – treated the same,
 in US, HIV-1 is predominant
 May present Sx differently
 Risk Factors
 Unprotected/Unsafe Sex
 Sharing Needles
 Any exchange of infected fluid
 Infected Blood (been tested since 1985 in US), Organ
 eg Ryan White, hemophiliac who got HIV from clotting factorsdiedmoney for AIDS
 Part A– Money to clinics to manage AIDS, for physicians, nurses, etc.
 Part B– AIDS Drug Assistance Program (ADAP), set up through health department
 Part C– Research
 Part D– AIDS education training(health care providers) centers
 Neonatal Transmission
 Progression of Disease
 Determinants of Effectiveness/Monitoring Parameters
 CD4 (protein receptor found primarily on T4 helper cells), normal=1000
 Opportunistic infections, when CD4<350
 HIV RNA/ Viral Load (controlled HIV/AIDS – 48,000)
 1st 72 hours
 Can treat prophylactically (100% effective)
 Acute HIV Infection - 30-50% of newly infected have symptoms in first week
 very general Sx – diarrhea, fever, swollen lymph nodes, ~etc
 1st 3 months, Viral load increases, CD4 count decreases
 ~ 3 months antibody production (For 90% of people)
 Can test for HIV/AIDS now by looking for antibodies w/ ELISA (main screening)
 Western Blot – more accurate test
 Up to 20 years – Dormant period
 Dormant period ends AIDS
 CD4 <350AIDSOpportunistic infections, cancers
 ~200 Fungal infections ~ Candidiasis, PCP
 ~ 50 MAC
 Therapy
 Can increase CD4 by 100-150 cells/yr
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Drug pressure on virusvirus mutate
 Must use drugs every day to prevent resistant,
 Adherence must > 95%
May Genotype the patient if Viral Load >1000 to determine drug resistance
For Naïve patient (with no drugs before)
 Use 3 drugs
 2 from NRTI class (NRTI=Backbone Class) in combination
 Zidovudine + Lamivudine (Combivir)
 Tenofovir + Emtricitadine (Truvada)
 Abacavir + Lamivudine (Epzicom)
 3rd drug – Choose one from other class)
 NNRTI – Efavirenz (Susteva), Neirapine (Viramune) popular
 Tenofovir + Emtricitiadine + Efavirenz (Atripla), qd
 PI – eg Ritonavir (Kaletra)
 SI - Raltegrovir (Isenstress) only one
 Leave a couple classes untouched at first
Monitor CD4, viral load every 3 months
 Viral load should change log 10
 If not completely controlled after 3-6 months, change therapy
Only use <3 for prophylaxis
With low compliance/experienced patients
 Don’t re-genotype – presence of wild virus + mutated virus
 genotype not reliable
Main Dis with PIs and NNRTIs
Cancer
 Mechanism
 Oncongenes - cause rapid growth
 Tumor suppressor genes/TNF – suppress oncogenes
 Anticancer agents
 Cytotoxic
 Cancer drugs grow fast need more supply, take up more drugs
 But lack specificitySmall TI → toxic side effects
 Often drugs dosed in mg/m2 (BSA)
 Adverse Effects
 Severe NV - Promote release of 5HT
 tx Prochlorperazine(Compazine),
 Dronabinol (Marinol) – active ingredient in THC, po
 Nabilone (Cesnet) – analog of THC, po
 Metoclopramide (Reglan) – D2 antagonist↑AcH↑GI motility
 5HT3 blockers “-setron”
 work locally in GI Tract and Centrally in CTZ, po and IV
 Ondansetron (Zofran) – po, IV
 Granisetron (Kytril) – po, IV
 Dolasetron (Azimet) - IV
 Palosetron (Aloxi) – IV
 Apepitant (Emend)
 Neurokinin-1 Receptor Inhibitor
 in CNS, po
 Fosaprepitant (Emend for injection)
 IV, 1 hr before chemotherapy, daily for 2 days after
 Myelosuppession Hemorrhaging, Infection
 Filigastrin – stimulates neutrophil production
 Epoetin – recombinant erythropeoitin, stimulates RBC
 Emetogenic Chemotherapy
 Destroy cellsexcess DNA/RNApurinesuric acidhyper uricemia
 Xanthine Oxiase inhibitors (po)
 Allopurinol (competitive)
 Febuxostat (Uloric) – noncompetitive
 Immunosuppression →Opportunistic infections
 PCP – Bactrim, Septra
 Serratia Narcesseus – Cephalosporins, Ceftrixaone
 Alopecia
 Carcinogenic
 Teratogenic, esp w/combination chemotherapy (up to 6 diff. drugs)
 Alkylating Agents
 Forms covalent bonds w/ DNA and other biomolecules
 Mustards (Nitrogen)
 Mustard Gas
 CLCH2CH2-S-CH2-CH2-Cl
 Sulfur changed to Nitrogen
 Liquid and Vesicant, IV
 Tx Hodgkins, Lymphoma, Leukemia
 AE – Myelosuppression
 Cyclophosphamide (Nitrogen mustard prodrug)
 M- P450 alkylating agent (not vesicant)
 Tx – multiple myeloma, lymphoma, leukemias, retinoblastoma, neuroblastoma,
ovarian, breast cancr
 AE – Urotoxicity (hemorrhagic cyptitis, hematuria c/o cytotoxic substances in urine)
 adm /Mesna
 Mesna (Hs-CH2Ch2-SO2 Na) very polar
 Restricted to intravascular compartment
 reduces incidnece of hematuria, hemmorhagic cystitis
 Mechlorethamine
 AE - ~Cyclophospamide + MyeloSup
 Ifosfamide
 testicular cancer, w/ Mesna
 Nitrosylureas
 Lomustine (Ceenu) – po, IV
 Carmustine (Bicnu) - IV
 Produces reactive intermediatesreact with DNA
 D – into CNS
 tx brain tumors (globlastomasa, astrocytomas)
 Adm – q 6 weeks
 AE – MyelTox, NV,
 Platinum Derivatives
 A – IV, E – Renal,
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MOA – Bind covalently to DNA
Cisplatin (Platinol)
 AE - NV(100%), NeuroTox, NephroTox, MyS, OtoTox
 Adm - Frequently in combo
 Tx – bladder, testicular, ovarian
 Carboplatin (Paraplatin)
 Less toxic than Cisplatin
 Tx – ovarian, lung
 Oxaloplatin (Eloxatin)
 + 5-fluorouracil + Leucovorin for colon cancer
 AE – persistent NeuroTox (parasthesia) esp. on contact w/ cold
 Temozolomide (Temodar)
 Purine-like analog
 M – hydrolyzed in vivo reactive triazine derivativealkylates DNA
 A – orally, IV
 Tx – brain tumors - astrocytomas (resistant to nitrosylureas), glioblastomas
 AE - MyS
 Antimetabolites
 Antifolates
 Inhibit DHFA reductase
 Methotrexate
 A- po, IV, IM, intrathecally
 D- 50% protein-bound
 NSAIDS, sulfonamides can displace MTX
 E – renal excretion (aTS)
 Compete with same transporter as Pencillins, NSAIDS
 Probenecid interferes with secretion
 tx cancer daily, tx Rheumatoid arthritis weekly, narrow TI
 DOC for Choriocarcinoma
 15-30 mg qd, or 1mg/kg qod 75%cure rate
 Maintenance of remission for acute lymphoblastic lymphoma (ALL)
 Breast cancer, Epidermoid, Head, Neck, Lung Cancers
 Osteocaricnoma
 rescue therapy – lethal dose of methotrexate t/ antidote leucovorin
 Leucovorin – 5-formylTHFA, antidote to DHFA-reductase blockade
 dose measured w/ BSA
 Psoriasis
 Rheumatoid Arthritis
 Tox - MyS, HepTox, Diarrhea, Ulcerative Stomatitis (Open Sores in mouth)
 Pemetrexid (Alinta)
 MOA – Inhibits DHFA reductase, thymidilate synthetase,
also glucinamide ribonuclotide formyl transferase (purine biosynthesis)
 A – IV infusion w/ Cisplatin
 Required – Adm/ Low-dose folic acid, B-12 on week preceding + on day of
 Recomm – Corticosteroid (Dexamethasone 4mg po bid) day of and after
 Tx malignant pleural mesothelioma, non-small cell lung cancer (NSCLC)
 AE – NV, Pruritis, Erythema, MyS?,
 Pyrimidine Analogs
 Converted to nucleotide (phosphorylation) intracellularly,
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5-Fluorouracil
 M – 5-F deoxyuridine Monophosphate (5F-dUMP) – active form
 MOA – Inhibits thimydylate synthetase
 A – IV(cream, solution), topical
 Tx – GI (gastric, colon, rectal), Breast, Ovarian
Head, neck, sqaumous cell carcinoma
 Topically for premalignant keratoses, basal cell carcinoma
 ~Systemically Adm w/ Leucovorin
 AE – MyS, oral sores
 Cytrarabine (Ara-C)
 ~Cytosine w/ arabinose instead of ribose
 Tx IV Acute lymphocytic leukemia (ALL), acute myelocytic leukemia (AML)
 Copecitabine (Xeloda)
 Analog of cytidine
 M(thymidine phosphorylase)5-Fluorouracil
 Thymidine phosphorylase – higher in tumor cells than in normal cells
 A- po
 AE – Hand-Foot syndrome (become irritatednumbness/paresthesia, blister)
Diarrhea, MyS
 Gemcitabine (Gemzan)
 IV, Analog of Cytidine
 MOA – Interferes with DNA biosynthesis
 Tx pancreatic cancer (problem – no problem until major symptomsliver)
Also, breast, ovarian
 Azacitadine (Vidaza)
 MOA - Incorporated into DNAhypomethylation , prevents protein binding
 Tx myeloplastic syndrome denovo radiation
 Sx anemia, leukopeniainfection, thrombocytopeniableeding
 A – sq, IV
 Purine Analogs
 6-mercaptopurine
 po, MOA – interferes with DNA synthesis
 M (xanthine oxidase)→6-mercaptouric acid (inactive)
 %Competes with Allopurinol for XO
 Tx Leukemias
 Pentostatin (Dipent)
 Tx IV, Hairy Cell Leukemia
 MOA – Inhibits Adenosine deaminase
 AE - MyS
 Plant/Natural Products
 Antimitotic - Interfere with mitosis by decreasing microtubule function
 Cell cycle specific for mitosis
 Vinca Alkaloids
 From Vinca Rosea (periwinkle plant), large dihydroketo molecules
 MOA - Bind to α-tubulinprevents formation of microtubule↓cell division
 Vinlastine,
 tx choriocarcinoma(MTX-resistant), Hodgkin’s disease
 AE –MyS
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Vincristine
 tx neuroblastoma, Wilms tumor(kidney), ALL
 AE – neurotoxicity (paresthesias, areflexia, pruritis), ~MyS
 Vinorelbine – semi-synthetic
 tx NSCLC, AE-~NeurTox, MyS
Taxane Derivatives
 MOA - Stabilize formation of microtubules, halts mitosis
 Paclitaxel (Taxol) from Yew tree bark (slow-growing tree)
 Use precursor in leaves to make it
 insoluble in water
 IV Cremophor EL (Castor oil(?)Polyoxyethylated castor oil)
 possibly allergy to solvent
 pretreat patient with diphenhydramine, cimetidine/ ranitidine, and corticosteroid
 Tx ovarian, breast, squamous cell (head and neck), AIDS-related, kaposi’s sarcoma
 Docetaxel (Taxotere)
 insoluble in solution, lower incidence of hypersensitivity
 tx breast, gastric, prostate, NSCLC, squamous cell cancer (head, neck)
 still need antiinflammatory pretreatment
 Carboxitaxel (Jevtana)
 Still need pretreatment, dissolved in polysorbate 80, complex diluting process
 tx prostate cancer refractory to docetaxel
 nab-paxitaxel (Abraxane)
 Paxitaxel attached to nanosized albumin particles (nab), suspension given IV
 particles – 0.4-0.6 mcm (must be less than 7mcm)
 suspensions also given IV – propofol(emulsion), amphotericin B (colloid)
 tx breast cancer
 no premeds needed for nab
Epothilones – from swine bacterium (Sorangium cellulosum)-myxobacterium
 MOA ~ taxanes
 Ixabepilone (Exempra)
 Given in polyoxyethylated castor oilrequires premedication
 AE – NeurTox, MyS, NV
Camptothecins – from Campotheca accuminata
 MOA – Inhibit topoisomerase I (cuts and ligates DNA strands)prevents from
unwinding/relieving torsional stress
 Topotecan (Hycamptin) – IV, po
 tx ovarian cancer, nFDA – small cell lung cancer
 AE – MyS
 Irinotecan (Camptosar) – only IV
 M(liver, hydrolysis) SN-38, much more active
 tx colon + rectal cancer
 Adm/ 5-FU + leucovorin
 AE – Diarrhea , MyS
 early onset D (due to AChE inhibitionChol)ttx atropine
 late onset D (24hrs after) SN-38 metaboliteexcreted in bile~inflammation
 severe, life-threatening
 ttx loperamide + fluids to replenish electrolytes


Anthracycline Antibiotics
 All given IV, all color urine red (in addition to rifamycins, and phenazopyridine)
 Intercalate with DNA
 Doxorubicin
 tx ALL, AML, bone, bladder, wilms tumor, Neuroblastoma, lung, lymphoma
 CardioTox may be enhanced by cyclosphamide
 Epirubicin
 Idarubicin
 Valrubicin
 AE – CardioTox(affinity for DNA in tissueEKG abnormality, arrhythmia, CHF
resistant to digitalis), MYS
 Tyrosine Kinase inhibitors
 Tyrosine Kinase – 1tm cell surface receptor
 binding site for growth factors (EGF, VEGF, PDGF)
 activationcellular proliferation
 in normal cells receptor down regulation
 mutated cellsget overgrown
 Tinibs - Small Molecule TKIs
 MOA - Competitively inhibit tyrosine phosphorylation at ATP site
 A – po, M ~P450,
 AE – diarrhea, skin rash, yellowing of skin, (Mys – not major AE)
 Tx depends on specific GFr and tissue
 Imatinib (Gleevec)
 Gefitinib (Iressa)
 Saratenib (Nexavar)
 Nitatinib (Tasigna) - prolongs QT interval
 Sunitinib (Sutent)
 Lapatinib (Tykerb)
 Desatinib (Sprycel)
 Vandetanib (Zactema)
 Pazopanib (Votrient) – severe HepTox
 ~Pegaptanib (Mecugen) – pegylated oligonucelotide, VEGF antagonist
 tx neovascular (wet) macular degeneration (major cause of blindness in US)
 A – intravitreous inj
 MOA – reacts with VEGF, preventing VEGF from reacting with TK
 Large Molecule TKIs
 Bind to extracellular GF-receptor site
 A – IV, monoclonal antibodies
 Bevacizumab (Avastin) – tx Breast, Glioblastoma, Lung Cancer
 Cetuximab (Erbitux)
 Trastuzuab (Herceptiv) tx Breast, Gastric
 Panituumab (Vectibix) tx colorectal cancer