Antiprotozoals and Cancer Chemotherapeutic agents Maria Rosario F.

Cabansag, MD

Amoebiasis
Asymptomatic intestinal infection- Luminal agents Mild to moderate intestinal infection-Metronidazole + Luminal agent Severe intestinal infection- Metronidazole + Luminal agent Hepatic abscess- Metronidazole + Luminal agent or Dehydroemetine followed by Chloroquine METRONIDAZOLE is effective in the treatment of vaginal trichomoniasis, giardiasis, and all forms of amebiasis. Metronidazole is one of the most effective drugs against anaerobic bacteria and several protozoal species. The reduced metronidazole inhibits DNA replication by causing breaks and inhibiting repair of the DNA. The most common side effects are nausea, vomiting,and diarrhea. The drug can turn the urine dark or red-brown and cause a disulfiram-like reaction whentaken with alcohol. Iodoquinol- luminal amebicide Diloxanide furoate- luminal amebicide Paromomycin sulfate-luminal amebicide Emetine and dehydroemetine- can cause cardiac arrhythmias; used for severe intestinal infection and liver abscess Tinidazole- has better toxicity profile than Metronidazole Amoebiasis Other antibiotics which can be used for mild to moderate intestinal amoebiasis- Tetracycline or Erythromycin ANTIMALARIAL AGENTS STAGE EFFECTIVE DRUGS THERAPEUTIC GOAL Sporozoites None Destroy sporozoites to prevent infection Primary exoerythrocytic PRIMAQUINEPrevent erythrocytic

Secondary exoerythrocytic Erythrocytic

PRIMAQUINECHLOROQUINE, QUININE Mefloquine, Coartem PRIMAQUINE

infection Prevent relapse -Treatment of clinical symptoms Prevent spread of infection Back to mosquito

Mefloquine-combined with artesunate Adverse effects:GI disturbances,neuropsychiatric toxicities Primaquine-active against hypnozoites Nausea,Abdominal cramps,Leukocytosis,leukopenia,cardiac arrhythmias, hemolysis Atovaquone + Proguanil(Malarone) Atovaquone -Disrupts mitochondrial electron transport Adverse effects: fever , rash, GI disturbances Inhibitors of folate synthesis-slow acting Pyrimethamine+ Sulfadoxine- Fansidar (given once a week) Pyrimethamine + Dapsone- Maloprim Proguanil (given daily) Adverse effects: GI symptoms,Hematologic, CNS, Dermatologic-Stevens Johnson syndrome Antibiotics- Tetracycline, Doxycycline, Clindamycin, Azithromycin Halofantrine irregular absorption and cardiac toxicity Lumefantrine + artemether(Coartem) -GI disturbances, rash Prophylaxis (Prevention of Malaria) Chloroquine Malarone Mefloquine Doxycycline Primaquine-Terminal prophylaxis of vivax and ovale infections Other Antiprotozoals Pentamidine-for pneumocystosis and West African trypanosomiasis,Leishmaniasis; causes pancreatic toxicity Sodium stibogluconate-Cutaneous and visceral leishmaniasis, ECG changes Nitazoxanide-inhibits pyruvate-ferredoxin oxidoreductase pathway- for Giardia For Trypanosomiasis and Leishmaniasis Suramin-fever, neuropathies,renal abnormalities, for East African trypanosomiasis Melarsoprol-trivalent arsenical; may cause

Sexual

PRIMAQUINE is effective against liver forms (exoerythrocytic) and kills gametocytes. PRIMAQUINE can cause hemolytic anemia in G6PD-deficient patients. CHLOROQUINE (oral) and QUININE (parenteral) are used for the erythrocytic form of malaria. Chloroquine is also used for prophylaxis for travelers entering areas where chloroquinesensitive malaria is endemic. Chloroquine causes buildup of heme GI effects,hypotension, ECG changes,blurring of vision Amodiaquine + Artesunate Piperaquine + Dihydroartemisinin

Artemisinin derivatives
Artemisinin(Qinghaosu)lactone endoperoxide Artesunate- water soluble(oral , IV) Artemether-lipid soluble (oral, IM) Dihydroartemisinin- water soluble (oral) MOA: production of free radicals, inhibition of parasite Calcium ATPase GI disturbances, Elevated liver enzymes WHO recommendations for treatment of Falciparum malaria Artemether-lumefantrine (Coartem) Artesunate-amodiaquine Artesunate-mefloquine Artesunate-sulfadoxine-pyrimethamine Dihydroartemisinin-Piperaquine Quinine and Quinidine- for severe disease Adverse effects: cinchonism,hypersensitivity reaction,hypoglycemia, hypotension,ECG changes, Blackwater fever

reactive encephalopathy, for East African trypanosomiasis Eflornithine- inhibitor of ornithine decarboxylase; GI disturbances,hematologic (less toxicity than melarsoprol) Nifurtimox-for Chagas disease; GI disturbances, neuropathies Benznidazole- peripheral neuropathy New drugs for visceral Leishmaniasis: Amphotericin Miltefosine- increase in liver enzymes,nephrotoxicity Paromomycin-liver enzyme elevation,ototoxicity

ANTICANCER DRUGS
Many anticancer drugs have had several names over the years. Dont let this confuse you. Primary Induction Chemotherapy-Primary treatment in patients with advanced cancer Nonadjuvant chemotherapy-for localized cancer Adjuvant chemotherapy-Adjuvant to surgery or radiation ALKYLATING AGENTS A. Nitrogen Mustards Chlorambucil Cyclophosphamide Ifosfamide Mechlorethamine (nitrogen mustard) Melphalan B. Nitrosoureas Carmustine Lomustine C. Other Alkylating Agents Busulphan Dacarbazine Thiotepa ANTIMETABOLITES A.Folate Antagonist Methotrexate B. Purine Analogues cladribine fludarabine mercaptopurine (6-mercaptopurine) pentostatin thioguanine (6- thioguanine)

C. Pyrimidine Analogues cytarabine (cystosine arabinoside, ara-C) fluorouracil (5-FU) gemcitabine ANTIBIOTICS AND OTHER NATURAL PRODUCTS A. Anthracyclines Daunorubicin (daunomycin) Doxorubicin Idarubicin B. Other Antibiotics Bleomycin Dactinomycin (actinomycin D) Mitomycin (mitomycin C) Plicamycin (mithramycin) C. Vinca Alkaloids Vinblastine Vincristine Vinorelbine D. Other natural Products Docetaxel Paclitaxel Etoposide Teniposide HORMONAL AGENTS Tamoxifen Flutamide GnRH-leuprolide MISCELLANEOUS IMMUNOMODULATING AGENTS Carboplatin Cisplatin Hydroxyurea Mitotane Mitoxantrone Procarbazine (N-methylHydrazine,?alkylating) LH-RH, luteinizing hormone-releasing hormone. CELLULAR AGENTS interferons GROWTH FACTORS filgrastim (G-CSF) sargramostim (GM-CSF) Anticancer therapy is aimed at killing dividing cells. There are normal host cells that are also dividing. Effects on these cells cause side effects

-The log kill is an important concept to understand. -The anticancer drugs kill a constant fraction of cells instead of an absolute number. -Drug resistance to anticancer drugs is analogous to resistance to antimicrobials. -Combinations of drugs are frequently used in the treatment of cancer. -Bone marrow toxicity is caused by destruction of proliferating hematopoietic stem cells. This results in a decrease in all blood elements, including white cells and platelets. -Gastrointestinal toxicity takes two forms. The nausea and vomiting associated with cancer chemotherapy is felt to be due to a central effect. These drugs can also directly damage the proliferating mucosa of the GI tract. -Most anticancer drugs damage hair follicles and produce hair loss. -Many of the anticancer drugs can cause local tissue necrosis. -Renal tubular damage is the major side effect of cisplatin and high-dose methotrexate. -Cyclophosphamide can cause hemorrhagic cystitis. -Cardiotoxicity is associated with the use of doxorubicin and daunorubicin. -Bleomycin can cause pulmonary fibrosis, which can be fatal. -Vincristine is known for its nervous system toxicity. ALKYLATING AGENTS -Alkylating agents all work by adding an alkyl group to DNA. -The nitrogen mustards include: -Mechlorethamine- used Hodgkins lymphoma -Cyclophosphamide (hemorrhagic cystitis) -Chlorambucil -The nitrosoureas include carmustine and lomustine. They are useful in treating brain tumors, because they are lipid soluble enough to cross the blood-brain barrier . -The other alkylating agents are busulfan, thiotepa,melphalan,bendamustine and dacarbazine,procarbazine, platinum analogs

 Nonclassic Alkylating Agents Procarbazine-inhibits DNA synthesis and produces chromosome breaks Dacarbazine- myelosuppression Bendamustine--myelosuppression Platinum analogs(Cisplatin, Carboplatin, Oxaliplatin) ANTI-METABOLITES -The anti-metabolites compete for binding sites on enzymes or can be incorporated into DNA or RNA. -Methotrexate competitively inhibits dihydrofolate reductase -Leucovorin provides reduced folate to rescue normal cells from the action of methotrexate. -Methotrexate is used to treat psoriasis and severe rheumatoid arthritis in addition to a whole variety of cancers. Its major route of administration is renal. Pemetrexed- antifolate analog Causes myelosuppression, Skin rash, mucositis, diarrhea, fatigue Pralatrexate-anrtifolate analog -The purine analogues(used in leukemia and lymphoma) all have to be activated. They include thioguanine and mercaptopurine. The pyrimidine analogues also must be activated. They include cytarabine and fluorouracil Fluoropyrimidines Fluorouracil-myelosuppression Capecitabine-diarrhea, hand-foot syndrome Cytarabine-myelosuppression Gemcitabine-Neutropenia Purine antagonists Mercaptopurine *decrease dose if given with allopurinol Thioguanine-myelosuppression, GI toxicity Fludarabine- myelosuppression Cladribine-myelosuppresiion ANTIBIOTICS AND OTHER NATURAL PRODUCTS -The antibiotics all disrupt DNA function. -The anthracyclines have cardiac toxicity. They include doxorubicin, daunorubicin, and idarubicin. -Bleomycin can cause fatal pulmonary fibrosis. It does not have significant myelosuppressive effects. -Plicamycin(mithramycin) can be used to treat lifethreatening hypercalcemia associated with malignancy.

-The vinca alkaloids (vincristine, vinblastine) bind to tubulin and disrupt the spindle apparatus during cell division. -For vincristine, the neurological toxicity is doselimiting. -For vinblastine, the bone marrow toxicity is dose-limiting. Vinorelbinemyelosuppression Paclitaxel is a newer agent that is among the most active of all anticancer drugs. It works by preventing depolymerization of microtubules; Adverse effects: Myelosuppression, Hypersensitivity,Neurotoxicity Abraxane-not associated with hypersensitivity -Docetaxel -Cabazitaxel -Ixabepilone Etoposide and teniposide are plant products (mayapple root) that do not act by binding to microtubules. They inhibit topoisomerase Camptothecins-Topotecan, Irinotecan inhibit topoisomerase I CCNS -Myelosuppression,diarrhea

HORMONAL AGENTS
-These drugs are used to treat hormonally sensitive tumors, such as tumors of the breast, prostate, and uterus. -Tamoxifen and toremifene are competitive antagonists of the estrogen receptor, used in the treatment of breast cancer. -Flutamide is a competitive testosterone antagonist that is used to treat prostate cancer. -The LH-RH agonists (the most common one is leuprolide) block gonadotropin release: this results in decreased estrogen and testosterone production. -Hydroxyurea inhibits ribonucleotide reductase. -Mitotane is used to treat adrenocortical adenocarcinoma. -Carboplatin is an analogue of cisplatin. -Agents such as retinoids stimulate the growth of normal myeloid and erythroid progenitors and cause differentiation of myeloid leukemic cells. -Clinical trials have shown that trans-retinoic acid(tretinoin) induces remission in acute promyelocytic leukemia. IMMUNOMODULATING AGENTS -The goal is to enhance T-cell function and natural killer cells. Approaches have included administration of monoclonal antibodies, immuno-modulatory cytokines (interferons), immunocompetent cells, and vaccines. CELLULAR GROWTH FACTORS Filgrastim (granulocyte colony-stimulating factor) is used to accelerate recovery of neutrophils and sargramostim (granulocytemacrophage colony-stimulating factor) is used to accelerate bone marrow repopulation after chemotherapy, radiation, and bone marrow transplantation.

Antitumor antibiotics
Anthracyclines-Doxorubicin,Daunorubicin, Idarubicin,Epirubicin, Mitoxantrone Mitomycin-Hemolytic uremic syndrome Bleomycin-Pulmonary toxicity Miscellaneous anticancer drugs Imatinib,Dasatinib,Nilotinib-inhibitor of tyrosine kinase Growth Factor Receptor Inhibitors Cetuximab,Panitumumab- EGFR Adverse effects- Acneiform rash and hypomagnesemia Geftinib,Erlotinib Bevacizumab,Sorafenib, Sunitinib, Pazopanib-VEGF Adverse effects: Hypertension, bleeding complications and aftigue Sorafenib- skinrash and hand-foot syndrome Sunitinibincreased risk of cardiac dysfunction Asparaginase-hypersensitivity Retinoic Acid Derivatives-Tretinoin for Acute Promyelocytic Leukemia Arsenic Trioxide- for APL; ECG Changes