1

2 CHEMOTHERAPEUTIC AGENTS ANTIBACTERIAL ANTIPROTOZOAL ANTHELMINTIC U C U S M A R T ANTIVIRAL CHEMOTHERAPEUTIC AGENTS ANTIFUNGAL

3 CHEMOTHERAPEUTIC AGENTS What is Chemotherapeutic Agent? Chemotherapeutics are chemical entities used to treat or cure cancers. Kill the cancer cells better than they kill Normal Cells

4 CLASSIFICATION AND USE There are numerous chemotherapeutic agents in use today. The major classes, along with their subclasses and some specific agents, are as follows: >Alkylating agents >Antimetabolites >Microtubules targeting agents >Topoisomerase inhibitors >Antracyclines >Monoclonal antibodies

5 Alkylating agents  Attach alkyl groups to DNA, allows cross linking of base pairs, damaging DNA;cell cycle nonspecific  Typical alkylating agents: cyclophosphamide, ifosfamide,melphalan,busulfan,mechlorethamine, chlorambucil, thiotepa > Side effects: myelosuppresion (drop in WBC, Hb, crit), nausea/vomiting,second malignancies, infertility/impaired fertility, hemmorhagic cystitis (hematuria,dysruria, from direct irritation of bladder by acrolein metabolite  Atypical alkylating agents > Platinum compounds covalently bind purine DNA bases. Drugs (and side effects): *cisplatin (causes nephrotoxicity and n/v *carboplatin (causes thrombocytopenia) *oxaliplatin (causes cold sensitivity ) *all cause peripheral neuropathies,paresthesia

6 Antimetabolites  Inhibit DNA replication by mimicking normal cell compounds; S phase specific.  Folate inhibitor : Methotrexate inhibits DHFR, prevents regeneration of THF o Adjuvant leucovorin to protect healthy cells(adjuvant) o Side effect is mucositis, myelosuppression  Pyrimidine inhibitors o 5-fluorouracil inhibits thymidylate synthetase < Bolus dose causes myelosuppresion < continuous dose causes GI problems (mucositis, diarrhea) < synergistic leucovorin potentate mechanism of action (synergistic) o Capecitabine is essentially an oral prodrug for 5-FU < Side effects : hand foot syndrome- palms and hands and feet become red, can start blistering o Cytarabine (AraC) is a DNA chain terminator < Side effects : conjunctivitis and cerebellar neural defects

7 Microtubules targeting agents  These drugs inhibit mitosis, specifically Mphase  Vinca alkaloids destroy microtubules, obviously preventing their function o Vincristine, vinblastine, and vinorelbine o Side effects : peripheral neuropathy, myelosuppresion (blast > others) o Fatal if given intrathecally  Taxanes stabilize microtubules, preventing their function o Paclitaxol, docetaxol o Side effects : myelosuppresion, peripheral neuropathies o Hypersensitivity  from diluent : Cremophor diluent in paclitaxel > Tween80 in Docetaxel  avoid hypersensitivity with abraxane, protein-bound paclitaxel particles  less sensitivity but more neuropathy

8 Topoisomerase inhibitors  Topoisomerase I inhibitors prevent relaxation of supercoiled DNA o Topotecan, ironotecan  Both have side effects of myelosuppresion  Ironotecan causes Diarrhea : “ I ran to the can”  Topoisomerase II inhibitors prevent recolling of DNA after transcription o Etoposide, teniposide  Both have side effects of myelosuppresion, mucositis, secondary malignancies (AML)

9 Antracyclines  Various mechanism of action : intercalate DNA, inhibit topo II, generate ROS, perhaps Alkylation  -rubicins: doxorubicin, daunorubicin, idarubicin, epirubicin o Side effects: biventricular heart failure, necrotic with extravasation  The 3 in 7+3 chemotheraphy

10 Monoclonal antibodies  Origin determined from suffixes : -omab from mouse; -ximab is is chiremic (cross between human/ mouse); -umab is humanized ; -mumab is fully human

11 Other chemotherapeutics agents  Bleomycin causes lung toxicity o Side effects : pulmonary fibrosis, interstitial pneumonitis, hypersensitivity pneumonitis (cough, infiltrates)  Hormonal therapies o Antiestrogens block estrogen stimulation of breast cancer  Tamoxifen, fulvestrant, megestrol acetate o Aromatase inhibitors block synthesis od estrogen  Anastrozole, letrozole o Antiandrogens block androgen stimulation of prostate cancer  other targets for prostate cancer are LHRH agonists ( prevent testosterone production), GnRH antagonist, CYP17 inhibitor.

12 ANTIBACTERIAL 1.Beta-lactams (Penicillins & Cephalosporins) Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly. 2. Macrolides Inhibits translation (Protein synthesis) 3. Tetracyclines Inhibits translation (Protein synthesis) 4. Chloramphenicol Inhibits translation (Protein synthesis) 5. Lincosamides Inhibits protein synthesis in susceptible bacteria by binding to the 50S subunits of bacterial ribosomes. 6. Aminoglycosides Inhibits translation (Protein synthesis)

13 7. Quinolones Inhibition of bacterial DNA Gyrase Inhibition of bacterial Topoisomerase IV 8. Sulfonamides Inhibition of dihydropetroate synthase 9. Antimycobacterials

14 ANTIFUNGAL Fungi is a Eukaryote(contains cell nucleus and other organelles) which can be both unicellular and multicellular. Antifungal medications also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycoses which most commonly affect your skin, hair and nails.

15 I. MOST COMMON FUNGAL PATHOGENS CandidaCryptococcus AspergillusDermatophytes Rhizopus II.Categories of Fungi  Yeast -Unicellular organism such as Candida and Cryptococcus  Molds -multicellular organism; macroscopic; such as Aspergillus, Amphosarium and Zygomysiti  Dimorphics -Histoplasma, Blastomyces, Coccidioides, Paracoccidioides

16 II.ANTIFUNGAL DRUGS BY STRUCTURE Polyenes Azoles Fluorinated Pyrimidine Echinocandins Allylamines Morpholine Peptide-nucleoside Tetrahydrofuran Derivatives

17 III.MODES OF ACTION  Membrane disrupting agents Amphotericin B, nystatin –binds ergosterol, weaken the membrane, cause pore formation, leakage of K+ and Na+, fungal cell death Ergosterol synthesis inhibitors Azoles, allylamines, morpholine –inhibit synthesis of ergosterol Nucleic acid inhibitor Flucytosine – inhibit DNA synthesis 5-Flucytosine → 5-Fluorouracil Glucan synthesis inhibitors Echinocandins – inhibit the enzyme that synthesized β-glucan

18  Chitin synthesis inhibitor -Inhibit production of Chitin Nikkomycin  Protein synthesis inhibitors Sordarins, azasordarins

19 ANTIVIRAL  Viruses are infectious agents that need host cell in order to survive and multiply. Their structure are simple and designed to protect them from environment and to facilitate their entry into cells.  They have Many different shapes:

20 Antiviral drugs - Any agent that is used in the treatment of infectious diseased caused by a virus. OBECTIVE: To eradicate the virus while minimally impacting the host and prevent further viral invasion.

21 What are viruses? A microorganism that is smaller than a bacterium that cannot grow or reproduce apart from a living cell.

22 Groups of antiviral drugs Antiherpesvirus drugs Anti-influenza drugs Anti-HIV drugs Anti-Respiratory syncytial virus (RSV) drugs Interferons

23 Antiherpes virus drugs The nucleoside analogs (acyclovir and ganciclovir) actually mimic the normal nucleoside and block the viral DNA polymerase enzyme, which is important in the formation of DNA. nucleoside analogs must be activated by addition of a phosphate group before they have antiviral activity. Acyclovir are activated by a viral enzyme, so they are specific for the cells that contain viral particles. Idoxuridine are activated by cellular enzymes, so these have less specificity. Non-nucleoside inhibitors of herpesvirus replication include foscarnet, which directly inhibits the viral DNA polymerase and thus blocks formation of new viral DNA. Non-nucleoside inhibitors of herpesvirus replication include foscarnet, which directly inhibits the viral DNA polymerase and thus blocks formation of new viral DNA.

24 Anti-influenza drugs Amantadine and rimantadine used for the prevention and treatment of influenza A, but they have no effect against influenza B viruses. The action of amantadine is to block uncoating of the virus within the cell and thus prevent the release of viral RNA into the host cell. Zanamivir and oseltamivir are active against both influenza A and influenza B. These drugs are inhibitors of neuraminidase, a glycoprotein on the surface of the influenza virus. Inhibition of neuraminidase activity decreases the release of virus from infected cells, increases the formation of viral aggregates, and decreases the spread of the virus through the body. If taken within 30 hours of the onset of influenza, both drugs can shorten the duration of the illness.

25 Anti-HIV drugs Two groups of RT inhibitors. Nucleoside RT inhibitors (e.g., zidovudine, didanosine, zalcitabine, lamivudine, and stavudine) must be phosphorylated to become active. These drugs mimic the normal nucleosides and block reverse transcriptase Non-nucleoside inhibitors (e.g., delaviridine, efanvirenz, and nevirapine), which do not require activation and, because they act through a different mechanism, exhibit a synergistic inhibition of HIV replication when used with the nucleoside RT inhibitors.

26 A significant challenge with the use of RT inhibitors is the development of resistance; because HIV replicates continuously at a very high rate, there are many chances for mutation and hence the emergence of a virus resistant to many drugs. To combat the emergence of resistant virus, a class of HIV drugs called nucleotide RT inhibitors (e.g., tenofovir) has been developed. These drugs are “preactivated”; that is, they are already phosphorylated and require less cellular processing.

27 Protease inhibitors (e.g., ritonavir, saquinavir, and indinavir) block the spread of HIV to uninfected cells by inhibiting the viral enzymes involved in the synthesis of new viral particles. Act at a different point in the life cycle of HIV, use of a protease inhibitor with an RT inhibitor suppresses replication better than either drug alone. Protease inhibitors also slow the emergence of resistant virus.

28 The principal adverse effects of protease inhibitors are nausea and diarrhea. Long-term use can bring on a syndrome known as lipodystrophy (wasting of peripheral fat, accumulation of central fat, hyperlipidemia, and insulin resistance).

29 Anti-Respiratory syncytial virus (RSV) drugs The only pharmacological therapy available for treatment of the infection is the nucleoside analogue ribavirin, which can be administered orally, parenterally, or by inhalation. Ribavirin must also be activated by phosphorylation in order to be effective. An injectable humanized monoclonal antibody is available for prevention of RSV infection in high-risk infants and children. It provides passive immunity and must by given by intramuscular injection once a month during RSV season

30 Interferons Interferons represent a group of nonspecific antiviral proteins produced by host cells in response to viral infections as well as in response to the injection of double-stranded RNA, some protozoal and bacterial components, and other chemical substances. Interferon results in the production of a protein that prevents the synthesis of viral components from the viral nucleic acid template. They have broad-spectrum antiviral activity and because they inhibit the growth of cancer tissue

31 Antiprotozoal injections  Predator. An organism that eats more than one other organism during its life. usuaflly larger than prey( exception : social predators)  Parasite. An organism that lives at the expense of another (host), which it does not usually kill. It is smaller than host.  Parasitoid. A parasite that kill its host. It is smaller than host.

32 Parasites are usually much smaller than their hosts, they also do not kill before they eat.

33 Introduction to Amoeba:  Entamoeba histolytica Amoebic dysyntery  Naegleria Primary amoebic meningoencephalitis  Acanthamoeba Contact lens contaminant

34 Protozoa with no truly define shape Move and acquire food through the use of pseudopodia Found in water sources throughout the world Few cause disease

35 Classification Of Antiprotozoal Drugs:  TRYPANOMIASIS Benznidazole Melarsoprol Nifurtimox Pentamidine Suramin

36  AMEBIASIS Chloroquine Dehydroemetine Emetine Iodoquiol Metronidazole Paramomycin Tinidazole

37  MALARIA Artemisinin Chloroquine Mefloquine Primaquine Pyrimethamine Quinine / Quinidine

38  LEISHMANIASIS Sodium Stigluconate  TOXOPLASMOSIS Pyrimethamine  GIARDIASIS Metronidazole Nitazoxanide Tinidazole

39 THE COURSE OF AMOEBIASIS DUE TO ENTAMOEBA HISTOLYTICA

40 LIFE CYCLE OF ENTAMOEBA HISTOLYTICA

41 LIFE CYCLE OF THE MALARIAL PARASITE

42 TREATMENT AND TREVENTION OF MALARIA

43 ADVERSE EFFECT OF METRONIDAZOLE AND CHLOROQUINE

44 ANTHELMINTIC An agent that destroys or causes the expulsion of parasitic intestinal worms. Synonyms: -vermicide (kill) -vermifuge (expel)

45 HELMINTHS??? Helminths are parasitic worms that feed on a living host to gain nourishment and protection, while causing poor nutrient and absorption, weakness and disease in the host. Classes: - Nematodes ( roundworms) - Trematodes ( flukes or flatworms) - Cestodes ( tapeworms) - Monogenans ( also members of the flatworm phylum)

46 Pharmacokinetics After administration, anhelmentics are usually absorbed into the bloodstream and transported to different pats of the body, including the liver, where they may be metabolized and eventually excreted in he feces and urine Although many parasites reside in the lumen or close to the mucosa, others live at sites such as liver and lungs; for action against these, absorption of drug from the GI tract, injection site, or skin is essential.

47 Classification based on chemical structure: Piperazines: Diethylcarbamazine citrate( DEC), Piperazine citrate Benzimidazoles: Albendazole, Mebendazole, Thiabendazole Heterocyclics: Oxamniquine, Praziquantel Natural products: Ivermectin, Avermectin Viryl pyrimidines: Pyrantel, Oxantel Amide: Niclosamide Nitro derivative: Niridazole Imidazo thiazole: Levamisole

48 Contraindicated: Presence of known allergy to any of these drugs Lactation Pregnancy in most cases Caution should be used in the presence of renal or hepatic disease or severe diarrhea and malnourishment.