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135 Cards in this Set
- Front
- Back
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Polyene Antibiotics
Mechanism of Action and Drugs |
Selectively binds ergosterol in fungal membranes
Results in increased membrane permeability and subsequent release of cytoplasmic components Amphotericin B and Nystatin Antifungal Lecture 8 |
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Parenteral formulation
Extensive hepatic metabolism Slowly excreted in the urine Renal toxicity in 80% of patients Poor CNS accumulation Used for a wide variety of fungi |
Amphotericin B
Higher doses are used to treat infections caused by more resistant fungi, especially Aspergillus. Lower doses are generally used to treat esophageal and UTIs. Antifungal Lecture 8 |
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Structurally and functionally similar to amphotericin B
Useful only for candidiasis Mechanism of action Selectively binds ergosterol in fungal membranes Results in increased membrane permeability and subsequent release of cytoplasmic components |
Nystatin
Antifungal Lecture 8 |
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Azole Derivatives
Mechanism of Action |
Inhibit 14-α-demethylase
Prevent conversion of lanosterol to ergosterol Disrupts integrity of the cell membrane Accumulation of 14-α-demethylsterols Impairs membrane-bound enzyme systems: ATPase Enzymes of the electron transport system Antifungal Lecture 8 |
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Oral preparation
Capsule Absorbed best in the fed state Solution Absorbed best in the fasting state Metabolized by CYP3A4 isoenzyme system Many drug interactions -Drug of choice for blastomycosis (lung infection) -Also indicated for onychomycosis (nail infection) |
Itraconazole
Antifungal Lecture 8 |
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Absorption is not affected by food or gastric acidity
> 90% renal elimination Excellent BBB penetration Uses -Prevention of cryptococcal meningitis in AIDS patients -Candidiasis Esophagus, urinary tract and vagina |
Fluconazole
Antifungal Lecture 8 |
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“second-generation” triazole
Enhanced activity against Aspergillus and Candida species 60-100 times more potent than fluconazole against Candida (Yet fluconazole still listed as primary and voriconazole as alt.) |
Voriconazole
Antifungal Lecture 8 |
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Most common adverse effects of Voriconazole:
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Primary adverse effect is photophobia and chromatopsia
(visual disturbances: altered perception of light, abnormally colored vision (chromatopsia), and photophobia) Antifungal Lecture 8 |
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Second generation triazole
Specifically indicated for prophylaxis in immuncompromised individuals |
Poscaconazole
Antifungal Lecture 8 |
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Echinocandin Drugs
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Caspofungin, Anidulafungin
Antifungal Lecture 8 |
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inhibits glucan synthase
indicated for intra-abdominal abscess caused by Candida species and esophageal candidiasis |
Anidulafungin
Antifungal Lecture 8 |
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IV preparation
Inhibits the β(1,3)-D-glucan synthase enzyme complex Prevents formation of β(1,3)-D-glucans in the fungal cell wall Excellent activity against Candida species Particularly azole-resistant infections |
Caspofungin
Antifungal Lecture 8 |
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Accumulated by fungal cells
Converted to 5-fluorouracil (5-FU) by cytosine deaminase Subsequent metabolites are Incorporated into fungal RNA and disrupts subsequent protein synthesis Another metabolite, 5-fluorodeoxyuridylic acid potently inhibits thymidylate synthetase resulting in impaired DNA synthesis Human cells lack cytosine deaminase |
Flucytosine
Antifungal Lecture 8 |
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Very lipophilic
Absorption is increased when taken with fatty meal Induces CYP3A4 accumulates in keratin precursor cells of skin, hair and nails Interacts with polymerized microtubules and disrupts their function Binding sites are distinct from those of colchicine and vinca alkaloids (anti-inflammatory/gout and antineoplastic drugs respectively) Prevents mitosis of dermatophytes Not active against Candida |
Griseofulvin
Antifungal Lecture 8 |
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Topical formulation
Candida Mouth Throat Vagina Vulva Dermatophyte infections of the skin Athlete’s foot Jock itch Not effective against infections of the scalp or nails |
Clotrimazole
Antifungal Lecture 8 |
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Allylamines
Mechanism of Action and Drugs |
Inhibit squalene monooxygenase (instrumental in conversion of squalene to lanosterol)
Results in reduced ergosterol biosynthesis Naftifine and Terbinafine Antifungal Lecture 8 |
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Allylamine:
Oral treatment of onychomycosis (DOC) Accumulates in nails, skin and fat |
Terbinafine
Antifungal Lecture 8 |
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Allylamine:
Topical treatment of superficial dermatophyte infections |
Naftifine
Antifungal Lecture 8 |
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DOC for Tinea Capitis
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Terbinafine
Antifungal Lecture 8 |
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DOC for Tinea Pedis
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Terbinafine
Antifungal Lecture 8 |
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DOC for candidiasis
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Fluconazole
Antifungal Lecture 8 |
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DOC for Sporotrichosis
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itraconazole
Antifungal Lecture 8 |
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DOC for Cryptococcosis
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Non-meningeal: fluconazole
Meningitis: amphotercin B + flucytosine; then fluconazole alone or fluconazole alone Antifungal Lecture 8 |
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DOC for Histoplasmosis
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itraconazole
Antifungal Lecture 8 |
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DOC for Blastomycosis
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Amphotericin B then itraconazole
Antifungal Lecture 8 |
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DOC for Aspergillosis
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voriconazole
Antifungal Lecture 8 |
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DOC for Fusariosis
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Amphotericin B
Alternates: posaconazole or voriconazole Antifungal Lecture 8 |
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Kills trophozoites, but not cysts of E. hystolytica
t1/2 = 7.5 h Excreted in the urine Plasma clearance decreased with impaired liver function Mechanism of action: Reduction of the nitro group by the protozoal enzymes produces toxic, nitro free-radicals that damage DNA & protein |
Metronidazole
Also, drug of choice for Giardiasis and Trichomoniasis Tinidazole is similar Antiparasitic Lecture 11 |
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Luminal amebicide
90% of the drug remains in the intestine and is excreted in the feces. 10% enters the circulation. Mechanism of action is unknown |
Iodoquinol
Antiparasitic Lecture 11 |
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Aminoglycoside antibiotic
Luminal amebicide Not significantly absorbed Less toxic and more effective than diloxanide furoate |
Paromomycin sulfate
Antiparasitic Lecture 11 |
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-Used in children against G. lamblia and Cryptosporidium parvum.
-A prodrug -Active metabolite is tizoxanide -Inhibits the pyruvate:ferredoxin oxidoreductase pathway (critical for anaerobic energy metabolism in protozoa) |
Nitazoxanide
Antiparasitic Lecture 11 |
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First-line therapy for East African trypanosomiasis (Early Treatment)
Does not enter CNS, thus not effective in advanced disease Mechanism of action is unknown |
Suramin
Antiparasitic Lecture 11 |
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First-line therapy for advanced East African trypanosomiasis; (Late treatment)
-crosses BBB -Reacts with sulfhydryl groups of trypanothione, a reducing agent in the parasite |
Melarsoprol
Antiparasitic Lecture 11 |
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First-line therapy for West African trypanosomiasis (yet, best known for its use in the treatment of Pneumocystis jiroveci in immunocompromised individuals)
Mechanism of action is unknown Early Treatment |
Pentamidine
Antiparastiic Lecture 11 |
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First-line therapy for advanced West African trypanosomiasis; crosses BBB (Late Treatment)
Selective, irreversible inhibitor of ornithine decarboxylase Thus, it disrupts the synthesis of polyamines which are instrumental in nucleic acid and protein synthesis Less toxic than melarsoprol |
Eflornithine
Antiparasitic Lecture 11 |
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Used for American trypanosomiasis (Chagas’ disease)
Nitroaromatic compound that generates oxygen radicals which are toxic to the parasite (lacks catalase). |
Nifurtimox
Antiparasitic Lecture 11 |
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Treatment of cutaneous leishmaniasis
Mechanism of action is unknown |
Sodium Stibogluconate
Antiparasitic Lecture 11 |
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DOC for Visceral leishmaniasis
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liposomal amphotericin B
or stibogluconate Antiparasitic Lecture 11 |
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Nucleoside analogues are Prodrugs which are initially phosphorylated by ________________
Subsequently converted to active metabolite by __________ |
VIRAL Thymidine Kinase (selective for infected cells)
HOST kinases Antiviral Lecture 9 |
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Competitively inhibit viral DNA polymerase; thereby, preventing synthesis of viral DNA
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Nuceloside Analogues
Antiviral Lecture 9 |
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Effective against HSV and VZV
Prevent viral replication Reduce viral shedding Shorten time to heal Do not eliminate the virus |
Acyclovir, Famciclovir, Valacyclovir
Antiviral Lecture 9 |
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Prophylaxis of CMV
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acyclovir and valacyclovir
Antiviral Lecture 9 |
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Treatment of CMV
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Ganciclovir
Antiviral Lecture 9 |
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3 active metabolites
Inhibits thymidylate synthesis DNA synthesis is inhibited Incorporated into RNA Interferes with RNA processing and mRNA translation Incorporated into DNA Inhibits DNA synthesis Tx for Colorectal cancer |
Flurouracil (5-FU)
Antineoplastic Lecture 14 |
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A prodrug
Extensively metabolized in the liver Then converted to fluorouracil in the tumor cell by ________________. This enzyme is highly expressed in solid tumors Metestatic breast cancer |
Capecitabine
Thymdidine phosphorylase: tumors are high expressors of this enzyme Antineoplastic Lecture 14 |
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aka cytosine arabinoside or ara-C
Metabolized to the active triphosphate nucleotide, AraCTP An S-phase-specific antimetabolite Competitively inhibits ___________________. Also incorporates into DNA and RNA, interfering with chain elongation Mainly limited to treatment of acute myelogenous leukemia Highly schedule-dependent |
Cytarabine
DNA polymerase Antineoplastic Lecture 14 |
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These class of drugs are going after microtubules produced in the M phase of Mitosis
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Plant alkaloids
Vinblastine Vincristine Etoposide Topotecan Paclitaxel Antineoplastic Lecture 14 |
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Depolymerizes microtubule
Specifically binds tubulin resulting in assembly termination Mitotic arrest in ________________. Hodgkin’s disease, non-Hodgkin’s lymphoma and breast cancer |
Vinblastine
Metaphase Antineoplastic Lecture 14 |
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Related to vinblastine
Different spectrum of clinical activity and toxicities: Acute lymphoblastic leukemia in children, hematologic malignancies (Hodgkin’s disease, non-Hodgkin’s lymphoma), pediatric tumors (Ewing’s sarcoma and Wilm’s tumor) |
Vincristine
Antineoplastic Lecture 14 |
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Taxane
Binds microtubules and enhances tubulin polymerization Occurs in the absence of key microtubule components resulting in the inhibition of mitosis and cell division Extensively metabolized by the liver and excreted primarily in the feces Tx for Significant activity against a variety of solid tumors (Breast and ovarian cancer) |
Paclitaxel
Antineoplastic Lecture 14 |
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Blocks cell division in late S-G2 phase of cell cycle
Inhibits ________________ resulting in DNA strand breakage Germ cell cancer, lung cancer, hematologic malignancies and gastric cancer |
Etoposide
Topoisomerase type II Antineoplastic Lecture 14 |
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Inhibits ______________, which is instrumental in cutting and re-ligating single DNA strands
Advanced ovarian cancer (when platinum-based agents fail: Cisplatin, carboplatin, oxaliplatin) -Renal excretion |
Topotecan
Topoisomerase I Antineoplastic Lecture 15 |
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Anti-tumor antibiotics
(used in combination with other drugs) |
Doxorubicin
Daunorubicin Dactinomycin Mitomycin Bleomycin Antineoplastic Lecture 14 |
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Four mechanisms of action
Inhibition of topoisomerase II DNA binding and subsequent inhibition of DNA synthesis Bind cell membrane and alter fluidity and ion transport Generation of ROS ___________:broad spectrum against hematologic malignancies and solid tumors __________: acute myeloid leukemia |
Doxorubicin and Daunorubicin
Antineoplastic Lecture 14 |
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Binds DNA between adjacent guanine-cytosine base pairs inhibiting RNA synthesis
Pediatric tumors |
Dactinomycin
Antineoplastic Lecture 14 |
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Metabolized to an alkylating agent that cross-links DNA
Breast cancer (in combo with vincristine) |
Mitomycin
Antineoplastic Lecture 14 |
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Small peptide with a DNA-binding region at one end and an iron-binding domain at the other
Binds DNA and the iron component becomes oxidized leading to chromosomal abberations CCS drug; causes accumulation of cells in the G2 phase Broad spectrum; renal excretion; thus, dose reduction necessary in renal deficiency |
Bleomycin
(pulmonary toxicity) Antineoplastic Lecture 14 |
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Anti-steroid agent
Binds the estrogen receptor of estrogen-dependent tumors 10-fold lower affinity than estradiol; thus, endogenous estrogen must be ablated for optimal effect Breast cancer |
Tamoxifen
Antineoplastic Lecture 14 |
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Anti-steroid agent
Antiandrogen effects via binding to the androgen receptor Prostate cancer |
Flutamide
Antineoplastic Lecture 14 |
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hormone agonist
synthetic peptide analog of gonadotropin-releasing hormone activates the GnRH receptor leading to a transient release of FSH and LH followed by desensitization of the receptor. Results in reduced FSH and LH release, and decreased testosterone synthesis Androgen-receptor positive tumors (i.e. prostate cancer) |
Leuprolide
Antineoplastic Lecture 14 |
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Aromatase Inhibitor
Nonsteroidal inhibitor of aromatase Aromatase converts androgen to estrogen Metastatic breast cancer in post-menopausal women |
Anastrozole
Antineoplastic Lecture 14 |
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Aromatase Inhibitor
Steroidal hormone that irreversibly inhibits aromatase Lack of a cross-resistance between this drug and the nonsteroidal aromatase inhibitors |
Exemestane
Antineoplastic Lecture 14 |
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Inhibits oncoprotein tyrosine kinases
These mutated kinases promote abnormal proliferation and anti-apoptotic pathways Bcr-Abl (chronic myeloid leukemia) c-kit (gastrointestinal stromal tumors) |
Imatinib
Antineoplastic Lecture 14 |
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Bacterial derived enzyme
Hydrolyzes circulating L-asparginine to aspartic acid and ammonia Many tumor cells lack asparginine synthetase and require exogenous asparginine. Reduction in available asparginine prevents protein synthesis Normal cells express asparginine synthetase Childhood acute lymphocytic leukemia |
Asparginase
Antineoplastic Lecture 14 |
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Interfere with the cell cycle of activated lymphoid cells
Inhibit production of proinflammatory mediators such as leukotrienes, prostaglandins, histamine and bradykinin Inhibit leukocyte chemotaxis |
Prednisone
Immunomodulating Lecture 15 |
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Prevention of tissue rejection following transplant
Fat-soluble peptide antibiotic Binds to cyclophilin Cyclosporin-cyclophilin complex inhibits the cytoplasmic phosphatase, calcineurin. Calcineurin is essential for the activation of the T cell transcription factor NF-AT. NF-AT is involved in the synthesis of interleukins |
Cyclosporine
Decreases calcinuerin downregulating inflammatory response Immunomodulating Lecture 15 |
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Organ transplants
Macrolide antibiotic Mechanism of action is similar to cyclosporine However, _____________ complexes with a different immunophilin, FK-binding protein (FKBP). Similar inhibition of NF-AT. |
Tacrolimus
Immunomodulating Lecture 15 |
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Binds the immunophilin, FKBP
similar to tacrolimus But, does not inhibit calcineurin activity and subsequent IL-2 expression ___________-FKBP complex binds and inhibits mTOR mTOR is a kinase instrumental in cell-cycle progression from G1-S phase. Lymphocyte proliferation is inhibited |
Sirolimus
Immunomodulating Lecture 15 |
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Inhibit cell proliferation and activate NK cells
Melanoma, renal cell carcinoma and chronic myelogenous leukemia |
IFN-α and -β
Immunomodulating Lecture 15 |
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Antiviral actions used to treat hepatitis B and C
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IFN-α
Immunomodulating Lecture 15 |
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Used to treat multiple sclerosis
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IFN-β
Immunomodulating Lecture 15 |
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Derivative of mercaptopurine
An antimetabolite which inhibits de novo purine synthesis Purine synthesis is essential to nucleic acid production and subsequent lymphoid cell proliferation. The primary toxic effect of _____________ is myeloid suppression. |
azathioprine
Immunomodulating Lecture 15 |
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Rapidly hydrolyzed in the GI tract to mycophenolic acid
Reversible inhibitor of inosine monophosphate dehydrogenase Blocks de novo formation of guanosine phosphate Lymphocytes lack the salvage pathway for purine synthesis Similar to 6-MP, it deprives rapidly proliferating lymphocytes key components of nucleic acids Replacing azathioprine due to its increased safety and efficacy in prolonging graft survival |
Mycophenolate mofetil
Immunomodulating Lecture 15 |
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Hemolytic disease of the newborn
Administering the ___________ to Rh- mother within 72 h after delivery of Rh + newborn facilitates clearance of the newborn’s red blood cells (in mother’s circulation). Accomplished before the mother mounts a B-cell (antibody) response to the foreign Rh antigen. Hence, the mother will not have memory B-cells (to this antigen) to become activated in subsequent Rh + deliveries. |
anti-D Ab
Rh (D) Antibody Immunomodulating Lecture 15 |
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Recombinant human mAb that binds the epidermal growth factor receptor, HER-2/neu.
Down-regulates the receptor Breast cancer (HER-2/neu+) |
Trastuzumab
Immunomodulating Lecture 15 |
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Murine-human mAb that binds CD20 on normal and malignant B cells
Activates complement-mediated lysis, ADCC, and apoptosis. Follicular B cell non-Hodgkin’s lymphoma |
Rituximab
Immunomodulating Lecture 15 |
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Human mAb that binds CD25 (α subunit of the IL-2 Rc)
Functions as an IL-2 antagonist Suppresses lymphocyte activation Organ transplant In conjunction with glucocorticoids and cyclosporine __________________: mouse/human Ab with same characteristics, but higher affinity |
Daclizumab
Basiliximab Immunomodulating Lecture 15 |
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Binds the fusion protein of respiratory syncytial virus (RSV).
Prevents infection of cell Neonates at risk for RSV |
Palivizumab
Immunomodulating Lecture 15 |
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Drug of choice for treatment and prophylaxis of Malaria
Absorbed from GI tract Maximum plasma concentration in 3 h Excreted in urine, t1/2 = 1-2 mo |
Chloroquine
Antiparasitc Lecture 10 |
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Blood schizonticide
Concentrates in the food vacuole where it prevents polymerization of hemoglobin breakdown product, heme, into hemozoin. |
Chloroquine
Antiparasitic Lecture 10 |
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Contraindications of Chloroquine
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Psoriasis or porphyria
Retinal abnormalities Myopathy Kaolin (anti-diarrheal agent) and calcium/magnesium antacids reduce absorption Antiparasitic Lecture 10 |
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Unknown (similar to choloroquine?)
Blood schizonticide (against all 4 species) Gametocidal (P. vivax and P. ovale) Not active against liver stage parasites |
Quinidine
Antiparasitic Lecture 10 |
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Plasma levels are higher in infected individuals compared to controls (without increased toxicity) due to increased protein binding
18 hrs in those with severe malaria. 11 hrs in controls. |
Quinine and Quinidine
Quinidine has shorter half life due to decreased protein binding Antiparasitic Lecture 10 |
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Effective against P. falciparum
Typically given with doxycycline to reduce duration of use to 3 days maximum. |
Quinine
Antiparasitic Lecture 10 |
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What drug?
Cinchonism = term for the combination of these symptoms Caution in those with cardiac abnormalities (QT prolongation common) Contraindicated in those taking (or have recently taken) mefloquine Cardiac arrest and convulsions |
Quinine
Adverse effects: Tinnitus Headache Nausea Dizziness Flushing Visual disturbances Antiparasitic Lecture 10 |
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Effective against cholorquine-resistant strains of P. falciparum.
Oral only (severe local irritation parentally) Peak plasma concentration in 18 h t1/2= 20 days (weekly dosing for prophylaxis) mechanism of action: Unknown (similar to chloroquine?) Blood schizonticide |
Mefloquine
Antiparasitic Lecture 10 |
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Prophylaxis
Not indicated for severe infections, quinine preferred because of more rapid activity and resistance is less likely. |
Mefloquine
Antiparastic Lecture 10 |
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Drugs effective against Blood schizonticides:
Act on erythrocytic parasites |
chloroquine
quinine mefloquine pyrimethamine proguanil Antiparasitic Lecture 10 |
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Adverse effects of Mefloquine
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Nausea
Vomiting Dizziness Sleep and behavioral disturbances Contraindications Epilepsy Psychiatric disorders Cardiac conditions G6PD deficiency (susceptible to hemolysis) Should not be given with quinine or quinidine Antiparasitic Lecture 10 |
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Effective against liver forms and gametocidal
Oral Rapid absorption, peak in plasma by 1-2 h T1/2 = 3-8 h Rapidly metabolized, excreted in urine Mechanism of action is unknown |
Primaquine
Tissue schizonticides Eliminate developing or dormant liver forms Gametocides Kill sexual stages and prevent transmission to mosquitoes Antiparasitic Lecture 10 |
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Adverse effects of Drug:
Generally well tolerated Hemolysis in G6PD-deficient individuals Avoid in those with myelosupression Avoid in pregnancy (fetus is relatively deficient in G6PD and prone to hemolysis |
Primaquine
Antiparasitic Lecture 10 |
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Inhibition of plasmodial dihydrofolate reductase
Typically used in combination with chloroquine for chemoprophylaxis Active against the erythrocytic schizonts of all four malaria species |
Pyrimethamine & Proguanil
Pyrimethamine t1/2 = 3.5 days Proguanil t1/2 = 16 h Antiparasitic Lecture 10 |
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Prophylaxis for Malaria
Non-resistant and resistant regimen: |
Non-resistant: CQ
Resistance: Atovaquone + proguanil (Malarone), if pregnant: MQ Antiparasitic Lecture 10 |
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Treatment for Malaria
Non-resistant, resistant, severe infection regimen: |
CQ
Resistance: Atovaquone + proguanil OR quinidine/quinine + Doxy Severe: quinidine/quinine + Doxy OR Artesunate (alkylates heme in parasite…inhibits rbc schizogony) Antiparasitic Lecture 10 |
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Antibiotics that are effective against Malaria
Effective against erythrocytic schizonts of all 4 species |
(D.A.C.T)
Tetracycline Doxycycline Clindamycin Azithromycin Antiparasitic Lecture 10 |
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Drugs for Asymptomatic intestinal infection
E. histolytica: Amebiasis |
Luminal amebicides:
diloxanide furoate iodoquinol paromomycin Antiparasitic Lecture 11 |
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Drug for Amebic colitis and
Extraintestinal Infections |
metronidazole + luminal amebicide
Antiparasitic Lecture 11 |
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Nematode infections
Ascariasis, trichuriasis, hookworm, pinworm (P.A.T.H) A benzimidazole carbamate Active metabolite ______________ is generated in the liver Excreted in the urine Inhibits microtubule synthesis Results in decreased glucose uptake and ATP synthesis |
Albendazole
(albendazole sulfoxide) Teratogenic: Typical side effect is GI distress, but high dose can lead to bone marrow suppression (hematologic toxicity in those with hepatitis Antiparasitic Lecture 12 |
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Nematode infections
Ascariasis, trichuriasis, hookworm, pinworm A synthetic benzimidazole Inhibits microtubule synthesis Teratogenic |
Mebendazole
Antiparasitic Lecture 12 |
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Treatment of filiarasis, loiasis and tropical eosinophilia
Plasma t1/2 is 2-3 h if urine is acidic Plasma t1/2 is 10 h if urine is alkaline Microfilariae become more susceptible to host defenses Several mechanisms suggested: Vasoconstriction Enhanced neutrophil aggregation |
Diethylcarbamazine
Antiparasitic Lecture 12 |
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Strongyloidiasis (nematode-gut and skin) and onchocerciasis (nematode-river blindness)
A semisynthetic macrocyclic lactone derived from the soil actinomycete, Streptomyces avermitilis t1/2 is 16 h, excreted in feces Activates glutamate-gated chloride ion channels and enhances GABA-mediated transmission of signals in peripheral nerves of nematodes Cl- influx, hyperpolarization, paralysis |
Ivermectin
Antiparasitic Lecture 12 |
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Treatment may cause hypersensitivity response to dying microfilariae due to release of parasite antigens
fever, pruritis, arthralgia, headache |
Mazzotti reaction
Seen in Diethylcarbamazine and Ivermectin Corticosteroids are indicated Antiparasitic Lecture 12 |
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All Schistosome species (trematodes/flukes) and most other trematodes and cestodes
Synthetic isoquinolone pyrazine t1/2 < 2 h Increases calcium permeability leading to paralysis Dislodged and expelled |
Praziquantel
Antiparasitic Lecture 12 |
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Alternatives to Praziquantel:
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Oxamniquine for Schistosoma mansoni (but not other Schistoma species)
Niclosamide for cestode infections Antiparasitic Lecture 12 |
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Broad spectrum
Pinworm, ascaris and hookworm Not effective against trichuriasis or strongyloidiasis A tetrahydropyrimidine derivitive Poorly absorbed, active against luminal organisms Neuromuscular blocking agent: Causes acetylcholine release and inhibition of cholinesterase Paralysis and expulsion |
Pyrantel Pamoate
Antiparasitic Lecture 12 |
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Drug against the ectoparasites: pediculosis (lice) and scabies (mites).
Blocks sodium currents (slows the opening and closing of the sodium channels) in parasite neurons causing paralysis Resistance is an issue |
Permethrin
Treatment of choice Antiparasitic Lecture 12 |
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Used against ectoparasites (pediculosis)
Inhibits cholinesterase in most eukaryotes Cholinesterases catalyze the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation: Paralysis in the insect And in patient if overdosed |
Malathion
alternative to permethrin Antiparasitic Lecture 12 |
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DNA alkylating drug (cross-links)
Must be converted to active metabolite (4-hydroxycyclophosphamide) by P450 in the liver Further, nonenzymatic conversion to additional cytotoxic forms in non-hepatic tissue |
Cyclophoshamide
Adverse: (myelosuppresion and hemorrhagic cystitis) Antineoplastic Lecture 13 |
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DNA alkylating drug
Non-resistant with other alkylating agents Requires nonenzymatic conversion to active form Highly lipid-soluble and crosses the BBB spontaneously form active intermediates that cross-link DNA |
Carmustine
Brain tumors due to excellent CNS penetration Antineoplastic Lecture 13 |
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Inhibits synthesis of DNA, RNA and protein
presumably via alkylation azoprocarbazine and H2O2 generated during metabolism may cause DNA strand breaks |
Procarbazine
Antineoplastic Lecture 13 |
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An inorganic platinum complex
Cross-links DNA via interaction at the N7 guanine Aggressive i.v. hydration and/or diuretics are needed to reduce nephrotoxicity |
Cisplatin
Carboplatin: 2nd generation platinum compound with less renal toxicity (ovarian cancer) Oxaliplatin: 3rd generation agent; cells resistant to cisplatin and carboplatin are typically not resistant to this drug. (colon cancer) Antineoplastic Lecture 13 |
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Antimetabolite
Folic acid antagonist Binds to the catalytic site of dihydrofolate reductase (DHFR) Interferes with DNA, RNA and protein synthesis Polyglutamates of MTX are retained within tumor cells |
Mehtotrexate (MTX)
Drug resistance: Decreased drug transport Decreased polyglutamate formation Increased DHFR synthesis Reduced affinity of DHFR for MTX Antineoplastic Lecture 13 |
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Administration of a fully activated form of folic acid can prevent adverse reactions due to high doses of methotrexate
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Leucovorin (folinic acid)
(leucovorin rescue) |
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Antimetabolite
Purine antagonist: Metabolized by hypoxanthine guanine phosphoribosyl transferase (HGPRT) to the nucleotide form (6-thioinosinic acid) Inhibits several enzymes in purine nucleotide pathway Drug resistance Due to decreased HGPRT activity |
Mercaptopurine (6-MP)
Hyperuricemia associated with tumor cell lysis. Allopurinol (XO inhibitor) given to prevent nephrotoxicity and acute gout. Allopurinol + 6-MP requires a reduction in 6-MP dose (XO metabolizes/inactivates 6-MP) Antineoplastic Lecture 13 |
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Antimetabolite:
Purine antagonist: Resistant to adenosine deaminase, thus reaches high intracellular concentrations Incorporates into DNA leading to strand breaks |
Cladribine
(used primarily for hairy cell leukemia) Antineoplastic Lecture 13 |
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HSV, VZV and CMV
Does not require activation by viral or host kinases Blocks pyrophosphate-binding sites on viral DNA polymerase, thus prevents attachment of nucleoside precursors to DNA Adverse effects Renal toxicity and cardiac arrhythmias |
Foscarnet
Antiviral Lecture 9 |
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Synthetic derivatives of nucleosides
Converted to active triphosphate metabolite (nucleotide) by host kinases Compete for entry into viral DNA (rxn which is catalyzed by reverse transcriptase) Cause DNA chain termination Single-drug therapy increases risk of resistance administered in combination (see Table 43-3) |
Nucleoside Reverse Transcriptase Inhibitors (NTRI)
Purine :Didanosine Adverse effects: pancreatitis and peripheral neuropathy Pyrimidine Lamivudine: effective against Heptatis B Adverse effects: lactic acidosis and hepatic steatosis Stavudine Adverse effect: pancreatitis Zidovudine Adverse effects: bone marrow suppression, anemia and neutropenia Crosses BBB, Renal excretion Antiviral Lecture 9 |
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Do not require metabolic activation
Directly inhibit reverse transcriptase Single-drug therapy increases risk of resistance |
Nonnucleoside Reverse Transcriptase Inhibitors (NNTRI)
Efavirenz: teratogenic Nevirapine: Induces P450 and increases metabolism of other drugs Rash is the most common side effect Crosses BBB, renal and fecal excretion Antiviral Lecture 9 |
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Integrase Strand Inhibitor
Inhibits integrase Integrase is the enzyme that transfers viral DNA into host DNA Adverse effects Headache, GI distress |
Raltegravir (oral)
Antiviral Lecture 9 |
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Protease Inhibitors
Bind to the active site of HIV protease Results in the production of immature, noninfectious viral particles |
Atazanavir
Lopinavir Ritonavir Inhibits metabolism of other PI so given in combination to increase half-life of others Lopinavir + ritonavir is PI combo of choice Antiviral Lecture 9 |
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Fusion and Entry Inhibitors
Inhibits fusion of HIV with host cell gp120 directs virus to host cell gp41 facilitates viral entry ____________ binds gp41 CCR5 antagonist Prevents viral entry hepatotoxic |
Enfuvirtide (S.Q. inj)
Maraviroc (oral) Antiviral Lecture 9 |
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Inhibit neuraminidase in influenza A and B
Neuraminidase catalyzes release of virions from the surface of the infected cell Inactivates respiratory tract mucus (cleaves sialic acid residues) Reduce duration and severity of infection when given within 48 h of the onset of symptoms |
Oseltamivir and Zanamivir
can be used for prophylaxis Dose reduction NOT NECESSARY in renal impairment Antiviral Lecture 9 |
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Prevent uncoating of influenza A particles following cell entry
Inhibit the viral M2 proton selective ion channel This channel is needed for acidification and subsequent uncoating and nucleic acid transfer from the endosome into the host cell cytoplasm |
Amantadine and Rimantadine
Not effective against influenza B Amantadine crosses BBB; Rimantadine does not Doses should be reduced in renal insufficiency Antiviral Lecture 9 |
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Drug for RSV
A guanosine analog Inhibits synthesis of viral nucleic acid More specifically, it inhibits inosine monophosphate dehydrogenase; thereby, reducing guanosine triphosphate (purine) levels |
Ribavirin
Alone for RSV; combo with IFNalpha2b for hepatitis C Antiviral Lecture 9 |
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Ab directed at fusion protein on RSV
Used for prevention in high risk infants |
Palivizumab
Antiviral Lecture 9 |
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Drug for Hepatitis B and C
Produced through DNA recombinant technologies ______ is typically produced by host cell in response to viral infection Signals multiple immune pathways Induction of antiviral proteins in the host cells |
Interferon α
Pegylated interferon alpha-2b has extended half-life (40 h) Antiviral Lecture 9 |
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alternate choice against CMV
Adverse effects: Nephrotoxicity, neutropenia and metabolic acidosis activated independent of viral enzymes |
Cidofovir
contraindicated in renal insufficiency Antiviral Lecture 9 |
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is phosphorylated by a viral kinase in CMV infected cells
Competitively inhibits viral DNA polymerase 100X more active against CMV than ACV Adverse effects: Leukopenia, thrombocytopenia |
Ganciclovir
Antiviral Lecture 9 |
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Treatment of Chagas’ disease (American trypanosomiasis); Gi distress
Nitroaromatic compound that generates oxygen radicals which are toxic to the parasite (lacks catalase) |
nifurtimox
Antiparasitic Lecture 11 |
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treat malaria
A folate reductase inhibitor also used to treat toxoplasmosis |
pyrimethamine
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Disseminated strongyloides
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Thiabendazole
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Multidrug resistance
Resistant to a variety of drugs following exposure to a single agent i.e. increased expression of MDR1 which codes for P-glycoprotein (ATP-dependent drug efflux) |
Can reverse drug resistance experimentally with verapamil, a Ca++-channel blocker that inhibits the transporter
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is rather unique in that it does not cause bone marrow suppression (Vinblastine and vinorelbine do)
Neuropathies sensory: parathesias, hearing loss motor: muscle weakness and obtunded reflexes |
Vincristine
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Cisplatin- renal toxicity
Bleomycin- pulmonary toxicity Cyclophosphamide- toxic to bone marrow, gut mucosa and hair follicles Vincristine- peripheral nerve damage |
Doxorubicin
irreversible cardiomyopathy as a result of toxicity? |
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Renal toxicity: cisplatin (Mannitol is given along to reduce renal toxicity, sodium thiosulfate)
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Aggressive i.v. hydration and/or diuretics are needed to reduce nephrotoxicity
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