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Chemotherapeutic agents  pharmacology /certified fixed orthodontic courses by Indian dental academy
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Chemotherapeutic agents pharmacology /certified fixed orthodontic courses by Indian dental academy

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The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.

Indian dental academy provides dental crown & Bridge,rotary endodontics,fixed orthodontics,
Dental implants courses.for details pls visit www.indiandentalacademy.com ,or call
0091-9248678078

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    Chemotherapeutic agents  pharmacology /certified fixed orthodontic courses by Indian dental academy Chemotherapeutic agents pharmacology /certified fixed orthodontic courses by Indian dental academy Presentation Transcript

    • Clinical Pharmacology of Anti-cancer Chemotherapeutic Agents www.indiandentalacademy.com
    • INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com www.indiandentalacademy.com
    • Therapeutic Principles Diagnosis & Drug Selection I N P U T Absorption Distribution Metabolism Elimination Pharmacokinetics www.indiandentalacademy.com Toxicity &/OR Efficacy Pharmacodynamics
    • Therapeutic Endpoints Efficacy without toxicity   Human medicine: palliative therapy only Veterinary medicine: palliative therapy probably? Efficacy AND toxicity  Human and veterinary medicine: aggressive, curative therapy Toxicity without efficacy  Tentative administration You may affect bone marrow ONLY rather than bone marrow AND tumor  Drug Resistance Reduces tumor response, bone marrow still sensitive Neither toxicity nor efficacy www.indiandentalacademy.com
    • Dosing v. P’kinetic End Points EITHER  mg/kg (/M2) X interval X duration OR   Peak drug concentration, AUC (Concentration X Time), Time above target concentration, Cumulative dose, Cumulative AUC WHICH one depends on drug. Base choice on clinical trials! www.indiandentalacademy.com
    • Dose vs AUC Target Nagahiro Saijo, Chemotherapy: the more the better? Overview, Cancer Chemother Pharmacol (1997) 40 (Suppl): S100– S106 These are the SAME PATIENTS. What separates them on the Graph labeled “A” ? www.indiandentalacademy.com
    • Concentration Peak Concentration 90 80 70 60 50 40 30 20 10 0 0 6 12 Time www.indiandentalacademy.com 18 24
    • Concentration AUC 90 80 70 60 50 40 30 20 10 0 0 6 12 Time www.indiandentalacademy.com 18 24
    • Concentration Intensity / Time Above 90 80 70 60 50 40 30 20 10 0 0 6 12 Time www.indiandentalacademy.com 18 24
    • Absorption Oral   Variable concentration X time profile Typical factors affecting oral absorption Presence of food Concurrent disease  Likely produces a different efficacy / toxicity profile Etopside oral vs. IV www.indiandentalacademy.com
    • Absorption Intramuscular  VERY few anti-cancer drugs can be given this way Cytotoxicity associated with tissue damage at injection site  Used by this route: Hormones (glucocorticoids, leuprolide) L-asparaginase (lower toxicity than IV) www.indiandentalacademy.com
    • Activation Hepatic  e.g. cyclophosphamide, doxorubicin, daunorubicin, others Intracellular phosphorylation  e.g fludarabine Tissue metabolism with free radical production  e.g. doxorubicin www.indiandentalacademy.com
    • Distribution Most target intra-cellular sites  Combination solubility (water:lipid) Small number penetrate blood-brain barrier Protein binding   High protein binding increases interaction potential May or may not limit tissue “penetration” Consider both plasma and tissue proteins www.indiandentalacademy.com
    • Distribution Active Metabolite distribution  Ifosfamide metabolites cross blood-brain barrier Consider local factors   Tumor vascularity P-glycoprotein cell membrane pump (drug efflux pump – something like antibiotic resistance by bacteria) www.indiandentalacademy.com
    • Elimination Hepatic Metabolism  P450 metabolism Catabolism (especially anti-metabolites)  Normal degradation pathways for amino acids etc. to carbon dioxide and water Hydrolysis Renal elimination unchanged www.indiandentalacademy.com
    • Dosing Chemotherapeutics What are we really doing in veterinary patients?     Dosing for palliation in most cases Critiquing dose regimes with more emphasis on toxicity than efficacy Specifics of the approach to dosing become more important as the therapy becomes more aggressive. We should formulate clear and specific therapeutic goals www.indiandentalacademy.com
    • Dosing Chemotherapeutics Body surface area mg/kg Total dose Dose to pharmacokinetic target   AUC, Peak, etc. Therapeutic monitoring laboratory capability required. www.indiandentalacademy.com
    • Dosing Chemotherapeutics Traditional dosing on Body Surface Area   Correlates with metabolic rate, volume of distribution Correlation with tissue concentrations? Efficacy and toxicity   Extrapolated (with enthusiasm from human dose recommendations) Probably correct for SOME but not ALL protocols www.indiandentalacademy.com
    • Body Surface Area Dogs 10 × ( bw in grams ) 10,000 Cats 10.1× ( bw in grams ) 10,000 2/3 2/3 These are approximations.  Man/Woman – 5 formulas, all include height, some gender, some age… www.indiandentalacademy.com
    • Body Surface Area BSA Nomogram 1.8 Meters Squared 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 0 10 20 30 40 Weight (kg) www.indiandentalacademy.com 50 60 70
    • Body Surface Area Arrington et al. AJVR 55(11) 1587-92  30 mg/M2 Adriamycin Dogs <10 kg received more than 1.5 mg/kg  Increased incidence of toxicity Dogs >10 kg received less than 1.0 mg/kg   Study did not evaluate differential efficacy Potential for breed-related differences in toxicity. www.indiandentalacademy.com
    • Oral Chemotherapy Widely used in Veterinary Chemotherapy    Concerns for patient “discomfort” Infrequent use of “indwelling” lines Palliation is primary goal High peak concentrations or large AUC are not a concern Dosing control is not as critical www.indiandentalacademy.com
    • Oral Chemotherapy Alkylating Agents   melphalon (Alkeran) cyclophosphamide (Cytoxan) Excellent absorption characteristics Most widely used (therefore most experience) Oncology, immunology uses   busolfan (Myleran) procarbazine (Mutalane) www.indiandentalacademy.com
    • Oral Chemotherapy Antimetabolites  capecitabine (Xeloda) Oral pro-drug version of fluorouracil  Mercaptopurine (Purinethiol) Variable and incomplete absorption www.indiandentalacademy.com
    • Oral Chemotherapy Hormonal Oncologics  Tamoxifen Mitosis Inhibitors  Etopside (VP16, Vepised) Variable dose-dependent oral bioavailability Others  Hydroxurea Well aborbed www.indiandentalacademy.com
    • IM Chemotherapy aspariginase (Elspar)  IM is thought to produce fewer allergic reactions Not confirmed with large number of cases leuprolide (Lupron)  Short acting GnRH Agonist www.indiandentalacademy.com
    • Intravenous Chemotherapy Why?    Drugs, and sometimes vehicles, too irritating (cytotoxic) by other routes Produce high peak concentration OPPORTUNITY to exert extreme control over plasma concentrations. www.indiandentalacademy.com
    • Gemcitabine Controlled intravenous infusion   Metabolism to active compounds is saturable Rates of administration exceeding conversion capability waste drug e.g., Un-converted gemcitabine is eliminated in the urine.  Rates of administration exceeding conversion produce less activity per milligram of drug. 10 mg given slowly -> ‘10 mg of activity’ 10 mg given rapidly -> ‘8 mg of activity’ www.indiandentalacademy.com
    • Dose Form Manipulation Liposomes  Drug contained in lipid spheres Essentially artificial liposomal membranes Actively acquired by some cell lines  Improved therapeutic index Reduced cardiotoxicity Enhanced activity (although certain other toxicities may be enhanced) www.indiandentalacademy.com
    • Dose Form Manipulation Chemoembolization  Arterial infusion of methylcellulose microcapsules filled with chemotherapeutics Implantable polymers  Surgical implantation of biodegradable polymers containing chemotherapeutics www.indiandentalacademy.com
    • www.indiandentalacademy.com Leader in continuing dental education www.indiandentalacademy.com