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PHARMACOLOGY

PHARMACOLOGY. IMEC INC. Quick Learning Technique. Routes of Administration. Enteral Oral Rectal Sublingual Parental IV IM Sub-Cutaneous Topical Transdermal Other Inhalation-- Albuterol Intrathecal- Apho B for Meningitis Intranasal- desmopresson. Absorbtion of Drugs.

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PHARMACOLOGY

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  1. PHARMACOLOGY IMEC INC. Quick Learning Technique

  2. Routes of Administration • Enteral • Oral • Rectal • Sublingual • Parental • IV • IM • Sub-Cutaneous • Topical • Transdermal • Other • Inhalation-- Albuterol • Intrathecal- Apho B for Meningitis • Intranasal- desmopresson

  3. Absorbtion of Drugs • Passive Diffusion • From a higher concentration to a lower concentration • Active transport • Is a process that may use a carrier protein or a simple H+ ion gradient to move a drug across a structural membrane

  4. Physical Factors • Blood flow to absorption site • Total surface area for absorbtion • Contact time at the absorption site

  5. Bioavailabilty • This is the fraction or percentage of a drug that reaches circulation in an unchanged form • INFLUENCED BY • First–pass Hepatic Metabolism • Solubility of the drug • Chemical instability • Nature of the drug formulation

  6. Volume of distribution • When accessing VD, we must take into account all WATER COMPARTMENTS • Total Body Water = 42 Liters • Intracellular volume = 28 Liters • Extracellular volume = 14 Liters • Interstitial Volume = 10 Liters • Plasma Volume = 4 Liters

  7. Binding of Drugs to Plasma Proteins • Binding of drugs to Albumin • Many HydroPHILIC drugs do not bind to albumin • NOTE: many Hydrophobic drugs are by design done this way for absorption • Competition for binding • Class I – Highly bound to Albumin • Class II – Drug given that greatly exceed binding sites to Albumin

  8. Volume of Distribution

  9. Binding to Plasma Protiens • Drug binding to plasma proteins (specifically Albumin) may be of great importance • CLASS I DRUGS: are those drugs that are administered in a lesser amount than binding sites so displacement occurs • CLASS II DRUGS: are those drugs that are given in a greater than binding sites scenerio • The importance of displacement comes into play with drugs such as Tolbutamide in which it is highly bound but only a small portion is free in plasma

  10. P450 Metabolism

  11. Isoenzyme: CYP2C9/10

  12. Isoenzyme: CYP2D6

  13. Isoenzyme: CYP3A 4/5

  14. Renal Clearance • Cx= Ux V/Px • This equals volume of plasma from which the substance is cleared completely/ per unit time

  15. First Order Kinetics • Michaelis-Menten kinetics V= rate of metabolism = V max ( C ) Km Rate of Drug Metabolism is directly proportional to concentration of the free drug

  16. Zero Order Kinetics V = rate of metabolism = V max ( C ) ( C ) The enzyme is saturated , so metabolism is constant ASPIRIN, ETHANOL, PHENYTOIN

  17. Steady State Drug Levels Css = Ro/KeVd Where as: Ro = Rate of infusion Ke = 1st Order Elimination Vd = Volume of Distibution

  18. 99 % • Therefore if we follow a drug washout with a continual steady state we reach 99% of the Css in 3.3 T ½

  19. Dose Response Curse • Is a sigmoidal curve in which EC50 comes into play • The effect of and magnitude of binding is simply Receptors Bound Total Receptors

  20. Therapeutic Index • Therapeutic Index = TD50/ED50 • TD 50 = toxic effect in 50% of People • ED50 = Effective dose in 50% of People Warfarin has a small therapeutic index Penicillin has a large therapeutic index

  21. Major Receptors and Ligands • Ligand-gated Channels • NICOTINIC CHOLINERGIC • G-Protein Coupled Receptors • ADRENERGICS • Enzyme Linked Receptors • INSULIN • Intracellular Receptors • STEROIDS

  22. ANTICANCER DRUGS

  23. Therapeutic of Log Kill • This means that when diagnosed at 109 cells, if 99% were killed it would still leave 104 cells. • 2nd is tumor cells are not readily eliminated • Note—Leukemic cells and other tumor cells find sanctuary in tissue that chemotherapy drugs cannot enter

  24. Principles • Eradication of neo-plastic cells • Cell burden is reduced by surgery and/or radiation • Chemotherapy can help reduce size as is with surgery, • Radiation is used to reduce micro-metastasis • Cells become increasingly susceptible during growth phase • Divided into PALLATIVE and CURATIVE CHEMOTHERAPY

  25. Acute Lymphocytic Leukemia • MOPP therapy • Methchloramine • Oncovirin • Prednisone • Procarbazine • POMP therapy • Prednisone • Oncovirin (Vincristine) • Methotrexate • Purinethol (Mercaptopurine)

  26. Target Site for Chemotherapy • Cause a lethal cyto-toxic lesion that can arrest the tumors progression • THE ATTACK IS DIRECTED AGAINST THE METABOLIC SITES ESSENTIAL TO CELL REPLICATION—EXAMPLE BEING THE AVAILABILTY OF PURINE AN PYRIMIDINE PRECURSORS FOR DNA AND RNA SYNTHESIS

  27. Common side effect • Most CHEMO drugs have a low therapeutic index • Severe vomiting—controlled by cannabinoids • Stomatitis-- • Alopecia • Myelo suppression • Cardiotoxicity--Doxirubicin • Pulomonary Fibrosis—-Bleomycin • Megaloblastic Anemia– Methothrexate Countered by Leukovorin TREATMENT INDUCED NEOPLASM ARE A SPECIAL PROBLEM AFTER AKLYLATING AGENTS

  28. Cell Cycle • S-Phase----DNA is replicated • G2-Phase----Synthesis of cellular components required for mitosis • M-Phase—Mitotic division • G0-Phase----Resting Phase • G1-Phase----Enzyme are synthesis for DNA synthesis

  29. CELL CYCLE

  30. ANTI-CANCER DRUGS • ANTI-METABOLITES • Methotrexate • 6-Mercaptopurine • 6-Thioguanine • 5-Flourouricil • Cytarabine

  31. METHOTREXATE • Structurally related to Folic acid and is and antagonist of the vitamin • Folateis key in replicating cells for biosynthesis of methionine; the purine nucleotides adenine and guanine, and pyrimidine nucleotides dTMP • It is no wonder Methotrexate adversely effects cell survival

  32. METHOTREXATE • Undergoes reduction to (FH4) by intracellular NADPH dependant di-hydrofolate • AT HIGH CONCENTRATION it enters the cell by diffusion • Methotrexate has a strong affinity for Dihydrofolate reductase, and its inhibition can only be reversed by a thousand fold excess of natural substrate, dyhydrofolate (FH2) or Leukovorin • This leads to decreased biosynthesis of thymidylic acid, and methionine, purines (A & G) and leads to depressed RNA and DNA synthesis and cell death

  33. Methotrexate resistance • Resistance is characteristic of non-proliferating cells-The following mechanisms have been detected • Increased enzyme—Amplification of the gene that codes for dihydrofolate reductase (therefore higher doses are required) • Modified enzyme----enzyme affinity for methotrexate is diminished • Less drug pumped into cell—apparent changes in carrier mediated transport

  34. Methotrexate—Therapeutic applications • A-L-L-(Acute Lymphocytic Anemia) • Chorio-carcinoma • Burkitt’s lymphoma • Breast Cancer • Head and Neck Carcinoma, • Severe Neoplastic diseases • Severe Psoriasis, and Rheumatoid Arthritis • HIGH DOSES causes Osteogenic Carcinoma and be followed by Leukovorin to rescue bone marrow

  35. Methotrexate Administration • IM • IV • Orally-well absorbed • Intra-thecally- because it does not cross blood brain barrier • FATE-they are converted to POLYGLUTAMATES-this is important**** because they remain in the cell even when there is an absence of extra-cellular drug

  36. Methotrexate-adverse effects • Most frequent arestomatitis, myelosuppression, erythema, alopecia, nausea, vomiting and diarrhea • DOSES of LEUCOVORIN must be kept minimal to avoid interference with the anti-tumor action of the methotrexate • OTHER Adverse Effects • Renal Complications • Pulmonary Toxicity- especially in children • Hepatic Fibrosis • Neurological toxicities-especially associated with intra-thecal administration

  37. 6-Mercaptopurine • 6-MP is a Thiol analog of the Purine-Hypoxanthine • Of the purines analogs tested, only 6-MP and Thioguanine (6-TG) have proved beneficial in treating neoplastic disease • It works in on the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) pathway and must penetrate the cell and be converted to a corresponding nucleotide {6MP-ribose phospshate, also known as Thio-IMP} • 6MP-RP, can inhibit the first step in de novo synthesis of AMP, and XMP (xanthinylic acid) from IMP(inosinic acid) • Resistance is associated to Lesch-Nyhan Syndrome,where patients lack HGPRT, or in increased metabolism of the drug to thio-uric acid, which is excreted in the urine • Must reduce dose of 6-MP when administering Allupurinol, because it is a xanthine-oxidase inhibitor.

  38. 6-Mercaptopurine- • IT IS USED WITH AZATHIOPRINE FOR THE TX OF CHROHNS DISEASE • Excretion of parent drug and metabolytes is by the Kidney • Adverse Effects • Nausea, vomiting, diarrhea • Mild myelotoxicity • THOMBOCYTOPENIA

  39. 6-Thioguanine • This purine analog is primary to Acute Myelocytic Leukemia (AML) • Used in combination with Daunorubicin and Cytarabine • Like 6-MP is must be converted to a nucleotide form, which then inhibits bio-synthesis of the purine ring and the phosphorylation of GMP to GDP • Unlike 6-MP, Allopurinoldoes not potentiate 6-TG action • Other toxicities are the same

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