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Definitions

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  1. Definitions Physiology- science which treats the functions of the living organism & its parts Pharmacology- science of the effect of drugs in all aspects a- A/D/M/E b- effects & mechanism of action c- toxicity & drug interactions Pharmacognacy - (neutraceuticals/herbs) Pharmacy- science of preparation, compounding & dispensing of drugs Therapeutics- application of pharmacology to the therapy of disease

  2. agonist (A) ↔ (A) (receptor) ↔ response Agonist: stimulus (ex. specific ligand for receptor mediated response) experimental value: reveals potential for response. however, endogenous agonist may not exist. Antagonist: (ex. specific inhibitor of receptor mediated response) experimental value: response indicates blockade of endogenous functional agonist Placebo: inert medication essential component of experimental analysis 30% response to placebo in some situations

  3. please limit your answer to 3 single sided pages

  4. think: Specificity

  5. “tissue Space” Vracko: Am J Pathology 77;313,1974 think: GIliverbloodGU(prostateprostate fluidbacteria)

  6. Absorption: - generally viewed as absorption from site of administration into blood

  7. Absorption: think: Specificity

  8. routes of drug administration: key factors in absorption into vascular system - perfusion of site - chemistry of drug preparation - disintegration/dissolution for solid - dissolution for suspension - solutions - diffusion: - lipid/water partition - size/molecular weight - transport systems “enteral vs. parenteral” “via intestine vs. other”

  9. Oral route of administration Advantages: - convenient, human acceptance (other species?) - relatively safe Issues: - bioavailability(fraction of dose appearing in blood)* - inert with respect to GI acid, enzymes & food - lipid/water partition & size - resistance to hepatic metabolism (i.e. minimal “first pass effect”) - super-infection in GI tract with antibiotics

  10. ideal bioavailability & mechanisms ??

  11. Oral route of administration Advantages: - convenient, human acceptance (other species?) - relatively safe Issues: - bioavailability (fraction of dose appearing in blood) - inert with respect to GI acid, enzymes & food - lipid/water partition & size* - resistance to hepatic metabolism (i.e. minimal “first pass effect”) - super-infection in GI tract with antibiotics

  12. drug penetration through cell membranes: - aqueous channels <100 mw - most important process: passive diffusion due to lipid/water partition & size - methodology for partition coefficient

  13. impact of size & partition coefficient (olive oil/water) on permeability

  14. Oral route of administration Advantages: - convenient, human acceptance (other species?) - relatively safe Issues: - bioavailability (fraction of dose appearing in blood) - inert with respect to GI acid, enzymes & food - lipid/water partition & size - resistance to hepatic metabolism (i.e. minimal “first pass effect”)* - super-infection in GI tract with antibiotics

  15. “first pass” effect, hepatic metabolism & bioavailability:

  16. Oral route of administration Advantages: - convenient, human acceptance (other species?) - relatively safe Issues: - bioavailability (fraction of dose appearing in blood) - inert with respect to GI acid, enzymes & food - lipid/water partition & size - resistance to hepatic metabolism (i.e. minimal “first pass effect”) - super-infection in GI tract with antibiotics*

  17. relevant to super-infection in GI tract if unabsorbed active drug

  18. normal GI flora: relevance to potential superinfection

  19. Distribution: think: Specificity

  20. Drug Distribution Generally implies initial distribution from blood to tissue space (fluids & cells) & epithelium - protein binding in plasma - organ perfusion - specialized capillary barriers - lipid/water partition & size for diffusion - transport systems - ion trapping in cellular/extracellular fluid* - protein binding in cells (host or bacteria)*

  21. drug distribution ideal ? total body water? (think specificity)

  22. “tissue Space” Vracko: Am J Pathology 77;313,1974 think: GIliverbloodGU(prostateprostate fluidbacteria)

  23. Metabolism & Excretion think: Specificity

  24. Understanding constant half-life with first order kinetics:

  25. - oral dosing @ half-life intervals - steady state (peak/trough) @ 4-5 half-lives - note: rate of decline should be slower at lower blood levels ideal?

  26. ideal plasma kinetics? first order: - constant half-life - predictable dosing regimens (therapeutic vs. toxic range) t1/2 = practicality (? hours)

  27. - oral dosing @ half-life intervals - steady state (peak/trough) @ 4-5 half-lives - note: rate of decline should be slower at lower blood levels Consider a Loading Dose

  28. good & bad of hepatic metabolism

  29. - hepatic portal vein from intestine - portal venous & arterial blood perfuse into capillary spaces (sinusoids) between cells (hepatocytes) - hepatocytes form bile & water soluble metabolites primarily for renal excretion - selective active secretion into bile; little diffusion - central vein to vena cava

  30. Hepatic metabolism* to increase water solubility & enhance excretion by kidney/urine & liver/bile/intestine Phase I (oxidation/reduction) in smooth ER - oxidation via cytochrome P450 enzymes - other Phase II (conjugation) in cytosol with: - sulfate - glucose - acetate - glutathione - amino acids * primarily in liver (smooth ER & cytosol)

  31. Cytochrome P450: - hydroxylations - hydrophilic - isozymes

  32. Hepatic endoplasmic reticulum: - smooth ER - site for P450 oxidation - surface area & enzymatic activity may double in 2-3 days in response to drug substrate

  33. Metabolism to Enhance Excretion:

  34. superinfection with GI antibiotics: issue of GI-hepatic recycling

  35. GI-hepatic recycling:

  36. isoniazid (INH) toxicity via metabolism

  37. hepatic metabolism & biliary excretion: ideal? (inert as a substrate) avoid issues of : - bioavailability (first-pass effect) - plasma t1/2 variations (genetics, age, other drugs) - toxic metabolites - secretion of antibiotic into intestine

  38. Renal Excretion: ideal? - GFR

  39. Theoretical mechanisms for selective concentration at site of action: ion trapping; bio-activation; receptor binding

  40. Pharmacokinetics: - tissue fate (effect of target on agonist/antagonist) - ion trapping - bioactivation - receptor specificity (tissue & chemical)

  41. Ion trapping plasma pH = 7.4 infected prostate fluid pH = 8.2 weak acid antibiotic - equal plasma-prostate fluid concentrations of non-ionized drug - greater ionization of drug in basic fluid than plasma - greater total drug in basic fluid then plasma

  42. ion trapping & differential total drug concentration based on pH difference relevant if ionized & non-ionized are each biologically active weak acid drug concentrated in basic (pH 8.2) fluid of infected prostate relative to plasma (pH 7.4) - due to greater ionization (A-) at basic pH - ionized form (A-) “trapped”

  43. pH = pKa + log [A-]/[HA] calculating total drug concentrations: - know pH, pKa & total plasma concentration - calculate [A-]/[HA] at plasma pH - calculate [HA] at plasma pH, assume same at prostate fluid pH - calculate [A-]/[HA] at prostate fluid pH - use [HA] to determine [A-] at prostate fluid pH & sum

  44. ideal fate in prostate fluid?

  45. specificity & concept of bioactivation • theoretical application to specificity of antibacterial action ? - site of bioactivation - pharmacodynamic action of substrate vs. product - kinetics of product note: precedent for testosterone action

  46. E. Jensen et al.: Fate of s.c. 3H-estadiol in the female rat - significance of the organ-specific estrogen receptor (accumulation/retention in estrogen-dependent organs) - significance of competitive antagonism by an anti-estrogen (PD) predict much greater accumulation/retention of PD vs. estradiol think: potential analogy to bacteria & antibiotic

  47. Estrogen(E) + Receptor(R)  ER  response  anti-estrogen receptors: general concepts - tissue specificity - chemical specificity & high affinity - requisite interaction with ligand for response think: antibiotic interaction with bacterial receptor (blocks interaction of endogenous bacterial ligand with its receptor)

  48. administration of 3 different drugs acting on same receptor - potency @ ED50 - intrinsic activity @ maximum - drug “c” is a partial agonist

  49. Affinity vs. Efficacy Complex  Drug + Receptor Response affinity efficacy