1 / 64

Definitions

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)

vail
Télécharger la présentation

Definitions

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related