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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 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 Test Question: (resource text- Lippincott; Chapters 1 & 2) Discuss the relevant pharmacokinetic and pharmacodynamic characteristics of a theoretically ideal antagonist to be applied in the following specific situation. The goal is to employ the antagonist (antibiotic) to cure a bacterial infection in the prostate gland fluid, and that the pH of infected prostate fluid is basic relative to plasma. Assume that the mechanism of antagonist action will be to prevent a requisite endogenous cell-cycle specific ligand-receptor interaction in the bacterial cell wall. The antagonist will be administered to an individual suffering from vascular pathology associated with long-standing poorly controlled diabetes mellitus. please limit your answer to 3 single sided pages think: Specificity “tissue Space” Vracko: Am J Pathology 77;313,1974 think: GIliverbloodGU(prostateprostate fluidbacteria) Absorption: - generally viewed as absorption from site of administration into blood Absorption: think: Specificity 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” 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 ideal bioavailability & mechanisms ?? 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 drug penetration through cell membranes: - aqueous channels <100 mw - most important process: passive diffusion due to lipid/water partition & size - methodology for partition coefficient impact of size & partition coefficient (olive oil/water) on permeability 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 “first pass” effect, hepatic metabolism & bioavailability: 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* relevant to super-infection in GI tract if unabsorbed active drug normal GI flora: relevance to potential superinfection Distribution: think: Specificity 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)* drug distribution ideal ? total body water? (think specificity) “tissue Space” Vracko: Am J Pathology 77;313,1974 think: GIliverbloodGU(prostateprostate fluidbacteria) Metabolism & Excretion think: Specificity Understanding constant half-life with first order kinetics: - 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? ideal plasma kinetics? first order: - constant half-life - predictable dosing regimens (therapeutic vs. toxic range) t1/2 = practicality (? hours) - 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 good & bad of hepatic metabolism - 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 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) Cytochrome P450: - hydroxylations - hydrophilic - isozymes Hepatic endoplasmic reticulum: - smooth ER - site for P450 oxidation - surface area & enzymatic activity may double in 2-3 days in response to drug substrate Metabolism to Enhance Excretion: superinfection with GI antibiotics: issue of GI-hepatic recycling GI-hepatic recycling: Bile Liver: conjugated water soluble steroids Plasma: E 2and P Intestinal lumen Bacterial deconjugation and reabsorption Oral administration Fecal excretion isoniazid (INH) toxicity via metabolism 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 Renal Excretion: ideal? - GFR Theoretical mechanisms for selective concentration at site of action: ion trapping; bio-activation; receptor binding Pharmacokinetics: - tissue fate (effect of target on agonist/antagonist) - ion trapping - bioactivation - receptor specificity (tissue & chemical) 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 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” 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 ideal fate in prostate fluid? 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 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 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) administration of 3 different drugs acting on same receptor - potency @ ED50 - intrinsic activity @ maximum - drug “c” is a partial agonist Affinity vs. Efficacy Drug + Receptor Complex Response affinity efficacy Affinity vs. Efficacy Drug + Receptor Complex Response affinity efficacy Insulin resistance in Type II diabetes: - reduced receptor concentration with obesity Consider the changes in the dose response curve with these abnormalities Understanding the dose response curve: - affinity - efficacy Affinity vs. Efficacy Drug + Receptor Complex affinity Agonist- Antagonist (ideal?) - Response efficacy Competitive antagonism: effect of agonist (a) alone & in the presence of increasing doses (b-d) of an antagonist antagonism: a) doses of agonist alone b-d) agonist dose response the presence of increasing concentrations of irreversible, competitive antagonist (note same ED50) advantages of irreversible antagonist: (t1/2 & maximum @ saturation) plasma concentrations with oral dosing @ plasma half-life - consider fate in bacteria from ion trapping of antibiotic in prostate fluid & longer t1/2 in bacteria due to receptor binding ideal? bacterial receptor saturation due to selective accumulation Vascular Pathology (angiopathy) in Diabetes macroangiopathy: not diabetic-specific, but accelerated rate and greater incidence - atherosclerosis of coronary & peripheral arteries - occlusive lesion due to abnormal smooth muscle proliferation & migration toward lumen; fatty deposits & calcification microangiopathy: specific to uncontrolled diabetes (hyperglycemia) - impairment of microcirculation (arterioles & capillaries) - notable in skin (ulcers), retina (blindness), glomerulus of kidney (renal failure) and peripheral nerves (sensory systems & organs innervated by voluntary/motor & involuntary/autonomic neurons) - initially non-occlusive, subsequently occlusive → ↓ perfusion - ↑ intra-capillary pressure (endothelial damage, ↓NO, inability to dilate/autoregulate on efferent side of capillary beds)* -↑ permeability/leakage of plasma proteins/growth factors - ↑ capillary basement membrane thickening * supportive evidence: less pathology in capillaries distal to an arterial stenosis (reduced perfusion pressure to downstream capillaries) Consider the impact of atherosclerosis & capillary basement membrane thickening of diabetes on: Dosing regimen (?) Fick’s Law of Diffusion: rate = (concentration gradient) (permeability) (surface area) __________________________________________ (molecular weight) (thickness) Choice of a cell-cycle specific or cell-cycle-independent antagonist (?) Antagonist (antibiotic): cell-cycle specific: constant drug (antagonist) exposure to maximize chance for interaction during susceptible phase cell-cycle independent: potential for maximal lethal effect with short-term occupancy Ideal? Cell-cycle specific of independent? Ideal plasma kinetics for cell-cycle dependent? Method of administration? Loading dose? pharmacodynamics: - effect of agonist/antagonist on target tissue - think: specificity for desired effect & safety i.e. bacterial cell wall perturbation via interaction with bacteria-specific receptormediated process Therapeutic Index toxic or lethal dose 50 / therapeutic or effective dose 50 LD50 / ED50 Therapeutic Index: theoretical dose-response curves for ideal drug? ED50 vs TD50 or LD50 Consider the theoretical adjustments required in the doseresponse curve with diabetic-induced impaired perfusion/drug diffusion. Advantages of 24 hour constant release transdermal (patch) route relative to oral (4 doses/day) • Bioavailability ? • Superinfection ? • Need to increase dose with impaired perfusion? • Cell-cycle dependent action?