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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)
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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
“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
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
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
- 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
superinfection with GI antibiotics: issue of GI-hepatic recycling
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
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 Complex Drug + Receptor Response affinity efficacy