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• Pharmacokinetics


  The science that studies the relation of physicochemical properties of drug, dosage form, & route of administration on rate and extent of drug absorption

  
• Pharmacokinetics


  The study of the kinetics of absorption, distribution, metabolism, and excretion (ADME) of drugs and their pharmacologic, therapeutic, or toxic effects in animals and man
• Drugs given IV go directly into blood
• Elimination


  Refers to both metabolism and excretion
• Drug in blood


  Exists in equilibrium with drug in tissues
• Concentration of the drug in blood can be different (greater or lesser) than the concentration of the drug in tissues due to the physicochemical properties of the drug
• Rate of transfer of a drug


  Proportional to concentration of the drug in the compartment from which it exits
• Metabolites of a drug substance

  • Pharmacologically active
  • Inactive
  • Both active and inactive
• Metabolism of a drug to inactive products is an irreversible process
• Prodrug


  A pharmacologically inactive drug administered for known effects of its active metabolites
• Elimination rate constant (kel)


  Describes the rate of elimination of a drug from the body
• Passive diffusion


  • From high to low concentration
  • Depends on the molecule's lipid solubility, particle size, degree of ionization, and area of absorptive surface
  • Primary mechanism for most drugs
  • No need for energy or carrier
• Fick's law of absorption


  Drug molecules diffuse from a region of high drug concentration to a region of low drug concentration
• Permeability coefficient (P)


  A combined constant that accounts for D, A, K, and h under usual conditions for absorption
• Carrier-mediated transport


  • From high to low concentration
  • Need carrier in the membrane that combines reversibly with the substrate molecule outside the cell membrane
  • No need for energy
  • Specific molecular configuration
  • Limited number of carrier
• Active transport


  • Against concentration gradient
  • Selective
  • Requires energy
  • Limited to drugs structurally similar to endogenous substances (eg, ions, vitamins, sugars, amino acids)
  • These drugs are usually absorbed from specific sites in the small intestine
• Many body nutrients, such as sugars and amino acids, are transported across the membranes of the gastrointestinal tract by carrier processes
• Certain vitamins and drug substances require active transport mechanisms for their absorption
• Dissolution


  The process by which a drug particle dissolves
• For a drug to be absorbed, it must first dissolve in the fluid at the absorption site
• Diffusion layer


  The saturated layer of drug solution that envelops the surface of the solid drug particle as it undergoes dissolution
• If dissolution is rapid or if the drug is administered as a solution

  The rate at which the drug becomes absorbed depends mainly on its ability to traverse the membrane barrier
• If dissolution is slow


  Dissolution is a rate-limiting step in absorption
• Drug remains in the stomach for 2 to 4 hours and in the small intestine for 4 to 10 hours
• Gamma scintigraphy


  A technique used to determine gastric emptying time by tracking dosage forms labeled with gamma-emitting radionuclides
• Gastric emptying time is rapid with a fasting stomach and slower as food content increases
• Changes in gastric emptying time or intestinal motility


  Can affect drug transit time and thus opportunity for drug dissolution and absorption
• Effects of drugs on gastric emptying

  • Anticholinergic drugs slow gastric emptying, increasing drug absorption from the stomach and reducing absorption from the small intestine
  • Drugs that enhance gastric motility, like laxatives, reduce the amount of drug absorbed
• Aging decreases drug absorption (in geriatrics)
• Decreased gastric emptying time

  Is advantageous for drugs absorbed from the stomach but disadvantageous for drugs prone to acid degradation or inactivation by stomach enzymes
• Noyes-Whitney equation


  Describes the rate of dissolution
• Noyes-Whitney equation


  dw/dt = D * A * (cs - ct) / L
• The rate of dissolution is governed by the rate of diffusion of the solute through the diffusion layer
• Factors that increase the rate of dissolution

  • Increasing surface area (reducing particle size)
  • Increasing the solubility of the drug in the diffusion layer
  • Increasing the rate of agitation of the dissolving medium
  • Reducing the viscosity of the solvent
  • Changes in pH or nature of solvent that influence the solubility of the drug
• pH-dependent solubility


  For acidic drugs: pH = pKa + log (ionized/unionized)

  For basic drugs: pH = pKa + log (unionized/ionized)
• Very weak acids and bases are completely non-ionized at physiological pH, so their transfer is rapid and pH-independent
• Strong acids and bases are completely ionized, so their transfer is usually slow and pH-independent
• Drugs with pKa values in the range of 3 to 7.5 for acids and 7 to 11 for bases are affected by pH
• Stomach pH is 1-2, duodenum pH is 2-4, small intestine pH is 4-6, and large intestine pH is 6-7.8
• Micronized powders


  Drug particles reduced in size to about 5 μm and smaller, used to increase surface area