Pharmacokinetics, dynamics, and interactions

• Pharmacokinetics


  The study of the drug movement throughout the body, including drug metabolism, drug excretion and passage of drugs across membranes
• Pharmacokinetic processes


  • Absorption
  • Distribution
  • Metabolism (biotransformation)
  • Excretion
• The combination of metabolism and excretion is called elimination
• Applying knowledge of pharmacokinetics can maximize the beneficial effects of a drug and analyze the harm of the drug
• Cell membrane crossing


  • Through channels and pores
  • Transport systems, such as the P-glycoprotein system
  • Direct penetration of the membrane (most common)
• 1. glycoprotein


  A transmembrane protein that transports a wide variety of drugs out of cells
• Organs that transport drugs

  • Liver (into bile for elimination)
  • Kidney (into urine for excretion)
  • Placenta (back into maternal bloodstream)
  • Brain (into blood to limit access)
• Lipid solubility


  The more lipid soluble a drug is, the easier it is for it to cross membranes
• Ionization


  Ions are unable to cross membranes, so they have to become nonionized to cross from one side to the other
• pH partitioning/ion trapping


  Acidic drugs accumulate on the alkaline side, and basic drugs accumulate on the acidic side
• Absorption


  Movement of a drug from its site of administration into the blood
• Factors affecting absorption


  • Rate of dissolution
  • Surface area
  • Blood flow
  • Lipid solubility
  • pH partitioning
• Commonly used routes of administration

  • Intravenous
  • Intramuscular
  • Subcutaneous
  • Oral
  • Topical
  • Transdermal
  • Inhaled
  • Rectal
  • Vaginal
  • Direct injection
• Drug distribution


  Determined by blood flow to tissues, ability to exit the vasculature, and ability to cross the blood-brain barrier
• Blood-brain barrier


  Tight junctions between cells in the capillaries of the central nervous system that prevent drug passage
• Placental drug transfer


  Most drugs cross the placenta via simple diffusion
• Protein binding


  Drugs can form reversible bonds with proteins, which can restrict drug distribution and be a source of drug interactions
• Drug metabolism (biotransformation)


  Enzymatic alteration of drug structure, primarily in the liver
• Cytochrome P450 system


  • A group of 12 closely related enzyme families that metabolize drugs
  • 3 families (CYP1, CYP2, CYP3) metabolize drugs, the other 9 metabolize endogenous compounds
• Therapeutic consequences of drug metabolism

  • Promotion of renal drug excretion
  • Conversion of active compounds to inactive forms
  • Conversion of inactive prodrugs to active forms
  • Decrease in toxicity
  • Increase in potential for harm
• Inducers


  Drugs that increase the rate of drug metabolism
• Inhibitors


  Drugs that decrease the rate of drug metabolism
• First-pass effect


  Rapid hepatic inactivation of certain oral drugs before they enter systemic circulation
• Enterohepatic recirculation


  A repeating cycle in which a drug is transported from the liver into the duodenum through the bile duct and then back to the liver through the portal blood
• Excretion


  The removal of drugs and their metabolites from the body, primarily through the kidneys
• Renal excretion process


  • Glomerular filtration
  • Passive tubular reabsorption
  • Active tubular secretion
• If renal failure occurs, the duration and intensity of drug responses can increase
• Renal drug excretion


  1. Glomerular filtration

  2. Passive tubular reabsorption

  3. Active transport systems in kidney tubules
• Renal drug excretion


  • Varies from person to person
  • Conditions like chronic renal disease can cause profound alterations
  • Factors to consider: pH dependent ionization, competition for active tubular transport, patient age
• Elderly population lose nephrons, kidneys are smaller, resulting in decreased blood filtration and decreased drug excretion
• Non-renal routes of drug excretion

  • Breast milk
  • Bile
  • Feces
  • Lungs
  • Sweat
  • Saliva
• Plasma drug levels


  Measurements to regulate drug responses
• Minimum effective concentration (MEC)

  Drug level less than which therapeutic effects will not occur
• Toxic concentration


  Plasma drug level at which toxic effects begin
• Therapeutic range


  Range of plasma drug levels between MEC and toxic concentration
• Therapeutic range


  • Wider range is easier to administer safely
  • Narrower range is more difficult to administer safely
• Plasma drug levels


  1. Rise during absorption

  2. Decline during metabolism and excretion
• Drug half-life


  Time required for the amount of drug in the body to decrease by 50%
• It takes 4.5 to 5 half-lives for a drug to reach steady state
• Drug half-life


  Determines dosing interval