L6 Quantative

• Fu equation


  The fraction of drug unbound in plasma
• Plasma concentration-time curve


  • Provides information on dose, frequency of drug administration, and toxicity
• Routes of administration


  • Intravenous
  • Oral
• Therapeutic window


  A concentration range bounded at the lower end by the minimum concentration that produces the desired clinical effect and at the upper end, the concentration that produces unacceptable effects or where no further benefit is observed
• C(max)


  Peak plasma concentration
• T(max)


  The time required to achieve Cmax
• AUC


  Area under the curve
• Minimum toxic concentration (MTC)


  The upper limit of the therapeutic window. Drug concentrations above the MTC increase the risk of undesired effects
• Minimum effective concentration (MEC)

  The plasma drug level below which therapeutic effects will not occur
• First-order kinetics


  Change by a constant fraction per unit time
• Zero order kinetics


  Change by a constant amount per unit time
• First-order kinetics


  • Elimination of most drugs follows first order kinetics, clearance and half-life are constant, constant fraction of drug is eliminated per unit time, can change from first order to zero order as the drug concentration increases and elimination mechanisms become saturated
• Margin between MTC and MEC

  The larger the margin, the better for drugs
• Zero-order kinetics


  • Drugs are removed at a constant rate which is independent of plasma concentration, elimination of a few drugs (e.g., alcohol*ethanol bc of al) follows zero-order kinetics, all the active sites on an enzyme or transporter are occupied - saturated elimination mechanisms
• Plasma-conc graph I.V drug conc starts at 1, Oral drug conc starts at 0
• Drug clearance


  Drug clearance refers to the efficiency of drug elimination, defined as the ratio of the elimination rate (e.g., mg∙h-1 ) to the concentration of drug in plasma (e.g., mg∙L-1 )
• Total body clearance


  Total body clearance = hepatic clearance + renal clearance + clearance by other routes
• Renal clearance


  Renal clearance = glomerular filtration + active secretion - reabsorption
• fe


  The fraction of administered drug excreted unchanged in the urine
• Low fe


  Hepatic clearance because metabolites are excreted
• High fe


  Renal clearance because parent drug is excreted
• Drug bioavailability


  The fraction of administered dose of the parent drug that reaches the systemic circulation
• First order kinetic graphs

  • Plasma-time curve is curved, can also be straight if natural/inverse log
• Zero order kinetic graph

  • Straight graph
• Alcohol Dehydrogenase


  Enzyme of ethanol
• Alcohol Dehydrogenase is easily saturated
• Drug bioavailability must be given in fraction or percentage
• Determine bioavailability of an orally administered drug

  Obtain plasma concentration-time curve of the drug via i.v. and oral routes
• Determine total body clearance

  Administer a single dose of drug (i.v. bolus or oral), collect blood samples and measure drug plasma concentration at defined time points, plot a plasma concentration-time curve, and calculate the AUC
• Compartmental modelling


  Requires modelling
• Non-compartmental analysis


  Requires NCA
• Calculate AUC


  Use the trapezoidal method
• Elimination rate constant (k)

  The slope of the ln[plasma concentration]-time curve for drugs that follow first-order kinetics, indicates the fraction of a drug removed per unit time, related to CL(total) and -V(d)
• Drug elimination half-life (t1/2)

  The time taken for the drug plasma concentration to decrease by 50% and is calculated during the elimination phase, related to CL(total) and -V(d)
• Steady-state concentration


  The concentration of drug in the plasma reached when the rate of drug absorption is equal to the rate of drug elimination following repeated or continuous dosing
• To get higher steady-state concentration

  Higher doses and/or more frequent dosing will result in higher steady-state concentrations
• To achieve clinical response rapidly

  Loading dose (= Vd × target plasma-concentration) followed by maintenance dose
• Drug elimination half-life (t1/2)

  Proportional to V(d) and inverse proportional to CL(total)
• Increased Vd, e.g., in pregnancy and decreased Cltotal, e.g., liver/kidney disease

  Lead to an increase in drug elimination half life