Week 1

• Pharmacokinetics


  The study of the effect the body has on the drug
• Pharmacodynamics


  The study of the effects of the drug on the body
• Clinical pharmacology


  • The science of drugs and their clinical use
• Pharmacodynamics


  Describes the relationship between concentration of drug in the body and the response over time
• Pharmacokinetics


  Describes the relationship between the drug dose and the resulting concentration of drug in the body overtime
• Pharmacokinetic and pharmacodynamic data can be combined to provide a description of the time course of drug response
• ADME


  • Absorption
  • Distribution
  • Metabolism
  • Excretion
• Clinical pharmacokinetics


  • Studying the movement of drug into (absorption), within (distribution) and out of (elimination) the body (systemic circulation)
• The most important aspect from a dosing viewpoint is to achieve the desirable drug concentration at the site of action for the desired period of time
• Since the concentration of drug at the site of action is often unknown or theoretical it is usual to measure the plasma, blood or serum concentration of drug as a surrogate of the effect-site concentration
• We assume changes in the drug plasma, blood or serum concentration is related to changes in drug concentration at the receptor sites, as well as in other tissues
• Normally we take a blood sample and measure drug concentration in plasma, blood or serum as a 'surrogate' measurement of the effect-site concentration
• Most drug movement processes are due to passive diffusion; therefore, the driving factor is concentration
• The higher the concentration the greater the amount that crosses the membrane - until equilibrium is reached
• First-order process


  Concentration-dependant movement of drugs across the membrane
• Zero-order process


  Active movement of drugs across a membrane, independent of concentration
• In a first-order elimination process a constant proportion of the drug is eliminated per unit of time
• In zero-order elimination drug elimination is constant and it is independent of the concentration of drug in the body, a constant amount of drug is eliminated per unit of time
• Zero-order elimination


  • The rate of elimination is constant, regardless of drug concentration. i.e. a constant amount of drug is eliminated per unit of time
  • Drug concentration in plasma (Cp) decreases linearly with time
• First-order elimination


  • The rate of elimination is proportional to drug concentration
  • A constant proportion of drug is eliminated per unit time
  • Drug concentration in plasma (Cp) decreases exponentially with time
• Measurement of drug concentration in the blood, plasma or serum is used as a proxy measurement for drug concentration at this site of action
• Clearance


  Describes the efficiency of irreversible elimination of a drug from systematic circulation
• Elimination


  • Excretion of the unchanged drug into the urine, expired air, sweat and other sources
  • Biotransformation of the drug into a different chemical compound, predominantly in the liver, but also to a small extent in other organs
• When the drug has been metabolised, the parent drug has been cleared or eliminated, even though the metabolite may still be in the body
• Rate of elimination (RE)


  The slope of tangent to curve (mg/h)
• Elimination rate constant (K)


  A constant that describes the relationship between the amount of drug in the body (A) and the rate of elimination for drugs that display a first-order process
• Rate of elimination (RE)


  RE = A x K
• Rate of elimination


  The elimination rate constant x amount of blood in the body
• Clearance (CL)


  A constant that describes the relationship between the plasma drug concentration {C} and rate of elimination (RE)
• Rate of elimination (RE)

  RE = CL x C
• C has units if mass/volume, mg/L
• RE has units of mass/time, mg/h
• CL is the ration of RE to C
• Clearance (CL)


  A constant relating the rate of elimination to the plasma constant
• At steady state


  • The rate of water from the tap = the rate of water draining
  • RE = MDR (maintenance dose rate)
  • MDR (mg/h) = CL (L/h) x Css,ave (mg/L)
• The driving force for drug elimination is the concentration in the plasma
• For any drug dosed to steady state the only PK parameter that describes the relationship between dose rate and average plasma concentration is clearance
• Since most drugs are dosed on multiple occasions (i.e. to steady state) then CL is the most important PK parameter
• Clearance


  The volume of blood cleared of a drug per unit time, with units of volume per time, such as L/h or ml/min
• Clearance (2nd definition)


  The most common definition of clearance is the volume of blood cleared of drug per unit time, but this is impossible to achieve in reality