Pharmacology

• Absorption


  Drug is absorbed from the site of administration and enters the plasma
• Distribution


  Drug reversibly leaves the bloodstream and is distributed into interstitial and intracellular fluids
• Metabolism


  Drug transformation by metabolism by the liver and other tissues
• Excretion


  Drug and/or drug metabolites excreted in urine, faeces or bile
• ADME


  Absorption, Distribution, Metabolism and Excretion
• The kidneys are the principal organs for drug elimination
• Drug elimination


  1. Renal filtration of blood plasma

  2. Water and most electrolytes are reabsorbed into blood circulation in the renal tubules

  3. Drug metabolites rendered polar (and water soluble) by phase II metabolism are not reabsorbed, thus excreted in the urine
• Increasing plasma concentration of drug


  • Sub-therapeutic Effects
  • Therapeutic Effects
  • Toxic Effects
• Clearance (CL)


  Volume of blood removed (or cleared) of drug per unit of time (e.g., L/hour or mL/minute)
• Clearance (CL)


  A flow parameter, it does NOT tell you how much drug is removed
• Types of clearance


  • Renal (CLR)
  • Hepatic (CLH)
  • Other elimination routes (CLO)
  • Total clearance (CLT)
• Clearance helps determine the dosage rate needed to maintain a desired [D]plasma
• Clearance is independent of Vd but both determine the elimination half life of a drug
• Estimating Clearance (method 1)


  CL = Rate of Drug Elimination / [Drug]Plasma
• Estimating Clearance (method 2)


  CL = Dose / Area under the curve
• Area under the curve (AUC)


  Calculated using the trapezoidal rule
• Increasing dose increases AUC
• First order kinetics


  Rate of drug elimination increases as plasma drug concentration increases
• Zero order kinetics


  Elimination mechanisms become saturated and reach Vmax, the maximal elimination rate
• Michaelis-Menten kinetics


  Describes first order elimination rate
• At steady state, the Rate of Drug Administration (R0) = Rate of Drug Elimination (RE)
• Calculating dosage rate for IV infusion of theophylline


  Dosage Rate = [Drug]PlasmaSS x CL
• Doubling the dosage rate


  Increases [Drug]PlasmaSS to toxic levels
• Elimination half-life (t1/2)


  Time required for [Drug]Plasma to decrease by 50%
• Elimination t1/2 determines the time required for [Drug]Plasma to achieve [Drug]PlasmaSS
• Elimination t1/2 determines how much time is required for drug to be eliminated from body
• Elimination rate constant (Ke)


  Fraction of drug eliminated per unit of time measured at any particular instant (e.g., hour-1)
• Calculating Ke


  Ke = 0.693 / t1/2
• Calculating CL


  CL = Ke * Vd
• 5 half-lives are normally required to reach steady state
• 5 half-lives are normally required to wash out a drug from the body
• Factors affecting Elimination Half-Life (t1/2)


  • CL increases, t1/2 decreases
  • CL decreases, t1/2 increases
  • Vd increases, t1/2 increases
  • Vd decreases, t1/2 decreases
• Effects on Volume of Distribution


  • Aging (decrease in muscle mass) decreases t1/2
  • Obesity (increase in adipose tissue) increases t1/2
  • Pathologic fluid increase increases t1/2
• Effects on Clearance


  • Cytochrome P450 induction decreases t1/2
  • Cytochrome P450 inhibition increases t1/2
  • Cardiac failure increases t1/2
  • Hepatic failure increases t1/2
  • Renal Failure increases t1/2
• Further Reading: Rang and Dale's Pharmacology 9th Edition, Chapters 9, 10 & 11