L45 - Extravascular Administration 1

• What is extravascular administration?


  Administration by any route ofther than intravenous.

  
  

  Absorption occurs.

  
• What are some benefits to oral dosage forms?

  - Convenient, easier.

  
  

  - Low infection risk.

  
  

  - Preferred route as GI tract designed for absorption.

  
  

  - Broad diversity of oral forms eg tablet, liquid etc.

  
  

  - Can have dif mechanisms for drug release eg immediate/delayed delivery.
• What is absorption?


  Passage of drug from absorption site to systematic site of measurement (blood).

  
  

  1st order process.
• What is absorption rate proportional to in active/passive absorption.

  Passive= absorption rate proportional to [drug] atg absorption site.

  Active= mediated by transporters. Rate proportional to amount of drug at absorption site if transporters are not saturated.

  
• When will absorption rate be highest?

  - Just after t=0.

  
  

  - Just after administration of oral dose.

  
  

  - Will decrease with time.

  
• What does the one compartment model for extravascular administration assume?

  - Elimination and absorption are 1st order.

  
  

  - Linear kinetics: no enzymes/transporters involved in ADME processes are saturated.

  
• Give an eqn linking concentration, amount of drug and volume of distribution.


  Conc = A/V
• What eqn describes the variation of A (amount of drug) in the body with time?

  
  

  What does X refer to?

  dA/dt = Ka x X - k x A.

  
  

  
  

  X = [drug] at absorption site - use when talking about absorption.

  
  

  A = amount of drug in compartment/body - use when talking about elimination.

  
• Give the eqn used to find [drug] C at time t in extravascular adminisation.


  C = (B x e^-Kt) - (B x e^-Kat)

  
• What is "B"?

  
  

  What's the eqn to find it?

  A constant given by a group of different constants.

  B = (Ka x F x D) / V (Ka - k).

  whereF= bioavailability/% absorbed.D= dose.V= Vd.K= elimination rate constant.Ka= absorption rate constant.

  
• What happens in terms of absorption/elimination rate at t=0?

  - All drug at absorption site, none in body.

  
  

  - Maximum absorption rate. X0 = dose.

  
  

  - Rate of elimination is 0 as there's no drug in body yet.

  
• What happens in terms of absorption/elimination rate at the absorption phase?

  - As more drug is absorbed, absorption rate declines.

  
  

  - Elimination increases.

  
  

  BUT

  
  

  as long as Ka x X > k x A, Cp increases until Cmax is reached at Tmax.

  
• What happens in terms of absorption/elimination rate at the peak/Cmax?

  - Elimination rate increases.

  
  

  - Absorption rate decreases to the point that Ka x X = k x A.

  
  

  - Cmax will be observed at Tmax.

  
• What is Cmax?


  Peak Cp/plasma [drug] concentration.

  
• What is Tmax?


  The time at which Cmax is reached.

  
• What does Tmax depend on? What has the bigger effect?

  
  

  Eqn? (given)

  Tmax depends on Ka and K.

  
  

  - Ka (absorption) has a bigger effect on Tmax than K (elimination).

  
  

  Tmax = ln (Ka/k) / Ka - K

  
• What happens to Tmax as Ka decreases?

  Tmax increases: slower absorption takes longer to reach the peak.

  
  

  - The faster the absorption (Ka), the shorter the time to get to Cmax.

  
• How can we predict Cmax?

  Substitute Tmax value into the general eqn:

  
  

  Cmax = (B x e^-KTmax) - ( B x e^-KaTmax).

  
  

  May need to work out B first.

  
• What does the value of Cmax depend on?

  - Dose.

  
  

  - Fraction absorbed/bioavailability (F).

  
  

  - Volume of Distribution.

  
• Describe the terminal phase (elimination) in extravascular administration.

  
  

  Ie, what happens after Tmax?

  - Amount of drug in body (A) and its elimination rate (k) has increased.

  
  

  - Amount of drug at absorption site (A) and absorption rate (Ka) has decreased. Becomes 0.

  
  

  - Ka x X < k x X.

  
  

  - The amount of drug in body and Cp decreases.