L29 - Recap of Bioavailability, Dissolution, and Membrane Transport

• Define Bioavailability

  The quantitative measure of the amount of a drug that reaches the site of action in the body and the rate at which it gets there
• What's the bioavailability of IV administration?

  100%
• Define Pharmacokinetics

  what the body does to the drug

  
• define pharmacodynamics

  what the drug does to the body

  
• What determines pharmacokinetics?

  LADME:- Liberation- Absorption- Distribution- Metabolism- Excretion

  
• Cmax

  Maximum plasma concentration of a drug

  
• Tmax


  time when Cmax is reached:time of peak plasma concentration on a measuring curve

  
• Cp


  plasma concentration, commonly seen on y axis
• What does extravascular refer to in terms of administration routes?

  anything that's not IV
• Release vs absorption

  release = drug dissolves at administration siteabsorption = drug crosses biomembrane to reach blood

  
• what is a Metabolite?

  A product of drug metabolism, eg anabolism (forming) or catabolism (breaking down)
• what is micronisation?


  making particles very small (increasing SA) to improve solubilityeg micronised progesterone

  
• What are the two steps in the dissolution process?

  1) Solvation - drug dissolves at crystal surface to create stagnant layer of saturated solution2) Diffusion - dissolved molecules diffuse across stagnant layer into bulk solution
• Which eqn describes dissolution rate?

  Noyes-Whitney equationwhere dissolution rate = change in mass/change in time

  
• What is the Noyes-Whitney equation?


  dissolution rate = D S / h x (Cs - Cb)where:D = diffusivityS = SA of drugh = membrane thicknessCs = solubility of drugCb = concentration of drug in bulk solution

  
• What do we need to predict solubility of a weak acid/base?

  - pH of solution- pKa- intrinsic solubility
• Define intrinsic solubility

  solubility of the unionised (free) form of the drug
• What's the eqn to predict the pH at which a weak acid might precipitate?

  Henderson-Hasselbalch:log Cs-S0/S0 = pH - pKawhere Cs = solubilityS0 = intrinsic solubility

  
• What's the eqn to predict the pH at which a weak base might precipitate?

  Henderson-Hasselbalch:log S0/Cs-S0 = pH - pKa

  
• Transcellular pathway


  across the cell

  
• Paracellular pathway


  between adjacent cells

  
• What equation describes Fick's Law?what is flux directly proportional to?

  flux = conc x velocity x areaORflux = ADk/h (C1-C2)where A = membrane SAh = membrane thicknessk = partition coefficientC1-C2= [conc] difference on either side of the membraneflux directly proportional to change in concentration across membrane

  
• what membrane properties affect flux?

  membrane thickness (h) , membrane SA (A),diffusivity (D)
• what drug properties affect flux?

  concentration gradient, partition coefficient
• Lipophilic molecules- solubility?- permeability?- ionisation state?

  poor solubility (slow release), readily permeates membrane- unionised
• Hydrophilic molecules- solubility?- permeability?- ionisation state?

  highly soluble (rapid release), slow to permeate membraneionised
• Partition coefficient (k)/ log P

  k quantifies drug distribution between membrane and aqueous phaseK = Coil/Cwaterk = drug's relative affinity for oil as compared to waterLog P = octanol-water partition coefficient (k)

  
• Why is lipophilicity important for drugs?What measures lipophilicity?


  Drugs have to be lipophilic to cross csm, but if too lipophilc then they could get deposited in fatty tissues, so need a balancemeasured by octanol-water partition coefficient (logP)

  
• What's the pH partition hypothesis?

  drug accumulates on side of membrane that favours ionisation
• What are limitations of the pH Partition Hypothesis?

  - type of epithelium- SA of absorption site- ionised drugs will be absorbed to small extent- active transport of drugs- residence time of drug at target- mass fluid transfer- charged drugs may form ion pairs w/ oppositely charged species