SUMMARY

• Week 2


  • Surface area of small intestine
  • Mucous membrane
  • Villi
  • Microvilli - brush border give high SA for absorption of drugs and can help control what comes in and out
  • Why is large SA important
  • Dissolved drugs can move from gut lumen via passive diffusion, transport proteins and paracellular diffusion
  • Blood perfuses via hepatic portal vein to intestine to to liver to move drug into systemic circulation - hence why large SA and good blood supply important
  • Cells then have a system to push the drug out
  • Function of the pancreas
  • Pancreatic juice for lipid digestion
  • Proteolytic enxzyme trypsin and chymotrypsin for protein digestion
  • Biscarvonate for stomach acid neutralisation
  • Why is water reabsorption important
  • Important for dissolution of oral administered drugs
• Drug solubility


  • Efficacy dependent on site of administration
  • Relevant solubility
  • Highest conc of drug that can be in biological fluid
  • Bioavailaibility of drug - determined by it solubility influencing its dissolution rate
  • Poor aq solubility - leads to lower bioavailability so lower conc of drug in blood- lower efficacy
• Dissolution


  1. Liberation

  2. Migration through the boundary layer
• Melting point


  Higher the mp higher rate of solubility
• Enthalpy of fusion


  Energy needed to break solid-solid bonds to form the liquid
• Enthalpy of mixing


  Energy required to break solvent-solvent bonds AND form the new bonds between solute and water
• Enthalpy of solution


  Add enthalpy of fusion and enthalpy of mixing together
• pKa and log D

  • Ionisation affects lipophilicity and permeability of a drug
  • Drugs have to be in their UNIONISED form to pass through membrane
  • Acidic drugs have higher permeability in pH 6.5 or below
  • Basic drugs have higher when pH 7.4 or above
  • But in vivo is 7.4 so drugs have to adjust pH to be effective
  • Stomach - conc of unionised drug high because of the pH however less absorption because of its thick muscular walls and low SA of stomach
  • Higher logP lower solubility - rather not dissolve in polar environment
  • Higher logP have better membrane permeability
  • A good drug needs to be lipid soluble but still dissociate to form ionised water soluble form

  
• Movement of drug molecules across membrane

  1. Diffusion

  2. Transcellular

  3. Paracellular

  4. Carrier mediated transport

  5. Endocytosis

  6. Transcytosis
• Oral solubility


  Minimum vol for a drug to dissolve fully in stomach
• Absorption


  Solute soaked into substance - particles through substance
• Adsorption


  Dependent on container - particles accumulate at surface

  
• Importance of interfacial phenomena in pharmacy
• Interface


  Boundary between the phases
• Surface tension


  • When gas and liquid are in contact - water meets air
  • Tension at the surface of the water
  • Try to reduce SA to minimise tension but liquid has hydrogen bonds
  • To reduce increase temp
• Emulsions


  • Oil and water
  • Large SA so don't mix well
• Surfactants


  • Need surfactants to reduce surface tension
  • Adsorption of surfactants allow the insoluble particles to disperse in suspension
• Spreading or wetting


  • Diff skin reacts different
  • Reduce surface tension on skin for better wettability y using chemical enhancer
  • Allows it to penetrate stratum corner
• Contact angle


  • Measure of angle at interface between solid and liquid
  • Smaller than 90 degrees - better spreading therefore increased wettability
• Solid wettability and why this is important
• Adsorption


  • Irreversible chemiadsorption
  • Reversible physiadsorption

  
• Examples of adsorption


  • Overdose - haemoperfusion
  • TLC
• Week 2

  • Powder: diameters less than 1mm
  • Powder flow:ability of powder to flow in specific manner
  • Need a smooth consistent flow from bulk to tablet machines
  • Uniform particle packings = consistent mass
  • Each get same amount - dosage accuracy
  • Prevent air bubbles in the powder tablet formation
  • Capping and lamination - tablet breaking and layers separate
  • Die-wall friction - lubrication problems
  • Dust contamination risks
  • Manufacturing
  • Gravity feeding
  • Mechanically assisted feeding
  • Pneumatic air pressure
  • Hydraulic
  • Fluidisation
  • Adhesion
  • Cohesion
  • Between two different particles
  • Between like particles
  • Between particle and wall
  • Same components in bulk
  • Forces
  • Van der Waals
  • Surface tension
  • Electrostatic forces
  • IMF increase as particle size decrease
  • Between adsorbed layer and container
  • Contact and frictional charge between substance and walls
  • Force balance
  • Sum driving - sum drag
  • Particle size
  • Wider = less good flowability
  • Too small leads to agglomerates due to more IMF
  • 355um to 125 very fine
  • Larger
  • Smaller
  • More gravitational
  • Less gravitational
  • Less surface tension
  • More surface tension
  • Stronger adhesion
  • Lower adhesion
  • Particle shape - affects flow
  • Spheres
  • Rods flake shaped
  • Irregular interlocking
  • Minimum contact - low SA
  • High contact - high surface area
  • Highest contact due to interlocking
  • Low electrostatic attraction
  • High electrostatic attraction
  • High electrostatic
  • Good flowability
  • Low flowability
  • Low flowability - particles present
  • True density and bulk
  • Bulk less true
  • True - how much drug NO AIR GAPS
  • Bulk - how much drug including air gaps
  • Higher density - less adhesive - less adhesive forces - less likely to stick - improved flowability
  • Powder density AVERAGE of ALL particles together
  • Different bulk densities - dependent on how particles packed into container
  • Very poor flow is above 38
  • Hopper
  • Hopper width
  • Height of powder in hopper
  • Hopper wall angle
  • Angle of repose - smaller the angle the better flowability
  • Max angle at which pile of powder remains stable without slumping
  • Flow through orifice
  • Measure rate of flow with laser beam or digital balance
  • Improving powder flow
  • Particle size and distribution
  • Particle shape and texture
  • Additives
  • Process design
• LADME


  Liberation, absorption, distribution, metabolism and excretion
• Bioavailability


  Cmax, tmax, t1/2, volume and clearance and protein binding as they apply to medicines administration
• ADME processes


  1. Liberation - release of drug from dosage form

  2. Absorption - how drug moves in to systemic

  3. Steep increase in plasma conc- drug absorbed from GI tract

  4. Until Cmax is reach

  5. Decline because drug DISTRUBUTES and ELIMINATES FROM body

  
• Drug absorption mechanisms for common administration routes

  Explain which routes are suitable for different drug modalities
• Drug metabolism and excretion

  1. Metabolism - biotransformation into another chemical species

  2. From parent drug to metabolite

  3. Change in physicochemical properties

  4. Pro-drug - inactive needs activating in liver

  5. Because they're less permeable in active state

  6. Metabolites more POLAR and less LIPOPHILIC than parent

  7. Oral GI tract and lumen - enterocytes - hepatic pearl vein and liver - systemic circulation

  8. Using cP450 liver enzyme for catalysis

  9. Decreased lipophilicity

  10. Increased lipophilicity

  11. Increased permeability

  12. Decreased permeability

  13. More aq solubility

  14. Decreased aq solubility

  15. More likely to be excreted

  16. Less likely to be excreted

  Excretion - irreversible loss of drug

  17. Glomerular filtration

  18. Bloodstream - renal tubules - kidneys - eliminated in urine

  19. Bile in liver - faeces

  20. Pulmonary excretion
• Capecitabine is an oral prodrug that undergoes metabolism to generate its active form , 5-fluorouracil and this 5FU is a chemotherapy agent used to treat cancer
• Using relevant examples encountered in this unit, demonstrate how the drug interacts with its biological target(s)

  • Functional groups determine how molecule binds to target
  • Conformational chair not receptor
  • What happens to cell
  • How the drug is formulated and administered
  • Specificity of drug
  • Adverse effects
  • Metabolism and excretion
  • Agonists are a
• Lipophilicity


  Increased lipophilicity leads to increased permeability, decreased lipophilicity leads to decreased permeability
• Aqueous solubility


  Increased aqueous solubility leads to being more likely to be excreted, decreased aqueous solubility leads to being less likely to be excreted
• Capecitabine


  An oral prodrug that undergoes metabolism to generate its active form, 5-fluorouracil, which is a chemotherapy agent used to treat cancer
• Excretion


  Irreversible loss of drug
• Excretion process


  1. Bloodstream - renal tubules - kidneys - eliminated in urine

  2. Bile in liver - faeces

  3. Pulmonary excretion

  
• Clinical endpoints


  Measure concentration of drug in biological fluid and spaces by taking plasma to see concentration of drug in plasma

  
• How drug interacts with biological target(s)

  1. Functional groups determine how molecule binds to target

  2. Conformational changes, not just receptor binding

  3. What happens to the cell

  4. How the drug is formulated and administered

  5. Specificity of drug

  6. Adverse effects

  7. Metabolism and excretion
• Agonists


  Activating drugs that mimic the natural ligand
• Affinity


  Attraction between drug and receptor
• Efficacy


  Response produced by the drug