Week 3

• Intravascular administration


  Medication administered within a blood vessel
• Extravascular administration


  Medication administered outside of a blood vessel, such as in the surrounding tissue or muscle
• Parenteral administration


  Medication administered by a route other than the digestive tract
• Absorption


  The movement of drug from the site of administration to the site of measurement, usually the systemic circulation
• Absorption


  • Affected by route of administration, formulation, physicochemical properties of drug, and physiological factors at site of absorption
• Tmax


  Time taken to reach maximum concentration
• Ka


  First order absorption rate constant
• Cmax


  Highest (peak) maximum concentration
• Ae


  Amount excreted unchanged in urine
• Oral absorption - stomach


  1. Disintegration and dissolution of medicine

  2. Minimal absorption into circulation

  3. Protective mucous barrier

  4. Acidic pH environment
• Oral absorption - small intestine


  1. Disintegration and dissolution

  2. Large surface area

  3. Highly vascularised

  4. pH around 6.6
• Oral absorption - large intestine


  1. Slower absorption

  2. Mucous lining, no villi

  3. Can increase extent of absorption for some drugs with poor bioavailability
• Determinants of drug absorption from gut


  • Dissolution
  • Gastric emptying
  • Intestinal motility
  • Drug interactions in gut lumen
  • Passage through gut wall
• Dissolution


  Affected by excipients, physicochemical properties of drug, dosage form design, and changes in gut pH
• Gastric emptying and intestinal motility


  Affect time available for drug dissolution and absorption
• Drug interactions in gut lumen


  Can reduce drug absorption through complexation, adsorption, or metabolism
• Passage through gut wall


  Influenced by drug's physicochemical properties, gut wall enzymes, and efflux transporters
• The Henderson-Hasselbalch equation is important for understanding how the pH of the site and the drug pKa affect the ionisation and absorption of weak acids and bases
• Complexation


  Interaction between the metal cation and the fluroquinolone drug molecule
• Complexation


  Reduces the solubility and subsequent absorption of the fluroquinolone antibiotic, leading to a significant reduction in its antimicrobial activity
• Henderson-Hasselbalch equation


  Describes the ratio of lipid-soluble to aqueous-soluble forms for weak acids and bases
• Many drugs are weak acids and bases
• pH and drug pKa


  Important in determining the ionisation state of the drug
• For acids


  1. pH = pKa + log (concentration[A-]) / (concentration [HA])

  2. The lipid soluble form of an acid is protonated
• For bases


  1. pOH = pKa + log (concentration [B]) / (concentration [BH+])

  2. The lipid soluble form of a base is non-protonated
• pH + pOH = 14
• In acidic conditions


  1. Drugs that are acids tend to be protonated, unionised and can cross membranes more easily

  2. Drugs that are basic tend to be protonated, ionised and are less easily able to cross membranes
• In basic conditions


  1. Drugs that are acids tend to be unprotonated, ionised and are less easily able to cross membranes

  2. Drugs that are basic tend to be unprotonated, unionised and can cross membranes more easily
• Fastest to slowest drug absorption


  • Solution
  • Suspension
  • Capsules
  • Tablets
  • Coated tablets
  • Controlled-release formulation
• Weak organic acids or bases


  • Exist in un-ionised and ionised forms in an aqueous environment
  • The unionized form is usually lipophilic and diffuses readily across membranes
  • The ionized form is usually hydrophilic with high electrical resistance and thus cannot penetrate cell membranes easily
• pKa


  The pH at which concentrations of ionized and un-ionized forms are equal
• When pH is lower than the pKa


  The un-ionised form of a weak acid predominates, but the ionized form of a weak base predominates
• In plasma (pH 7.4)


  • The ratio of un-ionised to ionised forms for a weak acid is 1:1000
  • In gastric fluid the ratio is reversed
• When a weak acid is given orally


  Most of the drug in the stomach is un-ionised, favouring diffusion through the gastric mucosa
• For a weak base with a pKa of 4.4


  Most of the drug in the stomach is ionised
• Weakly acidic drugs are more readily absorbed from an acid medium than are weakly basic drugs
• Most absorption occurs in the small intestine because the surface area is larger and membranes more permeable
• Cellular mechanisms of drug absorption


  • Passive diffusion
  • Paracellular transport
  • Active transport
  • Facilitated transport
  • Ion-pair transport
  • Pinocytosis
• Passive diffusion


  • Most important absorption mechanism
  • Drug moves down the concentration gradient
  • Energy is not required
  • Drug must be in solution at absorption site
  • Lipid to water partition coefficient important
• Active transport


  • May involve transport against a concentration gradient
  • Carriers are in lipoprotein membranes
  • Important role in nutrient transport
  • Some drugs can use this "natural" system