Organic

• Drug Distribution


  1. Drug must pass through many barriers

  2. Survive alternate sites of attachment and storage

  3. Avoid significant metabolic destruction before reaching site of action
• Oral Administration


  • Drug must go into solution to pass through gastrointestinal mucosa
  • Factors affecting drug dissolution: chemical structure, particle size, particle surface area, crystal form, tablet coating, tablet matrix
• Drugs administered orally may not remain in solution as they enter acidic stomach and alkaline intestinal tract
• Prodrug


  Inactive compound that is easily metabolized to the active agent
• Prodrugs


  • Olsalazine
  • Chloramphenicol palmitate

  
• Olsalazine and chloramphenicol palmitate are cleaved to smaller compounds, one of which is the active drug

  
• Enalapril is the ethyl ester of enalaprilic acid, an active ACE inhibitor. The ester prodrug is more readily absorbed orally than the active carboxylic acid
• Parenteral Administration


  1. Bypasses intestinal barrier

  2. Advantages: for patients who cannot tolerate oral drugs, for drugs rapidly metabolised in liver

  3. Obstacles: rapid distribution, slow distribution from injection site, difficulty crossing blood-brain barrier
• Protein Binding


  • Drug can bind to serum proteins, usually albumin
  • Effects: increases effective solubility, limits biodistribution, increases half-life and duration of action, can lead to drug-drug interactions

  
• Tissue Depots


  • Lipophilic drugs can concentrate in neutral fat depots
  • Affects duration of action
• Drug Metabolism


  1. Drugs pass through liver where they may be metabolised to inactive chemicals (first-pass effect)

  2. Metabolic fate of a drug must be studied for new drug products
• Lidocaine is a classic example of the first-pass effect, with over 60% metabolised on first pass through liver
• Tocainide was developed as an analog of lidocaine with a longer half-life due to reduced first-pass metabolism
• Metabolic Fates

  • Active parent drug converted to inactive metabolites
  • Inactive parent drug converted to active metabolite
  • Both parent drug and metabolite are active
• Metabolism can be a hindrance but also fortunate that the body can metabolise foreign molecules
• Excretion Routes

  • Kidney
  • Enterohepatic circulation
  • Breast milk
• Frequent dosing regimens may be required due to rapid excretion, enterohepatic circulation, or excretion in breast milk
• It is fortunate that the body has the ability to metabolize foreign molecules (xenobiotics), otherwise many of these substances could remain in the body for years, especially certain lipophilic chemical pollutants, including the once very popular insecticide dichlorodiphenyltrichloroethane (DDT)

  
• Excretion


  1. Through the kidney

  2. Enterohepatic circulation (drug reenters the intestinal tract from the liver through the bile duct and be excreted in the feces)

  3. Milk of nursing mothers (drugs and their metabolites can be excreted in human milk and be ingested by the nursing infant)
• If the situation does not favor formation of the drug–receptor complex

  Higher and usually more frequent doses must be administered
• If partitioning into tissue stores or metabolic degradation and/or excretion is favored


  It will take more of the drug and usually more frequent administration to maintain therapeutic concentrations at the receptor
• Pharmacological response


  Drug binding to a specific receptor
• Many drug receptors are the same as those used by endogenously produced ligands
• Binding of drugs to receptors

  • May produce desired or undesired effects depending on the biological distribution of these receptors
  • Depends on the biological distribution of drugs, i.e. the organs and tissues that can be reached by the drug and contain these receptors
  • Various receptors with similar structural requirements are found in several organs and tissues
• Drug-receptor interaction


  An equilibrium process

  
• Variables contributing to a drug's binding to the receptor

  • Structural classes
  • 3D shape of the molecule
  • Types of chemical bonding involved
• Lock-and-key concept


  Initial receptor model based on the drug (key) fitting into a receptor (lock)
• Recent model


  Both the drug and the receptor can have considerable flexibility, the receptor can undergo an adjustment in 3D structure when the drug makes contact
• Drug-receptor association may produce productive changes in the configuration of the macromolecule, leading to agonist responses, an antagonistic or blocking response
• Strong drug-receptor associations may lead to unproductive changes in the configuration of the macromolecule, leading to an antagonistic or blocking response
• Acid


  Proton donor
• Base


  Proton acceptor
• Un-ionized acids


  Donate their protons forming ionized conjugate bases
• Ionized acids


  Donate proton and yield un-ionized conjugate bases
• Un-ionized bases


  Accept protons and yield their ionized conjugated acids
• Ionized bases


  Accept protons and yield their un-ionized conjugated acids
• Water is an amphoteric molecule, can be either a weak base accepting a proton from acidic drugs to form the strongly acidic hydrated proton or hydronium ion (H3O+), or a weak acid donating a proton to a basic drug to form the strongly basic hydroxide anion (OH-)
• pKa

  The negative logarithm of the modified equilibrium constant, Ka
• The pKa or Ka indicates the extent to which the acid (proton donor) reacts with water to form conjugate acid and conjugate base

  
• Strength of acids and bases based on pKa

  • pKa < 2: strong acid; conjugate base has no meaningful basic properties in water
  • pKa 4 to 6: weak acid; weak conjugate base
  • pKa 8 to 10: very weak acid; conjugate base getting stronger
  • pKa >12: essentially no acidic properties in water; strong conjugate base