Chapter 3

• What happens to a dosage when it gets administered orally

  1. Dose of formulated drug

  2. Administration

  3. Disintegration of dosage form

  4. Dissolution

  5. Absorption

  6. Drug in systemic circulation

  7. Drug distributed to organs and tissues and site of action

  8. Pharmacological response

  9. Adverse effect (toxicity)

  10. Clinical response (efficacy)

  11. Drug metabolised or excreted

  12. Elimination
• Absorption


  Process of input into the systemic circulation from an extravascular administration site
• Distribution


  Reversible movement of drug between the systemic circulation and other organs and tissues of the body

  
• Metabolism


  Chemical modification of the drug's structure ("biotransformation")
• Elimination


  Irreversible loss of drug from the body by Metabolism (liver) or Excretion (kidney- urine, biliary, feces)
• Time course of Oral Drug

  • The shape of the curve provides information about how the PK processes are occurring

  The area under the plasma concentration-time curve (or AUC) provides a quantitative measure of drug exposure

  
• Drug Absorption


  The process by which unchanged drug proceeds from the site of administration into the blood

  
• Molecular aspects of absorption

  • Passive Diffusion (through lipids/or aqueous channels): from high concentration to low concentration

  Carrier-mediated transport: specific proteins called solute carriers, transport a drug across the membrane either by active transport, which requires the use of ATP or via facilitated diffusion

  
• Factors Determining the extent of Drug Absorption

  • Lipophilicity (the extent to which the drug is soluble in lipids)

  Charge (degree of ionization)

  The size of the drug molecule
• The drugs which are unionized, low polarity and higher lipid solubility are easy to permeate membrane
• The drugs which are ionized, high polarity and lower lipid solubility are difficult to permeate membrane
• How does pH affecting degree of ionization and absorption of weak acidic and basic drug?

  Weak acid drugs are best absorbed in stomach (unionized form in acidic medium)

  Weak base drugs are best absorbed in the small intestine (unionized form in less acidic medium)
• Absorption rate


  • Inhalation

  Sublingual

  Rectal

  Intramuscular

  Subcutaneous

  Oral

  Transdermal
• Bioavailability


  The proportion of the administered dose that reaches the systemic circulation
• Drug Distribution


  The reversible transfer of drug between two compartments within the body (one of which is usually the blood)

  
• Body Fluid Compartments


  • Extracellular fluid: plasma, interstitial fluid, and lymph

  Intracellular fluid: comprises the content of all cells in the body

  Fat: or adipose tissue
• Factors affecting drug distribution

  • Drug size

  Drug charge

  Drug lipophilicity

  Blood flow to the compartment

  Permeability of the tissue barrier (e.g. blood-brain barrier)

  Extent of protein binding within a compartment
• Blood Brain Barrier


  Reduces drug penetration into CNS as endothelial cells are tightly bound with essentially no pores, and contain pump transporters that pump drug outside the CNS
• Volume of distribution (Vd)

  The fluid volume that would be required to contain all the drug (uniformly distributed) in the body at the same concentration measured in blood

  
• Volume of distribution (Vd)

  • Indicates the capacity for a drug to leave the blood stream and collect or accumulate within the tissue

  Is a major determinant of half life (or the duration to which an individual is exposed to a drug)

  
• Volume of distribution (Vd)

  While not a real volume does tell us a number of important things about a drug, in particular: The capacity for a drug to leave the blood stream and collect or accumulate within the tissue (large Vd means the drug is accumulating in peripheral tissues), Vd is a major determinant of half life (or the duration to which an individual is exposed to a drug) (large Vd means longer half-life)
• Drugs with low volume of distribution

  • Large molecules (big molecular size harder to distribute)
  • Charged molecules
  • Highly bound to plasma proteins
  • E.g: warfarin Vd = 8 L
• Drugs with large Vd

  • Small, lipophilic, uncharged, unbound to plasma protein
  • E.g. Amiodarone Vd= 4600 L
• Drug Metabolism


  Detoxification / termination of activity, Clearance: By converting the drug into another compound, metabolism 'clears' the parent drug, Enhance Elimination: The products of metabolism are more readily excreted by the kidney, Minimizing oral exposure: 1st pass metabolism is a protective barrier against exposure to toxic orally ingested chemicals
• Types of metabolism reactions

  • Functionalization (Phase I) Reactions, Conjugation (Phase II) Reactions
• Functionalization reaction


  Involve the introduction or 'unmasking' of a polar functional group into the molecule such as –OH or –NH2
• Functionalization enzymes


  Cytochrome P450 (CYP450) enzymes, Oxidation enzymes (e.g. xanthine oxidase), Esterases (hydrolyses esters)
• Cytochrome P450 (CYP450) enzymes


  They are the functionalization enzyme of greatest importance to drug metabolism, mainly oxidative enzymes: Catalyses transfer of one atom of atmospheric oxygen to substrate, More than 50 human cytochromes P450 identified to date, About 18 of these able to metabolize drugs and other foreign chemicals, Each enzyme has a different amino acid sequence which determines which substrates can bind
• The LIVER contains the highest abundance of all drug metabolizing enzymes
• Conjugation reactions


  Conjugation enzymes are all transferases, Glucuronidation is the most common conjugation reaction!
• Renal Excretion


  Renal elimination involves 3 processes: Filtration, Secretion, Reabsorption: negative contributor to renal clearance
• Biliary excretion


  Some drugs or their metabolites are excreted via the bile into the gastrointestinal tract, From the gastrointestinal tract, they can be eliminated through feces, Biliary excretion is particularly important for drugs that undergo enterohepatic circulation, where they are reabsorbed from the intestines into the bloodstream and then re-secreted into bile
• Summary of drug elimination

  Drug elimination occur through two main processes: Liver Metabolism also called hepatic metabolism or Hepatic Clearance (CLH), Renal Excretion (unchanged drug) also called Renal Clearance (CLR), Clearance from other tissues (breast, lung, sweat) CLother (negligible), Total systemic clearance CLs = CLH + CLR + CLother
• Half-Life (t1/2)


  The half-life of a drug refers to the time it takes for the concentration of a drug in the body to decrease by half, Influenced by systemic clearance (Cls) and volume of distribution (Vd), t1/2 = 0.693 Vd / CL
• Half-Life (t1/2)


  • If a drug has a half-life of 7 hours, after 7 hours, half of the drug will be eliminated from the body. After an additional 7 hours (14 hours total), half of the remaining drug will be eliminated, and so on.
• The third step is to analyze the data gathered from the investigation.
• The second step is to gather information about the problem.
• The first step is to identify the problem.
• The fourth step is to draw conclusions based on the analysis.
• The endocrine system is made up of glands that secrete hormones into the bloodstream.