WEEK 3: DRUG DISTRIBUTION

• Drug distribution


  The movement (reversible flow) of absorbed drug in the systemic circulation to and from the blood and different tissues of the body
• Mechanics in distribution of drugs


  1. Some proportion of drug distributed to the tissue may remain in the tissue compartment

  2. Distributed drug molecules binds with the receptors at various tissues and exert the pharmacological action

  3. After pharmacological action its bio-transformed (Metabolized) and eliminated (through Urine, Feces, Saliva, Sweat, ect)

  4. All the drug molecules are metabolized and excreted generally as metabolite or a metabolic product

  5. In some cases the drugs are not metabolized or partially not metabolized and eliminated unchanged
• Plasma protein Binding


  • A drug in blood exists in two forms: bound and unbound
  • Depending on a specific drug's affinity for plasma protein, a proportion of the drug may become bound to plasma proteins, with the remainder being unbound
  • If the protein binding is reversible, then a chemical equilibrium will exist between the bound and unbound states
  • Bound is Pharmacologically inactive
  • Unbound (free drug) is pharmacologically active
  • Protein binding is essential for drug transportation
  • Drug should be released from binding at the site of action
• Human Serum Albumin (HSA)


  Plasma protein that drugs can bind to
• Pharmacokinetic Process- Distribution


  1. Once in the bloodstream, a drug is distributed throughout the body

  2. Very little of the drug is in contact with receptors at any given time

  3. Most of the drug is in areas remote from the site of action (of interest), such as plasma binding sites, muscle tissue, adipose tissue (fat), liver, kidneys
• Volume of Distribution (Vd)


  Apparent volume of distribution - Presuming that the body behaves as a single homogeneous compartment with volume V into which drug gets immediately and uniformly distributed
• Free drug (Active) vs. Bound


  • Only free (unbound) fraction of drug can interact with site of action & cause biologic response
  • Percentage free depends on physiologic & biochemical parameters: Age, pregnancy, hepatic disease, nephrotic syndrome, malnutrition, acid–base balance, Competing drugs or other chemicals for binding sites
  • At a standard dose, total plasma content may be within the therapeutic range, but the patient experiences toxic adverse effects (high free fraction) or does not realize the therapeutic benefit (low free fraction)
• Barriers of drug distribution


  • Distribution through membrane and size of drug

  example:

  • simple capillary endothelial barrier
  • simple cell membrane barrier
  • blood-brain barrier
  • cerebrospinal fluid
  • placental
  • blood-testis barrier
• Perfusion-limited tissue distribution


  • Initial rate of drug distribution to various sites depends on blood flow to the tissue
  • First phase: Rapid distribution to organs of high blood flow: brain, heart, liver, and kidneys
  • Second phase: Slower drug delivery to muscle, most organs, skin and fat which have moderate blood flow
• Permeability-limited tissue distribution


  Certain compartments have restricted access, e.g. Central nervous system (blood-brain barrier), Placenta
• Therapeutic drug monitoring (TDM)


  • The clinical practice of measuring specific drugs at designated intervals to maintain a constant concentration in a patient's bloodstream, thereby optimizing individual dosage regimens
  • Low blood proteins (albumin & globulin), causes less pharmacotherapeutic effect
  • Important to know the plasma concentration of certain drugs
  • Amount of protein content in patient's body
  • Can improve the concentration of drug by administering total parenteral nutrition (TPN)
• Volume of Distribution (Vd)


  Apparent volume of distribution = Amt of drug in body/plasma drug conc
• Drug binding to plasma proteins

  • protein-bound drug-> inactive
  • lower effective concentration-> greater binding=less available free active drug
  • slows distribution to target site-> greater binding= less metabolised & eliminated, longer half-life
  • reversible binding serve as storage depot to prolong action