Quartz 5

Pharmacokinetics of Distribution

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Pharmacokinetics

Distribution: Transport of the drug from the blood stream to other compartments

  • Distribution is reversible: Redistribution from a compartment, to the blood, to another compartment is possible
    • Barbiturates can redistribute from the Brain to the Fat tissue > Decreased the local concentration in the brain for fat animals > Decreased sedation / anesthesia effects in obese animals

Fluid compartments:

  1. Total body water = 60% of the Body Weight BW
    1. Age, Gender and Species dependent
    2. IC fluid = 40% of BW
    3. EC fluid = 20% of BW
      1. Interstitial fluid = 14% of BW
      2. Blood plasma = 5-7% of BW
        1. Plasma water = 55% of Blood plasma = 0.0385 L / kg of BW
      3. Transcellular fluid = 1% of BW
  2. Volume of distribution Vd = Apparent volume of the compartments a drug is distributed in:
    1. Vd = Total amount of the drug in the body (mg) / Concentration of the drug in the blood plasma (mg/L) = Dose / C plasma
      1. Drug staying in the IV compartment: Vd = V plasma water = 0.0385 L / kg
      2. Drug distributed evenly in the EC fluid (Plasma + Interstitium + Transcellular) = 0.25 L / kg
        1. Ex: Penicillins, NSAIDs
      3. Drug distributed evenly in the IC and EC compartments = 0.65 L / kg
        1. Ex: Sulfonamides, Prednisolone
      4. Drug distributed in the EC and IC and concentrated 3x in IC compartment (Ex: Ion trapping in Macrolides) = 1.45 L / kg
        1. The “Apparent” term in the definition makes sense here because in this case the Vd is higher than the real Volume of water in the body
    2. Decreasing the volume of compartments (Ex: By tissue dehydration, Cachexia) can reduce the volume of distribution and increase the plasma concentration C plasma for a same dose

Factors influencing drug distribution:

  1. Drug:
    1. Dose
    2. Application route
  2. Rate of distribution:
    1. Membrane permeability
    2. Blood perfusion:
      1. Depends on the capillary filtration:
        1. Continuous capillary: Only allows for passage of small molecules in fragile tissues (Ex: Brain, Lungs)
        2. Fenestrated: Allows for passage of many molecules (Ex: Kidney glomerulus and GI mucosa)
        3. Sinusoid (Discontinuous) capillary: Allows for passage of large particles and cells (Ex: Liver, Bone marrow)
      2. Depends on the tissues perfusion rate:
        1. Kidneys have the highest perfusion rate of the body
        2. The liver has a medium perfusion rate but takes a high proportion of the cardiac output because it is a large organ
        3. The brain has a medium perfusion rate and is of medium size (Compared to the other organs), it takes a medium proportion of the cardiac output
  3. Extent of distribution:
    1. Lipid solubility (Kow)
    2. pKa
    3. Plasma protein binding (Transport protein)
    4. IC binding (Ion trapping)
  4. Physiological:
    1. Age
    2. Diseases
    3. Pregnancy
    4. Body condition
    5. Volume of fluid compartments

Types of barriers

  1. Physiological
    1. Blood Brain Barrier BBB: The least permissive
    2. Blood Milk Barrier BMB
    3. Placenta: The most permissive
    4. Prostate
    5. Blood Retina Barrier
  2. Pathological:
    1. Abscess
    2. Inflamed tissues

Transport proteins:

  1. Bind the drugs for transport, and release them to enter their site of action
  2. Drugs that bind the same transport proteins can have toxic drug-drug interaction effects
    1. Ex: Warfarin and Phenylbutazone competing for Albumin
  3. Albumin binds: Mostly acidic drugs
    1. Barbiturates, Benzodiazepines (BDZ), NSAIDs, Phenytoin, Penicillins, Sulfonamides, Tetracyclines, Warfarin, Tolbutamide (Sulfonylureas, Valproic Acid
  4. α1-Acid Glycoprotein binds: Mostly basic drugs
    1. Bupivacaine, Lidocaine, Disopiramine, Imipramine, Methadone, Prazosine, Quinidine, Verapamil β blockers (Sympatholytics)

Birds, Fish, Amphibians, Reptiles: Drugs injected in the lower body parts accumulate in the ipsilateral (= Same side) kidney > Avoid injecting nephrotoxic drugs here

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