Flashcards

• Drug distribution


  The process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues
• Drug distribution


  • It is a Passive process in which the driving force is the concentration gradient between the involved compartments i.e. Blood and extravascular tissue
  • It occurs by diffusion of free drug until equilibrium is attained
• Phases of drug distribution

  1. Initial distribution phase

  2. Redistribution
• Initial distribution phase


  • Mainly determined by cardiac output and regional blood flow
  • Drugs are initially distributed to tissues with the highest blood flow (heart, brain, lungs, kidneys, and liver)
  • Enables a rapid onset of action of the drugs affecting these organs
• In hypovolemic states


  The effect of the drug increases so the dose must be reduced
• Redistribution


  • Highly lipid soluble drugs get initially distributed to organs with high blood flow i.e. brain, heart, kidney, etc.
  • Later, less vascular but more bulky tissues (skeletal muscles, skin, adipose tissues) take up the drug which leads to fall in the plasma concentrations and the drug is withdrawn from the highly perfused sites
  • If the site of action of the drug was in one of the highly perfused organs, redistribution results in termination of drug action
  • Greater the lipid solubility of the drug, the faster is its redistribution
• The variation in blood flow between the two phases

  Partly explains the short duration of hypnosis produced by an IV bolus of Propofol
• High blood flow combined with the high lipophilicity nature of propofol


  Leads to rapid distribution in the CNS and produces anaesthesia
• A subsequest slower distribution to the skeletal muscles and adipose tissues

  Lowers the plasma concentration, causing the drug to diffuse out of the CNS, down the concetration gradient, and consciousness is regained
• Oral diazepam exerts a short hypnotic action lasting 6-8 hours


  Due to redistribution despite their elimination t½ of > 30 hr
• When the same drug is given repeatedly or continuously over long periods


  The low perfusion-high capacity sites get progressively filled up and the drug becomes longer acting
• Patterns of drug distribution

  • Non-uniform distribution
  • Plasma
  • Throughout body water
  • Sequestered in specific body parts/tissues
• Non-uniform distribution


  Most common pattern, largely determined by ability of the drug to cross membranes and their lipid/water solubility
• Plasma


  Drugs remain within the vascular system as they have large size or are highly bound to plasma protein, hence cannot cross capillary wall easily
• Throughout body water


  Low molecular weight water soluble compounds like ethanol and some sulphonamide become uniformly distributed throughout the body water
• Sequestered in specific body parts/tissues

  Concentrated specifically in one or more tissues that may or may not be the site of action (few drugs)
• Sequestered in specific body parts/tissues

  • Iodine is concentrated in the thyroid gland
  • Chloroquine may be present in the liver at a concentration 1000x more than that in plasma
  • Tetracycline is almost irreversibly bound to bone and developing teeth
• Factors affecting drug distribution
• Tissue permeability to drugs

  • Physicochemical properties of the drug
  • Physiological barriers
• Physiological barriers


  • Simple Capillary Endothelial Barrier
  • Simple Cell Membrane Barrier
  • Blood-Brain Barrier
  • Blood-CSF Barrier
  • Blood-Placental Barrier
  • Blood-Testis Barrier
• The membrane of capillaries that supply blood to most tissues is not a perfect barrier because all drugs, whether ionized or not ionized, with a molecular weight <600 Daltons, diffuse through the capillary endothelium

  
• Drugs that are bound to blood componentns are restricted because they have a large molecular size of complex
• Blood-Brain Barrier


  Made up of a tight junction of capillary cells unlike the capillaries of other organs making it difficult for drugs to pass through

  
• Blood-CSF Barrier


  Similar permeability to the BBB- highly lipid soluble drugs can easily cross this barrier, however, moderately soluble and ionized drugs may permeate slowly
• The brain is consequently inaccessible to many drugs whose lipid solubility is insufficient to allow penetration of the blood–brain barrier

  
• Inflammation can disrupt the integrity of the blood–brain barrier, allowing normally impermeant substances to enter the brain; consequently, penicillin can be given intravenously (rather than intrathecally) to treat bacterial meningitis (which is accompanied by intense inflammation)

  
• Blood-Placental Barrier


  • It is the barrier between the maternal and fetal blood vessels, separated by fetal trophoblast basement membrane and endothelium
  • Highly lipid soluble drugs and those with molecular weight <1000 Daltons, cross the barrier by simple diffusion

  
• P Glycoprotiens form a functional barrier between maternal and fetal blood circulation in the placenta thus protecting the fetus from exposure to the xenobiotics during pregnancy

  
• Drugs safe in pregnancy

  • Water soluble
  • Large size
  • Highly protein bound
• Drugs safe in pregnancy

  • Propylthiouracil (PTU) is chosen over methimazole due to its highly protein bound feature
  • Phenobarbitone is considered safe compared to phenytoin, carbamazepine and valproic acid due to its high protein bound feature
• Blood-Testis Barrier


  Located at the Sertoli-Sertoli junction, which is a tight junction between the Sertoli cells and acts as a barrier which restricts the passage of drugs to the spermatocytes and spermatids
• Extravascular/Tissue protein binding


  • 60% of the drug is binded by the plasma protein
  • 40% can pass the cell membrane and bind directly to the organs
• Plasma protein binding


  • Forms a reservoir of drug but only the free(unbound) drug is available to the tissue to exert the therapeutic effect
  • Plasma albumin is a major drug binding protein and may act as a reservoir
  • Alpha Glycoprotien, Lipoprotien, Globulin are other plasma proteins that bind drugs
• • One drug can bind to more than one site of albumin
  • More than one drug can bind to the same site
• Warfarin and Sulfonylurea


  • Both these drugs bind to plasma albumin and each of these drugs has been noted to be more than 99% bound
  • They compete for binding sites on plasma albumin
  • Since only an unbound drug is active, any decrease in binding would result into an increased pharmacologic effect
• Miscellaneous factors affecting drug distribution
• Volume of distribution


  • The theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma at a steady state
  • Provides a reference for the plasma concentration expected for a given dose but provides little information about the specific pattern of distribution
  • Each drug is uniquely distributed in the body

  
• Volume of distribution


  • If 1000 mg of a drug is given and the subsequent plasma concentration is 10 mg/L, that 1000 mg seems to be distributed in 100 L (dose/volume = concentration; 1000 mg/x L = 10 mg/L; therefore, x= 1000 mg/10 mg/L = 100 L)
• Typical liquid volumes in average 70kg man

  • Total water 60% (50-80%) 42L
  • Intracellular volume 40% 28L
  • Extracellular volume 20% 14L
  • Plasma volume 4% 3L
  • Blood volume 8% 5.5L
• For a drug that is highly tissue-bound

  Very little drug remains in the circulation; thus, plasma concentration is low and volume of distribution is high