Question 12

Describe the blood brain barrier (50% of marks). What characteristics does a drug need to effectively penetrate the blood brain barrier? (50% of marks)

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College Answer

The BBB is the separation of the blood from the brain extracellular fluid and serves to 
maintain consistent internal environment in the brain and protect the brain from large 
harmful substances and microorganisms. Most answers displayed some knowledge of the 
structure of the BBB but many answers did not include its function. Better answers included 
substances to which the BBB is permeable, how permeability changes with age and a 
mention of the circumventricular organs and their significance (i.e. are outside the BBB). 
Most candidates correctly identified the characteristics of drugs that cross the BBB. Marks 
were also allocated for giving examples.


  • The blood brain barrier is a diffusion barrier which impedes influx of most compounds from blood to brain.
  • Cellular and physical components of the blood brain barrier:
    • Endothelial cells (tight junctions, no fenestrations)
    • Basement membrane (20-30nm)
    • Pericytes
    • Perivascular fluid space (Virchow-Robin space)
    • Astrocyte foot processes
  • Barrier functions of the blood brain barrier:
    • Tight junctions prevent paracellular diffusion of small hydrophilic molecules
    • Metabolic enzymes can degrade substances or biotransofrm them into daughter molecules which are less able to cross the blood-brain barrier
    • Active transport mechanisms are selective for which substances can pass
  • Transport functions of the blood brain barrier:
    • Passive transport of small lipophilic molecules
    • Active facilitated diffusion and pinocytosis of molecules of interest, eg. metabolic substrates, peptides, vitamins, etc
    • Specific substances which are actively transported include glucose, amino acids, thiamine, lactate, fatty acids and antibodies.
  • Drug characteristics which favour drug penetration of the blood brain barrier:
    • Small molecular weight, high lipophilicity
    • High concentration gradient (low protein binding, small volume of distribution, low potency of drug i.e. large concentration of drug)
    • Substrate for active transport (resemble endogenous ligand)
  • Areas of the brain where the blood brain barrier is interrupted:
    • Area postrema (senses toxins for emesis, senses vasopressin and angiotensin for autonomic regulation)
    • Choroid plexus (secretes CSF)
    • Pineal gland (secretes melatonin into the systemic circulation)
    • Organum vasculosum lamina terminalis (acts as osmosensor)
    • Subfornical organ (osmosensor, also detects Angiotensin-II)
    • Median eminence (secretes hypothalamic hormone-releasing hormones into the pituitary portal circulation)
    • Posterior pituitary (secretes vasopressin and oxytocin)
    • Preoptic recess (senses sex hormones)


Abbott, N. Joan, et al. "Structure and function of the blood–brain barrier." Neurobiology of disease 37.1 (2010): 13-25.

Ballabh, Praveen, Alex Braun, and Maiken Nedergaard. "The blood–brain barrier: an overview: structure, regulation, and clinical implications." Neurobiology of disease 16.1 (2004): 1-13.

Daneman, Richard, and Alexandre Prat. "The blood–brain barrier." Cold Spring Harbor perspectives in biology 7.1 (2015): a020412.

Bechmann, Ingo, Ian Galea, and V. Hugh Perry. "What is the blood–brain barrier (not)?." Trends in immunology 28.1 (2007): 5-11.