#The blood brain barrier

#Define the blood brain barrier

The blood brain barrier (BBB) is a specialised physiological barrier that restricts the passage of many substances from the bloodstream into the brain. Its primary role is to maintain a stable and tightly regulated internal environment for optimal neuronal function.

#Outline the structure of the blood brain barrier

The blood brain barrier is composed of several closely related structural components:

Endothelial cells

• Form the inner lining of cerebral capillaries
• Characterised by:
  • Absence of fenestrations (unlike systemic capillaries)
  • Presence of tight junctions between adjacent cells, creating a highly selective seal

Basement membrane

• Similar in structure to the basal lamina found elsewhere in the body
• Composed predominantly of collagen and extracellular matrix proteins
• Provides structural support

Pericytes

• Embedded within the basement membrane
• Contribute to structural integrity and regulation of capillary blood flow

Perivascular space

• A small compartment between vascular and neural elements
• Plays a role in fluid exchange and immune surveillance

Astrocyte foot processes

• Astrocytes extend projections that envelop the capillaries
• Provide biochemical support and help regulate BBB function

#Describe the functions of the blood brain barrier

#1. Barrier Function

Tight junctions between endothelial cells and the absence of fenestrations prevent the free movement of hydrophilic substances. Molecules must traverse multiple lipid bilayers to enter the brain, significantly limiting passive diffusion. This protects the central nervous system from toxins and pathogens.

#2. Transport Mechanisms

Passive Diffusion

• Small, non-polar, lipophilic molecules can diffuse across the BBB
• Examples include gases and many sedatives - propofol, midazolam, ketamine
• BBB permeability may increase with ageing

Facilitated diffusion

• Most essential nutrients require specific transport systems
• These include:
  • GLUT1 and GLUT3 transporters for glucose
  • Amino acid transporters
  • Fatty acid transport systems
  • Ion channels and pumps

Primary active transport

• Involves direct use of ATP to move substances against their concentration gradient
• Typically functions in efflux (removal) of substances from the CNS back into blood
• Important for neuroprotection by limiting accumulation of toxins and drugs
• Key example - P-glycoprotein efflux pump
  • Pumps a wide range of drugs (e.g. chemotherapy agents, digoxin, morphine, apixaban) out of the brain

Secondary active transport

• Does not use ATP directly

• Relies on ion gradients (usually Na⁺) established by primary active transport (e.g. Na⁺/K⁺-ATPase)

• Couples movement of one substance down its gradient to drive another against its gradient

• Two main types:

  • Symport (co-transport): both substances move in the same direction
  • Antiport (exchange): substances move in opposite directions

• Examples at the BBB:

  • Na⁺-dependent amino acid transporters
  • Monocarboxylate transporters (MCTs) for lactate and ketones (important during fasting)

Pinocytosis

• Enables transport of larger molecules by endocytosis/exocytosis, for example antibodies.

#3. Circumventricular Organs (Areas Without BBB)

Certain specialised brain regions known as circumventricular organs lack a fully developed BBB to allow direct communication between blood and brain. This allows the brain to interface with the rest of the body, for example by detecting toxins or releasing hormones. These areas can be remembered as the '5 Ps':

Posterior pituitary

• Releases oxytocin and vasopressin directly into the bloodstream
• Contains osmoreceptors involved in fluid balance

Pituitary portal system

• Allows hypothalamic releasing hormones to enter the portal circulation and act on the anterior pituitary

Pineal gland

• Secretes melatonin into the bloodstream

Choroid Plexus

• Produces cerebrospinal fluid (CSF)

Area Postrema

• Detects circulating toxins and triggers vomiting
• Plays a role in autonomic regulation via sensing vasoactive substances and angiotensin

#What characteristics does a drug need to effectively penetrate the blood brain barrier?

#Fick’s Laws of Diffusion

The rate of diffusion across the BBB can be approximated by:

$$\text{Diffusion} \propto \frac{\text{Solubility}}{\sqrt{\text{Molecular Weight}}} \times (C_1 - C_2) \times \frac{A}{T}$$

Where:

• Higher lipid solubility increases diffusion
• Lower molecular weight favours diffusion
• Greater concentration gradients (C1-C2) enhance movement
• Larger surface area and thinner membranes facilitate transfer

More on Fick's laws on diffusion here.

#Drug Properties That Enhance BBB Penetration

#Fick's factors

High lipid solubility

• Enables passage through cell membranes
• Non-ionised/non-polar drugs are more lipid soluble than ionised/polar drugs (e.g. propofol, fentanyl)
• Acidic drugs are more ionised above their pKa (e.g. aspirin)
• Basic drugs are more ionised below their pKa (e.g. lignocaine, bupivicaine)

Low molecular weight

• Smaller molecules diffuse more readily
• Example: oxygen, carbon dioxide

High concentration gradient

• Increased free plasma concentration promotes diffusion across the BBB
• Drugs with the following characteristics will have a higher plasma concentration:
  • Low protein binding (e.g. ketamine)
  • Low volume of distribution
  • Lower potency drugs requiring higher doses

#Other factors

Some drugs cross the BBB via mechanisms independent of simple diffusion:

Structural similarity to endogenous molecules

• When drugs have similar structure to endogenous ligands, they may be able to utilise existing transport systems
• Examples:
  • Lithium shares properties with sodium and can interact with sodium transport pathways
  • Valproate is structurally similar to lactate, and can utilise the same monocarboxylate transporters

Receptor-mediated transport

• Larger molecules such as monoclonal antibodies may cross via specialised transcytosis pathways