Blood-brain barrier
A sheet of capillary endothelium sealed by tight junctions that decides what reaches the brain — and therefore why some drugs work centrally and others cannot, why CNS infection is hard to treat, and how the brain swells.
What it normally does
Brain capillaries have no gaps. The endothelial cells are welded edge to edge by tight junctions (claudin-5, occludin) and have almost no pores and very little vesicle traffic, so nothing slips between cells — everything must be taken through them.
Explains why bacteria in the CSF are hard to reach with antibiotics, and why anything that prises those junctions apart floods white matter with fluid (vasogenic oedema).
To cross a cell you must be small and fat-soluble (lipophilic) — oxygen, carbon dioxide, alcohol, anaesthetic gases, ammonia — or have a carrier: glucose on GLUT1, large neutral amino acids and levodopa on LAT1.
Explains hepatic encephalopathy, because ammonia walks straight in, and why dopamine cannot be given for Parkinson disease but levodopa can.
The blood-facing (luminal) membrane is studded with efflux pumps (P-glycoprotein) that catch lipophilic molecules that did get in and throw them back into the blood.
Explains why the brain is a sanctuary site where chemotherapy and many antibiotics fail, and why loperamide is an opioid that does not sedate at normal doses.
The barrier is not everywhere. A few small regions that must sample the blood have leaky, fenestrated capillaries (the circumventricular organs) — chiefly the vomiting trigger zone in the floor of the fourth ventricle (area postrema) and the hypothalamic sensing areas. Astrocyte end-feet and pericytes induce and maintain the barrier everywhere else.
Explains why blood-borne toxins and chemotherapy cause vomiting, and why domperidone stops levodopa nausea without worsening parkinsonism.
What goes wrong
- Bacterial meningitis← from “Brain capillaries have no gaps. The endothelia…”
Bacteria that reach the CSF land in a compartment with almost no antibody, no complement and no resident phagocytes — protected by the very tight junctions that protect the brain (physiology 0). Cell wall fragments trigger TNF and IL-1, which pull claudin-5 and occludin apart. Neutrophils, protein and water pour in. The inflammation that finally lets antibiotic through is the same inflammation that raises intracranial pressure and damages the cochlea and cochlear nerve.
Antibiotics first — before CT, before lumbar puncture — with dexamethasone given at or just before that first dose. Invasive meningococcal and pneumococcal disease rates are several times higher in Aboriginal and Torres Strait Islander communities, especially in central and northern Australia, and meningococcal B vaccine is funded for them on the National Immunisation Program.
You would find: Fever, headache, neck stiffness, photophobia, drowsiness; a non-blanching purpuric rash points to meningococcus. CSF shows neutrophils, high protein, and a CSF:blood glucose ratio under 0.4 because bacteria and neutrophils consume glucose faster than GLUT1 can carry it in.
- Vasogenic oedema around a tumour, metastasis or abscess← from “Brain capillaries have no gaps. The endothelia…”
Vessels grown under tumour VEGF are built without proper tight junctions (physiology 0). Plasma protein leaks into the extracellular space of white matter and drags water after it. The skull will not expand, so intracranial pressure rises and tissue is pushed across the midline.
Vasogenic oedema is fluid around cells and it is steroid-responsive. This is the one cerebral oedema where dexamethasone transforms the patient within hours.
You would find: Headache worse in the morning or on coughing and straining, vomiting, papilloedema, and a focal deficit or seizure out of proportion to a small lesion. On imaging the lesion enhances with contrast and is surrounded by finger-like low density spreading through white matter.
- Hepatic encephalopathy← from “To cross a cell you must be small and fat-solu…”
Ammonia made by gut bacteria bypasses a failing or shunted liver. It is tiny and lipid-soluble, so it walks straight through the endothelial cells (physiology 1). Astrocytes are the only brain cells that can detoxify it: glutamine synthetase joins ammonia to glutamate, making glutamine, which is osmotically active and pulls water into the astrocyte. The cells swell, glutamate handling fails, and in acute liver failure the whole brain swells.
The drugs for this brain problem never enter the brain. Lactulose acidifies the colon so ammonia is trapped as ammonium and passed out; rifaximin is a non-absorbed antibiotic that stays in the gut lumen and suppresses the ammonia-producing bacteria. Treating the brain here means treating the bowel.
You would find: Day-night reversal and confusion first, then a coarse flapping tremor of the outstretched wrists (asterixis) and constructional apraxia. Always hunt the precipitant: constipation, gastrointestinal bleed, infection, or dehydration from diuretics.
- CNS sanctuary — treatment fails behind an intact barrier← from “The blood-facing (luminal) membrane is studded…”
Most drugs are either water-soluble, so they never get in, or lipophilic P-glycoprotein substrates, so they are pumped straight back into the blood (physiology 2). Leukaemic blasts, HIV and some tumour cells therefore sit in a compartment where a good blood level means nothing.
Before expecting any drug to act centrally, ask three questions: is it small and fat-soluble, does it have a carrier, and is it a P-glycoprotein substrate? Loperamide is an opioid that does not sedate at normal doses because the answer to the last question is yes. Fexofenadine (and, less completely, loratadine and cetirizine) is kept out of the brain the same way; promethazine and diphenhydramine cross freely and cause sedation and anticholinergic delirium in the elderly.
You would find: A child with acute lymphoblastic leukaemia in haematological remission develops headache, vomiting and a sixth nerve palsy; blasts are found on CSF cytology. This is why CNS-directed therapy — intrathecal methotrexate delivered by lumbar puncture, past the barrier rather than through it — is standard from the beginning of treatment.
- Ischaemic stroke: cytotoxic oedema, then barrier breakdown← from “Brain capillaries have no gaps. The endothelia…”
In the first hours the barrier is still shut (physiology 0). What fails is the Na/K ATPase in the membranes of neurons and astrocytes, so sodium and water move into the cells themselves — cytotoxic oedema. Nothing leaks, so there is no enhancement and nothing for a steroid to reseal. Over the next one to five days matrix metalloproteinases digest the junctions and basement membrane; now the barrier leaks, oedema worsens, and blood can escape into the dead tissue.
Steroids do nothing in stroke and are harmful in head injury — the water is inside cells, not around them. The barrier breakdown timeline is also why thrombolysis has a tight window: the later you reopen the artery, the leakier the vessels you are perfusing, and the higher the risk of haemorrhagic transformation.
You would find: A large middle cerebral artery infarct where the patient's conscious state drops on day two to five with a dilating pupil (malignant MCA syndrome). Early CT shows loss of grey-white differentiation without enhancement; a later CT shows blood inside the infarct.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- Penicillin-binding proteins — the bacterial transpeptidase enzymes that cross-link the cell wall.
- Which does
- The drug acylates the enzyme so peptidoglycan strands are never stitched together. The wall weakens, the cell's own autolysins finish it off, and it bursts under its internal osmotic pressure.
- So you see
- CSF is usually sterile within a day; fever settles and conscious state lifts. Because entry depends on inflammation, it is given intravenously at high dose — and penetration actually falls as the patient improves.
- And the same mechanism causes
- The beta-lactam ring is a structural mimic of GABA. Once a leaky barrier lets enough drug in, it antagonises GABA-A receptors and strips inhibition off the cortex: twitching, myoclonus, confusion, seizures. This is a real risk with high doses in renal impairment (classically cefepime and benzylpenicillin, but reported with ceftriaxone). The penetration you wanted is exactly what makes beta-lactams neurotoxic.
- Handling
- Give the first dose immediately — before CT, before lumbar puncture. Dexamethasone goes in with, or just before, that first antibiotic dose, but never delay the antibiotic to find it. Blood cultures first only if that costs no time.
Catches people out: Ceftriaxone precipitates with calcium; use cefotaxime in neonates and avoid calcium-containing fluids in the same line.
- Binds
- The intracellular glucocorticoid receptor.
- Which does
- The bound receptor moves into the nucleus and rewrites transcription: more tight junction protein (claudin-5, occludin), less VEGF, fewer inflammatory cytokines. The leaking junctions are restored.
- So you see
- Headache, vomiting and focal deficit improve within hours to a couple of days, well before any tumour has shrunk. Dexamethasone is picked because it is lipophilic, potent at the glucocorticoid receptor and has almost no mineralocorticoid activity, so it does not add salt and water to a patient who already has raised pressure — which is also why prednisolone is a poor substitute here.
- And the same mechanism causes
- The same receptor sits in liver, muscle and immune cells. It switches on gluconeogenic enzymes, so blood glucose climbs and many patients need insulin. It switches on muscle protein breakdown, giving a proximal myopathy: the patient cannot rise from a chair while the scan is improving, and the weakness gets blamed on the tumour.
- Handling
- Useless for the cytotoxic oedema of ischaemic stroke — there is no leak to seal — and harmful in traumatic brain injury, where steroids increase mortality.
Catches people out: Do not start steroids before biopsy if CNS lymphoma is possible; the lesion melts away and the tissue diagnosis is lost.
- Binds
- No receptor at all. Mannitol is a sugar alcohol with no carrier and no way between tight junctions, so it is trapped in plasma and raises plasma osmolality.
- Which does
- Water follows the osmotic gradient out of brain tissue, across the intact barrier, into blood. Falling blood viscosity also lets arterioles constrict autoregulatorily, shrinking cerebral blood volume.
- So you see
- Intracranial pressure falls within minutes and a blown pupil may come back. It buys time for the real treatment — decompressive craniectomy, clot evacuation, thrombectomy — and treats nothing itself.
- And the same mechanism causes
- The same non-absorbable osmotic load reaches the renal tubule and holds water there: a heavy diuresis. Overshoot and the patient becomes hypovolaemic and hypotensive, cerebral perfusion pressure falls, and the brain is worse off than before, with a rising sodium and acute kidney injury on top. Worse, wherever the barrier is already broken, mannitol seeps into brain tissue, the gradient reverses and oedema rebounds — which is why repeated dosing loses its effect.
- Handling
- Hypertonic saline is often chosen when the patient is hypovolaemic or hypotensive, because it expands the circulation rather than draining it.
Catches people out: Monitor sodium and osmolality; osmotic therapy is a bridge, never a plan.
- Binds
- Levodopa is a substrate of the large neutral amino acid transporter (LAT1) on brain endothelium; inside the brain it is the substrate for DOPA decarboxylase (aromatic L-amino acid decarboxylase). Carbidopa inhibits that same enzyme in the gut, liver and blood vessels.
- Which does
- Levodopa is carried across the barrier and decarboxylated to dopamine in surviving nigrostriatal terminals, which then release it. Carbidopa blocks decarboxylation outside the brain, so far more of each dose survives to reach the carrier.
- So you see
- Bradykinesia and rigidity improve, often dramatically. Dopamine itself is useless for this: it is charged, has no carrier and never crosses — given intravenously it acts only on the heart, kidney and vasculature.
- And the same mechanism causes
- Carbidopa cannot follow levodopa in, so some dopamine is still made peripherally. It reaches the vomiting trigger zone in the area postrema, which sits outside the barrier — hence nausea — and vascular dopamine receptors, hence postural hypotension. Inside the brain, years of pulsatile delivery to a denervated striatum produce involuntary writhing movements (dyskinesia).
- Handling
- A protein-rich meal loads LAT1 with dietary amino acids and competes levodopa off the carrier, so 'off' periods track meals. Nausea is treated with domperidone: it is a dopamine antagonist that P-glycoprotein pumps straight back out, so it blocks the trigger zone without entering the brain. Metoclopramide does enter, and makes the parkinsonism worse.
Catches people out: Never stop levodopa abruptly — abrupt withdrawal can trigger a neuroleptic-malignant-like syndrome.
Contrast enhancement within brain parenchyma means one thing: the blood-brain barrier is broken there (the structures that normally have no barrier — pituitary, choroid plexus, pineal, dura — enhance in everyone). Contrast agents are water-soluble and cannot cross an intact barrier. So an abscess and a metastasis both ring-enhance, an acute infarct does not enhance for the first day or two, and the same broken barrier that lets contrast in is what lets your antibiotic in — which is why meningitis is treated hardest at the moment the patient is sickest.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.