Drugs and BBB, Cerebral Blood Flow, CSF, AP/CTZ, PET (Week 2--Melega) Flashcards
4 mechanisms involved in control of cerebral blood flow (CBF)
1) Metabolic coupling: cerebral metabolic demand for oxygen and glucose coupled to volume of blood flowing through that tissue (vasodilation/constriction)
2) Neural control: both extrinsic and intrinsic neural pathways
3) PaCO2: increases in CO2 cause vasodilation
4) Autoregulation: maintenance of constant flow over moderate range of perfusion pressures
Cerebral blood flow (CBF)
CBF = CPP/CVR
(CPP: cerebral perfusion pressure; CVR: cerebrovascular resistance)
Functions of BBB and blood-CSF barrier
Anatomical, biochemical and transport mechanisms regulate access of molecules in the peripheral circulation to the CNS
Anatomic location for BBB is endothelial cells of arterioles, capillaries, veins and for blood-CSF barrier is epithelial cell surface of choroid plexus
Structural basis of barriers is tight junctions between cells
Anatomical components of BBB
Microvascular endothelial cells with tight jucntions
Basement membrane
Astrocyte end feet: biochemical support for endothelial cells; secondary barrier to diffusion
Pericytes: wrap around endothelial cells that provide structural support and vasodynamic capacity to microvasculature
How do drugs cross the BBB and enter the brain?
No paracellular diffusion!
1) Diffusion
2) Facilitated transport by carrier systems
3) Receptor mediated endocytosis
Diffusion of drugs into the brain across the BBB
However, drug must be lipid soluble, free (not bound by albumin etc), nonionized form of weak electrolyte, small molecular weight
Ion trapping can result in higher drug concentration in the brain than in the plasma
What properties of drugs would reduce or block diffusion into the brain?
Permanently charged cation (quaternary compound)
Substrate for a BBB active efflux transporter (like P-glycoprotein)
P-glycoprotein (P-gp) Efflux Pump
Membrane glycoprotein does ATP-dependent reverse transport (efflux) to clear drug from cells (acts on analgesics, antiepileptics, antidepressants, anti-HIV agents, antimicrobials)
Multidrug resistance proteins (MRPs)
Overexpressed in epileptogenic tissue
Consequence: lower drug concentration in brain so drug efficacy reduced
Facilitated transport by carrier systems
Amino acid transporters: large neutral amino acids (LNAA), basic and acidic AAs
D-glucose (GLUT1) transporter
Also transport systems for vitamins (ascorbate, folate, B12, riboflavin, thiamine, niacin, pyridoxine)
Receptor mediated endocytosis
Receptors in plasma membrane of endothelial cells of BBB
Upon ligand binding, ligand-receptor complex internalized
Examples: transferrin, leptin, insulin
Pathway of drug from bloodstream to brain to elimination
BBB –> extracellular fluid space (15% of brain volume) –> diffusion or transport into neurons, oligodendrocytes or microglia –> extracellular fluid space –> CSF –> cerebral circulation –> venous return
Cerebrospinal fluid (CSF)
Clear, colorless liquid
Low in protein, otherwise similar to plasma in ionic composition
Secreted by choroid plexus of ventricles
Found within 4 ventricles, and in subarachnoid space surrounding brain and spinal cord
Total volume of CSF is 140mL, volume of ventricles is 25mL
Function: surrounds and cushions brain from shocks in free communication with extracellular fluid bathing neurons and glia; sink for potentially harmful metabolites that can be removed by flow through arachnoid villi
Formation of CSF
Actively secreted by choroid plexus of ventricular system
Choroid plexus consists of tufts of capillaries that protrudes into the ventricles
CSF formed primarily within ventricles (lateral, 3rd and 4th)
Lateral ventricles –> interventricular foramen of Monro –> 3rd ventricle –> central aqueduct of Sylvius –> 4th ventricle –> foramen of Magendie and 2 foramina of Luschka –> subarachnoid space (fluid-filled cisterns at the base of the brain) –> over convexity of brain and down into spinal canal and over brain surface, assisted by arterial pulsations –> absorbed into arachnoid villi (one way valves) into venous circulation
Choroid plexus
Blood vessels in the choroid plexus are fenestrated (“leaky”)
Epithelial cells over choroid plexus provide barrier much like endothelial cells of brain vessels
As CSF travels along brain vasculature, picks up additional contribution of volume from products of brain metabolism (H2O, AAs, etc)
Circumventricular organs (CVOs)
Midline structures bordering 3rd and 4th ventricles
Unique areas of brain outside BBB (vasculature is fenestrated capillaries)
Communicate with CSF and between brain and peripheral organs via blood borne products
Ex: neurohypophysis, median eminence, lamina terminalis, subfornical organ, habenula, pineal gland, area postrema
