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
Area postrema
Is a circumventricular organ (lacks tight junctions between endothelial cells; densely vascularized structure with fenestrated capillaries)
Medullary structure lying at base of 4th ventricle
Chemotrigger zone is emetic region located bilaterally in area postrema
Small rounded eminence immediately rostral to obex (V shape) on each side of 4th ventricle
Chemotrigger zone (CTZ)
Bilateral in area postrema (which is a CVO)
Noxious chemical stimulants in blood can induce the emetic reflex
Multiple receptors located at CTZ
Pathological and physiological conditions that can induce nausea and vomiting by activation of receptors in the CTZ
Drug/treatment induced: cancer chemotherapy, opioids, nicotine, antibiotics, radiotherapy
Labyrinth disorders: motion, Meniere’s disease
Increased intracranial pressure: hemorrhage, meningitis
Post-operative anesthetics: analgesics, procedural
CNS causes: anticipatory, migraine, bulimia nervosa
Endocrine causes: pregnancy
Infectious causes: gastroenteritis, viral
7 classes of antiemetic drugs
5HT-3 antagonists: ondansetron, granisetron
Dopamine-D2 antagonists: metoclopramide, prochlorperazine
Corticosteroid: dexamethasone, methylprednisolone (often used in combo with other antiemetic agents)
Neurokinin-1 antagonist: aprepitant
Muscarinic M1 antagonists: scopolamine (predominantly prophylaxis against motion sickness)
Histamine H1 antagonist: diphenhydramine
Cannabinoid agonists: nabilone (note that this is the only agonist!)
Which neuronal inputs stimulate the final effector pathway of vomiting center
Afferent stimuli from:
Higher cortical centers (reflex afferent pathways from cerebral cortex = anticipatory)
Vestibular system (motion sickness)
CTZ (monitors blood and CSF)
Vagal pathway in GI system
Midbrain afferents
Positron Emission Tomography (PET)
Noninvasive way to measure alterations in neurochemical activities related to development, aging and disease states
Can measure glucose metabolic rates, NT synthesis and release, receptor subtype densities
Tiny concentrations of radioactively labeled biological probes used that do not perturb process being measured; ligand is nonpharmacologic and acts like a tracer
Note: does not give anatomical information
FDG metabolism pathway and application for FDG-PET imaging
2-FDG and glucose are transported across BBB into brain by same glucose transporter
FDG is in trace amounts but uptake is proportional to glucose uptake
Both compounds enter glycolysis cycle, are phosphorylated by hexokinase to G-6-P or FDG-6-P
FDG-6-P is not substrate for further metabolism so remains trapped in tissue
FDG-6-P accumulation is proportional to glucose metabolic rate of that region
Aging and regional cerebral metabolic rate of glucose (rCMRglu)
Normal aging is associated with decreases in rCMRglu (and some increases in general cortical atrophy)
Neostigmine vs. Physostigmine
Both AChE inhibitors
Neostigmine is quaternary amine and does not enter brain
Physostigmine is tertiary amine and does enter the brain
