Drugs and BBB, Cerebral Blood Flow, CSF, AP/CTZ, PET (Week 2--Melega) Flashcards Preview

Block 5: Neuroscience > Drugs and BBB, Cerebral Blood Flow, CSF, AP/CTZ, PET (Week 2--Melega) > Flashcards

Flashcards in Drugs and BBB, Cerebral Blood Flow, CSF, AP/CTZ, PET (Week 2--Melega) Deck (24):
1

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

2


Cerebral blood flow (CBF)


CBF = CPP/CVR

(CPP: cerebral perfusion pressure; CVR: cerebrovascular resistance)

3


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

4


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

5

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

6


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

7


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)

8


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

9


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)

10

Receptor mediated endocytosis


Receptors in plasma membrane of endothelial cells of BBB

Upon ligand binding, ligand-receptor complex internalized

Examples: transferrin, leptin, insulin

11


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

12


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

13


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

14


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)

15


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

16


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

17


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

18


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

19


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!)

20


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

21


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

22


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

23


Aging and regional cerebral metabolic rate of glucose (rCMRglu)


Normal aging is associated with decreases in rCMRglu (and some increases in general cortical atrophy)

24

Neostigmine vs. Physostigmine

Both AChE inhibitors

Neostigmine is quaternary amine and does not enter brain

Physostigmine is tertiary amine and does enter the brain

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