View
215
Download
0
Category
Tags:
Preview:
Citation preview
VM 8314
Dr. Wilcke
Vascular space = Plasma/plasma water + (extracellular space)Many RBC’s (intracellular space) +A few WBC’s (intracellular space)
Tissue space Interstitial fluid (extracellular space) +Cells of the body (intracellular space)
Physical and Physical and Physiologic “spaces”Physiologic “spaces”
VM 8314
Dr. Wilcke
Physical and Physical and Physiologic “spaces”Physiologic “spaces”
ICF ECF ECF
ICF
Vascular Tissue
VM 8314
Dr. Wilcke
Physical and Physical and Physiologic Physiologic “spaces”“spaces”
Point to:
Tissue ECFTissue ICFVascular ECF & ICF
VM 8314
Dr. Wilcke
Vascular spaceVascular space ~ 7% of body weight (mammals)Equilibria
Water ↔ plasma and serum proteins
Ioniozed drug ↔ unionized drug
Plasma water ↔ inside of WBCs and RBCs
Uniform mixing and distribution in 10 to 30 minutes.
VM 8314
Dr. Wilcke
Tissue spaceTissue space the rest of the volume (water)
neither structural proteins nor bone matrix (no water)
EquillibriaWater ↔ tissue proteins (e.g. albumin)
Ionized drug ↔ unionized drug
Extracellular fluid ↔ intracellular fluid
Reaches equillibrium in minutes to hours (even days and weeks is possible)
VM 8314
Dr. Wilcke
Extracellular spaceExtracellular spacePresent in both vascular and
tissue spaces~15 – 20% of body (by weight) Larger in neonates
EquillibriaIonized and unionized (Protein) bound and unbound
VM 8314
Dr. Wilcke
Intracellular spaceIntracellular spacePresent in both vascular and
tissue spaces~35 – 45% of body (by weight)
EquilibriaIonized and unionized drug
Distribution in 30 minutes to +12 hours
VM 8314
Dr. Wilcke
Reserved spacesReserved spaces“Protected tissues”
CSFAqueous humorProstatic fluid
Distribution in minutes to neverMost dosing situations not
relevantImportant if the disease is in the
reserved space.
VM 8314
Dr. Wilcke
Movement between Movement between spacesspacesVascular (ECF) ↔ Tissue (ECF)
Transcytotic http://www.bio.davidson.edu/people/kabernd/BerndCV/Lab/EpithelialInfoWeb/Transc
ytosis.html
Endothelial junctionsEspecially with inflammation
DiffusionCarried in WBCs (rare)
VM 8314
Dr. Wilcke
Movement between Movement between spacesspacesECF to ICF
DiffusionActive uptake
WBCs seem to be particularly able…
VM 8314
Dr. Wilcke
““Diffusion limited” Diffusion limited” distributiondistributionIn general, diffusion is the
rate-limiting step drug distribution TO the tissues
ECF ↔ ICF
VM 8314
Dr. Wilcke
““Blood flow limited” distributionBlood flow limited” distribution
IF diffusion is rapidTissue saturation by the drug (reaching
equilibrium) is controlled by drug delivery to tissue
Drug delivery to tissues is controlled by blood flow
Tissue blood flow is not uniformBrain and kidneys - high portion of flowMuscles intermediateSkin and fat - small portion
VM 8314
Dr. Wilcke
““Blood flow limited” Blood flow limited” distributiondistributionUltra-short acting barbiturates
Brain is saturated FIRSTMuscle is saturated LATER
Animals wake up because the muscle keeps soaking up drug (not because drug is metabolized)Not all barbituratesDoes not apply to gas anesthetics
VM 8314
Dr. Wilcke
Enterohepatic circulationEnterohepatic circulationHow does it work
Drug taken up by liver cellsDrug or phase II conjugate excreted
in bileDrug reabsorbed from intestine
(Phase II conjugate cleaved to liberate drug if necessary)
VM 8314
Dr. Wilcke
Enterohepatic circulationEnterohepatic circulationWhat does it mean
Volume of distribution is increasedThe cycle itself is a space where drug
“remains”
It takes longer to eliminate the drug than you might expect(for drugs excreted by the liver)
VM 8314
Dr. Wilcke
Enterohepatic circulationEnterohepatic circulationWhy do you care?
Interrupt to improve drug eliminationPoisonings, barbiturate overdoses, etc.
VM 8314
Dr. Wilcke
Mammary excretionMammary excretionDistribution from one perspective
Simple diffusion of unionized drugIon trapping (normal milk is slightly acidic v blood)
Inflammation reduces barrierElimination from another
Drug actually does leave the body if it’s in milkJust not much of it
(Absorption from a third ;-)If you’re the baby…
Recommended